Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([C:28]([O:30]C)=[O:29])=[C:8]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([B:18]3[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]3)[C:13]=2[CH3:27])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].O>C(O)(C)C>[C:1]([C:5]1[S:6][C:7]([C:28]([OH:30])=[O:29])=[C:8]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([B:18]3[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:26])([CH3:25])[O:19]3)[C:13]=2[CH3:27])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(C(C)(C)C)nc1CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1c(NCc2nc(C(C)(C)C)sc2C(=O)O)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 40 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A mixture of methyl 2-tert-butyl-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)methyl)thiazole-5-carboxylate 109d (1.80 g, 4.05 mmol) and lithium hydroxide (970.0 mg, 40.50 mmol) in isopropyl alcohol (15 mL) and water (15 mL, 830 mmol) was stirred at 40° C. overnight. The reaction mixture was concentrated to ˜50% of original volume, acidified to pH˜2 with conc. hydrochloric acid, and extracted with 9:1 isopropyl acetate/isopropyl alcohol. The extract was dried with anhydrous magnesium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to afford 2-tert-butyl-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)methyl)thiazole-5-carboxylic acid 109e (1.74 g, 92%), which was used without further purification.
Reaction SMILES: Cl.[CH2:2]([NH:4][C@@H:5]1[C:10]2[CH:11]=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[S:13][C:9]=2[S:8](=[O:19])(=[O:18])[N:7]([CH2:20][CH2:21][O:22]C)[CH2:6]1)[CH3:3].C(N(CC)CC)C.BrB(C)C>ClCCCl>[CH2:2]([NH:4][C@@H:5]1[C:10]2[CH:11]=[C:12]([S:14]([NH2:17])(=[O:15])=[O:16])[S:13][C:9]=2[S:8](=[O:18])(=[O:19])[N:7]([CH2:20][CH2:21][OH:22])[CH2:6]1)[CH3:3]
Reactant: CCN[C@H]1CN(CCOC)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Agent: CB(C)Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCN[C@H]1CN(CCO)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Reaction time: 4 h
Yield: 90 %

Procedure:
To a stirred solution of (R)-(+)-4-Ethylamino-3,4-dihydro-2-(2-methoxyethyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride (6.03 g, 15.0 mmol) in 1,2-dichloroethane (50 mL) was added triethylamine (210 mL, 1.5 mmol) followed by bromodimethylborane (5.79 mL, 59.0 mmol) at 0° C. After 4 h at room temperature, the reaction was quenched by adding a saturated aqueous solution of sodium bicarbonate; this mixture was extracted with ethyl acetate (4×50 mL). The combined extracts were washed with brine (20 mL), dried (MgSO4) and evaporated to give the desired alcohol product as a syrup (4.8 g, 91%).
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Br[C:31]1[CH:32]=[C:33]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[OH:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:36]2[CH:35]=[CH:34][C:33]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])=[CH:32][CH:31]=2)=[CH:16][CH:17]=1
Reactant: CNC(=O)Cc1cccc(Br)c1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
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: CCO
Solvent: Cc1ccccc1
Product: CNC(=O)Cc1ccc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)cc1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 11)), 2-(3-bromophenyl)-N-methyl-acetamide (0.244 g, Example 24a)), 2M aqueous sodium carbonate (0.265 ml) and tetrakis(triphenylphosphine)palladium (0) (0.1 g) in toluene (5 ml) and ethanol (2 ml). The reaction was heated at 110° C. for 6 hours. After cooling, the solution was concentrated under reduced pressure the residue was dissolved in methanol (10 ml), concentrated hydrochloric acid (1 ml) was added and the solution stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure the residue was neutralised using saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil which was converted to the oxalic acid salt by treatment with a saturated ethereal solution of oxalic acid to give the title compound as a gum (0.123 g).
Reaction SMILES: [NH:1]1C=NC=N1.P(Cl)(Cl)(Cl)=O.[N:11]1([C:19]([CH2:21][C@H:22]([CH2:35][OH:36])[O:23][CH2:24][P:25]([O:31][CH:32]([CH3:34])[CH3:33])([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])=[O:20])[CH:18]=[CH:17][C:15](=O)[NH:14][C:12]1=[O:13]>N1C=CC=CC=1>[N:11]1([C:19]([CH2:21][C@H:22]([CH2:35][OH:36])[O:23][CH2:24][P:25]([O:31][CH:32]([CH3:34])[CH3:33])([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])=[O:20])[CH:18]=[CH:17][C:15]([NH2:1])=[N:14][C:12]1=[O:13]
Reactant: c1nc[nH]n1
Reactant: CC(C)OP(=O)(CO[C@@H](CO)CC(=O)n1ccc(=O)[nH]c1=O)OC(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)OP(=O)(CO[C@@H](CO)CC(=O)n1ccc(N)nc1=O)OC(C)C
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
To the solution of 1,2,4-triazole (662 mg, 9.6 mmol) in 15 mL pyridine was added phosphorousoxychloride (223 μL, 2.4 mmol) at room temperature. The mixture was stirred for 10 minutes. Then the solution of 21 (289 mg, 0.80 mmol) was added to the mixture. The reaction mixture was stirred for 4 hours. Then ammonia gas was bubbled in to the reaction mixture for 1-3 hours and the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (CH2Cl2:MeOH=12:1) to give compound 22 (220 mg, 0.58 mmol) as a colorless foam, in 73% yield, which was characterized as follows:
Reaction SMILES: [O:1]=[C:2]1[N:7]2[N:8]=[CH:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]2=[C:5]([C:15]([OH:17])=[O:16])[CH:4]=[C:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[OH-].[K+]>[C:9]([C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:6]1[NH:7][C:2](=[O:1])[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][C:5]=1[C:15]([OH:17])=[O:16])#[N:8]
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2ncc3ccsc3c12
Agent: [K+]
Agent: [OH-]
Product: N#Cc1ccsc1-c1[nH]c(=O)c(-c2ccccc2)cc1C(=O)O
Yield: 99.8 %

