Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H][H]>C1COCC1.[Pd]>[F:1][C:2]1[C:7]([CH:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1ncccc1C1=CCC2(CC1)OCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Fc1ncccc1C1CCC2(CC1)OCCO2
Temperature: 40 °C
Reaction time: 5 h

Procedure:
To a solution of 2-fluoro-3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine (7.99 g, 34.0 mmol) in THF (40 mL) under argon atmosphere was added palladium on carbon (10% activated, 0.80 g). The mixture was placed under 1 atmosphere of hydrogen and stirred for 5 h at 40° C. After placing the mixture back under argon atmosphere, the mixture was filtered through celite and the filtrate was concentrated in vacuo to give 2-fluoro-3-(1,4-dioxaspiro[4.5]decan-8-yl)pyridine MS (ESI, pos. ion) m/z: 238.1.
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:24]=[C:23]2[C:25]3[C:19]([CH3:26])([CH2:20][CH2:21][CH2:22]2)[CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][N:2]([C:13]1[CH:24]=[C:23]2[C:25]3[C:19]([CH3:26])([CH2:20][CH2:21][CH2:22]2)[CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=1)[C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(N(C)c2cc3c4c(c2)CCCC4(C)CCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(c1ccc(C(=O)O)cc1)c1cc2c3c(c1)CCCC3(C)CCC2
Temperature: 50 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A suspension of methyl 4-[N-methyl-(6a-methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)amino]benzoate (0.031 g) in ethanol (10 ml) was added with 20% aqueous sodium hydroxide (2 ml), and the mixture was stirred overnight at 50° C. The reaction mixture was left to cool and then made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethanol to obtain the title compound (0.027 g, yield: 90%) as colorless needles (melting point: 257-258° C.).
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[CH:8]=[C:9]([C@@H:18]([CH3:23])[C:19]([O:21]C)=[S:20])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:6])([CH3:5])[CH3:4].Cl>O.O1CCCC1>[C:14]([C:11]1[CH:10]=[C:9]([C@@H:18]([CH3:23])[C:19]([OH:21])=[S:20])[CH:8]=[C:7]([C:3]([CH3:5])([CH3:4])[CH3:6])[C:12]=1[OH:13])([CH3:15])([CH3:16])[CH3:17]
Reactant: COC(=S)[C@H](C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](C(O)=S)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 4.5 g (80 mmol) of potassium hydroxide in water (200 mL) and tetrahydrofuran (200 mL) was added 21.46 g (70 mmol) of methyl (2R)-2-(3,5-di-t-butyl-4-hydroxyphenyl)thiopropanoate (31). The reaction mixture was allowed to stir overnight at room temperature. The reaction solution was acidified to pH 1.2 with concentrated hydrochloric acid and and extracted with t-butyl methyl ether (3×100 mL). The combined extracts were washed with an aqueous saturated sodium chloride solution (1×300 mL) and dried (MgSO4). Filtration, concentration and recrystallization from hexane and ethyl acetate afforded 18.35 g (90%) of (2R)-2-(3,5-di-t-butyl-4-hydroxyphenyl)thiopropanoic acid (32) as a white crystalline material: m.p. 111°-112° C.; 1H NMR (CDCl3) δ1.33-1.46 (m, 21 H), 3.58-3.65 (q, J=7.1 Hz, 1 H), 5.34 (s, --OH, 1 H), 7.33 (s, 2 H), 9.12 (b, --CO2H, 1 H); 13C NMR (CDCl3) δ178.8, 154.8, 136.7, 131.8, 121.6, 46.0, 34.4, 30.2, 17.1; IR (KBr) 3608 (s), 3570 (s), 2960 (vs), 1692 (vs), 1424 (vs), 1287 (s), 1239 (vs), 1121 (vs), 884 (s), 774 (w) cm-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:25])(=[O:24])[NH:11][C@H:12]([C:21](=[O:23])[NH2:22])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([O:26]CC2C=CC=CC=2)[CH:5]=1>CCO.[Pd]>[CH3:1][O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:24])(=[O:25])[NH:11][C@H:12]([C:21](=[O:23])[NH2:22])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([OH:26])[CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(O)c1

