Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=S.CI.O.[NH2:16][NH2:17]>CCOCC.C(O)C.O>[NH:16]([C:3]1[N:2]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:17]
Reactant: CN1Cc2ccccc2NC1=S
Reactant: NN
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: NNc1ncc2ccccc2n1

Procedure:
A mixture of 3-methyl-1,2,3,4-tetrahydroquinazolin-2-thione (5.87 g., prepared as described in J. Pharm. Sci., 1961, 50, 866), methyl iodide (6 ml) and ethanol (230 ml) was refluxed for 1 hour, cooled and diluted with ether. The precipitate (8.27g) was suspended in ethanol (42 ml), treated with hydrazine hydrate (42 ml) and the mixture refluxed for 1 hour, cooled, diluted with water and extracted with chloroform. The extracts were washed, dried and evaporated to give the 2-hydrazinoquinazoline (4.55g). This was dissolved in a mixture of 2N hydrochloric acid (27 ml.) and acetic acid (13 ml), cooled, and treated, dropwise below 5°, with a solution of sodium nitrite (2.04 g) in water (13 ml). The mixture was allowed to stand for a further hour at room temperature, basified with 10N sodium hydroxide solution and the precipitate filtered off and dried. Recrystallization from methanol gave the title compound (1.25 g., m.p. 134°-5° ).
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])[CH:2]([CH3:4])[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:28][C:29]1[C:37]2[C:32](=[N:33][CH:34]=[N:35][C:36]=2[NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=2)[NH:31][N:30]=1>C1COCC1.C(O)C>[Cl:45][C:41]1[CH:40]=[C:39]([NH:38][C:36]2[N:35]=[CH:34][N:33]=[C:32]3[NH:31][N:30]=[C:29]([NH:28][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[O:7])[C:37]=23)[CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)COC(=O)NCC(=O)O
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CN1CCOCC1
Product: CC(C)COC(=O)NCC(=O)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12

Procedure:
Analogously to Example 5. 502 mg (2.86 mmol) of N-isobutyloxycarbonyl-glycine in 5.9 ml of THF and 580 μl (5.3 mmol) of NMM are activated with 375 μl (2.86 mmol) of isobutyl chloroformate and then reacted with 745 mg (2.86 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6). Stirring in 7.5 ml of boiling ethanol and filtering while hot yield 4-(3-chloro-phenylamino)-3-([N-iso-butyloxycarbonyl-glycyl]-amino)-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=12.8; FAB-MS: (M+H)+=418.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Br[CH2:13][C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].N12CCCN=C1CCCCC2>CN(C)C=O.CC(C)=O>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:13]([C:14]#[N:15])[O:1][C:2]=2[CH:9]=1
Reactant: N#CCBr
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1ccc2cc(C#N)oc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
To a mixture of 2-hydroxy-4-methoxybenzaldehyde (10.0 g), bromoacetonitrile (5.04 mL) and acetone (100 mL) was added potassium carbonate (18.1 g), and the mixture was stirred at room temperature for 3 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a pale-brown solid. To a solution (100 mL) of the obtained solid in N,N-dimethylformamide was added 1,8-diazabicyclo[5.4.0]undec-7-ene (9.83 mL), and the mixture was stirred at 140° C. for 1.5 hr. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:17, volume ratio) to give the title object compound (5.32 g, 47%) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]([C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)[C:18]([NH2:20])=[NH:19]>C1C=CC=CC=1.N1C=CC=CC=1>[N:25]1[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[NH:22][C:21]=1[N:17]=[C:18]1[NH:20][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:20][C:18](=[N:17][C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)[NH:19][C:9]2([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:19]1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: c1ccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccccc2)NC(=Nc2nc4ccccc4[nH]2)N3)cc1
Yield: 17.8 %

Procedure:
A mixture of benzil (1.05 g, 5.0 mmol) and 2-guanidinobenzimidazole (1.57 g, 9.0 mmol) in benzene (25 mL) was refluxed in pyridine (10 mL) for 1 h. After evaporating most of the pyridine under reduced pressure, the residue was treated with hot toluene and the resulting precipitate was filtered. The precipitate was then dissolved in 9:1 water:acetic acid (30 mL); the solution was filtered and the filtrate was neutralized to pH 7 with phosphate buffer. A precipitate formed, that was then collected and triturated with water to afford the title compound (0.42 g, 16%). 1H NMR (300 MHz, d6-DMSO) d 11.5 (br s, NH, 2 H), 10.0 (br s, NH, 2 H), 8.6 (br s, NH, 2 H), 7.28-7.10 (m, 14 H), 6.97 (dd, J=6.0, 3.0 Hz, 4 H); MS (ESI) m/z 525 [M+H]+; Anal. Calcd. for C30H24N10 . ½CH3CO2H ¾H2O: C, 65.37; H, 4.88; N, 24.65. Found: C, 65.36; H, 4.79; N, 24.48.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([C:26]([CH3:31])([CH3:30])[C:27](O)=[O:28])[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].[Cl-].C[NH3+].[CH3:35][N:36](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(Cl)Cl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([C:26]([CH3:30])([CH3:31])[C:27]([NH:36][CH3:35])=[O:28])[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C(C)(C)C(=O)O)c3)cc12
Agent: C[NH3+]
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(C)(C)n1cc(-c2cnc3[nH]cc(C(C)c4c(Cl)ccc(F)c4Cl)c3c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(4-{3-[1-(2,6-Dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyrazol-1-yl)-2-methylpropionic acid (20 mg, 0.04 mmol), methylammonium chloride (14.6 mg, 0.217 mmol), TBTU (28 mg, 0.087 mmol), DIPEA (37.8 μL, 0.217 mmol) and DCM (0.6 mL, 9 mmol) was stirred at rt for 1 h. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography (eluent: 2% MeOH in DCM) to give desired product. MS (ES+): m/z 474.09, 476.03 (100, 90) [MH+]. HPLC: tR=3.45 min (ZQ3 polar—5 min). 1H NMR (400 MHz, CD3OD): δ=1.81 (s, 6H), 1.88 (d, J=7.3 Hz, 3H), 2.71 (s, 3H), 5.29 (q, J=7.2 Hz, 1H), 7.14-7.23 (m, 1H), 7.36 (d, J=1.5 Hz, 1H), 7.43 (s, 2H), 7.65 (s, 1H), 8.00 (s, 1H), 8.39 (br. s., 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[C:13]([CH3:17])[N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:18]([O:21][CH2:22][C:23]1[C:24]([N:38]2[CH2:49][CH2:48][N:47]3[C:40](=[CH:41][C:42]4[CH2:43][C:44]([CH3:51])([CH3:50])[CH2:45][C:46]=43)[C:39]2=[O:52])=[N:25][CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1)(=[O:20])[CH3:19].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:38]2[CH2:49][CH2:48][N:47]3[C:40](=[CH:41][C:42]4[CH2:43][C:44]([CH3:51])([CH3:50])[CH2:45][C:46]=43)[C:39]2=[O:52])=[N:25][CH:26]=[CH:27][C:28]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[C:13]([CH3:17])[N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:20])[CH3:19]
Reactant: Cc1nc(Nc2cc(Br)cn(C)c2=O)cn1C
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cn(C)c(C)n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 95 °C
Yield: 52.4 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 337d (20 mg, 0.67 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (270 mg, 0.67 mmol), Pd(dppf)Cl2 (42 mg, 0.050 mmol), sodium acetate (82 mg, 1.0 mmol), K3PO4 trihydrate (266 mg, 1.0 mmol), water (6 drops), and acetonitrile (6 mL). After three cycles of vacuum/nitrogen flush, the mixture was heated at 95° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 337e (200 mg, 50%) as a brown solid. LCMS-ESI: [M+H]+ 570.3
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C:21]1([C:29]([OH:31])=[O:30])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][N:19]([CH2:20][C:21]1([C:29]([OH:31])=[O:30])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[CH:1]=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)CCC(CNOCc2ccccc2)(C(=O)O)CC1
Reactant: O=CO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC1(C)CCC(CN(C=O)OCc2ccccc2)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a cold solution of formic acid (12.8 mL, 0.33 mol) in dichloromethane (50 mL) at 0° C. under a nitrogen atmosphere was added acetic anhydride (4.8 mL, 51 mmol). After 1 h, a solution of 1-(benzyloxyamino-methyl)-4,4-dimethyl-cyclohexanecarboxylic acid from Preparation 30 (5.11 mmol theoretical) in dichloromethane (50 mL) was added. The reaction was stirred at room temperature for 18 h and was concentrated in vacuo. Water (100 mL) was added and the mixture was extracted with dichloromethane (50 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo to yield the title compound (1.55 g, 95%). MH+320.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].CC(C)=O.C(=O)=O.[Li]CCCC.[C:22]([N:26]1[C:30]2[NH:31][C:32](=[O:44])[CH2:33][CH:34]([C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[F:43])[C:29]=2[C:28]([CH:45]2[CH2:48][C:47](=[O:49])[CH2:46]2)=[N:27]1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([N:26]1[C:30]2[NH:31][C:32](=[O:44])[CH2:33][CH:34]([C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[F:43])[C:29]=2[C:28]([CH:45]2[CH2:48][C:47]([C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=3)[C:5]#[N:6])([OH:49])[CH2:46]2)=[N:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: N#Cc1cccc(Br)c1
Reactant: CC(C)(C)n1nc(C2CC(=O)C2)c2c1NC(=O)CC2c1cc(F)c(F)cc1F
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(C)n1nc(C2CC(O)(c3cccc(C#N)c3)C2)c2c1NC(=O)CC2c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
To a stirring solution of 3-bromobenzonitrile (3.7 g, 20.4 mmol) in 50 mL of THF at −78° C. (acetone/CO2 bath) was added a solution of n-BuLi (8.2 mL, 20.4 mmol, 2.5 M in hexanes). After 15 min, a solution of 1-tert-butyl-3-(3-oxo-cyclobutyl)-4-(2,4,5-trifluoro-phenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-b]pyridin-6-one (2.0 g, 5.1 mmol in 10 mL of THF) was added. After one hr, the reaction mixture was quenched cold by the addition of a saturated NH4Cl solution, and was then allowed to warm to room temperature. The reaction mixture was diluted with CH2Cl2, and the layers were separated. The organic layer was dried over MgSO4, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure to give a tan solid. Purification of this material was accomplished by MPLC using a 35 g ISCO cartridge on a Biotage® system eluting with a gradient of 25-50% EtOAc/hexanes. The product-containing fractions were collected and concentrated to yield the title compound (0.98 g, 40% yield) as a tan solid. Rf=0.29 (50% EtOAc/hexanes).
Reaction SMILES: S(O)(=O)(C1C=CC([NH2:9])=CC=1)=O.C(=O)([O-])[O-].[Na+].[Na+].N([O-])=O.[Na+].Cl.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[OH:31].[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH3:23][C:24]1[CH:29]=[C:28]([NH2:9])[CH:27]=[C:26]([CH3:30])[C:25]=1[OH:31]
Reactant: Cc1cccc(C)c1O
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: Cc1cc(N)cc(C)c1O
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
Sulphanilic acid (43.3 g, 0.25 mol) and sodium carbonate (13.25 g, 0.125 mol) were dissolved in water (250 ml) and cooled to 15° C. Sodium nitrite (18.63 g, 0.27 mol) in water (100 ml) was added in one portion, and the mixture added immediately to concentrated hydrochloric acid (53 ml) and ice (300 g), with stirring. After 30 minutes, the resulting suspension was added to an ice-cold solution of 2,6-dimethylphenol (30.54 g, 0.25 mol) and sodium hydroxide (55 g) in water (550 ml), stirring vigorously. After 2 hours, the temperature was raised to 50°, and sodium dithionite (115 g, 0.66 mol) added portionwise. On heating to 75° the red colour discharged, and after a further 10 minutes, the solution was cooled to room temperature. The resulting white solid was filtered, washed and dried to give the title compound (27.33 g), m.p. 135°-7°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][NH:43]6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:48][O:49][C:50]([NH:52][C@@H:53]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:54](O)=[O:55])=[O:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:47])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([C@@H:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:54](=[O:55])[CH:53]([NH:52][C:50]([O:49][CH3:48])=[O:51])[C:57]6[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.8 %

Procedure:
To a slurry of {2-Methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester (0.045 g, 0.06 mmol) and (S)-methoxycarbonylamino-phenyl-acetic acid (0.02 g, 0.09 mmol, 1.5 equiv.) in CH2Cl2 (0.6 mL) was added HATU (0.03 g, 0.08, 1.25 equiv.) and K3PO4 (0.05 g, 0.22 mmol, 3 equiv.). The reaction mixture was stirred at room temperature for 18 hours and diluted with CH2Cl2. The salts were filtered and the filtrate was concentrated. The crude oil was purified by preparative HPLC (Gemini, 15-40% MeCN in H2O (0.1% formic acid)) and lyophilized to provide [1-(2-{5-[6-(4-{2-[1-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 65%) as a white powder. LCMS-ESI+: calc'd for C47H50N8O6: 822.4 (M+); Found: 823.5 (M+H+). 1H-NMR: 400 MHz, (CDCl3) δ: (Mixture of rotomers) 7.64-8.03 (m, 9H), 7.20-7.40 (m, 6H), 7.17 (s, 2H), 6.14 (m, 1H), 5.53 (dd, 2H), 5.25-5.33 (m, 2H), 4.33 (t, 1H), 3.85 (m, 1H), 3.73 (m, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.27 (m, 1H), 2.86-2.96 (m, 3H), 2.35 (m, 1H), 1.94-2.23 (m, 6H), 0.87-0.90 (m, 6H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=O.Cl.[NH2:42][OH:43].N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:43]/[N:42]=[CH:1]/[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:13][CH:14]=1
Reactant: NO
Reactant: O=Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3/C=N/O)cc1)C2
Yield: 89 %

Procedure:
To a solution of 10-[(2′-formyl-1,1′-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 56 (0.500 g, 0.95 mmol) and hydroxylamine hydrochloride (0.132 g, 1.90 mmol) in methanol (15 mL) was added pyridine (0.155 mL, 1.90 mmol) and the reaction mixture heated to reflux under nitrogen for 1 hour. The cooled reaction mixture was then poured into 5% w/v aqueous sodium carbonate solution (100 mL) and extracted with ethyl acetate (100 mL). The organic extract was washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a white foam. Crystallization of the crude product from dichloromethane gave the title compound (0.458 g, 89%) as a white crystalline solid, m.p. 165-167° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)=[O:2].[CH3:12][C:13]([OH:19])([C:15]([CH3:18])(O)[CH3:16])[CH3:14]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:12][C:13]1([CH3:14])[C:15]([CH3:18])([CH3:16])[O:11][B:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH:1]3[O:19][C:13]([CH3:14])([CH3:12])[C:15]([CH3:18])([CH3:16])[O:2]3)[CH:4]=2)[O:10]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2cccc(C3OC(C)(C)C(C)(C)O3)c2)OC1(C)C
Yield: 76.8 %

