Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[C:11]([OH:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:20]([O-:22])=[O:21])[CH:9]=2)[N:4]=[CH:3]1.[C:23]1(=[O:37])[N:27]([CH2:28][C:29](Cl)=[O:30])[C:26](=[O:32])[C:25]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:24]12>N1C=CC=CC=1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([C:10]1[CH:9]=[C:8]([N+:20]([O-:22])=[O:21])[CH:7]=[CH:6][C:5]=1[N:4]([CH:3]=[N:2][NH:1][C:29](=[O:30])[CH2:28][N:27]1[C:23](=[O:37])[C:24]2[C:25](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:26]1=[O:32])[C:29](=[O:30])[CH2:28][N:27]1[C:26](=[O:32])[C:25]2[C:24](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:23]1=[O:37])=[O:19]
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: NN1C=Nc2ccc([N+](=O)[O-])cc2C1(O)c1ccccc1Cl
Solvent: c1ccncc1
Product: O=C(CN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1, 3-amino-6-nitro-3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline with pyridine is reacted with α-phthalimidoacetyl chloride to give 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-nitrophenyl]-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1ccc(Cl)cc1C(=O)c1cnccn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cnccn2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 117 mg of (2-Amino-5-chloro-phenyl)-pyrazin-2-yl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1N-NMR (400 MHz, CDCl3): δ 1.24 (s, 9H), 7.38 (dm, 2H, J=6.8 Hz), 7.50 (dd, 1H, J=9.2 Hz, 1.6 Hz), 7.70 (m, 2H), 7.76 (m, 1H), 7.80 (m, 1H), 8.62 (m, 1H), 8.77 (m, 1H), 9,06 (m, 1H), 10.37 (s, 1H). MS: m/z 430.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[C:33]([C:35]([NH:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[CH:40]=2)=[O:36])[CH:32]=[CH:31][C:3]=1[C:4]([NH:6][C@H:7]([C:27]([O:29][CH3:30])=[O:28])[CH2:8][NH:9]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)=[O:5].N1CCCCC1>ClCCl.CO>[NH2:9][CH2:8][C@@H:7]([C:27]([O:29][CH3:30])=[O:28])[NH:6][C:4](=[O:5])[C:3]1[CH:31]=[CH:32][C:33]([C:35]([NH:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[CH:40]=2)=[O:36])=[CH:34][C:2]=1[Cl:1]
Reactant: COC(=O)[C@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](CN)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
A solution of N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester (1.17 g, 1.9 mmol) in dichloromethane/methanol (2:1) was added to piperidine (1.1 mL, 11.2 mmol). The reaction mixture was stirred for 4 h at room temperature and then more piperidine (1.1 mL, 11.2 mmol) was added. The solution was stirred at room temperature overnight, then it was concentrated and the residue was chromatographed (0–40% methanol/dichloromethane) to give 3-amino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester (760 mg, 100%) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]4[C:20]([C:23]5[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=5)=[CH:21][N:22]=[C:16]4[CH:15]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.CN(C)N>CO.[Fe](Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]4[C:20]([C:23]5[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=5)=[CH:21][N:22]=[C:16]4[CH:15]=3)=[CH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ncc(-c3ccn4c(-c5ccc([N+](=O)[O-])cc5)cnc4c3)cn2)CC1
