Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)C1CC1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a stirred solution of (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (18 mg, 50 μmol) in dichloromethane (2 ml) was added triethylamine (100 μl), followed by cyclopropanecarbonyl chloride (15 mg, 150 μmol). The stirring was continued for 20 min at r.t., then the solvent was removed under reduced pressure, and the product purified by semi-preparative HPLC. Yield 20 mg (95%).
Reaction SMILES: [CH:1]1([S:7][CH2:8][CH2:9][N:10]([N:16]=[O:17])[C@H:11]([C:13]([OH:15])=O)[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N(N[C@H](C(O)=O)C)=O.C(OC(=O)C)(=O)C>O>[CH:1]1([S:7][CH2:8][CH2:9][N+:10]2[N-:16][O:17][C:13](=[O:15])[C:11]=2[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@@H](C(=O)O)N(CCSC1CCCCC1)N=O
Agent: C[C@H](NN=O)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1c(=O)o[n-][n+]1CCSC1CCCCC1
Reaction time: 96 h

Procedure:
The oil obtained in Example 3, N-[2-cyclohexylthio)ethyl]-N-nitrosoalanine, is treated with 54 parts of acetic anhydride and allowed to stand for 4 days at room temperature. After that time, the reaction mixture is added to 500 parts of water and extracted with methylene chloride. The organic extracts are washed with water and aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness. The oil remaining is crystallized from ether by seeding and cooling. The crystalline material is recovered by filtration and dried to afford pure 3-[2-(cyclohexylthio)ethyl] -4-methylsydnone, melting at about 82°-83°. That compound is represented structurally by the following formula ##STR7##
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.[C:23]([C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1)#[N:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][N:14]([C:28]([C:25]4([C:23]#[N:24])[CH2:27][CH2:26]4)=[O:29])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: N#CC1(C(=O)O)CC1
Reactant: CO[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A solution of (±)-6-bromo-4-((cis-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (0.30 g, 0.62 mmol) in DMF (0.5 mL), was added 1-cyanocyclopropanecarboxylic acid (0.073 g, 0.65 mmol), BOP (0.30 g, 0.68 mmol) and DIPEA (0.23 mL, 1.31 mmol). The mixture was stirred at rt for 2 h, quenched with water, stirred, filtered and rinsed with water. The brown solid was dried under vacuum to afford (±)-6-bromo-4-((cis-1-(1-cyanocyclopropanecarbonyl)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (250 mg, 90% yield) as a brown solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.17 (d, J=6.6 Hz, 1H), 7.68 (d, J=7.0 Hz, 1H), 7.11 (d, J=17.8 Hz, 1H), 5.09-4.92 (m, 2H), 4.55 (br. s., 2H), 4.46-3.93 (m, 3H), 3.88-3.59 (m, 2H), 3.50 (d, J=14.1 Hz, 3H), 1.75-1.46 (m, 4H); MS (ES+) m/z: 446.1, 447.2 (M+H); LC retention time: 3.1 min (analytical HPLC Method J).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:23]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:24]#[CH:25]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[N:26]1([CH2:23][C:24]#[C:25][C:2]2[N:7]=[CH:6][C:5]([C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)=[CH:12][CH:11]=3)=[O:9])=[CH:4][CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C#CCN1CCCC1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Cl)nc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(C#CCN2CCCC2)nc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
A 100 mL Schlenk flask was charge with (6-chloropyridin-3-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (4.0 g, 12.6 mmol), tetrakis(triphenylphosphine) palladium(0) (1.5 g, 1.3 mmol, 10 mol %), cuprous iodide (0.48 g, 2.5 mmol, 20 mol %), triethylamine 50 mL and 1-(prop-2-ynyl)pyrrolidine (2.8 g, 25.2 mmol). The flask was flushed with nitrogen three times and the mixture was stirred at 80° C. for 2 h. The solvent was evaporated under vacuum and the residue was purified by column chromatography to afford the desired product as a yellow solid (2.2 g, 44.9%).
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](Cl)=[O:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH2:22])[CH2:20][CH3:21]>C(Cl)Cl>[CH2:19]([NH:22][C:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=1)=[O:17])[CH2:20][CH3:21]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc2c1OCC2(C)C
Reactant: CCCN
Solvent: ClCCl
Product: CCCNC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2

