Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:17](O)=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:33]([C@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][NH:36]1)[CH3:34]>C1(C)C=CC=CC=1>[CH2:33]([C@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:18])[CH3:34]
Reactant: CC[C@H]1CCCCN1
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2)n1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC[C@H]1CCCCN1C(=O)c1cc2ccccc2c(-c2ccccc2)n1
Yield: 86.8 %

Procedure:
Operations are carried out as for Example 7, starting from 2.5 g of 1-phenyl isoquinoline 3-carboxylic acid, 1.15 g of triethylamine, 1.24 g of ethyl chloroformate and 1.2 g of 2(S)-ethyl piperidine in 100 ml of toluene. After chromatography, 3 g of 2(S)-ethyl 1-[(1-phenyl 3-isoquinolyl) carbonyl]piperidine in the form of oil are obtained. αD23 =-2.4° (2% in ethanol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11](=[O:16])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:17][N:18]([CH3:36])[C:19]([C:21]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:24]2[N:25]=[C:26](Cl)[N:27]=[CH:28][C:23]=2[CH:22]=1)=[O:20]>>[CH3:17][N:18]([CH3:36])[C:19]([C:21]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:24]2[N:25]=[C:26]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][N:9]4[CH2:14][CH2:13][N:12]([CH3:15])[C:11](=[O:16])[CH2:10]4)=[CH:6][N:7]=3)[N:27]=[CH:28][C:23]=2[CH:22]=1)=[O:20]
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1=O
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CCN(C)C(=O)C4)cn3)nc2n1C1CCCC1
Yield: 20.4 %

Procedure:
Following Buchwald method B, 4-(6-amino-pyridin-3-ylmethyl)-1-methyl-piperazin-2-one (30 mg, 0.136 mmol) and 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (33 mg, 0.113 mmol) give 7-cyclopentyl-2-[5-(4-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (11 mg, 21%) [following SiO2 chromatography eluting with 1-10% (2M NH3 in MeOH)/DCM]
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[CH:13][CH:12]=[CH:11][CH:10]=3.[C:22]1([CH3:30])[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1.O>CO>[CH3:30][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[N:1][C:2]2[N:6]3[CH:7]=[CH:8][C:9]4[C:14]([C:5]3=[N:4][C:3]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:24][CH:23]=1
Reactant: Cc1ccccc1-c1nc2c3ccccc3ccn2c1N
Reactant: Cc1ccc(C=O)cc1
Solvent: CO
Solvent: O
Product: Cc1ccc(C=Nc2c(-c3ccccc3C)nc3c4ccccc4ccn23)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 78.6 %

Procedure:
To a solution of 5.0 g of 3-amino-2-(2-methylphenyl)imidazo[2,1-a]isoquinoline (Compound 3) in 50 ml of methanol was added 2.2 g of p-tolualdehyde. After the mixture was stirred at room temperature for 22 hours, it was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, and recrystallization from ethyl acetate/petroleum ether gave 5.4 g of the title compound as yellow crystals.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:30]=[C:29]([NH:31][C:32](=[O:41])[C:33]2[CH:38]=[C:37](C)[CH:36]=C[C:34]=2F)[CH:28]=[CH:27][C:4]=1[O:5][C:6]1[C:11]2=[C:12]([CH3:26])[C:13]([C:15]([NH:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:16])=[CH:14][N:10]2[N:9]=[CH:8][N:7]=1.Cl.FC1C=C(C(C(NC2C=CC(F)=CC=2)=O)C(N)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=C[N:52]=1>>[ClH:1].[ClH:1].[F:2][C:3]1[CH:30]=[C:29]([NH:31][C:32](=[O:41])[C:33]2[CH:38]=[CH:37][CH:36]=[N:52][CH:34]=2)[CH:28]=[CH:27][C:4]=1[O:5][C:6]1[C:11]2=[C:12]([CH3:26])[C:13]([C:15]([NH:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[O:16])=[CH:14][N:10]2[N:9]=[CH:8][N:7]=1
Reactant: Cc1ccc(F)c(C(=O)Nc2ccc(Oc3ncnn4cc(C(=O)NCCN5CCOCC5)c(C)c34)c(F)c2)c1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(C(=O)NCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)c4cccnc4)cc3F)c12
Yield: 39 %

Procedure:
Following a procedure similar to that for the synthesis of Compound D of Example 50, 4-(4-amino-2-fluorophenoxy)-5-methyl-N-(2-morpholinoethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (30 mg, 0.07 mmol, Compound C of Example 50) was converted the title compound (16 mg, 39%) as a 2.HCl salt. 1H NMR (CD3OD) δ 9.08 (s, 1H), 8.70 (s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.87 (m, 2H), 7.38 (m, 2H), 7.22 (m, 2H), 3.82 (s, 4H), 3.61 (m, 2H), 2.75 (m, 9H); MS(ESI+) m/z 520.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:13][C@H:12]([NH2:23])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[N:37]=[C:36](Cl)[N:35]=[C:34]([NH:39][C@@H:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][C@@H:41]2[O:49][CH3:50])[N:33]=1>C1COCC1>[CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:20])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[CH2:13][C@H:12]([NH:23][C:36]2[N:35]=[C:34]([NH:39][C@@H:40]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][C@@H:41]3[O:49][CH3:50])[N:33]=[C:32]([Cl:31])[N:37]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](N)C[C@H]1COCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1nc(Cl)nc(N[C@@H]2C[C@@H](COCc3ccccc3)[C@@H](O[Si](C)(C)C(C)(C)C)C2)n1
Reaction time: 2 h
Yield: 31.5 %

Procedure:
To a solution of (1R,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}cyclopentanamine (486.5 mg, 0.001450 mol) and triethylamine (0.55 mL, 0.0040 mol) in THF (2.1 mL) was added 4,6-dichloro-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazin-2-amine (410 mg, 0.0013 mol) and the mixture was stirred for 2 hours. The reaction was concentrated and the residue was purified by flash chromatography (0 to 25% EtOAc/hexanes) to obtain 250 mg (31%) of the title compound. LC/MS: Rt=2.96 min, ES+ 610 (FA standard).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16](B(O)O)[O:15][C:14]=12)=O)(C)(C)C.Br[C:29]1[C:37]2[C:32](=[CH:33][N:34]=[N:35][CH:36]=2)[S:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[S:31]1[C:32]2=[CH:33][N:34]=[N:35][CH:36]=[C:37]2[C:29]([C:16]2[O:15][C:14]3=[C:9]([NH2:8])[N:10]=[CH:11][CH:12]=[C:13]3[CH:17]=2)=[CH:30]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(B(O)O)oc12
Reactant: Brc1csc2cnncc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: Nc1nccc2cc(-c3csc4cnncc34)oc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
A suspension of {7-[bis(tert-butoxycarbonyl)amino]furo[2,3-c]pyridin-2-yl}boronic acid (200.0 mg, 0.5288 mmol), 3-bromothieno[2,3-d]pyridazine (77.1 mg, 0.358 mmol), Pd(PPh3)4 (21.8 mg, 0.0189 mmol), and potassium carbonate (150.5 mg, 1.089 mmol) in a 4:1 mixture of 1,4-dioxane to water (3.5 mL) was heated conventionally to 70° C. for 2.5 h. To the stirring reaction at 70° C., 4.0 M hydrochloric acid in 1,4-dioxane (2.0 mL) was added and was stirred for 1 h. The reaction mixture was cooled to ambient temperature, poured into saturated aqueous sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by ISCO chromatography (3 to 15% methanol:dichloromethane) afforded 30.6 mg (31%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMF-d7): δ 10.43 (d, J=1.52 Hz, 1H), 10.10 (d, J=1.52 Hz, 1H), 8.92 (s, 1H), 7.83 (d, J=5.31 Hz, 1H), 7.67 (s, 1H), 6.95 (d, J=5.31 Hz, 1H), 6.66 (br s, 2H); MS (ESI): 269.13 [M+H]+; HPLC tR=2.16 min.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][N:6]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[C:7]=1[CH3:8].CN(C=O)C.S(Cl)([Cl:22])=O.O>ClCCl>[Cl:22][CH2:2][C:3]1[N:4]=[CH:5][N:6]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[C:7]=1[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)ncn1S(=O)(=O)N(C)C
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(CCl)ncn1S(=O)(=O)N(C)C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