Agent: Cl[Fe](Cl)Cl
Agent: CN(C)N
Solvent: CO
Product: CN1CCN(c2ncc(-c3ccn4c(-c5ccc(N)cc5)cnc4c3)cn2)CC1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
Combine 7-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-3-(4-nitro-phenyl)-imidazo[1,2-a]pyridine (0.318 g, 0.765 mmol), iron(III) chloride (0.006 g, 0.038 mmol), and 1,1-dimethylhydrazine (0.58 mL, 7.65 mmol) in methanol (10 mL). Attach a reflux condenser, and heat the mixture to 70° C., stir overnight (15 hours), and cool to room temperature. Slurry the mixture into additional methanol and filter through Celite® 521. Concentrate the solution in vacuo. Purify by column chromatography (ethyl acetate→5% methanol in dichloromethane→8% methanol in dichloromethane→10% methanol in dichloromethane) to afford a yellow solid intermediate amine, 4-{7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-imidazo[1,2-a]pyridin-3-yl}-phenylamine. Use as is. MS(ES), m/z 386 (M+1).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1>>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH:13]=1
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: OB(O)c1cccnc1
Product: Nc1nc2c(-c3cccnc3)cccn2n1

Procedure:
8-Pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.0 g, 4.7 mmol) and 3-pyridylboronic acid (0.81 g, 6.6 mmol) in a manner analogous to Step 2c. The product of the reaction was isolated as a white solid (0.92 g, 93%). MP=185-187° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.28 (d, J=2.1 Hz, 1H), 8.62-8.58 (m, 2H), 8.49 (ddd, J=8.1, 1.8, 1.8 Hz, 1H), 7.82 (dd, J=7.4, 0.7 Hz, 1H), 7.53 (dd, J=8.0, 4.7 Hz, 1H), 7.01 (t, J=7.0 Hz, 1H), 6.18 (br s, 2H). MS=212 (MH)+. 6b) (4-Morpholin-4-yl-phenyl)-(8-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine and phenyl-(8-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine were prepared from 8-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (70.0 mg, 0.331 mmol) and 4-(4-bromo-phenyl)-morpholine (100.0 mg, 0.4130 mmol) in a manner analogous to Example 2d. (4-Morpholin-4-yl-phenyl)-(8-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine was isolated as a yellow solid (0.025 g, 20%). MP=226-228° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.16 (d, J=1.9 Hz, 1H), 8.66 (dd, J=4.8, 1.4 Hz, 1H), 8.46-8.41 (m, 2H), 7.61 (dd, J=7.4, 1.1 Hz, 1H), 7.54-7.49 (m, 2H), 7.45 (dd, J=7.9, 4.8 Hz, 1H), 7.00-6.93 (m, 3H), 6.69 (s, 1H), 3.90-3.86 (m, 4H), 3.14-3.09 (m, 4H). MS=373 (MH)+.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Br:11][C:12]1[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=1>O1CCCC1>[Br:11][C:12]1[N:17]=[C:16]([NH:18][CH:5]=[O:7])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(Br)n1
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CNc1cccc(Br)n1
Temperature: 55 °C
Reaction time: 0.75 h

Procedure:
To acetic anhydride (1.5 mL) was added dropwise formic acid (0.73 mL) under ice-cooling, and the mixture was stirred at 55° C. for 45 min. The mixture was allowed to be warmed to room temperature, tetrahydrofuran (20 mL) was added thereto, and a solution of 6-bromopyridin-2-amine (1.00 g) in tetrahydrofuran (10 mL) was added dropwise thereto over 3 min under ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure, and the obtained white solid was subjected to azeotropy with toluene, and washed with hexane to give the title compound (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:11]=[C:10]([N:25]3[C:29](=[O:30])[CH2:28][CH2:27][C:26]3=[O:31])[N:9]=2)[CH:7]=1.[O:33]1CCCC1.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[N:11]=[C:10]([NH:25][C:26](=[O:31])[CH2:27][CH2:28][C:29]([OH:30])=[O:33])[N:9]=2)[CH:7]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(C(F)(F)F)cc2)nc(N2C(=O)CCC2=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(C(F)(F)F)cc2)nc(NC(=O)CCC(=O)O)n1
Reaction time: 1 h

Procedure:
To a stirred solution of 1-[4-(5-chloro-2-methyl-phenyl)-6-(4-trifluoromethyl-phenylamino)-pyrimidin-2-yl]-pyrrolidine-2,5-dione (0.15 g, 0.33 mmol), tetrahydrofuran (15 ml), and water (15 ml), cooled in an ice bath, was added aqueous sodium hydroxide solution (0.25 M, 4.0 ml, 1.0 mmol) dropwise. After stirring for 1 hour, hydrochloric acid (0.25 M, 8.0 ml, 2.0 mmol) was added dropwise. Evaporation of the tetrahydrofuran under reduced pressure and filtration provided the title compound as hydrochloride salt (93% yield). 1H NMR (CD3OD) δ 2.48 (s, 3H, CH3), 2.73-2.76 (m, 2H, CH2), 2.89-2.92 (m, 2H, CH2), 6.81 (s, 1H, Ar), 7.45 (d, 1H, J=8.3 Hz, Ar), 7.54 (dd, 1H, J=8.3 Hz, J=2.2 Hz, Ar), 7.60 (d, 1H, J=2.2 Hz, Ar), 7.76 (d, 2H, J=8.6 Hz, Ar), 8.04 (d, 2H, J=7.9 Hz, Ar).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[N:18]=1.[H-].[Na+].[N:21]1([CH2:26][CH2:27][CH2:28]Cl)[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[N:7]([CH2:28][CH2:27][CH2:26][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:6]=2[N:18]=1
Reactant: Cc1ccc2c(n1)Nc1ccccc1N(C)C2=O
Reactant: ClCCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)N(CCCN1CCCC1)c1ccccc1N(C)C2=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture consisting of 7.2 gm of 6,11-dihydro-2,6-dimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 1.9 gm of 50% sodium hydride in mineral oil and 100 ml of dimethyl formamide was stirred at 60°-70° C. for 45 minutes. Thereafter, the mixture was cooled to room temperature, 7.4 gm of 3-pyrrolidino-propyl chloride were added dropwise and the mixture was refluxed for 3 hours. The solvent was then distilled off in vacuo, and the residue was recrystallized twice from acetonitrile, yielding 46% of theory of the compound named in the heading, which had a melting point of 134°-136° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].CO.[BH4-].[Na+].Cl>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:10][OH:11])[CH:12]=[CH:13][CH:14]=1
Reactant: COCCCCc1cccc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COCCCCc1cccc(CO)c1
Reaction time: 1 h

Procedure:
To a solution of the title D compound, 3-(4-methoxy-butyl)-benzaldehyde (0.1 g, 0.52 mmol) and MeOH (0.063 mL, 1.56 mmol) in 2 mL of THF is added portion wise sodium borohydride (20 mg, 0.52 mmol). The reaction mixture is stirred for 1 hour at room and poured into aqueous 1M HCl. The aqueous layer is extracted twice with ethyl acetate and the combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (hexane/EtOAc 3/1) to afford the title compound as a colorless oil: TLC, Rf (hexane/AcOEt 2/1)=0.34. MS 212.1 [M+18].