Procedure:
48.7 g of 7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]-pyridazine-10-carboxylic acid were added to a methanolic potassium hydroxide solution (prepared from 72 g of potassium hydroxide and 640 ml of methanol) and the mixture was heated to boiling under reflux for about 24 hours. The reaction mixture wass evaporated to half in a vacuum, treated with 80 ml of water and adjusted to pH 1 by the addition of 1N hydrochloric acid. The separated crystals were filtered off under suction, washed with water and dried in a vacuum. There was obtained 48.6 g of 2-(3-cyano-2-thienyl)-1, 6-dihydro-6-oxo-5-phenylnicotinic acid as yellow crystals with a m.p. of 255°-257° (methanol/N,N-dimethylformamide).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:27][S@](C(C)(C)C)=O)([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[N:6][CH:7]=1.Cl.[CH:35]1([N:40]=[C:41]=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:27][C:41]([NH:40][CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:42])([C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[N:6][CH:7]=1
Reactant: O=C=NC1CCCC1
Reactant: Cc1csc(C[C@](N[S@@](=O)C(C)(C)C)(c2cc(F)cc(C(F)(F)F)c2)c2ccc(Cl)cn2)n1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Product: Cc1csc(C[C@](NC(=O)NC2CCCC2)(c2cc(F)cc(C(F)(F)F)c2)c2ccc(Cl)cn2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
(S)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(4-methylthiazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide (29 mg, 0.058 mmol) in MeOH (1.0 mL) was added HCl (0.5 mL, 2 mmol, 4N solution in dioxane) and the reaction was stirred at room temperature for 0.5 h. The mixture was concentrated, diluted with EtOAc (20 mL), washed with sat. NaHCO3 (20 mL), dried over Na2SO4, filtered and concentrated. The residue was dissolved in DCM (1 mL) and cyclopentyl isocyanate (9 mg, 0.083 mmol) was added followed by two crystals of citric acid. The reaction was stirred overnight, concentrated and purified by Prep TLC (Uniplate, Silica Gel GF, 20×20 cm, 1000 Microns) using Hexane/EtOAc (1/1) to yield (S)-1-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(4-methylthiazol-2-yl)ethyl)-3 -cyclopentylurea as a clear oil (10 mg, 70% yield) LCMS: 1.91 min [M+1] 527.2 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.91 min (4 min gradient, MeOH/H2O 0.2% PPA); Purity 100%; NMR: 400 MHz 1H (CDCl3) 8.29 ppm, 1 H, d, J=2.64 Hz; 7.54 ppm, 1 H, dd, J=8.57, 2.42 Hz; 7.40 ppm, 1 H, s; 7.32 ppm, 1 H, s; 7.26 ppm, 1 H, d, J=9.67 Hz; 7.12 ppm, 2 H, d, J=8.35 Hz; 6.60 ppm, 1 H, s; 4.58 ppm, 1 H, d, J=13.62 Hz; 4.43 ppm, 1 H, d, J=7.03 Hz; 4.08 ppm, 1 H, d, J=13.62 Hz; 3.92 ppm, 1 H, m; 2.20 ppm, 3 H, s; 1.93 ppm, 2 H, m; 1.61 ppm, 2 H, m; 1.53 ppm, 2 H, m; 1.40 ppm, 1 H, m; 1.32 ppm, 1 H, dd, J=13.18, 7.03 Hz.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.O>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(CCl)cc1
Reactant: CC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(OCc2ccc(F)cc2)CC1
Reaction time: 3 h
Yield: 57.4 %

