Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35].C(O)(=O)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[N:12]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[O:34][CH3:35])[C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)c(OC)c1
Reactant: O=C1CC[C@@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)cn2)N1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CC[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cn2)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6.72 g (20.92 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one (Example 121, Step F) in DMF (˜0.5M) at 0° C. was slowly added a dispersion of 60% sodium hydride in mineral oil (2.51 g, 62.8 mmol). The reaction was stirred 0° C. for 30 min, followed by addition of 1-(chloromethyl)-2,4-dimethoxybenzene (7.81 g, 41.8 mmol). Upon completion, the reaction was quenched at 0° C. with a small excess of acetic acid (4.79 mL, 84 mmol). It was neutralized with sat. aq. NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and the filtrate as concentrated under reduced pressure to yield a reddish oil. Purification by flash chromatography on silica gel (eluent: 0 to 30% ethyl acetate/DCM, gradient elution) provided the title compound as a pale yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][C:16](=[O:18])[C:15]([OH:19])=[C:14]2[C:20]2[CH:25]=[CH:24][C:23]([CH:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:8][CH:9]=1)=[O:4].CS(C)=O.P([O-])([O-])([O-])=O>C(Cl)Cl>[OH:19][C:15]1[C:16](=[O:18])[CH2:17][C@H:13]([CH2:12][CH2:11][CH2:10][C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)[C:14]=1[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=1
Reactant: CCCCCC(O)c1ccc(C2=C(O)C(=O)C[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCCC(O)c1ccc(C2=C(O)C(=O)C[C@@H]2CCCc2ccc(C(=O)O)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
A mixture of 31 (5 mg, 0.011 mmol), rabbit liver esterase (3 mg, Aldrich), DMSO (50 μL) and pH 7.2 phosphate buffer (0.5 mL) was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 and washed with H2O and brine. The resulting organic solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (0%→30% methanol/dichloromethane) gave the title compound (1 mg, 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=S)([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)(=[O:25])C>C1(C)C=CC=CC=1.OO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:25])([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: S=P(c1ccccc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(=O)O
Agent: OO
Solvent: Cc1ccccc1
Product: O=P(c1ccccc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 92 %

