Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=O)[S:29][C:30]=1[Cl:31]>ClCCCl>[Br:25][C:26]1[CH:27]=[C:28]([CH2:32][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[S:29][C:30]=1[Cl:31]
Reactant: O=Cc1cc(Br)c(Cl)s1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Clc1sc(CN2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
Morpholine (15.2 mL), acetic acid (9.1 mL), and then sodium triacetoxyborohydride (50.3 g) is added to a solution of 4-bromo-5-chloro-2-thiophenecarbaldehyde (Preparation 61, 35.7 g) in 1,2-dichloroethane (600 mL) at 0° C. The mixture is allowed to warm to room temperature, and after 18 h, it is quenched with a 2N NaOH solution (200 mL) with ice bath cooling. The organic layer is separated and washed with 1 N NaOH solution (2×200 mL). The aqueous layers are extracted with CH2Cl2 (2×100 mL). The combined organic layers are extracted with 0.25 M HCl solution (2 L) and the resulting aqueous layer is made basic with 2N NaOH solution. The mixture is then extracted with CH2Cl2 (2 L) and the organic layer is dried (Na2SO4) and concentrated to afford 39.24 g (84%) of the title compound as a light yellow oil. Physical characteristics: 1H NMR (400 MHz, DMSO-d6) δ 7.03, 3.63, 3.57, 2.42; 13C NMR (100 MHz, CDCl3) δ 140.9, 127.3, 125.9, 109.2, 66.9, 57.6, 53.3; MS (ESI+) m/z 296 (72, (M+H)+), 298 (100).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][O:27][CH2:28][C:29]4[N:30]=[N:31][N:32]([CH2:34]CF)[CH:33]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:10](=[O:11])[C:8]2=[O:9])=[CH:4][CH:3]=1.[F:39][CH2:40][CH2:41][CH2:42]CN=[N+]=[N-]>>[F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][O:27][CH2:28][C:29]4[N:30]=[N:31][N:32]([CH2:34][CH2:42][CH2:41][CH2:40][F:39])[CH:33]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:10](=[O:11])[C:8]2=[O:9])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCCCCF
Reactant: O=C1C(=O)N(Cc2ccc(F)cc2)c2ccc(S(=O)(=O)N3CCC[C@H]3COCc3cn(CCF)nn3)cc21
Product: O=C1C(=O)N(Cc2ccc(F)cc2)c2ccc(S(=O)(=O)N3CCC[C@H]3COCc3cn(CCCCF)nn3)cc21

Procedure:
is prepared according to the procedure for compound 12, with the exception that 4-fluorobutylazide is used in place of the 2-fluoroethylazide.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:23][C:24]1[CH:28]=[N:27][N:26]([CH3:29])[C:25]=1[C:30]([OH:32])=O.[N:33]1([C:39]2[N:44]3[CH:45]=[C:46]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:47]=[C:43]3[CH:42]=[C:41]([NH2:54])[N:40]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C=O)C.C(OCC)(=O)C>[N:33]1([C:39]2[N:44]3[CH:45]=[C:46]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:47]=[C:43]3[CH:42]=[C:41]([NH:54][C:30]([C:25]3[N:26]([CH3:29])[N:27]=[CH:28][C:24]=3[Cl:23])=[O:32])[N:40]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1
Reactant: Cn1ncc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ncc(Cl)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.5 %

Procedure:
Under an atmosphere of nitrogen, N—N-diisopropylethylamine (121 mg) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 120 mg) were added to a solution of 4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (50 mg, 0.31 mmol, Art-Chem B000148) in DMF (3 ml). After 30 min, 5-morpholin-4-yl-2-phenyl-imidazo[1,2-c]pyrimidin-7-ylamine (110 mg, 0.37 mmol) was added, and the black solution was stirred at r.t. overnight. The reaction mixture was taken up in ethyl acetate and washed with water. After drying (Na2SO4), the solvent was evaporated and the title compound (2 mg, 1.1%) was isolated by preparative, inverse-phase HPLC (Agilent Zorbax XdB-C18 column, time per run ˜7 min, flow rate 30 ml/min, solvent gradient H2O/CH3CN=95:5-5:95). MS (m/e)=438.2 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[NH3:29]>C(O)C>[NH2:29][C:23]([C:20]1[N:19]=[C:18]([C@H:8]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[O:22][N:21]=1)=[O:24]
Reactant: N
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)c1nc(C(N)=O)no1

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (400 mg, 1.01 mmol) in ethanol saturated with ammonia gas (20 ml) was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient system of hexane:ethyl acetate (90:10) gradually changing to hexane: ethyl acetate (60:40) to afford the title compound as a white solid ( 260 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([N+:31]([O-])=O)[CH:25]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:34].[CH:35](O)=O>[Pd]>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]3[NH:30][CH:35]=[N:31][C:26]=3[CH:25]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:34]
Reactant: CC1CCN(C(=O)C(Cc2ccc(N)c([N+](=O)[O-])c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Reactant: O=CO
Agent: [Pd]
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Temperature: 50 °C
Reaction time: 1.33 h

Procedure:
1.06 g (2 mMol) of 4-amino-N-[1-((4-amino-3-nitro-phenyl)methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide are suspended in 20 ml of formic acid and hydrogenated, with the addition of 0.1 g palladium/charcoal, in an autoclave under a hydrogen pressure of 5 bar at ambient temperature for 80 minutes. Then the catalyst is filtered off and the filtrate is heated to 50° C. for 2 hours. It is then concentrated by evaporation, mixed with 30 ml of water, made alkaline with concentrated ammonia and extracted twice with ethyl acetate. The organic phase is washed twice with water, dried over magnesium sulphate and evaporated down. The residue obtained is purified on a silica gel column (ethyl acetate/methanol/ammonia=95:5:0.5). After evaporation the residue is recrystallised from isopropanol.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C@@H:34]([OH:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:23])[F:24])=[C:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][C@@H:34]([OH:36])[CH3:35])=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: C[C@H](O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](O)CNC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 47.1 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), (S)-1-aminopropan-2-ol (7.84 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). The reaction mixture was stirred for 1 h and it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.9 min) to provide (R/S)-2-hydroxy-N—((S)-2-hydroxypropyl)-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (18 mg, 0.033 mmol, 47.1% yield) as a mixture of diastereomers. LCMS=489.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.09-8.20 (2 H, m), 7.55-7.86 (7 H, m), 5.15 (1 H, s), 3.80-3.94(1 H, m, J=9.11, 6.67, 6.67, 4.62 Hz), 3.09-3.37 (2 H, m), 1.14 (3 H, dd, J=6.27, 1.21 Hz); HPLC peak RT=8.4 min (Method A).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[CH:23]=[O:24])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-n2cncn2)cc1
Product: O=C/C=C/c1ccc(-n2cncn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1H-1,2,4-triazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 200 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].I[CH2:24][CH2:25][CH3:26]>CC#N>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][CH3:26])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCCI
Reactant: CS(=O)(=O)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCN(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
A suspension of 1-(3-methanesulfonyl-phenyl)piperazine (350 mg) and ground K2CO3 (403 mg) was stirred in CH3CN (25 mL) at room temperature. 1-Iodo-propane (712 μL) was added. The mixture was refluxed overnight. The reaction mixture was filtered and the volatiles were evaporated in vacuum. The oily residue was chromatographed on a silica column with MeOH:CH2Cl2 (1:30 (v/v)) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded pure 1-(3-methanesulfonyl-phenyl)-4-propyl-piperazine (220 mg). The amine was converted into the HCl salt and recrystallized from ethanol/diethylether: m.p. 233° C. MS m/z (relative intensity, 70 eV) 282 (M+, 30), 254 (15), 253 (bp), 210 (17), 70 (21).
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:55])([CH3:54])[C:29]([F:53])([F:52])[C@:30]([C:33]3[CH:38]=[C:37]([C:39]4[CH:40]=[N:41][N:42]([C:44]5[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=5)[CH:43]=4)[CH:36]=[CH:35][C:34]=3[F:51])([CH3:32])[N:31]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O>ClCCl>[ClH:50].[Cl:50][C:46]1[CH:45]=[C:44]([N:42]2[CH:43]=[C:39]([C:37]3[CH:36]=[CH:35][C:34]([F:51])=[C:33]([C@:30]4([CH3:32])[C:29]([F:52])([F:53])[C:28]([CH3:54])([CH3:55])[O:27][CH2:26][C:25]([NH2:24])=[N:31]4)[CH:38]=3)[CH:40]=[N:41]2)[CH:49]=[CH:48][CH:47]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4cnn(-c5cccc(Cl)c5)c4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OCC(N)=N[C@](C)(c2cc(-c3cnn(-c4cccc(Cl)c4)c3)ccc2F)C1(F)F
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 133.5 %

Procedure:
A solution of [bis-(4-methoxy-phenyl)-phenyl-methyl]-((R)-5-{5-[1-(3-chloro-phenyl)-1H-pyrazol-4-yl]-2-fluoro-phenyl}-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-amine (174 mg, 228 μmol) in dichloromethane (4 ml) was treated at room temperature with trifluoro acetic acid (178·1, 2.28 mmol). The reaction mixture was stirred at room temperature for 16 hours. For the workup, the reaction mixture was evaporated at reduced pressure and the dark red residue was directly purified by chromatography on an amine-silica phase using a gradient of heptane/ethyl acetate=100:0 to 30:60 as the eluent. For further purification, the product (146 mg) was treated with a solution of hydrochloric acid in dioxane (4M, 1 ml). After evaporation at reduced pressure, the residue was triturated with diethyl ether (2 ml). The solid residue was dried at high vacuum an yielded the (R)-5-{5-[1-(3-chloro-phenyl)-1H-pyrazol-4-yl]-2-fluoro-phenyl}-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine hydrochloride (76 mg, 67% yield) as a white solid. MS (ISP): m/z=463.2 [M+H]+ and 465.2 [M+2+H]+.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[C:15]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1>>[C:15]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:6]2[CH:7]([C:30]3[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH:28][CH:29]=3)[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:24])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: c1ccc2[nH]ccc2c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: CC(C)(C)c1ccc(C(=O)N2c3ccccc3-c3ccccc3C2c2c[nH]c3ccccc23)cc1