Procedure:
1-Acetylpiperidin-4-ol (Preparation 193, 10 g, 70 mmol) in N,N-dimethylformamide (50 ml) was added dropwise to a stirred suspension of sodium hydride (50% wt dispersion in oil, 3.8 g, 80 mmol) in N,N-dimethylformamide (50 ml) at room temperature under nitrogen. After stirring the reaction mixture for 3 hours, 4-fluorobenzyl chloride (10.1 g, 70 mmol) in N,N-dimethylformamide (50 ml) was added dropwise and the reaction mixture was stirred for a further 4 h. The reaction mixture was filtered and the filtrate was evaporated to give an orange oil. Water was added and the mixture was extracted with petroleum ether (3×100 ml) and then with diethyl ether (3×100 ml). The combined organic extracts were washed with sodium hydroxide solution (1 M, 3×100 ml), before drying (Na2SO4) and concentrating to give the title compound as an oil (10.1 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[NH2:26].[C:27]([N:35]=[C:36]=[S:37])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O.C(OCC)(=O)C>[C:27]([NH:35][C:36]([NH:26][C:4]1[CH:5]=[C:6]([N:9]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[S:37])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc1NC(=S)NC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
To a stirred solution of 400 mg (1.15 mmol) 4-methoxy-N1,N1-bis-(4-methyl-benzyl)-benzene-1,3-diamine in 8 ml acetone was added dropwise a solution of 0.18 ml (1.34 mmol) benzoyl isothiocyanate in 4 ml acetone and stirring continued for 30 minutes at room temperature. The mixture was then diluted with ethyl acetate and washed with water and then with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/9 ethyl acetate/hexane) afforded 320 mg (80%) 1-benzoyl-3-{5-[bis-(4-methyl-benzyl)-amino]-2-methoxy-phenyl}-thiourea as a yellow oil. ES-MS m/e (%): 510 (M+H+, 100).
Reaction SMILES: [N:1]1S[N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][N:11]3[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]4[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=4)=[N:12]3)[CH:8]=[CH:9][C:2]=12>C1COCC1.[Ni]>[NH2:4][C:3]1[CH:6]=[C:7]([CH:8]=[CH:9][C:2]=1[NH2:1])[CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[CH:19]=[C:20]([F:26])[C:21]([F:25])=[C:22]([F:24])[CH:23]=2)=[N:12]1
Reactant: O=c1ccc(-c2cc(F)c(F)c(F)c2)nn1Cc1ccc2nsnc2c1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(Cn2nc(-c3cc(F)c(F)c(F)c3)ccc2=O)cc1N
Reaction time: 17 h

Procedure:
3.5 g (9.4 mmol) of 2-benzo-1,2,5-thiadiazol-5-ylmethyl-6-(3,4,5-tri-fluorophenyl)-2H-pyridazin-3-one are dissolved in 35 ml of THF and hydrogenated under a hydrogen atmosphere in an autoclave at 30° C. under a pressure of 2 bar with 2 g of Raney Ni (70%, water-moist). After 17 h, a further 3 g of Raney Ni (70%, water-moist) are added, and the mixture is hydrogenated at 35° C. under a pressure of 2 bar for a further 16 h. The catalyst is separated off, rinsed, and the filtrate is evaporated to dryness.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[C@H:10]([NH:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][N:20]=[C:19]2[N:24]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:25]=[C:26]([C:27](O)=[O:28])[C:18]=12)[C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>>[Cl:23][C:22]1[C:17]2[CH2:16][N:15]([C@H:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:40])[C:27](=[O:28])[C:26]3=[CH:25][N:24]([S:30]([C:33]4[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=4)(=[O:32])=[O:31])[C:19]([C:18]=23)=[N:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@@H](C(=O)OCc4ccccc4)C(C)(C)C)c(Cl)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)n2cc3c4c(c(Cl)cnc42)CN([C@@H](C(=O)OCc2ccccc2)C(C)(C)C)C3=O)cc1

Procedure:
Crude (R)-4-((1-(benzyloxy)-3,3-dimethyl-1-oxobutan-2-ylamino)methyl)-5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid was heated in HATU (124 mg, 0.326 mmol) and 4-methylmorpholine (82 mg, 0.814 mmol) at reflux for 3 h. The reaction mixture was subsequently concentrated and dried in vacuo to afford the title compound. [M+H] calc'd for C29H28ClN3O5S, 566; found, 566.0.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH2:27](Br)[CH3:28]>>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:12]=1[O:25][CH3:26])([CH2:27][CH3:28])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2Cl)c1OC
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C#N)(CC)c1cccc(Oc2ccccc2Cl)c1OC
Yield: 91 %

Procedure:
Sodium hydride (50%, 920 mg), ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenoxy)phenyl]acetate (6 g) and ethyl bromide (2.84 g) were treated in a similar manner to that of Example 10-(5) to give oily ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenoxy)phenyl]butyrate (5.9 g).
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:27][C:28]1[S:29][C:30]2[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:31]=2[N:32]=1.Cl.C(OCC)(=O)C>C(O)=O>[ClH:27].[Cl:37][C:35]1[CH:34]=[CH:33][C:31]2[N:32]=[C:28]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=3)[S:29][C:30]=2[CH:36]=1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1nc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2,6-dichloro-1,3-benzothiazole as starting materials and by an operation similar to that of Example 303-3 was treated with formic acid and 4 mol/L hydrochloric acid-ethyl acetate, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[C:15]([F:22])[CH:16]=[CH:17][C:18]=3[O:20]C)[N:13]([CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([NH2:29])=[O:28])[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[C:15]([F:22])[CH:16]=[CH:17][C:18]=3[OH:20])[N:13]([CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([NH2:29])=[O:28])[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C(N)=O)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(O)ccc(F)c32)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-7-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}benzamide (for a preparation see Example 68) (15.7 mg, 0.032 mmol) in anhydrous DCM (2 mL) under nitrogen atmosphere was treated with boron tribromide solution in DCM (1M, 0.032 mL) at room temperature. The reaction mixture was stirred at room temperature for 45 min and then saturated aqueous sodium bicarbonate solution was added dropwise to quench the reaction. The mixture was then partitioned between further saturated aqueous sodium bicarbonate solution and 10% methanol in ethyl acetate (white precipitate was present which was insoluble in both the organic and aqueous layer). The organic layer was separated, passed through an hydrophobic frit and evaporated in-vacuo to yield a yellow solid (13 mg). This was dissolved in MeOH:DMSO (1:1) (0.5 mL) and purified by MDAP on Sunfire C18 column, eluting with solvents NB (A: 0.1% v/v solution of formic acid in water, B: 0.1% v/v solution of formic acid in acetonitrile). Appropriate fraction was evaporated in-vacuo to yield the title compound as a yellow solid (8.5 mg, 56%). LCMS (System B) RT=2.41 min, ES+ve m/z 481/483 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][NH2:19])([O-:8])=[O:7].O.[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[N+:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][N:19]=[C:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([O-:8])=[O:7]
Reactant: O=C1CCCCC1
Reactant: NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(NN=C2CCCCC2)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 95 %