Procedure:
A solution of 3-benzyloxy-4-((S)-2-tert-butoxycarbonyl-1-carbamoyl-ethylsulfamoyl)-benzoic acid methyl ester (7.40 g, 15.0 mmol) in EtOH (100 mL) was shaken with 20% Pd/C (1.0 g) under H2 (50 psi) for 1.5 h using a Parr apparatus. The reaction mixture was filtered through celite and concentrated. 4-((S)-2-tert-Butoxycarbonyl-1-carbamoyl-ethylsulfamoyl)-3-hydroxy-benzoic acid methyl ester was obtained (6.03 g, 99%) as an off white foam. MS m/z 401.2 (M−1).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([F:39])[CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:35]3[CH:34]=[C:33]([F:32])[CH:38]=[C:37]([F:39])[CH:36]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cc(F)cc(F)c1)N1CCN(C2CCC2)CC1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3,5-difluorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (69%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:13]=[N:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]2[N:13]=[N:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: N#Cc1ccc(NC2CCNCC2)nn1
Reactant: Clc1cccc(CBr)c1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC2CCN(Cc3cccc(Cl)c3)CC2)nn1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 39.2 %

Procedure:
A mixture of 6-(piperidin-4-ylamino)-pyridazine-3-carbonitrile (D3) (0.150 g, 0.74 mmol), 3-chlorobenzyl bromide (0.102 ml, 0.78 mol) and diisopropylethylamine (0.196 ml, 1.11 mol) in acetonitrile (2 ml) was stirred at 120° C. for 5 min., under microwave irradiation (Biotage MW-oven). The reaction mixture was then diluted with dichloromethane and extracted with a saturated solution of sodium carbonate. The organic layers were separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was then purified by column chromatography (silica gel; 0-2.5% ammonia in methanol (7 M)/dichloromethane). The desired fractions were collected and evaporated in vacuo, and the residue triturated with diisopropylether to yield E13 (0.095 g, 39%) as a white solid. C17H18ClN5 requires 327. Found 328 (MH+); mp: 151° C.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)=[CH:20][C:21]=1[CH2:22][CH3:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:22]([C:21]1[CH:20]=[C:19]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)[S:18][C:17]=1[C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])[C:3]([OH:37])=[O:2])=[O:16])[CH3:23]
Reactant: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (S)-2-({3-Ethyl-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (28.0 mg, 0.052 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (22 mg, 2.0 mmol) in water (5 mL). The mixture was then stirred at room temperature 2 d. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 19.2 mg (70%). MS m/e 525.9 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.BrC1C(N2CCN([S:52]([CH3:55])(=[O:54])=[O:53])CC2)=C([N+]([O-])=O)C(N)=NC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CN(C1C=CC(C=O)=CC=1)C>C(O)C.CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2nc3c(N4CCN(S(C)(=O)=O)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 39 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-4-(4-(methylsulfonyl)piperazin-1-yl)-3-nitropyridin-2-amine (100 mg, 0.26 mmol), DMF (1.6 mL), ethanol (0.2 mL), 1M Na2S2O4 (4 eq, 1.05 mmol, 1.05 mL) and 4-(N,N-dimethylamino)benzaldehyde (1.1 eq, 0.29 mmol, 43 mg). After 6 h, filtration of the precipitate and washing with cold ethanol (1 mL) and cold water (1 mL) gave the product (49 mg, 39%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 2.97 (s, 3H, SO2CH3), 3.01 (s, 6H, N(CH3)2), 3.34-3.38 (m, 4H, piperazine N(CH2)2), 3.70-3.73 (m, 4H, piperazine N(CH2)2), 6.83 (d, J=9.0 Hz, 2H, N,N-dimethylaminophenyl) 8.05 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 8.21 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.21 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]([CH3:28])[CH2:26][OH:27]>>[OH:27][CH2:26][CH:25]([NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)[CH3:28]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(N)CO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC(C)CO)cn1
Yield: 89 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (150 mg, 0.5 mmol) was converted, using rac-2-amino-1-propanol instead of methylamine, to the title compound (158 mg, 89%) which was obtained as a white solid. MS: m/e=368.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C=O)C>[CH2:22]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: COC(=O)CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN(CC(=O)OC)Cc1ccccc1
Reaction time: 4 h
Yield: 70 %