Procedure:
(4-tert-Butyl-phenyl)-[6-(1H-indol-3-yl)-6H-phenanthridin-5-yl]-methanone was prepared from phenanthridine, 4-tert-butylbenzoyl chloride, and indole according to GP 2. Yield, 34%. 1H-NMR (DMSO-d6): δ=1.21 (s, 9 H), 6.20 (dd, J=2.5 Hz, J=0.8 Hz, 1H), 6.40 (d, br., J=7 Hz, 1H), 6.82 (t, J≈8 Hz, 1H), 6.99-7.08 (m, 2H), 7.11 (ddd, J=J=7.6 Hz, J=1.1 Hz, 1H), 7.14-7.19 (m, 3H), 7.22-7.27 (m, 1H), 7.30 (“d”, J≈8.6 Hz, 2H), 7.43 (ddd, J≈J≈7.5 Hz, J=1.2 Hz, 1H), 7.50-7.57 (m, 2H), 7.85-7.90 (m, 1H), 7.95 (dd, J=7.8 Hz, J=1.3 Hz, 1H), 8.09 (“d”, J≈7.5 Hz, 1H), 10.69 (s, 1H); (+)-ESI-MS: m/z=457 [M+H]+, 340 [M-indole+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:25][CH2:24]2)=[CH:4][C:5]([CH:20]2[CH2:22][CH2:21]2)=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].[CH:36]1([C:39]2[O:40][CH:41]=[C:42]([C:44](O)=[O:45])[N:43]=2)[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[CH:20]1([C:5]2[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])=[CH:19][C:2]([NH:1][C:44]([C:42]3[N:43]=[C:39]([CH:36]4[CH2:38][CH2:37]4)[O:40][CH:41]=3)=[O:45])=[C:3]([N:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[CH2:27][CH2:28]3)[CH:4]=2)[CH2:21][CH2:22]1
Reactant: O=C(O)c1coc(C2CC2)n1
Reactant: Cc1ccccc1N1CCN(c2cc(C3CC3)c(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccccc1N1CCN(c2cc(C3CC3)c(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2coc(C3CC3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
5-Amino-2-cyclopropyl-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 5b (89.0 mg, 0.19 mmol, 100 mol %), 2-cyclopropyl-oxazole-4-carboxylic acid 1h (43.0 mg, 0.28 mmol, 150 mol %) and N,N-diisopropylethylamine (0.10 ml, 0.56 mmol, 300 mol %) were combined in N,N-dimethylformamide (3.0 ml) and HATU (106.7 mg, 0.28 mmol, mol %) was added and the reaction was stirred at room temperature for 16 h. The reaction was then diluted with water and extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate and then concentrated to a residue that was purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to afford 2-cyclopropyl-oxazole-4-carboxylic acid [4-cyclopropyl-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 5c (34.0 mg; 0.06 mmol, 29.8%) as a white solid.
Reaction SMILES: [CH3:1][O-].[Na+].[C:4]([O:8][C:9]([C@H:11]1[N:15]=[C:14]([NH2:16])[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].Cl.[C:18]1(=[O:29])O[CH:23](OC(C)C)[O:22][C:20](=[O:21])[CH2:19]1>CO>[CH3:23][O:22][C:20]([C:19]1[C:18](=[O:29])[N:15]2[C@H:11]([C:9]([O:8][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:10])[CH2:12][CH2:13][C:14]2=[N:16][CH:1]=1)=[O:21]
Reactant: CC(C)OC1OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(N)=N1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc2n(c1=O)[C@H](C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A solution of freshly prepared sodium methoxide (Na, 50% by weight in paraffin, 0.084 g, 1.84 mmol, 2.25 mL anh MeOH) was added slowly to a solution of (S)-2-amino-3,4-dihydro-5H-pyrrole-5-carboxylic acid t-butyl ester.HCl (0.41 g, 1.84 mmol) in 2.25 mL anh MeOH cooled to -10° C. After 1 h, the resulting white precipitate (NaCl) was filtered, and the solution of this free base was slowly added to a solution of dimethylmethoxymethylene malonate (0.32 g, 1.84 mmol) in 2.25 mL anh MeOH at -10° C. The reaction mixture was stirred at 0° C. overnight at which time it was concentrated under vacuum, and the residue was purified by column chromatography on silica gel (2% MeOH/CHCl3) to afford (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-α]pyrimidine-3,6-dicarboxylic acid 6-t-butyl ester 3-methyl ester (0.22 g, 40%) as a yellow oil. 1H NMR (CDCl3) δ 1.49 (s, 9H), 2.31 (m, 1H), 2.57 (m, 1H), 3.09-3.33 (m, 2H), 3.90 (s, 3H), 5.03 (m, 1H), 8.69 (s, 1H). MS calcd C14H18N2O5 +295, found 295.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[C:38]3[C:33](=[CH:34][C:35]([F:40])=[C:36](F)[CH:37]=3)[C:32](=[O:41])[N:31]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:30]2=[O:50])[CH:26]=[CH:27][CH:28]=1>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[C:38]3[C:33](=[CH:34][C:35]([F:40])=[C:36]([N:11]4[CH2:12][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]4)[CH:37]=3)[C:32](=[O:41])[N:31]([O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:30]2=[O:50])[CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(F)cc32)c1
Solvent: CCN(CC)CC
Product: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCC(NC(=O)OC(C)(C)C)C4)cc32)c1
Yield: 86.7 %

