Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O)=[CH:4][CH:3]=1.[NH2:15][C:16]([OH:22])(CO)[CH:17]([CH3:19])O.C1(C)C(C)=CC=CC=1.[OH2:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([C:8]2[O:10][CH:17]([CH3:19])[C:16]([OH:22])([OH:31])[N:15]=2)([CH3:12])[CH3:11])=[CH:13][CH:14]=1
Reactant: CC(O)C(N)(O)CO
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Reactant: O
Solvent: Cc1ccccc1C
Product: CC1OC(C(C)(C)Oc2ccc(Cl)cc2)=NC1(O)O

Procedure:
21.45 g (0.1 moles) of 2-(p-chlorophenoxy)-2-methyl-propionic acid and 15.14 g (0.125 moles) of 2-amino-2-hydroxy-methyl-1,3-propane-diol are boiled for 12 hours in 900 ml. anhydrous xylol in an appratus provided with a water-separating column. The water formed during the course of the reaction is accumulated as an azeotropic mixture in the water-separating column from where it is removed from time to time. When no more water is evolved from the system the boiling is stopped. The hot xylene solution is discharged from the insoluble part. After cooling the white crystals precipitated from the xylene solution are filtered off and washed with benzene. After drying, the crude product 2-[(p-chlorophenoxy)-isopropyl]-4,4-bis-hydroxy-methyl-2-oxazoline obtained (21.8 g, m.p.: 133°-135° C.) is recrystallized from 70% aqueous ethanol. The pure product (12 g, yield 40%) has a m.p. of 141.5°-142.5° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[C:4]1=[O:10].C(N(CC)CC)C.O=C1CCC(=O)N1[C:25]1[C:33]2[C:28](=[CH:29][C:30]([C:43]([O-])=[O:44])=[C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])[CH:32]=2)[N:27]([CH2:46][CH:47]([CH3:49])[CH3:48])[N:26]=1>CN(C)C=O.C(OCC)(=O)C>[F:42][C:36]1[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=1[O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[C:43]([NH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[C:4]1=[O:10])=[O:44])[N:27]([CH2:46][CH:47]([CH3:49])[CH3:48])[N:26]=[CH:25]2
Reactant: CN1CCC[C@H](N)C1=O
Reactant: CC(C)Cn1nc(N2C(=O)CCC2=O)c2cc(Oc3ccc(F)cc3F)c(C(=O)[O-])cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCCN(C)C3=O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.6 %

Procedure:
(S)-3-Amino-1-methylpiperidin-2-one hydrochloride (56 mg, 0.34 mmol) was dissolved in triethylamine (95 μL, 0.68 mmol) and N,N-dimethylformamide (1.5 mL). To this solution was added 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (prepared according to Example 16, Step A; 152 mg, 0.34 mmol), and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on a silica gel column, eluting with 70% ethyl acetate/hexanes to yield pure (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(1-methyl-2-oxopiperidin-3-yl)-1H-indazole-6-carboxamide (Ie) (94 mg, 60%). Mass spec: 457 (M+1). 1H NMR (CDCl3) δ 8.61 (br, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.18 (m, 1H), 7.01 (m, 2H), 6.90 (m, 1H), 4.48 (ddd, 1H), 4.22 (d, 2H), 3.36 (m, 2H), 2.97 (s, 3H), 2.73 (m, 1H), 2.36 (m, 1H), 1.99 (m, 2H), 1.66 (m, 1H), 0.92 (d, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH2:17][CH3:18])[N:4]=[C:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2O.[OH-].[NH4+].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:6]1[C:5]2=[N:4][N:3]([CH2:16][CH2:17][CH3:18])[C:2]([CH3:1])=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCn1nc2c(O)nc3ccccc3c2c1C
Agent: [NH4+]
Agent: [OH-]
Product: CCCn1nc2c(Cl)nc3ccccc3c2c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ol (5.11 g, 21.2 mmol) in phosphorus oxychloride (50 mL) was heated at reflux for 30 minutes, allowed to cool to room temperature, and stirred for two days. The reaction mixture was poured into ice water (500 mL) with stirring, and concentrated ammonium hydroxide (169 mL) and ice were added. A solid was present and was isolated by filtration, washed with water, and purified by automated flash chromatography (eluting with 5% to 25% CMA in chloroform). The resulting orange solid (5.5 g) was recrystallized from acetonitrile (25 mL). The crystals were washed with acetonitrile and dried for five hours to provide 3.85 g of 4-chloro-1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinoline as a white solid, mp 145-147° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[C:4]([OH:13])[CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.[C:25](=[O:28])([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:14][CH2:7][C:6]2[CH:12]=[CH:2][C:3]([O:28][CH3:25])=[CH:4][CH:5]=2)=[C:4]([O:13][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(O)c(O)c(Cl)c1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CBr)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Cl)c(OCc2ccc(OC)cc2)c(OCc2ccc(OC)cc2)c1