Procedure:
Concentrated sulfuric acid (2 mL) and 0.4456 g of 2,4-dinitrophenylhydrazine (2,4-DNP) were combined in a 25-mL Erlenmeyer flask. Water was added (2 to 3 mL) dropwise with swirling until the 2,4-DNP dissolved. This was followed by 10 mL of 95% ethanol. This solution was added, dropwise with swirling, to a solution of cyclohexanone, 0.5725 g, dissolved in 20 mL of 95% ethanol. A precipitate formed within 5 minutes. The mixture was refrigerated overnight. The precipitate was filtered to yield a yellow-orange crystalline solid. The product was re-crystallized from approximately 30 mL of absolute ethanol to afford 0.4 g of cyclohexanone 2,4-dinitrophenylhydrazone as orange flakes. The yield was 95%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)C(=O)OCC)[N:5]=[C:4]2[NH:22][CH:23]=[N:24][C:3]=12.O.[NH2:26]N>>[NH2:26][C:2]1[CH:7]=[C:6]([NH:8][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[N:5]=[C:4]2[NH:22][CH:23]=[N:24][C:3]=12
Reactant: CCOC(=O)N(CCC1CCCCC1)c1cc(Cl)c2nc[nH]c2n1
Reactant: NN
Solvent: O
Product: Nc1cc(NCCC2CCCCC2)nc2[nH]cnc12

Procedure:
A mixture of 100 mg ethyl N-(7-chloro-3H-imidazo[4,5-b]pyridin-5-yl)-N-(2-cyclohexylethyl)-carbamate in 1 ml of hydrazine monohydrate is heated at 120° in a sealed tube for 24 hours. The solvent is evaporated in vacuo and 5 ml of methanol saturated with ammonia is added to the residue. This is followed by 0.1 ml of a suspension of Raney nickel in methanol saturated with ammonia. The mixture is heated in a sealed tube at 130° for 24 hours. The catalyst is filtered and washed with methanol, and the solvents are evaporated in vacuo to give a residue which is purified by flash chromatography (10% methanol saturated with ammonia/methylene chloride) to give 7-amino-N-(2-cyclohexylethyl)-3H-imidazo[4,5-b]pyridin-5-amine.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][CH2:20][CH2:21]Cl)[NH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>O1CCOCC1.[OH-].[Na+]>[CH:23]([NH:26][CH2:21][CH2:20][CH2:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:10]([S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[CH:11][NH:12]2)([CH3:25])[CH3:24]
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2cccc(CCCCl)c12
Reactant: CC(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)NCCCc1cccc2[nH]cc(S(=O)(=O)c3ccccc3)c12
Temperature: 70 °C
Yield: 84.9 %

Procedure:
To a solution of 3-phenylsulfonyl-4-(3-chloro-propyl)-1H-indole (0.255 g, 0.76 mmol) in anhydrous dioxane (5 mL) was added isopropylamine (0.65 mL, 7.64 mmol) and the reaction mixture heated to 70° C. in a sealed vessel for 7 days. The cooled reaction mixture was then diluted with 1 N aqueous NaOH (50 mL) and the resulting milky suspension extracted with ethyl acetate (50 mL). The organic phase was separated, washed with water (50 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford a yellow foam. Purification by flash chromatography (0 to 10% ammonia saturated methanol/dichloromethane) afforded N-isopropyl-3-[3-(phenylsulfonyl)-1H-indol-4-yl]propan-1-amine as a yellow foam (0.23 g, 86%). The product was dissolved in absolute ethanol (10 mL), 1.25 N HCl in ethanol (0.78 mL, 0.98 mmol, 1.5 equivalents) added, the mixture stirred for 15 min and then concentrated in vacuo to afford a yellow foam. The product was crystallized from 1:1 v/v ethanol:tert-butyl methyl ether (10 mL) to give the title compound as white crystals (0.172 g, 57%). MS (ES+) m/z 357.3 (M+H).