Procedure:
To a solution of (7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl) carboxylic acid chloride (450 mg, 1.69 mmol) in CH2Cl2 (10 mL) is added in a single portion n-propylamine (2 mL). After the exothermic reaction subsides, the mixture is evaporated and suspended in 1N HCl (10 mL). The insoluble material is filtered and crystallized from isopropanol/H2O, to yield N-propyl (7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)carboxamide as white needles.
Reaction SMILES: Cl.C([N:9]([CH2:22][CH:23]([OH:31])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)C1C=CC=CC=1.C(OCC)(=O)C>CO.[Pd]>[ClH:30].[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][NH:9][CH2:22][CH:23]([OH:31])[C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(CCN(Cc2ccccc2)CC(O)c2ccc(Cl)cc2)cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(CCNCC(O)c2ccc(Cl)cc2)cc1OC
Reaction time: 1.5 h

Procedure:
Similarly 5.42 g. (0.02 mol) of N-benzyl-3,4-dimethoxyphenethylamine and 4.64 g. (0.03 mol) of p-chlorostyrene oxide are reacted in methanol to give N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-chlorophenyl)ethylamine. The hydrochloride of this ethylamine is dissolved in methanol and hydrogenated with 0.5 g. of 10% palladium-on-carbon in 10 ml. of ethyl acetate at room temperature and 60 psi. for about 90 minutes. The filtered reaction mixture is evaporated in vacuo to yield N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-chlorophenyl)ethylamine hydrochloride, m.p. 167°-171° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[NH:10][C@H:11]([CH2:36][OH:37])[CH2:12][CH2:13][C:14](=[O:35])[NH:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:44](Cl)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>CN(C=O)C.CC(OC)(C)C>[CH2:1]([O:8][C:9](=[O:38])[NH:10][C@H:11]([CH2:36][O:37][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:12][CH2:13][C:14](=[O:35])[NH:15][C:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC[C@@H](CO)NC(=O)OCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H](CCC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 71 %

Procedure:
Intermediate B1, prepared above, was dissolved in DMF (10 mL). Imidazole (2.69 g, 39.5 mmol, 2.3 equiv) and tert-butyldimethylsilyl chloride (2.86 g, 19.0 mmol, 1.1 equiv) were added. The reaction mixture was stirred overnight, then diluted with MTBE (500 mL) and washed sequentially with 2.5% KHSO4, H2O, NaHCO3, H2O, and brine (100 mL each). The organic phase was dried over MgSO4 and evaporated. The residue was purified by flash column chromatography (gradient elution, 25→40% EtOAc in hexanes) to provide the title intermediate (7.6 g, 71%) as a white amorphous solid: IR (cm−1) 3307, 1708, 1660, 1496, 1249; 1H NMR (CDCl3) δ-0.01-0.05 (m, 6H), 0.89 (s, 9H), 1.76-1.93 (m. 2H), 2.29-2.40 (m, 2H), 3.56-3.77 (m, 3H), 5.03-5.16 (m, 3H), 7.00 (s, 1H), 7.18-7.39 (m, 20 H); Anal. C38H46N2O4Si: C, H, N.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:6][CH:5]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[CH2:20]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:8][CH:9]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCc1ccc(Nc2ccc(C(N)=O)cn2)cc1
Reactant: O=Cc1ccccc1
Solvent: CO
Product: NC(=O)c1ccc(Nc2ccc(CCNCc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.9 %

Procedure:
Combine 6-[4-(2-amino-ethyl)-phenylamino]-nicotinamide (200 mg, 0.78 mmol) (step 2, Example 16), benzaldehyde (83 mg, 0.78 mmol), 3 Å molecular sieves (0.2 g), and methanol (10 mL) and stir overnight at room temperature. Filter off the sieves then add sodium borohydride (0.4 mg) to the reaction and stirred at room temperature for 4 hours. Add water (20 mL) then extract with dicholormethane (3×50 mL). Dry the dichloromethane extracts with sodium chloride/magnesium sulfate, filter, then concentrate on a rotary evaporator to yield 0.2 g of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with 10% conc. ammonium hydroxide in ethanol and chloroform to yield 6-[4-(2-Benzylamino-ethyl)-phenylamino]-nicotinamide (24 mg): 1H NMR (MeOD, 300.00 MHz): 8.66 (d, 1H, J=1.8 Hz), 8.00 (dd, 1H, J=9.0, 2.4 Hz), 7.55-7.15 (m, 10H), 6.81 (d, 1H, J=8.8 Hz), 3.80 (s, 2H), 3.38 (m, 1H), 2.84 (m, 5H); m/z=347.01 (M+1); HPLC=95%@5.54 minutes (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:13][C:12](=[O:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[C:18](=[O:21])([O-])[O-].[NH4+:22].[NH4+:23]>O.C(O)C>[NH:22]1[CH2:13][C:12](=[O:14])[NH:23][C:18]1=[O:21].[CH2:1]([O:8][CH2:9][CH:10]1[CH2:13][C:12](=[O:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C([O-])[O-]
Agent: O=C1CC(COCc2ccccc2)C1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1CNC(=O)N1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
3-(Benzyloxymethyl)cyclobutanone 4.0 g (21 mmol), sodium cyanide 2.1 g (42 mmol) and ammonium carbonate 10.1 g (105 mmol) were added into a 100-ml eggplant-shaped flask, and the mixture was dissolved in 50 ml of 50% water/ethanol. This eggplant-shaped flask was sealed and the mixture was stirred overnight at 60° C. After opening this flask with caution in a draft chamber, the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and filtered to remove insoluble inorganic salts. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=50:50). Thus, 3-(benzyloxymethyl)cyclobutanone hydantoin was obtained as a white crystal (cis-form 2.8 g, 11 mmol, 50%; trans-form 1.1 g, 4.3 mmol, 21%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][NH:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I>CN(C)C=O.C(OCC)(=O)C.[Ag]=O>[CH3:24][N:13]1[CH2:14][C@@H:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12]1=[O:23]
Reactant: CI
Reactant: CC(C)(C)OC(=O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: O=[Ag]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OCc2ccccc2)C1=O
Yield: 84.3 %

Procedure:
9.6 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are dissolved in 200 ml of dimethylformamide, and 14.0 g of silver oxide are added thereto. 42.6 g of methyl iodide are added to the mixture at room temperature under stirring, and the mixture is further stirred for 2 days in the dark. The reaction mixture is filtered to remove insoluble materials, and the filtrate is condensed under reduced pressure. The residue obtained is dissolved in ethyl acetate. Then, the ethyl acetate solution is washed with water, dried and condensed under reduced pressure. The residue thus obtained is washed with n-hexane. 8.45 g of tert.-butyl (4S)-1-methyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are thereby obtained as colorless crystals. Yield: 84.3% M.p. 102°-103° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:4].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][Br:15])=[CH:9][CH:8]=1)[CH3:4]
Reactant: BrCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCCCCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
Sodium hydride (1.55 g, 61 mmol) was suspended in DMF (150 mL) under an atmosphere of nitrogen. Ethyl-4-hydroxybenzoate (11) (5.06 g, 30 mmol) was added as a solution in DMF (30 mL) via syringe which was then washed with DMF (2×5 mL). The reaction mixture was then stirred at room temperature under an atmosphere of nitrogen for 2 hours. After this time, 1,10-dibromodecane (30.84 g, 103 mmol) was added as a solution in DMF (50 mL) via syringe which was then washed with DMF (2×5 mL). The reaction mixture was then stirred at room temperature under nitrogen for 19 hours. The reaction was quenched with water (200 mL) and the organic fragments extracted with diethyl ether (4×150 mL), dried over MgSO4, and excess solvent removed in vacuo to form a colorless oil. This was purified by flash column chromatography using CH2Cl2 /hexane (1:1) to CH2Cl2 /hexane (3:1) as eluting solvents to form a white crystalline solid. This was recrystallized from ethanol to form 4-(10-bromo-decyloxy)-benzoic acid ethyl ester (7.38 g, 19.1 mmol, 63%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>O1CCCC1>[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Yield: 92 %

Procedure:
To a suspension of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (2 g, 0.005 mol) and 0.5 g of triethylamine in 30 ml of tetrahydrofuran is added dropwise a solution of p-fluorophenylsulfonyl chloride in 10 ml of tetrahydrofuran over a 15 minute period. After complete addition, the resultant mixture is stirred for 1 hour at room temperature. The resulting mixture is filtered and the white solid is washed with more tetrahydrofuran and dried. This is re-crystallized from methanol/methylene chloride to give 2.5 g (92%) of white crystalline 1-[(4-fluorophenyl)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine of melting point 251°-253° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34]Cl>>[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][N:19]1[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:2]([F:1])=[CH:3][C:4]=2[C:26]([F:29])([F:27])[F:28])[CH:8]=[CH:9]3)/[S:21][C:20]1=[O:22]
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(F)cc3C(F)(F)F)c2)S1
Reactant: CN(C)CCCl
Agent: Cl
Product: CN(C)CCN1C(=O)S/C(=C\c2ccc3c(ccn3Cc3ccc(F)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-3-[2-(Dimethylamino)ethyl]-5-[(1-{[4-fluoro-2-(trifluoromethyl)-phenyl]methyl}-1H-indol-5-yl)methylidene]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-fluoro-2-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 249) and 2-(dimethylamino)ethyl chloride hydrochloride following General Procedure H.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Na+].O.[C:14]1(S(OCC#C)(=O)=O)[CH:19]=CC=C[CH:15]=1>C1(C)C=CC=CC=1>[CH2:19]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)[C:14]#[CH:15]
Reactant: C#CCOS(=O)(=O)c1ccccc1
Reactant: NC1CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C#CCNC1CCc2ccccc21
Yield: 62 %