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:17])[NH:13][C:12](=O)[C:11]([CH3:19])=[N:10]2>CN(C)C1C=CN=CC=1>[Cl:3][C:12]1[C:11]([CH3:19])=[N:10][C:9]2[C:14](=[CH:15][C:16]([Cl:17])=[C:7]([Cl:6])[CH:8]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2cc(Cl)c(Cl)cc2[nH]c1=O
Agent: CN(C)c1ccncc1
Product: Cc1nc2cc(Cl)c(Cl)cc2nc1Cl

Procedure:
POCl3 was added to 6,7-Dichloro-3-methyl-1H-quinoxalin-2-one (10 g, 44 mmol) and 4-dimethylaminopyridine (1 g) and the mixture was refluxed for 0.5 hours. After cooling, the mixture was poured onto ice (500 ml), filtered and washed with water to afford the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]2[CH:18]=[C:17]([CH2:19][CH2:20][CH:21]=O)[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:21][CH2:20][CH2:19][C:17]2[O:16][N:15]=[C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[CH:18]=2)[CH2:33][CH2:32]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCCc1cc(-c2cccc(Oc3ccccc3)c2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCc2cc(-c3cccc(Oc4ccccc4)c3)no2)CC1
Yield: 81.6 %

Procedure:
About 2 min after dissolving 3-[3-(3-phenoxyphenyl)isoxazol-5-yl]propanal (10 mg, 0.03 mmol) and 1-(2-methoxyphenyl)piperazine (13.2 mg, 0.07 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (22 mg, 0.10 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 18.5 hr and followed the same processes as in Example 1 to obtain 11.5 mg (71.8%) of the target compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]([OH:16])=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[N:39]=[CH:38][C:37]([C:43]#[N:44])=[C:36]2[NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([Br:52])[CH:47]=1.C([O-])(O)=O.[Na+]>C1COCC1.N1C=CC=CC=1>[Br:52][C:48]1[CH:47]=[C:46]([NH:45][C:36]2[C:35]3[C:40](=[CH:41][CH:42]=[C:33]([NH:32][C:14](=[O:16])[C:13]#[C:12][CH2:11][N:8]4[CH2:7][CH2:6][C:5]5([O:1][CH2:2][CH2:3][O:4]5)[CH2:10][CH2:9]4)[CH:34]=3)[N:39]=[CH:38][C:37]=2[C:43]#[N:44])[CH:51]=[CH:50][CH:49]=1
Reactant: O=C(O)C#CCN1CCC2(CC1)OCCO2
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: N#Cc1cnc2ccc(NC(=O)C#CCN3CCC4(CC3)OCCO4)cc2c1Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
To an ice cold solution of 1.75 g (7.78 mmol) of 4-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)but-2-ynoic acid in 100 mL of THF under N2 was added 0.942 g (9.33 mmol) of N-methylmorpholine followed by 0.852 g (6.22 mmol) of isobutyl chloroformate. After stirring in the cold for 30 min, a solution of 1.05 g (3.11 mmol) of 6-amino-4-[(3-bromophenyl)amino]-quinoline-3-carbonitrile in 8 mL of pyridine was added dropwise. After stirring in the cold for 5 h, the reaction was poured into ice water and satd NaHCO3 was added. The mixture was extracted with ethyl acetate and the extracts were dried and evaporated. Chromatography of the residue on silica gel (20% methanol in ethyl acetate) gave 0.590 g of 4-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)but-2-ynoic acid[4-(3-bromophenylamino)-3-cyanoquinol-6-yl]amide as a brown foam: mass spectrum (electrospray, m/e): M+H 546.0, 548.1.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH:9]2[CH2:18][CH2:17][C:12]3([O:16]CCO3)[CH2:11][CH2:10]2)[C:6]([CH3:19])=[CH:5][C:3]=1[NH2:4].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[C:24]([C:34]([F:37])([F:36])[F:35])=[CH:23][N:22]=1.Cl.CO>CC(O)C>[F:1][C:2]1[C:3]([NH:4][C:21]2[N:26]=[C:25]([NH:27][C:28]3[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=3)[C:24]([C:34]([F:35])([F:37])[F:36])=[CH:23][N:22]=2)=[CH:5][C:6]([CH3:19])=[C:7]([CH:9]2[CH2:10][CH2:11][C:12](=[O:16])[CH2:17][CH2:18]2)[CH:8]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2C(F)(F)F)n[nH]1
Reactant: Cc1cc(N)c(F)cc1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=O)CC4)cc3F)ncc2C(F)(F)F)n[nH]1