Procedure:
To a solution of methyl 2-(benzylamino)acetate (21.30 g, 119.2 mmol, 1.0 eq) in DMF (150 mL) was added anhydrous K2CO3 (8.02 g, 143.02 mmol, 1.2 eq) followed by allyl bromide (12.37 mL, 143.02 mmol, 1.2 eq) at room temperature. The mixture was stirred for 4 h, quenched with water and extracted with EtOAc (100 mL×3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) PE/EtOAc) to afford the title compound as colorless oil (18.30 g, 70%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ: 3.27 (2H, d, J=6.4 Hz), 3.32 (2H, s), 3.68 (3H, s), 3.78 (2H, s), 5.19 (2H, m), 5.88 (1H, m), 7.23-7.35 (5H, m) ppm.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[C:3]1=[O:20]
Reactant: CC(C)(C)N=C=O
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)NC(C)(C)C)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and t-butylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 281°-282° C.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[C:12]([CH2:13]Cl)=[N:11][C:10]([C:15]([OH:17])=[O:16])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[N:21]1[C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]2[N:9]=[C:10]([C:15]([OH:17])=[O:16])[N:11]=[C:12]2[CH2:13]1
Reactant: O=C(O)c1nc(CCl)n(-c2cccnc2Cl)n1
Reactant: Nc1ccccc1Cl
Product: O=C(O)c1nc2n(n1)-c1cccnc1N(c1ccccc1Cl)C2

Procedure:
using 31.40 g (0.115 mol) of 1-(2-chloro-3-pyridyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid and 206.00 g (1.61 mol) of 2-chloroaniline there is obtained 5-(2-chlorophenyl)-4,5-dihydropyrido[2,3-e][1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid and the methyl ester thereof which, after recrystallisation from methylene chloride/isopropanol, melts at 155°-163°;
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[N:12][N:13]([CH2:15][C:16](OC)=[O:17])[CH:14]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[BH4-].[Na+].O>CO.C1COCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[N:12][N:13]([CH2:15][CH2:16][OH:17])[CH:14]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[S:27][CH:28]=2)[N:3]=1
Reactant: COC(=O)Cn1cc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cnn(CCO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
80 mg (0.153 mmol) of the compound from Example 19A were initially charged in 3 ml of methanol and 3 ml of THF, and 17 mg (0.460 mmol) of sodium borohydride were added. The reaction mixture was stirred at RT for 1 h, another 17 mg (0.460 mmol) of sodium borohydride were then added and the mixture was stirred at RT for 1 h. A little water was added to the reaction, and the product was purified directly by preparative HPLC (acetonitrile/water 10:90→95:5, 0.1% TFA added).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH:18]1[CH2:23][CH2:22][C:21]([N:25]([CH2:29][CH:30]=[CH2:31])[CH2:26][CH:27]=[CH2:28])([CH3:24])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([O:48][CH3:49])[C:34]=1[OH:50]>>[Cl:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][CH:18]2[CH2:19][CH2:20][C:21]([N:25]([CH2:26][CH:27]=[CH2:28])[CH2:29][CH:30]=[CH2:31])([CH3:24])[CH2:22][CH2:23]2)[CH:36]=[C:35]([O:48][CH3:49])[C:34]=1[OH:50]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: C=CCN(CC=C)C1(C)CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: C=CCN(CC=C)C1(C)CCC(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(OC)c4)cc23)CC1
Yield: 35.3 %

Procedure:
Following general procedure F, {6-Bromo-4-[4-(diallylamino)-4-methylcyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (120 mg, 0.248 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (105 mg, 0.372 mmol) to afford the crude product (49 mg) as a brown-green solid: ESI MS m/z 560 [C33H38ClN3O3+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@H:5]2[CH2:4][N:3]1[CH2:11][C:12]([CH3:17])(C)[C:13]([OH:15])=[O:14].N[C@@H:19]1CCC[C@H:20]1C(OCC)=O>>[O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@H:5]2[CH2:4][N:3]1[C@@H:11]1[CH2:20][CH2:19][CH2:17][C@H:12]1[C:13]([OH:15])=[O:14]
Reactant: CC(C)(CN1C[C@@H]2CNCCN2C1=O)C(=O)O
Reactant: CCOC(=O)[C@@H]1CCC[C@H]1N
Product: O=C(O)[C@@H]1CCC[C@H]1N1C[C@@H]2CNCCN2C1=O