Procedure:
Using General Method 4, the reaction of 3-t-butoxycarbonylamino-pyrrolidine (0.162 g, 0.9 mmol), triethylamine (0.12 mL, 0.9 mmol), and 1-(3-methoxyphenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example E-1, 0.12 g, 0.3 mmol) provided 0.15 g of the title compound as a solid.
Reaction SMILES: O[CH:2]([C:4]1[N:15]([C@@H:16]2[CH2:21][O:20][C@@H:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].C(N)C.COCCN(S(F)(F)[F:38])CCOC>C(Cl)Cl>[F:38][CH:2]([C:4]1[N:15]([C@@H:16]2[CH2:21][O:20][C@@H:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3]
Reactant: CC(O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)OC1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: CCN
Solvent: ClCCl
Product: CC(F)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a cooled mixture of {(2R,5S)-5-[2-(1-hydroxyethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]tetrahydro-2H-pyran-2-yl}acetonitrile (8.0 mg, 0.023 mmol) in methylene chloride (0.2 mL) was added 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-44)-sulfanyl)ethanamine (4.7 μL, 0.026 mmol) (Deoxo-Fluor). The resulting mixture was warmed to room temperature and stirred overnight. Additional Deoxo-Fluor (5 μL) was added. After 6 h, the reaction was quenched with a few drops of water then concentrated. The residue was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 1.6 mg (20%) of the desired product. LCMS calculated for C17H18FN4OS (M+H)+: m/z=345.1. Found: 345.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH3:22][C:23]1[N:28]=[CH:27][C:26]([C:29]2[NH:30][C:31]3[CH:32]=[C:33]([NH3+:43])[CH:34]=[C:35]4[C:41](=[O:42])[NH:40][N:39]=[CH:38][C:37]=2[C:36]=34)=[CH:25][CH:24]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:22][C:23]1[N:28]=[CH:27][C:26]([C:29]2[NH:30][C:31]3[CH:32]=[C:33]([NH:43][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:12])[CH:34]=[C:35]4[C:41](=[O:42])[NH:40][N:39]=[CH:38][C:37]=2[C:36]=34)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Reactant: Cc1ccc(-c2[nH]c3cc([NH3+])cc4c3c2C=NNC4=O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2[nH]c3cc(NC(=O)[C@@H](CCc4ccccc4)NC(=O)OC(C)(C)C)cc4c3c2C=NNC4=O)cn1

Procedure:
To a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-4-phenylbutanoic acid and 2-(6-methylpyridin-3-yl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-aminium chloride 267(b) in 8 mL of anhydrous dimethylformamide containing triethylamine (0.3 mL, 2.3 mmol) stirred in an ice/water bath was added HATU (244 mg, 0.64 mmol), portion-wise. The mixture was then stirred overnight at room temperature.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]=1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH3:4])([CH3:3])[CH3:2].Br[CH2:33][CH:34]([S:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:38])=[O:37])O.C(=O)([O-])[O-:46].[Na+].[Na+]>COCCOC.O>[C:27]([O:26][C:24](=[O:25])[NH:23][C:9]1[CH:10]=[C:11]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[S:36]([CH2:34][CH2:33][OH:46])(=[O:38])=[O:37])[CH:12]=[CH:13][C:8]=1[NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:31])([CH3:29])([CH3:28])[CH3:30]
Reactant: O=S(=O)(c1ccccc1)C(O)CBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2S(=O)(=O)CCO)cc1NC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 82.1 %

Procedure:
A mixture of [2-tert-butoxycarbonylamino-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid tert-butyl ester (0.300 g, 0.691 mmol, Example 15, Step A), 2-bromophenylsulfonylethanol (0.153 g, 0.576 mmol), sodium carbonate (0.439 g, 4.15 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.153 g, 0.0576 mmol) in DME (6 mL) and H2O (1.5 mL) was heated at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue, which was purified by chromatography (silica, hexanes:EtOAc, 1:1) to afford the title compound as a yellow oil (0.233 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([CH3:30])([CH2:27][CH2:28][CH3:29])[C:24]([OH:26])=O)[CH:8]=2)[N:3]=1.[CH2:31]([NH2:33])[CH3:32]>>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([CH3:30])([CH2:27][CH2:28][CH3:29])[C:24]([NH:33][CH2:31][CH3:32])=[O:26])[CH:8]=2)[N:3]=1
Reactant: CCN
Reactant: CCCC(C)(C(=O)O)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Product: CCCC(C)(C(=O)NCC)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1

Procedure:
(Preparation by reaction of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl-2-methylpentanoic acid [“A67”] with ethylamine);