Procedure:
To a mixture of racemic 1-aminoindan (64 g), 15% aqueous sodium hydroxide solution (141 g), water (107 mL) and toluene (192 mL) there was added propargyl benzenesulfonate (94.3 g) during 20 minutes at ambient temperature. The resulting mixture was heater to 45° C. for 4 hours, at which time the pH was confirmed to be >12(45% sodium hydroxide added if necessary) and the phases were separated. To the organic phase water (64 mL) was added and the pH was adjusted to 2 with 33% aqueous sulfuric acid. The aqueous phase was separated, diluted with water and mixed with toluene. The pH was adjusted to 6 with 25% aqueous sodium hydroxide and the phases separated. The aqueous phase was extracted again with toluene, ensuring a pH=6. The combined organic layers were concentrated in vacuo to yield 51 g of crude racemic N-propargyl-1-aminoindan as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[C:4][CH2:5][OH:6].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.O>[Cl:1][CH2:2][C:3]#[C:4][CH2:5][O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1
Reactant: C1=COCCC1
Reactant: OCC#CCCl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: ClCC#CCOC1CCCCO1
Yield: 97.5 %

Procedure:
A solution of 4-chloro-but-2-yn-1-ol (2.16 g, 20.66 mmol), 3,4-dihydro-2H-pyran (2.83 mL, 30.99 mmol, 1.5 eq), and pyridinium p-toluenesulfonate (528.0 mg, 0.21 mmol, 0.10 eq) in anhydrous dichloromethane (50 mL) was stirred at room temperature under N2 for 17 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 3.80 g (97.4%) of the desired product as clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.80 (t, J=4.0 Hz, 1H), 4.39-4.22 (m, 2H), 4.19 (t, J=2.0 Hz, 2H), 3.88-3.80 (m, 1H), 3.57-3.51 (m, 1H), 1.89-1.70 (m, 2H), 1.68-1.50 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[F:24])=[C:4]([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)[CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.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>[F:24][C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[C:4]([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:3][C:2]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[N:7][CH:6]=1
Reactant: Cn1nccc1-c1cc(Cl)ncc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1F
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nccc1-c1cc(-c2cccnc2)ncc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1F
Yield: 49.2 %

Procedure:
10 mg (0.02 mmol) of 4-((6-chloro-4-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)oxy)-3-fluoro-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 3.9 mg (0.03 mmol) of (pyridin-3-yl)boronic acid was added thereto, and then 2.4 mg (10 mol %) of Pd(PPh3)4, 6.8 mg (0.64 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (45% yield) of the title compound.
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9])([CH3:3])[CH3:2].[NH2-].[Na+].C1(C)C=CC=CC=1.Cl[CH2:29][CH2:30][N:31]([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33]>O>[CH:16]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][C:7]([CH2:29][CH2:30][N:31]([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]#[N:9])([CH3:18])[CH3:17]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N(CCC(C#N)(CCN(C(C)C)C(C)C)c1ccccc1)C(C)C

Procedure:
A solution of 20 parts of α-[2-(diisopropylamino)ethyl]-α-phenylacetonitrile and 4 parts of sodium amide in 180 parts by volume of toluene is heated to about 100° C. over a period of 15 minutes and then 18 parts of 2-chloro-N,N-diisopropylethylamine in 70 parts by volume of toluene is added slowly over a period of 20 minutes. This mixture is heated at 105°-110° C. for an hour and then cooled to room temperature when 200 parts by volume of water is added. The organic layer is separated, dried over calcium sulfate, concentrated and distilled to afford α,α-bis[2-(diisopropylamino)ethyl]-α-phenylacetonitrile as an oil. This compound is identical with the compound of Example 2, Method A.