Procedure:
Compound 49-A was prepared in analogy to compound Q in Example 19 by using ethyl (1R,2R)-2-aminocyclopentanecarboxylate (Accela Chembio Co., Ltd, SY024586) instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[Cl:17][S:18]([OH:21])(=O)=[O:19]>>[CH3:1][N:2]1[C:15]2[C:10](=[CH:11][C:12]([S:18]([Cl:17])(=[O:21])=[O:19])=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]2[CH:7]=[C:6]([S:18]([Cl:17])(=[O:21])=[O:19])[CH:5]=[CH:4][C:3]1=2
Reactant: Cn1c2ccccc2c(=O)c2ccccc21
Reactant: O=S(=O)(O)Cl
Product: Cn1c2ccc(S(=O)(=O)Cl)cc2c(=O)c2cc(S(=O)(=O)Cl)ccc21
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture of 10-methylacridin-9(10H)-one (4.2 g, 20 mmole) and chlorosulfonic acid (100 mL, 1.5 mole) was heated at reflux for 5 hours. Reaction mixture was then condensed, cooled down to room temperature and poured carefully on 500 g of ice. The yellow precipitate of product was collected by filtration, washed with water and dried to provide 8.1 g of the title compound. This material was used for next step without purification.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[N:43]=[CH:42][C:41]([NH2:44])=[CH:40][N:39]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH2:34][N:35]([C:38]2[N:43]=[CH:42][C:41]([NH:44][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:40][N:39]=2)[CH2:36][CH2:37]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(N)cn2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a suspension of 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (771 mg, 3 mmol) in methylene chloride (10 mL) was added oxalyl chloride (2M, 3 mL, 6.0 mmol) and one drop of N,N-dimethylformamide. The mixture was stirred at room temperature for 1 hr and the solvents were evaporated. The residue was treated with benzene (5 mL) and the solvents were again evaporated. The oily residue was dried in vacuum and then dissolved in methylene chloride (10 mL). The solution was cooled in an ice bath. To this solution was added a methylene chloride solution of 4-(5-amino-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (3 mmol) and pyridine (0.73 mL). The mixture was stirred at 0° C. for 10 minutes and room temperature for 2 hrs. After concentration, the residue was partitioned between methylene chloride and water. The organic layer was washed with aqueous citric acid solution and dried over sodium sulfate. The solvents were evaporated and the residue was dried in vacuum. The resulting material was triturated with ethyl acetate and the precipitate was filtered to give 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (1.38 g). LC-MS calcd for C24H25F3N6O4 (m/e) 518.5, obsd 519.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [C:1]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].ClC(OCC)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>>[F:26][C:25]([F:27])([F:28])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:9]([C:6]2([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7][CH2:8]2)=[O:11])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1(C(=O)O)CC1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Yield: 50 %

Procedure:
1-Carboethoxycyclopropanecarboxylic acid (9.81 grams, 0.06 mole), ethyl chloroformate (6.73 grams, 0.06 mole) and 4-aminobenzotrifluoride (10.0 grams, 0.06 mole) were reacted sequentially in the presence of triethylamine (6.28 grams, 0.06 mole) in a manner similar to that described in Example XXXIII to give 10.25 grams (0.03 mole) of ethyl 1-(4-trifluoromethylphenylaminocarbonyl)cyclopropanecarboxylate having a melting point of 80.5° C.-82.0° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:19][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:11]=2)[NH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc2[nH]cc(Cl)c2c1
Reaction time: 0.5 h

Procedure:
To a solution of 5-(t-butoxycarbonylaminomethyl)-indole (0.51 g, 2.05 mmol) in CH2Cl2, (12 mL) under Argon at 15°-20° C. was added N-chlorosuccinimide (0.245 g, 1.82 mmol) portionwise over 1 hr. The reaction stirred 0.5 h and was partitioned with H2O and CH2Cl2. The aquesous layer was extracted with CH2Cl2 (2×), dried over MgSO4, filtered, and concentrated in vacuo to a brown residue. Purification via flash chromatography (25×150 mm column; gradient elution with EtOAc: hexanes, 1:4 to 1:3) yielded a colorless oil: