Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:44])[NH:14][CH2:15][C:16]([N:18]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[CH:21]([C:30](=[O:36])[NH:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:20][CH:19]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:17])[CH:9]=[CH:10][CH:11]=1)=[O:5])C.O.CO>[OH-].[K+]>[C:40]([O:39][C:37]([CH:19]1[CH2:20][CH:21]([C:30](=[O:36])[NH:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[N:18]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:44])[NH:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([OH:5])=[O:3])=[O:38])([CH3:42])([CH3:43])[CH3:41]
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)NCC(C)C)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)CNC(=O)C1CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C(=O)O)c2)C1c1ccccc1F
Yield: 16.2 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 4.2 g of tert-butyl (2RS,4SR,5SR)-1-{2-[3-(3-(ethoxycarbonyl)phenyl)ureido]acetyl}-5-(2-fluorophenyl)-4-(isobutylcarbamoyl)pyrrolidine-2-carboxylate in a mixture of 6.8 cm3 of a normal aqueous potassium hydroxide solution, 30 cm3 of distilled water and 140 cm3 of methanol. After treatment, there is obtained 0.65 g of (2RS,4SR,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-(2-fluorophenyl)-4-isobutylcarbamoyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid, melting at 160° C.
Reaction SMILES: OC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1NC(C)=O.C1C(=O)NC(=O)N([C@@H]2O[C@H](COP(OP([O:38][C@H:39]3[O:44][C@H:43]([C:45]([O-:47])=[O:46])[C@@H:42]([OH:48])[C@H:41]([OH:49])[C@H:40]3[OH:50])([O-])=O)([O-])=O)[C@@H](O)[C@H]2O)C=1.[Na+].[Na+].[Na+]>>[OH:38][CH:39]1[O:44][C@H:43]([C:45](=[O:46])[OH:47])[C@@H:42]([OH:48])[C@H:41]([OH:49])[C@H:40]1[OH:50]
Reactant: O=C([O-])[C@H]1O[C@H](OP(=O)([O-])OP(=O)([O-])OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Agent: [Na+]
Product: O=C(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
Saccharide chain fractions were prepared in the same manner as that of (A) except that UDP-GlcA was used instead of UDP-GalNAc to prepare sample solutions for MS.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:33]([F:36])([F:35])[F:34])[N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH2:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25](=[O:32])[NH:24][N:23]=4)[CH:17]=[CH:18][C:19]=3[F:20])=[O:13])[CH2:8][C:7]=12.[CH3:37][NH2:38].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O1CCCC1>[F:20][C:19]1[CH:18]=[CH:17][C:16]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[NH:24][N:23]=2)=[CH:15][C:14]=1[C:12]([N:9]1[CH2:10][CH2:11][N:6]2[C:5]([C:33]([F:36])([F:34])[F:35])=[N:4][C:3]([CH2:2][NH:38][CH3:37])=[C:7]2[CH2:8]1)=[O:13]
Reactant: CN
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(C(F)(F)F)nc(CCl)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CNCc1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Yield: 10.1 %

Procedure:
4-[[3-[1-(Chloromethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 9a (372 mg, 1.25 mmol) was dissolved in 5 mL of acetonitrile, followed by addition of 0.6 mL of a 2 M solution of methylamine in tetrahydrofuran and potassium carbonate (159 mg, 1.15 mmol). The reaction mixture was heated to reflux for 6 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure and was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[1-(methylaminomethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 9 (20 mg, yield 10.1%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12](OCC)=[O:13])[CH2:7][CH2:6]1.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([NH:22][NH2:23])=[O:13])[CH2:7][CH2:6]1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2c(F)cccc2Cl)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2c(F)cccc2Cl)CC1

Procedure:
Synthesized according to General Procedure C: 6{7} (8.65 g, 27.5 mmol, 1 equiv.), anhydrous hydrazine (2.6 mL, 82.4 mmol, 3 equiv.), ethanol (37.9 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{7} (8.27 g, 92%) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 8.14 (br s, 1H) 7.22-7.15 (m, 2H), 6.99-6.94 (m, 1H), 3.83 (br s, 2H) 3.70 (d, 2H, J=2.0 Hz), 3.04 (s, 2H), 2.55 (br s, 4H), 2.50 (br s, 4H). 13C-NMR (100 MHz, CDCl3): δ 170.5, 162.0 (d, JC-F=247.6 Hz), 136.5 (d, JC-F=5.9 Hz), 129.2 (br), 125.4 (br), 123.5 (d, JC-F=18.1 Hz), 113.9 (br), 60.5, 53.5, 52.6, 52.1.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:30][CH:31]1[CH2:45][C:34]2[C:35]3[NH:36][C:37](=[O:44])[C:38](=[O:43])[NH:39][C:40]=3[CH:41]=[CH:42][C:33]=2[CH2:32]1>O1CCCC1>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:30][CH:31]2[CH2:45][C:34]3[C:35]4[NH:36][C:37](=[O:44])[C:38](=[O:43])[NH:39][C:40]=4[CH:41]=[CH:42][C:33]=3[CH2:32]2)[CH2:12][CH2:13]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: NC1Cc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NC2Cc3ccc4[nH]c(=O)c(=O)[nH]c4c3C2)CC1
Temperature: 80 °C
Yield: 70 %

Procedure:
A mixture of N-Boc-piperidine-4-carboxylic acid (0.23 g, 1 mmol) and 1,1'-carbonyldiimidazole (0.16 g, 1 mmol) in tetrahydrofuran (5 mL) was heated at 80° C. for 15 min. After cooling, it was added to a solution of 8-amino-4,7,8,9-tetrahydro-1H-cyclopenta[f]quinoxaline-2,3-dione hydrochloride (0.11 g, 0.5 mmol) and the mixture was heated at 70° C. for 2 days. After filtration to remove precipitate, the filtrate was evaporated and the residue suspended in water. The resulting solid was collected by filtration, washed with diethyl and dried in vacuo (0.15 g, 70% yield).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:13]1[CH2:18][CH2:17][CH2:16][N:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N:15]1([C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:16][CH2:17][CH2:18][N:13]=[CH:14]1
Reactant: Cc1cc(F)cc(N)c1[N+](=O)[O-]
Reactant: C1=NCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(N2C=NCCC2)cc(N)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 67.2 %

Procedure:
To a stirred solution of 2.0 g (11.76 mmol) of the 5-Flouro-3-methyl-2-nitro aniline in 10 mL of DMSO was added 1.2 g (14.11 mmol) of 1,4,5,6-Tetrahydropyrimidine, and 2.43 g (17.64 mmol) of potassium carbonate, and the mixture was heated at 100° C. for 10 hrs, cooled, diluted with water, and extracted with Ethylacetate containing 5% methanol. The combined organic extract was washed with water, brine and dried (Na2SO4). Evaporation of the solvent furnished the residue, which was chromatographed (20% of 2M ammonia in methanol and dichloromethane) to produce 1.85 g (67%) of the product as red solid. 1H NMR (400 MHz, CD3OD) δ 7.89 (1H, s), 6.53 (1H, d, J=2.57 Hz), 6.44 ((1H, d, J=2.1 Hz), 7.04 (1H, d, J=2.1 Hz), 3.70 (2H, t, J=6.0 Hz), 3.41 (2H, t, J=5.65 Hz, 2.43 (3H, s), 2.05 (2H, m) LCMS (M+H)+ m/z 235 (t=0.78 min).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[CH3:10].[CH2:11]([CH:13]1[O:15][CH2:14]1)[Cl:12]>C1COCC1.CN(C=O)C.[Cu]I.BrCCBr>[Cl:12][CH2:11][CH:13]([OH:15])[CH2:14][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[CH3:10]
Reactant: ClCC1CO1
Reactant: Cc1c(F)cccc1Br
Agent: [Cu]I
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(F)cccc1CC(O)CCl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 104.9 %

Procedure:
0.867 g (35.67 mmol) of magnesium turnings were dried and suspended in 17 ml of anhydrous THF under argon. A solution of 1,2-dibromoethane (0.14 ml, 1.62 mmol) and 2-bromo-6-fluoro-toluene (6.74 g, 35.67 mmol) in 17 ml of anhydrous THF was then added dropwise so as to maintain a gentle reflux. Once the magnesium had been consumed, copper(I) iodide (0.432 g, 2.27 mmol) was then added, followed by a solution of epichlorohydrine (3.00 g, 32.42 mmol) in DMF (8 ml). The mixture was stirred for 3.5 h at room temperature and then quenched with a saturated solution of ammonium chloride (120 ml). The organic layer was separated, and the aqueous phase was extracted twice with EA. The combined organic phases were washed twice with a saturated solution of ammonium chloride, dried over sodium sulfate, filtered and evaporated to dryness. The product was purified by chromatography on silica gel (cyclohexane/EA, from 100:0 to 90:10) to give 6.89 g of 1-chloro-3-(3-fluoro-2-methyl-phenyl)-propan-2-ol. 3.92 g (16.23 mmol) of this alcohol were dissolved in DCM under argon, and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane reagent; 7.57 g, 16.23 mmol) was added. The mixture was stirred at room temperature overnight and then diethyl ether (150 ml) was added. The mixture was washed three times with 1 N hydrochloric acid (70 ml) and twice with a saturated solution of sodium chloride, and extracted with ether. The extracts were dried over sodium sulfate, filtered and evaporated to dryness. 2.69 g of the title compound were obtained as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:14]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH4+].[OH-]>C1COCC1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: NC(=O)c1cccc(Cl)c1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-amino-3-chloro-benzoic acid (2.57 g, 15.0 mmol) in THF (100 mL) were added EDCl (3.16 g, 16.5 mmol), HOBt (2.23 g, 16.5 mmol) and N-methylmorpholine (1.67 g, 16.5 mmol). The reaction mixture was stirred at room temperature for 20 minutes then 50% (v/v) aq. NH4OH solution (4.2 mL, 60.0 mmol) was added. The mixture was stirred for 20 hours at room temperature. Solvent was evaporated and the residue was taken in ethyl acetate (200 mL). Water (100 mL) was added. The organic phase was separated; the aqueous phase was extracted with ethyl acetate (200 mL). The combined organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous sodium sulfate. Solvent was evaporated and dried under vacuum to give 2-amino-3-chloro-benzamide as a white solid. Yield: 2.07 g (81%).
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:23][O:24][CH:25]1[CH2:28][N:27]([CH2:29][CH2:30][NH2:31])[CH2:26]1>COCCOC>[CH3:23][O:24][CH:25]1[CH2:28][N:27]([CH2:29][CH2:30][NH:31][C:2]2[N:3]=[N+:4]([O-:15])[C:5]3[CH:14]=[C:13]4[C:9]([CH2:10][CH2:11][CH2:12]4)=[CH:8][C:6]=3[N:7]=2)[CH2:26]1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: COC1CN(CCN)C1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: COC1CN(CCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Yield: 47 %

Procedure:
A solution of chloride 21 (1.32 g, 6.0 mmol), Et3N (1.65 mL, 11.8 mmol) and 2-(3-methoxy-1-azetidinyl)ethylamine (277) (950 mg, 7.3 mmol) in DME (30 mL) was heated at reflux temperature for 18 h. The solution was cooled, the solvent evaporated and the residue partitioned between dilute aqueous NH3 solution (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (4×50 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 34 (890 mg, 48%) as a yellow solid: mp 139-141° C.; 1H NMR δ 8.06 (s, 1H, H-9), 7.38 (s, 1H, H-5), 5.67 (br s, 1H, NH), 4.04 (p, J=5.8 Hz, 1H, CHO), 3.63-3.69 (m, 2H, CH2N), 3.47 (dt, J=5.9, 5.6 Hz, 2H, CH2N), 3.26 (s, 3H, OCH3), 2.93-3.03 (m, 6H, H-6, H-8, CH2N), 2.74 (t, J=5.9 Hz, 2H, NCH2), 2.14 (p, J=7.4 Hz, 2H, H-7); 13C NMR δ 158.7, 154.5, 148.7, 143.3, 129.8, 120.6, 114.6, 70.0, 61.4 (2), 58.0, 56.0, 39.3, 33.1, 32.3, 25.7; MS (APCI) m/z 316 (MH+, 100%). Anal. calcd for C16H21N5O2.¼H2O: C, 60.1; H, 6.8; N, 21.9. Found: C, 60.0; H, 6.6; N, 21.7%.
Reaction SMILES: NC1C=CC=CC=1.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[N:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].S([CH2:33][N+:34]#[C-:35])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.COCCOC.C(O)C>[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:35][N:34]=[CH:33]1
Reactant: CCOC(=O)C=Nc1ccc(C)cc1C
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)c1cncn1-c1ccc(C)cc1C
Temperature: 90 °C
Yield: 50.3 %

Procedure:
To 10 g (83 mmol) of 2,4-dimethylaniline in 200 mL of methanol was added 80 mL (50% solution in toluene, 410 mmol) of ethyl gyloxalate. The mixture was heated to 70° C. for 7 h and then allowed to stand at room temperature overnight. The reaction was concentrated in vacuo, dissolved in dichloromethane and concentrated onto silica gel. The product was eluted with a 93-100% ethyl acetate/hexanes gradient mixture to give 8.0 g (47%) of ethyl 2-(2,4-dimethylphenylimino)acetate as an oil containing approximately 20% starting aniline by LCMS analysis. This material was used without further purification. MS Calcd.: 205. Found: 206 (M+H). To 7.2 g (35 mmol) of ethyl 2-(2,4-dimethylphenylimino)acetate, 11 g (56 mmol) of tosylmethylisocyanide and 9.7 g (70 mmol) of potassium carbonate was added 200 mL of a 2:1 ethanol:1,2-dimethoxyethane mixture. The resulting slurry was heated to 90° C. for 1 h. The cooled mixture was diluted with 300 mL of ethyl acetate and filtered through GFF paper. The resulting filter cake was washed with an additional 500 mL of ethyl acetate and the resulting filtrate was added to the previous filtrate. The combined filtrates were then concentrated in vacuo to give a brown semisolid. The crude material thus obtained was then purified by flash chromatography eluting with a 45% ethyl acetate/hexanes mixture to give 4.3 g (62%) of the title compound as a tan solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:16][NH2:17])=[N:5][CH:6]=[C:7]([CH:15]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:18]([NH:17][NH:16][C:4]1[C:3]([Cl:2])=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])=[CH:6][N:5]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1cnc(NN)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cnc(NNC(=O)c2ccccc2)c(Cl)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 5-chloro-6-hydrazinonicotinate hydrochloride salt (3.0 g, 9.5 mmol) in N,N-dimethylformamide (20 mL) were added benzoic acid (1.62 g, 13.3 mmol), EDC (3.63 g, 19.0 mmol), HOAT (1.29 g, 9.48 mmol) and triethylamine (6.6 mL, 48.4 mmol). The reaction mixture was stirred at 60° C. After 1 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate (3×). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated: LC-MS [M+1]=348.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+].Cl>CO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:11]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[OH:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)c(F)c3)nc3ccccc23)n[nH]1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(C(O)c3ccc(F)c(F)c3)nc3ccccc23)n[nH]1
Reaction time: 0.5 h
Yield: 6.2 %

Procedure:
To crude (3,4-difluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (553 mg, 1.5 mmol) in 1:1 MeOH/THF (40 mL) at 0° C. was added sodium borohydride (0.09 g, 2.4 mmol), and the solution was stirred for 30 min, after which 6N HCl was added. The mixture was concentrated to dryness, and ca. 2/3 of the residue was purified by silica gel chromatography eluting with 0-15% MeOH/DCM to afford (3,4-difluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanol (34 mg). 1H NMR (300 MHz, DMSO-d6) δ 2.26 (s, 3H) 6.03 (s, 1H) 6.22 (s, 1H) 7.45-7.55 (m, 2H) 7.66 (t, 1H) 7.78 (t, 1H) 8.07 (t, 1H) 8.19 (t, 1H) 8.82 (d, 1H) 12.09 (bs, 1H) 12.67 (bs, 1H); LC-MS (ESI) m/z 368 (M+H)+.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C:3]([C:14]([O:16]C)=[O:15])=[C:4]1[CH:13]=[CH:12][CH2:11][CH2:10][N:5]12.[OH-].[K+].Cl>CO.O>[CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C:3]([C:14]([OH:16])=[O:15])=[C:4]1[CH:13]=[CH:12][CH2:11][CH2:10][N:5]12
Reactant: COC(=O)c1c2n(c3ccccc13)CCC=C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c2n(c3ccccc13)CCC=C2
Yield: 64 %