Temperature: 125 °C

Procedure:
A mixture of 2-fluoro-5-methyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline (318.6 mg, 1.2 mmol), 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine (333.0 mg, 1.2 mmol) and HCl (4 N in water, 0.3 mL, 1.2 mmol) in i-PrOH (4.0 mL) was heated at 125° C. in an oil bath overnight. The reaction mixture was concentrated in vacuo. The resulting crude mixture was dissolved in THF (4 mL), MeOH (2 mL) and HCl (4N in water, 0.3 mL, 1.2 mmol), and stirred at room temperature for an additional 2 h. The reaction mixture was concentrated in vacuo, and purified by silica chromatography (0-100% EtOAC in hexanes gradient) to afford 4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone; ESMS m/z 463.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5](C[CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.C([OH:18])C>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[O:18][CH2:7][CH2:8][CH:9]2[OH:12]
Reactant: O=C1CCCc2ccc(Br)cc21
Reactant: CCO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: OC1CCOc2ccc(Br)cc21

Procedure:
To a suspension of 7-bromo-3,4-dihydronaphthalen-1(2H)-one (3.95 kg, 17.4 mol) in ethanol (20 L) at room temperature add sodium borohydride (221 g, 5.84 mol) in portions over 3 hr. Concentrate the clear red solution. Add the residue into ice (about 3 kg) to form a suspension and then slowly add ice-cooled 0.5 M HCl (10 L) into the above suspension with stirring. Extract the mixture with methyl tert-butyl ether (20 L and 5 L). Wash the combined organic phase with saturated aqueous sodium bicarbonate (10 L) and brine (2×10 L), concentrate the solvent under reduced pressure and dry the wet solid in air overnight to obtain the title compound as a pale yellow solid (4.10 kg, quantitative). LC-ES/MS m/z 211 [M−H-2O+H]+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:8]([NH2:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].CCN(CC)CC.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:2][C@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[C:8]([NH2:10])=[O:9])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CC(C)C[C@@H](N)C(N)=O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
To a solution of (D)-leucinamide hydrochloride (0.25 g, 1.5 mmol), and Et3N (0.43 mL, 3.0 mmol) in CH2Cl2 (150 mL) was added 4-chlorobenzenesulfonyl chloride (380 mg, 1.8 mmol). The resulting solution was stirred at rt for 18 h. The reaction was then diluted with CH2Cl2 (200 mL) and washed with H2O, 0.5 N HCl, brine, and dried over MgSO4, to afford the titled compound (410 mg) as a white solid in 90% yield. MS (ESI), (M+H)+ 305.2; 1H NMR (DMSO-d6) δ 7.77 (d, 2H, J=8.7), 7.62 (d, 2H, J=8.7), 6.90 (br s, 1H), 3.67 (m, 1H), 1.54 (m, 1H), 1.31 (m, 2H), 0.81 (d, 3H, J=7.0), 0.71 (d, 3H, J=7.0).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][C:11]([O:13]C)=O)[NH2:9])=[CH:4][CH:3]=1.[CH3:15][N:16]=[C:17]=[O:18].C[O-].[Na+]>C(#N)C>[CH3:15][N:16]1[C:11](=[O:13])[CH2:10][N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[NH:9][C:17]1=[O:18]
Reactant: CN=C=O
Reactant: COC(=O)CN(N)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(N2CC(=O)N(C)C(=O)N2)cc1

Procedure:
To a solution of methyl [1-(4-methylphenyl)hydrazino]acetate (2.25 g) in acetonitrile (10 ml) was added methyl isocyanate (2 ml) and the mixture was heated under reflux for 30 min. The solvent was removed in vacuo to give a solid which was treated with a solution of sodium methoxide (27 ml; from sodium (4 g) and methanol (200 ml)) according to the method of Example 3 to give a solid which was purified by trituration with System A (1:1) to give the title compound (1.51 g), m.p. 193°-194°, t.l.c. (ether) Rf 0.56.
Reaction SMILES: [CH2:1]([CH:4]1[C:9](=O)[CH2:8][CH2:7][S:6][CH2:5]1)[CH2:2][CH3:3].Cl.[NH2:12][OH:13]>>[N:12](=[C:9]1[CH2:8][CH2:7][S:6][CH2:5][CH:4]1[CH2:1][CH2:2][CH3:3])[OH:13]
Reactant: NO
Reactant: CCCC1CSCCC1=O
Agent: Cl
Product: CCCC1CSCCC1=NO

Procedure:
Employing the procedure described in Example 2, step A, 3-propyl-tetrahydrothiopyran-4-one was reacted with hydroxylamine hydrochloride to form 4-oximino-3-propyl-tetrahydrothiopyran and was used directly in the subsequent reaction.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[CH:48][C:6]=1[CH2:7][N:8]([C:43]1[S:47][N:46]=[CH:45][N:44]=1)[S:9]([C:12]1[C:41]([F:42])=[CH:40][C:15]2[N:16]([C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3(O)[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]3)[CH3:21])[C:17](=[O:19])[O:18][C:14]=2[CH:13]=1)(=[O:11])=[O:10].CCN(S(F)(F)[F:60])CC>C(Cl)Cl>[CH3:3][O:4][C:5]1[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[CH:48][C:6]=1[CH2:7][N:8]([C:43]1[S:47][N:46]=[CH:45][N:44]=1)[S:9]([C:12]1[C:41]([F:42])=[CH:40][C:15]2[N:16]([C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3([F:60])[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]3)[CH3:21])[C:17](=[O:19])[O:18][C:14]=2[CH:13]=1)(=[O:10])=[O:11]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4ccccc4C4(O)CN(C(=O)OC(C)(C)C)C4)c3cc2F)c(OC)c1
Reactant: CCN(CC)S(F)(F)F
Agent: N#N
Solvent: ClCCl
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4ccccc4C4(F)CN(C(=O)OC(C)(C)C)C4)c3cc2F)c(OC)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In an oven-dried 2 dram vial under N2, added (R)-tert-butyl 3-(2-(1-(6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)ethyl)phenyl)-3-hydroxyazetidine-1-carboxylate (32-3, 55.8 mg, 0.075 mmol) to DCM (376 μl) and cooled to −78° C. Added DAST (19.88 μl, 0.150 mmol) dropwise. After 30 min at −78° C., removed from bath and allowed to slowly warm to RT. After 20 min, LCMS showed complete consumption of SM to desired product. Cooled reaction to 0° C., slowly quenched with 3 mL H2O. Diluted with 5 mL DCM, separated layers, back-extracted aqueous with 1×5 mL DCM. Washed combined organics with 1×5 mL H2O, 1×5 mL brine. Dried combined organics over Na2SO4, filtered, concentrated to give 32-5 as a white solid. Carried crude material forward to subsequent step.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([F:25])[F:24])=[CH:18][CH:17]=2)[CH2:13][CH:12]([C:26]([O:28]C)=[O:27])[CH2:11]1)(=[O:9])[CH3:8]>CO>[C:7]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([F:24])[F:25])=[CH:18][CH:17]=2)[CH2:13][CH:12]([C:26]([OH:28])=[O:27])[CH2:11]1)(=[O:9])[CH3:8]
Reactant: COC(=O)C1CC(c2ccc(CC(F)F)cc2)CN(C(C)=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)N1CC(C(=O)O)CC(c2ccc(CC(F)F)cc2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
410 mg (3.65 mmol) of potassium tert-butoxide were added at RT to a solution of 205 mg (0.365 mmol, purity 61%) of the compound from Example 58A in methanol (6.9 ml). The mixture was stirred at 60° C. overnight. For workup, the methanol was removed under reduced pressure, the residue was admixed with water and the mixture was acidified (pH 1) with aqueous 1 N hydrochloric acid solution. The mixture was extracted with ethyl acetate, and the organic phase was dried with magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 153 mg (67% of theory, purity 50%)
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([Cl:22])[CH:24]=3)[CH2:36][CH2:35]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1ccc(N2CCNCC2)cc1Cl
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccc(OC)c(Cl)c3)CC2)c(OC)nc1C
Yield: 62 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-chloro-4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.