A suspension of 4-(hydroxymethyl)-N,N,5-trimethyl-1H-imidazole-1-sulphonamide (2.86 g) in dry dichloromethane (200 ml) containing DMF (0.5 ml) was treated dropwise with a solution of thionyl chloride (1.178 g) in dichloromethane (10 ml). The reaction mixture was cooled in ice during the addition and blanketed with nitrogen. When addition was complete (ca. 5 min), stirring was continued at 0° for a further 30 min. Water (200 ml) was then added and the organic phase was separated, washed with 8% sodium bicarbonate (100 ml), dried and concentrated to give the title compound (2.3 g) as a solid, m.p. 115°-118°.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1F)[C:12]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])=[O:13]>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[C:12]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])=[O:13]
Reactant: Cc1cc(C)c(C(=O)c2ccc(F)c(Cl)c2)c(C)c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C(=O)c2ccc(-n3ccnc3)c(Cl)c2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a suspension of 2.3 g of sodium hydride (60% dispersion in mineral oil) in 50 ml of dimethylformamide is added 4.2 g of imidazole over a 5 minute period under occasional ice cooling. After stirring at room temperature for 30 minutes, a solution of 14.2 g of 3-chloro-4-fluoro-2',4',6'-trimethylbenzophenone in 10 ml of dimethylformamide is added and the mixture is stirred at 50° C. for 3 hours. The reaction mixture is poured into ice-cold water and extracted with benzene. After benzene is distilled off, the residue is purified column-chromatographically to give 15.6 g of 3-chloro-4-(1-imidazolyl)-2',4',6'-trimethylbenzophenone as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9](S)=[N:8][C:7]=2[CH:12]=1.S(Cl)([Cl:15])=O.C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:15][C:9]1[S:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=2[N:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2sc(S)nc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2sc(Cl)nc2c1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
A mixture of 5-methoxy-1,3-benzothiazole-2-thiol (500 mg), thionyl chloride (2 mL) and DMF (1 drop) was stirred at 50° C. for 3 days. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (211 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([OH:13])=O.CN.Cl.[CH3:17][N:18](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([NH:18][CH3:17])=[O:13]
Reactant: O=C(O)c1n[nH]c2ccc(Br)cc12
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)c1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
To a solution of 5-bromo-1H-indazole-3-carboxylic acid (1.2 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was added methyl amine (5 mL, 2 M in tetrahydrofuran, 10 mmol), 1, (3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (1.4 g, 7.5 mmol), 1-hydroxybenzotriazole hydrate (1.2 g, 7.5 mmol), and N-methylmorpholine (1.0 g, 10 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and purification by flash column chromatography gave the title compound (0.71 g, 56%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6, δ): 13.8 (br. s., 1 H), 8.41 (m, 1 H), 8.31 (s, 1 H), 7.60 (d, J=8.8 Hz, 1 H), 7.51-7.54 (m, 1 H), 2.80 (d, J=4.8 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][S:11][NH:10][C@@H:9]2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:28]([CH3:30])[CH3:29]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][S:11][N:10]([CH:28]([CH3:30])[CH3:29])[C@@H:9]2[C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc([C@H]2NSCC[C@@H]2c2cccc(Cl)c2)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1SCC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 85 °C