Procedure:
(3-formylphenyl)boronic acid (5 g, 33.3 mmol), 2,3-dimethylbutane-2,3-diol (19.70 g, 167 mmol) and p-toluensulfonic acid monohydrate (0.317 g, 1.667 mmol) were dissolved in toluene (278 mL) and refluxed with a Dean-Stark equipment for 3 h until reaction completion. The mixture was dried under reduced pressure and the residue diluted with AcOEt (250 mL) and washed three times with abundant water, once with saturated NaClaqueous (250 mL), anhydrified over Na2SO4 and the solvent removed under reduced pressure. The crude was purified via flash chromatography on silica gel using a Biotage 100G+50G SNAP with a gradient of hexane and AcOEt to give the title compound (8.5 g, 77%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]([CH2:22][CH2:23][CH2:24][OH:25])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:27].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[C:24]([CH2:23][CH2:22][N:17]([C:3]1[C:2]([Cl:1])=[C:11]([CH3:12])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[N:8]2)[S:18]([CH3:21])(=[O:20])=[O:19])([OH:27])=[O:25]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COc1nc2cc(C)c(Cl)c(N(CCCO)S(C)(=O)=O)c2nc1OC
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc2cc(C)c(Cl)c(N(CCC(=O)O)S(C)(=O)=O)c2nc1OC

Procedure:
N-(6-Chloro-7-methyl-2,3-dimethoxyquinoxalin-5-yl)-N-(3-hydroxypropyl)methanesulphonamide (0.94 g, 2.41 mmol) and pyridinium dichromate (2.42 g, 9.63 mmol) in DMF (24 ml) were stirred at room temperature for 18 hours. The reaction mixture was poured into water (25 ml) and extracted twice with dichloromethane. The combined dichloromethane extracts were extracted twice with 10% potassium carbonate solution. The potassium carbonate extracts were acidified to pH1 with 2M HCl and extracted twice with dichloromethane. These combined dichloromethane extracts were dried (MgSO4) and concentrated under reduced pressure to give N-(2-carboxyethyl)-N-(6-chloro-7-methyl-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide an off-white solid (0.49 g, 51%).
Reaction SMILES: C(OC([N:6]1[CH:10]=[C:9]([C:11]2[C:12]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:8]=[N:7]1)C)C.O1CCCC1.Cl.[OH-].[Na+]>O>[NH:6]1[CH:10]=[C:9]([C:11]2[C:12]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:8]=[N:7]1
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 88 %

Procedure:
To a reactor equipped with overhead stirring, condenser, thermowell, and nitrogen inlet was charged crude 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (15, 1030.9 g based on 100% conversion, 2.66 mol), tetrahydrofuran (THF, 0.9 L), water (H2O, 4.4 L), and a 10% aqueous HCl solution (2.7 L, 10.64 mol, 3.44 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 2-5 h. When the reaction was deemed complete by HPLC analysis, the reaction mixture was treated with a 30% aqueous sodium hydroxide (NaOH) solution (940 mL, 11.70 mol, 3.78 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 1-2 h. The solids were collected by filtration, washed with water (2×0.75 L), and dried in a vacuum oven at 45-55° C. to constant weight to afford the crude 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 826.8 g, 839.1 g theoretical, 98.5% yield) as off-white solids (94.2 area % pure by HPLC). This crude material was subsequently recrystallized in acetonitrile to afford pure compound 5 (738.4 g, 839.1 g theoretical, 88% yield) as white crystals (99.5 area % by HPLC), which was found to be identical in every comparable aspect to the material made from Method A.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6]C(=O)C2C=CC=CC=2)[CH2:3]1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]1([N:2]2[CH2:5][CH:4]([OH:6])[CH2:3]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1ccccc1
Reactant: O=C(OC1CNC1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: OC1CN(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
A suspension of azetidin-3-ylbenzoate hydrochloride (600 mg), bromobenzene (530 mg), Pd2(dba)3 (129 mg), Xantphos (134 mg) and sodium tert-butoxide (515 mg) in toluene (12 mL) was irradiated with microwave at 150° C. for 30 min under an argon atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in ethanol (12 mL), and 1N aqueous sodium hydroxide solution (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to give the title compound (131 mg).