Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].Br[CH:7](Br)[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[Cl:15][C:16]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][C:17]=1[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>O>[Cl:15][C:16]1[CH:28]=[CH:27][C:26]([NH:29][N:30]=[CH:7][C:8](=[O:9])[C:10]([F:13])([F:12])[F:11])=[CH:25][C:17]=1[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: CCOC(=O)C=Cc1cc(NN)ccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C=Cc1cc(NN=CC(=O)C(F)(F)F)ccc1Cl
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 975.2 %

Procedure:
First, 7.4 g (901 mmol) of sodium acetate and 8.0 g (28.2 mmol) of 1,1-dibromo-3,3,3-trifluoroacetone were mixed with 70 ml of water, and the mixture was stirred at 80° C. for 30 minutes and then cooled, to which 7.0 g of ethyl 2-chloro-5-hydrazinocinnamate was added at 10° C. or lower, and the mixture was stirred for 3 hours. The precipitated crystals were collected by filtration and dried, which afforded 9.6 g (275 mmol) of ethyl 2-chloro-5-(3,3,3-trifluoro-2-oxopropylidenehydrazino)cinnamate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Cl[C:11]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=[C:13]([Cl:21])[CH:12]=1>CCOC(C)=O>[N:1]1([C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=[C:13]([Cl:21])[CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(Cl)cc1-n1nnc2ccccc21
Temperature: 150 °C

Procedure:
A 1:1 mixture of benzotriazole and methyl 4,6-dichloronicotinate was heated neat in a preheated oil bath at 150° C. for a period of 10-15 min. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed successively with saturated NaHCO3 and brine. The organic phase was separated, dried over MgSO4 and filtered. After evaporation of the organic solvent, the isomers in the residue were purified and separated by flash chromatography (10-70% EtOAc in hexanes) to provide the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]#[N:13])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[NH2:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1>C(O)(=O)C>[Br:1][C:2]1[CH:10]=[C:6]2[C:5]([CH:11]=[C:12]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:13]=[C:7]2[OH:8])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Br)cc1C(=O)O
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc3ccc(Br)cc3c(O)n2)n[nH]1

Procedure:
Similar procedure as described in example 9B was used, starting from 5-Bromo-2-cyanomethyl-benzoic acid, 3-amino-5-methylpyrazol and acetic acid to give 7-Bromo-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol. LC-MS: m/e 319 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:30][N:31](C=O)[CH3:32]>>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:31]([CH3:32])[CH3:30])[CH:3]=1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)c1cc(N)c([N+](=O)[O-])cc1C(=O)Nc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 157) in DMF (1 mL) was added with of 10% aqueous K2CO3 solution (0.25 mL). The mixture was then subjected to microwave at 80° C. for 60 min. The contents were cooled to RT and poured into ice-cold water (20 L). The solid formed was collected by filtration, washed with water, and dried in vacuo to provide 4-amino-2-dimethylamino-N-(1H-indazol-6-yl)-5-nitrobenzamide.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][C:17]2[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=2)=[CH:8][CH:7]=1>ClCCl.O>[CH3:24][O:23][C:21]1[CH:20]=[C:19]([O:25][CH3:26])[N:18]=[C:17]([O:16][C:9]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[N:11][C:6]([N:5]=[C:1]=[S:2])=[CH:7][CH:8]=2)[N:22]=1
Reactant: S=C(Cl)Cl
Reactant: COC(=O)c1nc(N)ccc1Oc1nc(OC)cc(OC)n1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1nc(N=C=S)ccc1Oc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
0.82 g (7.15 mmol) of thiophosgene was dropwise added at room temperature to a solution of 2 g (6.5 mmol) of methyl 6-amino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate in 70 ml of dichloromethane and 50 ml of water. The mixture was stirred at room temperature for two hours. After completion of the reaction, the dichloromethane layer was separated and washed with water. Then, the organic layer was dried and concentrated. The obtained residue was recrystallized from a mixture of dichloromethane and diisopropyl ether to obtain the desired product as slightly yellow transparent crystals.
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1)=O)(C)(C)C>O1CCOCC1.ClCCl>[CH:19]1([C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][NH2:9])=[CH:12][CH:13]=2)=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)C2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCc1ccc(C(=O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
Add 4N hydrogen chloride in dioxane (1 mL) to a stirred solution of N-(tert-butoxycarbonyl)-4-cyclohexanecarbonyl-benzylamine (197 mg, 0.621 mmol) in anhydrous dichloromethane (4 mL) and stir the mixture at ambient temperature for 16 h. Concentrate in vacuo and partition the residue between dichloromethane and saturated aqueous NaHCO3. Extract the aqueous phase twice with dichloromethane. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to give the title compound (125 mg, 93%) that was used without any further purification. MS (ES+) m/z: 218 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[N:37]=[C:36]([N:38]([CH3:40])[CH3:39])[CH:35]=[CH:34][CH:33]=1)[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([N:38]([CH3:39])[CH3:40])[N:37]=2)[CH2:28][CH3:29])=[O:27])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: CCNCc1cccc(N(C)C)n1
Product: CCN(Cc1cccc(N(C)C)n1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with (6-ethylaminomethyl-pyridin-2-yl)-dimethyl-amine
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[C@@H:3]1[C@H:5]([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=2)[O:4]1.[CH2:18]([Li])CCC.CI>>[CH3:1][Si:2]([CH3:17])([CH3:16])[C@@H:3]1[C@:5]([CH3:18])([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=2)[O:4]1
Reactant: C[Si](C)(C)[C@H]1O[C@H]1c1ccc2ccccc2c1
Reactant: [Li]CCCC
Solvent: CI
Product: C[C@@]1(c2ccc3ccccc3c2)O[C@@H]1[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
Trimethyl[(2R,3S)-3-(naphthalene-2-yl) oxirane-2-yl]silane (9.8 μg, 0.40 mmol) was dissolved in THF anhydride (1.6 mL) in a nitrogen atmosphere and the resultant solution was cooled down to −78° C. Thereinto, n-butyl lithium (2.69 molL−1 in 180.3 μL, 0.48 mmol of hexane solution) was dropped and the resultant reaction mixture was stirred at −78° C. for 90 minutes. Thereto, methyl iodide (99.8 μL, 1.60 mmol) was added and the resultant reaction mixture was stirred at −78° C. for 15 minutes. Thereafter, the reaction mixture was returned to the room temperature and was further stirred for 1 hour. The reaction was quenched with water and the resultant mixture was extracted with ethyl acetate. The organic phase was washed with water and saline and was dried over Na2SO4. The obtained crude product was purified by silica gel column chromatography (n-pentane/diethyl ether=0/0) to produce trimethyl [(2R,3S)-3-methyl-3-(naphthalene-2-yl) oxirane-2-yl]silane in a yield of 71%. Trimethyl[(2R,3S)-3-methyl-3-(naphthalene-2-yl) oxirane-2-yl]silane
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].Cl[C:14]1[C:23]2[C:18](=[C:19]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([NH:35][CH3:36])[N:29]=[CH:28]4)[C:20]([CH3:24])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:7][C:14]1[C:23]2[C:18](=[C:19]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([NH:35][CH3:36])[N:29]=[CH:28]4)[C:20]([CH3:24])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CNc1ncc2cc(-c3c(C)ccc4c(Cl)nccc34)ccc2n1
Reactant: COc1ccc(CN)cc1OC
Solvent: O
Solvent: CN1CCCC1=O
Product: CNc1ncc2cc(-c3c(C)ccc4c(NCc5ccc(OC)c(OC)c5)nccc34)ccc2n1

Procedure:
Dissolved 3,4-dimethoxybenzylamine (3.04 ml, 20.2 mmol) in NMP (15.0 mL) and added 6-(1-chloro-6-methylisoquinolin-5-yl)-N-methylquinazolin-2-amine (2.25 g, 6.72 mmol) as a solid in a sealed vessel and heated the reaction to 220° C. in the microwave 20 minutes. Dripped the reaction mixture into water and isolated the resulting precipitate. Air-dried the solid and redissolved in 2M NH3/MeOH. Concentrated in vacuo, redissolved wet slurry in EtOAc and dried the slurry over Na2SO4. Concentrated and loaded the crude material on a column, and purified the crude eluting with 20-100% EtOAc/hexanes. The pure fractions were combined and concentrated to afford 6-(1-(3,4-dimethoxybenzylamino)-6-methylisoquinolin-5-yl)-N-methylquinazolin-2-amine. MS (M+H)+ 466.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].CC(C)([O-])C.[K+].Cl[C:13]1[C:22]2[C:17](=[C:18]([NH:23][C:24](=[O:33])[C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([Cl:31])[C:25]=1[C:24]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[N:16]=[CH:15][CH:14]=[C:13]2[O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:33]
Reactant: O=C(Nc1cccc2c(Cl)ccnc12)c1c(Cl)cccc1Cl
Reactant: COCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COCCOc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
To a stirred solution of 2-methoxyethanol (130 mg) in N-methylpyrrolidone (2 ml) was added potassium tert-butoxide (172 mg) under ice-cooling, and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added 4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (200 mg), and the mixture was stirred for 5 hours at 80° C. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-(2-methoxyethoxy)quinoline (175 mg).
Reaction SMILES: [C:1]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3Cl)[C@H:11](O)[C@@H:10]1O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(NC(C)C)(C)C.[C:41]1([CH:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:48][NH2:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH:10]=[CH:11]2)=[C:19]([NH:49][CH2:48][CH:47]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
(1S,2R,3S,5R)-3-(Di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol (13.0 g, 27.66 mmol) is dissolved in THF (250 mil) under an atmosphere of argon. Diisopropylamine (4.28 g, 33.19 mmol) is added followed by 2,2-diphenylethylamine (6.0 g, 30.43 mmol) and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 18 hours. The solvent is removed in vacuo and the reaction mixture is partitioned between dichloromethane (250 ml) and 0.1M HCl (250 ml). The organic layer is washed with water (200 ml) and brine (200 ml), dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 8.05(s, 1H), 7.30-7.10(m, 10H), 6.00(m, 1H), 5.70(m, 2H), 5.60(m, 1H), 5.20(m, 1H), 4.30(m, 1H), 4.20(m, 1H), 3.65(m, 1H), 3.05(m, 1H), 2.00(m, 1H), 1.70(m, 1H), 1.40(s, 18H), MS (ES+) m/e 631 (MH+).
Reaction SMILES: [C:1]([N:20]1[C:24]2[N:25]=[CH:26][CH:27]=[C:28]([C:29]([NH2:31])=O)[C:23]=2[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1COCC1.[Cl-].[Na+].O>[C:1]([N:20]1[C:24]2[N:25]=[CH:26][CH:27]=[C:28]([C:29](=[S:41])[NH2:31])[C:23]=2[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)c1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
A solution of 1-tritylpyrazolo[5,4-b]pyridine-4-carboxamide (2.843 g, 7.029 mmol) in THF (50 mL) was treated with Lawesson's reagent (2.843 g, 7.029 mmol) at RT under nitrogen. The resulting yellow solution was allowed to heat at 80° C. for 4 hours and then treated with brine and extracted with EtOAc (2×). The organics were dried (Na2SO4), filtered, concentrated and purified by column chromatography (2% MeOH/DCM) to give the product as a yellow foam (quantitative yield). 1H NMR (DMSO, 400 MHz) δ 7.18-7.30 (16H, m), 8.28 (1H, m), 8.40 (1H, s), 10.34 (1H, br s); MS (ES+) 421.16
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C@@H:27]2[CH2:31][CH2:30][CH2:29][NH:28]2)[NH:10][C:11]([N:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[N:18][C:17]([NH:23][CH:24]([CH3:26])[CH3:25])=[N:16][C:15]=3[CH2:14]2)=[O:12])=[CH:5][C:4]=1[F:32].[CH3:33][C:34](OC(C)=O)=[O:35].C(Cl)Cl>O>[C:34]([N:28]1[CH2:29][CH2:30][CH2:31][C@H:27]1[C@H:9]([C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([F:32])[CH:5]=1)[NH:10][C:11]([N:13]1[CH2:22][CH2:21][C:20]2[CH:19]=[N:18][C:17]([NH:23][CH:24]([CH3:25])[CH3:26])=[N:16][C:15]=2[CH2:14]1)=[O:12])(=[O:35])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@@H](c1ccc(Cl)c(F)c1)[C@@H]1CCCN1)CC2
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC[C@H]1[C@@H](NC(=O)N1CCc2cnc(NC(C)C)nc2C1)c1ccc(Cl)c(F)c1

Procedure:
A solution of 83 and Ac2O (6.45 μL, 0.0683 mmol), TEA (25.9 μL, 0.186 mmol) and DCM (5 mL) was stirred for 1 h then poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:10) to afford 0.020 g (65.9%) of I-87: MS m/z (APCI-pos) M+1=489.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][C:7]([Br:10])=[CH:8][CH:9]=1)=[O:4].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:2][C:3]([C:5]2[S:6][C:7]([Br:10])=[CH:8][CH:9]=2)=[O:4])=[CH:14][CH:13]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(CBr)c1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(COc1ccc(Cl)cc1)c1ccc(Br)s1
Yield: 52.2 %

Procedure:
28.4 g (0.1 mol) of 2-bromoacetyl-5-bromothiophene are heated under reflux with 19.3 g (0.15 mol) of 4-chlorophenol and 27.6 g (0.2 mol) of potassium carbonate in 200 ml of ketone for 3 hours, while stirring. The mixture is then poured into water, and the ether-ketone is extracted with methylene chloride. The organic phase is washed with dilute sodium hydroxide solution and then with water, and is dried over magnesium sulphate. After the organic phase has been evaporated down, the residue is recrystallized from ethanol. 17.3 g (52% of theory) of 2-bromo-thien-5-yl 4-chlorophenoxymethyl ketone of melting point 128°-130° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:17])=[C:13]([CH2:15]Cl)[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[CH3:23][N:24]([CH3:29])[CH2:25][C:26]([OH:28])=[O:27]>C(#N)C>[CH3:23][N:24]([CH3:29])[CH2:25][C:26]([O:28][CH2:15][C:13]1[N:14]=[C:7]2[C:6]([NH:5][CH2:4][C:3]3[C:2]([CH3:1])=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:22])=[CH:11][CH:10]=[CH:9][N:8]2[C:12]=1[CH3:17])=[O:27]
Reactant: CN(C)CC(=O)O
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(CCl)nc12
Solvent: CC#N
Product: Cc1cccc(C)c1CNc1cccn2c(C)c(COC(=O)CN(C)C)nc12
Yield: 31.5 %

Procedure:
8-(2,6-dimethylbenzylamino)-2-chloromethyl-3-methylimidazo[1,2-a]pyridine (0.3 g, 1.0 mmol) and N,N-dimethylglycine (0.1 g, 1.0 mmol) were added to acetonitrile (10 ml) and the mixture was refluxed for 20 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using, dichloromethane:methanol (10:2) as eluent. Recrystallization from acetonitrile gave 0.12 g (32%) of the title compound.
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH:12][S:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(=O)N1CCN(N)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(NS(=O)(=O)c2ccc(F)cc2)CC1
Yield: 47.8 %

Procedure:
To a mixture of 1-acetyl-4-aminopiperazine dihydrochloride (540 mg) and 4-fluorobenzenesulfonyl chloride (535 mg) in dichloromethane (5 ml) was added triethylamine (1.2 ml) in a few minutes with stirring in an ice bath. After stirring for half an hour at the same temperature, the mixture was washed with brine, dried, and concentrated in vacuo. The residue was crystallized from ethanol and recrystallized from a mixture of ethanol and diethyl ether to Yield N-(4-acetyl-1-piperazinyl)-4-fluorobenzenesulfonamide (360 mg) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2].Cl[CH2:23][C:24]1[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]([CH2:32][CH3:33])[CH2:34][CH3:35])=[CH:36][CH:37]=1)([S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:11])=[O:12])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCN(CC)CCOc1ccc(CCl)cc1
Reactant: CCCCC(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1
Product: CCCCC(Cc1ccc(OCCN(CC)CC)cc1)(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1

Procedure:
2-[4(2-Diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester was prepared according to the general method as outlined in example 12. Starting from 2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester (4 g, 12.7 mmol) and [2-(4-chloromethyl-phenoxy)-ethyl]-diethylamine (3.38 g, 14 mmol). Yield 8.21 g crude (100%); brown oil; MS: 520.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][NH:12][CH:11]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[F:27])[C:5]2=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].C1(C)C=CC=CC=1.[C:41](Cl)([Cl:43])=[O:42]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:14]([CH2:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:13][N:12]([C:41]([Cl:43])=[O:42])[CH:11]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[F:27])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)CC1CN(C(=O)Cl)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one prepared in Example 6 (0.12 g, 0.28 mmol) in dichloromethane (3 mL) was added saturated aqueous NaHCO3 solution (3 mL). The temperature of the mixture was lowered to 0° C., and a toluene solution (Aldrich, 20%) of phosgene (0.27 mL, 0.51 mmol) was added dropwise via a syringe. The reaction mixture was stirred at room temperature for 30 min, then diluted dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichlormethane twice. The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated to give crude rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonyl chloride as a light yellow oil, which was used in the next step without further purification (0.14 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]([C:16]#[C:17][C:18](OC)=[O:19])=[O:15]>>[F:11][C:8]([F:9])([F:10])[C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][CH:4]=1)[NH:1][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:17][C:18]2=[O:19]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: COC(=O)c1cc(=O)c2cc(C(F)(F)F)ccc2[nH]1
Yield: 2.7 %

Procedure:
Using the method described in Example 18a with 4-aminobenzotrifluoride (20 g) and dimethylacetylene dicarboxylate (17.5 g) as reagents gave methyl 6-trifluoromethyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.91 g), m.p. 289°-291° C., δ (360 MHz, DMSO-d6) 3.98 (3H, s, CH3), 6.74 (1H, s, 3-H), 8.02 (1H, dd, 7-H), 8.13 (1H, d, 8-H), 8.33 (1H, s, 5-H) and 12.40 (1H, s, NH).