Procedure:
To a solution of 1.21 g (3.40 mmol) of (3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,2-thiazinan (Example 117, Step C) in DMF (8.5 mL) was added cesium carbonate (4.31 g, 13.23 mmol), followed by 2-iodopropane (2.9 mL, 29.0 mmol). The resulting mixture was heated at 85° C. for 23 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. Purification by flash chromatography on silica gel (0 to 2% MeOH in DCM gradient) provided the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:33])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH2:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:36][S:37]([CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:39])=[O:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:33])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:38])=[O:39])[CH2:48][CH2:47]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH2:31][CH3:32])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ccccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1ccccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% of 1:1 ethanol/acetonitrile in carbon dioxide). HR-MS (ES, m/z) calculated for C34H41N4O4SCl2 [(M+H)+] 671.2220, observed 671.2218.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])[N:8]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1nc(-c2sccc2Cl)cs1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(-c2sccc2Cl)cs1

Procedure:
The title compound was prepared from 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (7.6 mg) with purity >90%. MS (pos) m/z 405.2, 407.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH2:10])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CN)CC1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1(CNC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
To a solution of ethyl1-(aminomethyl)cyclopropane-1-carboxylate (Intermediate 114; 20.65 g, 50 mmol) in DCM (200 mL) was added cyclohexanone (Aldrich; 5.28 mL, 51 mmol). After stirring at room temperature for 15 minutes, sodium acetate (4.185 g, 75 mmol) was added, followed by sodium triacetoxyborohydride (15.905 g, 75 mmol). The suspension was stirred at room temperature for 2 days then partitioned between DCM and saturated aqueous sodium hydrogen carbonate solution. The organic solution was dried over sodium sulphate and evaporated to yield the title compound as a colourless oil (7.2 g, 64%).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:12]C1C=CC(C(=O)C)=CC=1>>[OH2:9].[F:12][C:5]1[CH:6]=[CH:7][C:2]([C:8]([CH:10]=[O:11])=[O:9])=[CH:3][CH:4]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=CC(=O)c1ccccc1
Solvent: O
Product: O=CC(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared using essentially the same procedure as described by H. A. Riley and A. R. Gray in Organic Synthesis, Collective Volume II, p. 509 for the preparation of phenylglyoxal hydrate, but using 4′-fluoroacetophenone in place of acetophenone.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]2[C:10]=1[C:11](=[O:45])[C:12]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:13][N:14]2[C:22]1[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30]CC2C=CC(OC)=CC=2)[N:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH2:30][C:24]1[N:23]=[C:22]([N:14]2[C:15]3[C:10](=[C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:18]([F:19])=[C:17]([F:20])[C:16]=3[F:21])[C:11](=[O:45])[C:12]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:13]2)[C:27]([F:28])=[CH:26][C:25]=1[F:29]
Reactant: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(F)cc2F)c2c(F)c(F)c(F)c(NCc3ccccc3)c2c1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn(-c2nc(N)c(F)cc2F)c2c(F)c(F)c(F)c(NCc3ccccc3)c2c1=O
Reaction time: 0.33 h
Yield: 109.4 %

Procedure:
To 600 mg of ethyl 5-benzylamino-1-[3,5-difluoro-6-(p-methoxybenzylamino)pyridin-2-yl]-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate was added 2 ml of trifluoroacetic acid, and the mixture was allowed to stand at room temperature for 20 minutes. The solution was concentrated under reduced pressure, and 3 ml of ethanol was added to the residue, and the solution was again concentrated under reduced pressure. The precipitate was dispersed in ethanol, collected by filtration and washed with ethanol to obtain 530 mg of the title compound as a yellow powder.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.COCCOCOCCCCCCCCCC(O)=O.[CH:45]1([N:51]=[C:52]=[N:53][CH:54]2[CH2:59][CH2:58][CH2:57]CC2)CCCCC1>O1CCCC1>[CH3:1][N:51]([C:52]1[CH:57]=[CH:58][CH:59]=[CH:54][N:53]=1)[CH3:45]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COCCOCOCCCCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 400 mg of radicicol, 758 mg of 10-(methoxyethoxymethoxy)decanoic acid, 6 ml of dry tetrahydrofuran, 567 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 829 mg of the title compound were obtained.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](OS(C1C(C)=CC=CC=1)(=O)=O)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].Cl.[CH3:34][N:35]([CH2:37][CH2:38][SH:39])[CH3:36].C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([S:39][CH2:38][CH2:37][N:35]([CH3:36])[CH3:34])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH3:3]
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Reactant: CN(C)CCS
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=C(SCCN(C)C)CC12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl 6-(1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (46 mg), 2-(N,N-dimethylamino)ethyl mercaptan hydrochloride (14.2 mg), and triethylamine (14 μl) in anhydrous DMF (2 ml) is stirred at room temperature (25° C.) for 2 hrs. The mixture is added to ethyl acetate (20 ml), washed with 5% sodium bicarbonate (10 ml), water (4×10 ml) and brine, dried over MgSO4, filtered, concentrated in vacuo. Purification of the residue by chromatography on silica gel gives benzyl 6-(1-hydroxyethyl)-3-(2-dimethylaminoethylthio)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[Cl:16][O-].[Ca+2].Cl[O-]>ClCCl>[NH2:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: [O-]Cl
Reactant: COC(=O)c1ccccc1N
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)ccc1N
Temperature: 0 °C
Reaction time: 6 h
Yield: 65.2 %

Procedure:
1 liter of glacial acetic acid and 10 liters of ice-water are added to a solution of 2.0 kg of methyl 2-aminobenzoate in 15 liters of dichloromethane. 1.9 kg of calcium hypochlorite are added at 10° with vigorous stirring, during which the temperature should not rise above 15°. The mixture is stirred for a further 6 hours and left to stand for 16 hours. The dichloromethane is separated off, the aqueous phase is washed with dichloromethane, and the combined organic phases are washed with a 10% Na2SO3 solution (warming!). The combined dichloromethane phases are stirred with 2 kg of silica gel, 200 g of activated carbon and 2 kg of sodium sulfate. The phases are separated, the dichloromethane is removed, 10 liters of nhexane are added, the mixture is left to stand at 0-5° for 16 hours, and the product is separated off, giving 1.6 kg of methyl 2-amino-5-chlorobenzoate (“1”).