Procedure:
7.26 g (20 mmol) of bis(4-chlorophenyl)phenylphosphine sulfide, dissolved in 12.5 ml of glacial acetic acid/12.5 ml of toluene, and 0.72 g (21.1 mmol) (1.81 ml of a 35% solution) of hydrogen peroxide gave 6.4 g (92% of theory) of bis(4-chlorophenyl)phenylphosphine oxide after a reaction time of 60 minutes at 50° C. and working-up as in Example 8.
Reaction SMILES: [CH3:1][C:2](O)([CH3:14])[CH:3]=[C:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]([CH3:13])([CH3:12])[CH2:5]1.[Si]([N:20]=[N+:21]=[N-:22])(C)(C)C>C1C=CC=CC=1>[N:20]([C:2]([CH3:14])([CH3:1])[CH:3]=[C:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]([CH3:13])([CH3:12])[CH2:5]1)=[N+:21]=[N-:22]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(O)C=C1CC(C)(C)CC(C)(C)C1
Solvent: c1ccccc1
Product: CC1(C)CC(=CC(C)(C)N=[N+]=[N-])CC(C)(C)C1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
BF3Et2O (0.3 ml, 2.4 mmol) was added to a solution of alcohol 29 (0.42 g, 2 mmol) and TMSN3 (0.31 ml, 2.4 mmol) in benzene (4.5 ml) during 3 min, while cooling with an ice bath. The reaction mixture was stirred at 5-10° C. for 1 h and filtered through a short silica gel column. The solution was evaporated and the residue was purified by flash chromatography on silica gel (light petroleum ether) to give 30 (0.30 g, 64%) as a colorless oil. 1H-NMR (CDCl3, TMS): 0.92 and 0.98 (total 12H, both s, c-Hex-3,5-CH3); 1.27 (2H, s, c-Hex-4-CH2); 1.40 (6H, s, —C(CH3)2N3); 1.85 and 2.23 (both 2H, both s, c-Hex-2,6-CH2) and 5.27 ppm (1H, s, ═CH—).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[C:11]=1[NH2:24].[C:25](OCC)(=[O:29])[C:26]([CH3:28])=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:24]=[C:26]([CH3:28])[C:25](=[O:29])[N:16]([CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CCOC(=O)C(C)=O
Reactant: CCCC(CCC)Nc1ncnc(-c2ccc(OC)cc2Cl)c1N
Solvent: CCO
Product: CCCC(CCC)n1c(=O)c(C)nc2c(-c3ccc(OC)cc3Cl)ncnc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
6-(2-Chloro-4-methoxy-phenyl)-N4-(1-propyl-butyl)-pyrimidine-4,5-diamine (0.29 g, 0.83 mmol) was diluted in ethanol (8 ml) and ethyl pyruvate was added (0.92 ml, 8.3 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. The residue was diluted in glacial acetic acid (10 ml) and warmed to 100° C. for 1 hour. After concentrating the solution the product was purified by reverse phase HPLC to yield 13.5 mg of 4-(2-chloro-4-methoxy-phenyl)-6-methyl-8-(1-propyl-butyl)-8H-pteridin-7-one (Example 563). 1H NMR (300 MHz, CDCl3) δ ppm 9.02 (s, 1 H), 7.41 (d, J=8.42 Hz, 1 H), 7.05 (d, J=2.56 Hz, 1 H), 6.93 (dd, J=8.42, 2.56 Hz, 1 H), 3.86 (s, 3 H), 4.40 (m, 1H), 2.48 (m, 2 H), 2.31 (m, 2 H), 1.89 (m, 2 H), 1.19 (m, 5 H), 0.88 (t, J=7.32 Hz, 6 H). MS (AP) 321.2 [(M+H)+, 100]. MS (AP) 401.3 [(M+H)+, 100].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.CCOC(C)=O>C(Cl)(Cl)(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][Br:17]
Reactant: Cc1cc(Cl)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Br)c(CBr)c1
Reaction time: 4 h

Procedure:
A mixture of 2-bromo-5-chloro-toluene (2.00 g, 9.75 mmol), NBS (2.08 g, 11.7 mmol) and catalytic amount of AIBN in carbon tetrachloride (50 ml) was stirred under refluxing conditions for 4 h. TLC (EtOAc:hexane=5:95) showed no starting material. The mixture was filtered and the filtrate was concentrated. The title compound was obtained as a white solid after flash column using EtOAc:hexane=5:95 as the elute. 1H NMR (CDCl3, 500 MHz) δ 7.53 (d, J=9.0 Hz, 1H), 7.47 (d, J=2.5 Hz, 1H), 7.18 (dd, J=8.5, 2.5 Hz, 1H), 4.60 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[F:20][C:21]([F:37])([F:36])[CH2:22][NH:23][CH:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:27]=2[CH2:26][CH2:25]1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O.C(=O)(O)[O-].[Na+]>CC(O)C.C(Cl)Cl.O>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:35][C:32]2[CH:33]=[CH:34][C:27]3[CH2:26][CH2:25][CH:24]([NH:23][CH2:22][C:21]([F:20])([F:36])[F:37])[CH2:30][CH2:29][C:28]=3[CH:31]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc2c(c1)CCC(NCC(F)(F)F)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)(F)F)CC3)ncc1Cl
Temperature: 120 °C
Yield: 7.4 %

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (86.3 mg, 0.290 mmol) and N*7*-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine (75 mg, 0.290 mmol) were combined with DL-10-camphorsulfonic acid (101 mg, 0.436 mmol) in 2 ml IPA and heated in a microwave vial for 40 minutes at 120° C. for 40 minutes. The resulting reaction was poured into 25 ml saturated sodium bicarbonate solution and 50 ml water and extractred with 4×25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated. The crude product was purified via reverse phase preparative chromatography (Luna C18, 5 μm, 100 mm×21.2 mm column) using a gradient of 0-35% MeCN in water (both containing 0.1% TFA). 2-{5-Chloro-2-[7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide (11.18 mg, 7.4% yield) was isolated as an off white solid. 1H-NMR (CDCl3) δ 11.07 (s, 1H), 8.66 (d, J=8.44 Hz, 1H), 7.45 (m, 2H), 7.35 (s, 1H), 7.04 (m, 2H), 6.91 (s, 1H), 6.18 (s, 1H), 3.24 (q, J=19.4, 9.8 Hz, 2H), 3.03 (d, J=4.8 Hz, 3H), 2.87 (m, 3H), 2.66 (m, 2H), 2.06 (m, 2H), 1.32 (m, 5H). LC/MS (ESI+)=519 (M+H). MP=202-203° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:23]4[CH:24]=[N:25][C:26]([NH2:40])=[C:27]([O:28][C@@H:29]([C:31]5[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=5[Cl:39])[CH3:30])[C:22]=4[O:21][CH:20]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:41]Br>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:23]4[CH:24]=[N:25][C:26]([NH2:40])=[C:27]([O:28][C@@H:29]([C:31]5[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=5[Cl:39])[CH3:30])[C:22]=4[O:21][C:20]=3[Br:41])[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](Oc1c(N)ncc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: BrBr
Solvent: ClCCl
Product: C[C@@H](Oc1c(N)ncc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(Br)oc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-{6-amino-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-furo[3,2-c]pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.68 mmol) in anhydrous DCM (10 mL) was added a solution of bromine (430 mg, 2.7 mmol) in DCM (3 mL). The resulting mixture was stirred at rt for 30 min. The mixture was quenched with sat. aq. Na2S2O3 (15 mL) and diluted with DCM (50 mL), then washed with brine (20 mL), and dried over anhydrous sodium sulfate. Evaporation afforded a yellow residue, which was purified by silica gel chromatography (Hex.-EtOAc=30:70→100% EtOAc) to give the title compound as a light-yellow solid. LC-MS (ES+): 668.01/669.99/671.97 [MH+]. 1H NMR (CDCl3, 400 MHz): δ 1.49 (s, 9H), 1.90 (d, J=6.8 Hz, 3H), 1.95-2.04 (m, 2H), 2.18-2.21 (m, 2H), 2.93 (m, 2H), 4.31-4.38 (m, 3H), 5.19 (br s, 2H), 6.54 (q, J=6.6 Hz, 1H), 7.08 (dd, J=8.8, 8.0 Hz, 1H), 7.30 (dd, J=8.8, 4.8 Hz, 1H), 7.85 (s, 1H), 7.94 (s, 1H), 8.05 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22](O)=[O:23])=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:19]3[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:23])[CH:20]=3)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)c1)N1CCCC1
Yield: 47 %

Procedure:
3-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (31 mg) was coupled to pyrrolidine as in General Procedure 8 to give the title compound as a yellow solid (47% yield). LCMS: m/z=413.30 (M+H+), 1H-NMR (CD3OD, 400 MHz) δ 1.92 (2H, m), 2.02 (2H, m), 3.36 (1H, m), 3.40 (2H, t, J=6.6 Hz), 3.62 (2H, t, J=6.9 Hz), 4.49 (2H, s), 4.91 (1H, s), 5.36 (2H, s), 7.29 (1H, m), 7.37 (2H, d, J=1.8 Hz), 7.39 (2H, s), 7.49 (1H, s), 7.52 (3H, s), 7.53 (1H, d, J=1.5 Hz), 7.84 (1H, d, J=1.5 Hz).
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[C@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]1[CH:30]=[CH:29][N:28]2[N:31]=[CH:32][C:33]([C:34](O)=[O:35])=[C:27]2[CH:26]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([NH2:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[C@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]1[CH:30]=[CH:29][N:28]2[N:31]=[CH:32][C:33]([C:34]([NH:47][S:44]([C:41]3[CH:40]=[CH:39][C:38]([F:37])=[CH:43][CH:42]=3)(=[O:46])=[O:45])=[O:35])=[C:27]2[CH:26]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reactant: NS(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(F)cc1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reaction time: 20 h
Yield: 6.4 %

Procedure:
EDCI (111 mg, 0.5 mmol) was added to a solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (100 mg, 0.29 mmol) in DCM (4 mL) followed by DMAP (36 mg, 0.29 mmol) and 4-fluorobenzenesulfonamide (56 mg, 0.31 mmol) and stirring was continued at 20-35° C. for 20 h. Reaction mixture was quenched with water, extracted into EtOAc, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude. The crude compound was purified by Preparative HPLC [Column: 21.2×150×5 um, Zorbax, Eclipse, C-18, Mobile phase-A: Water, B:ACN, Gradient (Time/% B): 0/30, 2/40, 10/80 and Flow rate:20 mL/min] to afford 9.3 mg of the title compound.
Reaction SMILES: [CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[CH2:5][C:6]([S:21][CH2:22][CH2:23][NH:24]C(OCC1C=CC=CC=1)=O)=[C:7]2[C:11]([O:13]CC1C=CC=CC=1)=[O:12])[CH3:2]>[Pd].O1CCOCC1.O>[CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[CH2:5][C:6]([S:21][CH2:22][CH2:23][NH2:24])=[C:7]2[C:11]([OH:13])=[O:12])[CH3:2]
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccccc3)=C(SCCNC(=O)OCc3ccccc3)CC12
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O
Product: CCC1C(=O)N2C(C(=O)O)=C(SCCN)CC12
Reaction time: 1 h

Procedure:
A mixture of benzyl 6-ethyl-3-(2-benzyloxycarbonyl aminoethyl)thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (10 mg) and 10% Pd/C (20 mg) in 1:1 dioxane-H2O (4 ml) is hydrogenated at 40 psi for 1 hr. The mixture is filtered to remove the catalyst which is washed with more H2O (4 ml). The combined filtrate and washings are concentrated in vacuo to 2 ml and loaded onto a column of 200-400 mesh Dowex-50×4 (Na form) ion-exchange resin. The column is eluted with deionized H2O. The appropriate fractions are pooled and lyophilized to provide 6-ethyl-3-(2-aminoethyl)thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([C:12](OCCCC)=[O:13])[CH:9]=[CH:8][C:7]=1[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[F:27])[CH2:2][CH2:3][CH3:4].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:7]=1[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[F:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1ccc(-c2cc(OC)ccc2F)c(OCCCC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1cc(CO)ccc1-c1cc(OC)ccc1F
Reaction time: 1 h
Yield: 96.57 %

Procedure:
To a mixture of T9.3 (1.1530 g, 3.079 mmol) and THF (10 mL) at 0° C. was added LAH (1.0 M solution in THF (4.619 mL, 4.619 mmol)). The reaction was stirred for one hour and then carefully diluted with water, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered, and concentrated to provide T9.4 (0.9050 g, 96.57% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:15][CH2:16][C:17](Cl)=[O:18].Cl>ClC(Cl)C.C(OCC)(=O)C>[Cl:15][CH2:16][C:17]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)=[O:18]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1Cc2cc(C(=O)CCl)ccc2N1
Temperature: 45 °C
Yield: 97.6 %

Procedure:
2-Oxindole (6.7 g) was added to a stirred suspension of 23 g of aluminum chloride in 30 mL of dichloroethane in an ice bath. Chloroacetyl chloride (11.3 g) was slowly added and hydrogen chloride gas was evolved. After ten minutes of stirring, the reaction was warmed at 40 to 50° C. for 1.5 hours. Thin layer chromatography (ethyl acetate, silica gel) showed no remaining starting material. The mixture was cooled to room temperature and poured into ice water. The precipitate was collected by vacuum filtration, washed with water and dried under vacuum to give 10.3 g (98%) of 5-chloroacetyl-2-oxindole as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1Br.[CH2:10]([O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][NH:18][CH3:19])[CH2:11][CH3:12]>C(O)C>[Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[N:18]([CH2:17][C:16]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([O:13][CH2:10][CH2:11][CH3:12])[CH:15]=1)[CH3:19]
Reactant: CCCOc1cc(CNC)ccc1OC
Reactant: O=c1[nH]ncc(Br)c1Br
Solvent: CCO
Product: CCCOc1cc(CN(C)c2cn[nH]c(=O)c2Br)ccc1OC
Reaction time: 7 h

Procedure:
A mixture comprising 300 mg of 4,5-dibromo-3(2H)pyridazinone, 740 mg of 3-n-propoxy-4-methoxy-N-methylbenzylamine and 10 ml of ethanol, was refluxed under stirring for 7 hours. Then, ethanol was distilled off under reduced pressure, dilute hydrochloric acid was added to the residue thereby obtained, and the mixture was extracted with ethyl acetate. The extract was washed twice with water and dried over sodium sulfate. Then, the solvent was distilled off to obtain a yellow solid substance. The product was crystallized from ethyl acetate, to obtain 310 mg of the above identified compound having a melting point of from 149° to 150° C. as light yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].Cl[C:16]1[N:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][CH:17]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:16]1[N:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: N#Cc1cccc(Cl)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1COc1cccc(C#N)n1
Temperature: 50 °C
Yield: 24 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (189 mg, 1.0 mmol) and 6-chloropyridine-2-carbonitrile (150 mg, 1.0 mmol) in toluene (10 mL) was added sodium hydride (55% dispersion in mineral oil, 100 mg, 2.0 mmol) and the mixture heated at 50° C. for 6 h. Then 18-crown-6 (18 mg) was added and the mixture heated at 100° C. overnight. The mixture was then diluted with ethyl acetate and washed with water. The aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded the title compound (70 mg, 24%) as a white solid after trituration with diisopropylether. MS: m/e=292.0 [M+H]+.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]>C(O)C>[N+:15]([C:6]1[CH:7]=[C:8]([S:11](=[O:13])(=[O:12])[NH2:14])[CH:9]=[CH:10][C:5]=1[NH:2][NH2:3])([O-:17])=[O:16]
Reactant: NN
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: O
Product: NNc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
20 ml of hydrazine hydrate were added to a suspension of 47.33 g of 4-chloro-3-nitrobenzenesulfonamide [prepared as described in: J. Am. Chem. Soc. 73, 2558 (1951)] in 200 ml of abs. ethanol. The mixture was boiled under stirring for 30 minutes, then cooled down. The crystals were filtered by suction and thoroughly washed with water to obtain 43.38 g (93.4%) of 2-nitro-4-sulfamoylphenylhydrazine, m.p.: 217°-218° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][C:10]#[N:11].[NH2:12][CH2:13][CH:14](N)[CH3:15]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][C:10]1[NH:11][CH:14]([CH3:15])[CH2:13][N:12]=1
Reactant: Cc1cccc(C)c1CC#N
Reactant: CC(N)CN
Product: Cc1cccc(C)c1CC1=NCC(C)N1

Procedure:
rac-2-(2,6-Dimethyl-benzyl)-5-methyl-4,5-dihydro-1H-imidazole was prepared from 2,6-dimethyl-phenyl-acetonitrile and 1,2-diaminopropane in analogy to Example 19 b): orange powder; MS (EI): 202.3 (M+.).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][C:7]=1[NH2:8])[CH2:2][CH2:3][CH3:4].Cl.[C:23](=N)(OC)[CH3:24].C(=O)([O-])O.[Na+]>CO>[O:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[C:10]1[CH:11]=[CH:12][C:6]2[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:23]([CH3:24])=[N:8][C:7]=2[CH:9]=1
Reactant: COC(C)=N
Reactant: CCCCNc1ccc(-c2nc3ccccc3o2)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCn1c(C)nc2cc(-c3nc4ccccc4o3)ccc21
Yield: 89.7 %

Procedure:
To a methanol (5 mL) solution of 2-(2-n-butylaminoanilin-5-yl)benzoxazole (see Working Example 74-2) (300 mg, 1.07 mmol) was added methyl acetimidate hydrochloride (175 mg, 1.60 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The crystals obtained were purified by silica gel column chromatography to yield the title compound (293 mg, 90% yield) as white crystals.