Procedure:
A stirred solution of methyl 6,7-dihydropyrido[1,2-a]indole-10-carboxylate (T. Teitei and L. K. Dalton, Australian J. Chem 1969, 22, 997) (1.0 g, 0.0044 mole) in methanol (40 ml) was treated with a solution of potassium hydroxide (3.0 g, 0.054 mole) in water (50 ml) and heated under reflux for 3 h. The solution was allowed to cool, then acidified with HCl acid and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated under vacuum to leave the title compound (D8) as a yellow solid (600 mg, 64%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])O1.Cl[C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([N+:41]([O-:43])=[O:42])[CH:32]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.COCCOC.O>[C:24]([O:23][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([N+:41]([O-:43])=[O:42])[CH:32]=1)=[O:28])([CH3:25])([CH3:26])[CH3:27]
Reactant: COC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 96.5 %

Procedure:
Water (3.0 mL), sodium carbonate (1.1 g), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (1.5 g), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (30 mg) were added to an ethylene glycol dimethyl ether (10 mL) solution of methyl 4-chloro-2-nitrobenzoate (0.90 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then ethyl acetate and a 10% aqueous solution of citric acid were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] to obtain 1.5 g of methyl 4-(2-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(O[N:51]1[N:59]=[N:58][C:53]2[CH:54]=[CH:55][CH:56]=[N:57][C:52]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[N:58]1[C:53]2[C:52](=[N:57][CH:56]=[CH:55][CH:54]=2)[N:51]([O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[N:59]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)On2nnc3cccnc32)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with HATU to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester. MS (ES+) m/z calcd. for C36H32Cl2F2N7O4: [(M+H)+]: 734. found: 734.
Reaction SMILES: C(OC(=O)[N:7]([CH2:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH2:28])=[CH:23][C:22]=2[CH3:30])=[CH:16][C:15]=1[F:31])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[ClH:33]>ClCCl.O1CCOCC1>[ClH:33].[F:20][C:19]1[CH:18]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([NH2:28])=[O:29])=[CH:23][C:22]=2[CH3:30])[CH:16]=[C:15]([F:31])[C:14]=1[CH2:13][NH:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: Cc1cc(C(N)=O)ccc1-c1cc(F)c(CN(CCC(C)C)C(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(C(N)=O)ccc1-c1cc(F)c(CNCCC(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4′-Carbamoyl-3,5-difluoro-2′-methyl-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-1e: 40 g) was dissolved in 500 mL of dichloromethane and treated with 34 ml of a 4.0 M hydrogen chloride solution in dioxane. After stirring overnight at room temperature, the volatiles were removed under reduced pressure and the resulting crude material was suspended in ethanol (200 mL), heated at reflux for 20 minutes and stirred overnight at room temperature. The resulting slurry was collect via filtration, rinsing with chilled ethanol, and dried under vacuum to provide the title compound (E1-01: 25 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH3:10].[Li]C(C)(C)C.[B:16](OC)([O:19]C)[O:17]C>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:16]([OH:19])[OH:17])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: COc1cc(Cl)ccc1Br
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1B(O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
4-Chloro-2-methoxyphenylboronic acid ethylene glycol ester: To a solution of 2-bromo-5-chloroanisole (4.43 g, 20 mmol) in dry THF (100 mL) at −78° C. was added dropwise t-BuLi (14.1 mL, 1.7 M, 23.97 mmol). The mixture was stirred for 10 min at −78° C. and trimethyl borate (2.23 mL, 20 mmol) was added. The cooling bath was removed and the mixture was stirred for 30 min from −78° C. to room temperature and then for 3 h with a water bath. Hydrochloric acid (6N, 8 mL) and brine were added. The mixture was extracted with ethyl acetate, dried and evaporated to give 4-chloro-2-methoxyphenylboronic acid as a brown solid (3.33 g, 17.88 mmol) in 89.4% yield. This boronic acid was mixed with ethylene glycol (1.1 g, 17.88 mmol) and toluene (150 mL). The mixture was refluxed for 2 h under N2 with the help of a Dean-Stark trap to remove water generated. After being cooled to room temperature, the solution was transferred to another dry flask and rotary evaporated to provide 4-Chloro-2-methoxyphenylboronic acid ethylene glycol ester as a brown liquid (3.6 g, 16.97 mmol) in 84.8% yield.