Procedure:
Ethyl 5-chloro-3,4-dihydroxybenzoate is p-methoxybenzylated with p-methoxybenzyl bromide and potassium carbonate in dimethylformamide to give ethyl 5-chloro-3,4-bis(p-methoxybenzyloxy)benzoate. This is hydrolyzed with sodium hydroxide to give 5-chloro-3,4-di(p-methoxybenzyloxy)benzoic acid.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:39](=[O:73])/[C:40](/[C:48]2[N:49]=[C:50]([C:54]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[S:51][C:52]=2[NH2:53])=[N:41]\[O:42]C(OC)(C)C)[C:19]3=[O:74])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(OCC)(=O)C>CC(C)=O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:39](=[O:73])/[C:40](/[C:48]2[N:49]=[C:50]([C:54]([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)[C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)[S:51][C:52]=2[NH2:53])=[N:41]\[OH:42])[C:19]3=[O:74])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nn4c(=O)cc(C)nc4s3)CS[C@H]12)c1nc(C(c2ccccc2)(c2ccccc2)c2ccccc2)sc1N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](NC(=O)/C(=N\O)c5nc(C(c6ccccc6)(c6ccccc6)c6ccccc6)sc5N)[C@H]4SC3)sc2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 75.8 %

Procedure:
To a solution of the product obtained in Step 3 (1.5 g) in acetone (12 ml) was added 1 N hydrochloric acid (2.6 ml), and the resulting solution was stirred at room temperature for 3.5 hours. Ethyl acetate was added to the solution, and the organic layer was washed with water, 5% sodium bicarbonate solution and brine in that order, and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 1.06 g of the objective compound as milky white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:54])=[CH:48][CH:47]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(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>[C:32]([O:31][C:30]([NH:29][C:8]1[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:46]3[CH:47]=[CH:48][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:54])=[CH:50][CH:51]=3)=[CH:37][C:6]=2[N:7]=1)=[O:36])([CH3:34])([CH3:33])[CH3:35]
Reactant: CCCCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
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: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCOC(=O)Cc1ccc(-c2ccc3c(c2)N=C(NC(=O)OC(C)(C)C)CC(C(=O)N(CCC)CCCO[Si](C)(C)C(C)(C)C)=C3)cc1
Temperature: 100 °C

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded butyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate.
Reaction SMILES: Cl.[C:2]1([CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.Br[CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1.O>CN(C)C=O>[C:2]1([CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[CH2:10][CH2:9]1
Reactant: Cc1ccccc1C1CCNCC1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
To a stirring solution of 4.2 g of 4-(2-toluyl)piperidine hydrochloride and 4.0 g of triethylamine in 150 ml of dimethylformamide is added 3.8 g of 3-(2-bromoethyl)indole. The resulting solution is stirred at ambient temperature for 70 hours and stirring is continued while 500 ml of water are added dropwise. An oil appears which is extracted from the solution with chloroform, the combined chloroform extracts are dried and the excess chloroform is removed, leaving an oil which crystallizes upon standing. The solid product is recrystallized from cyclohexane and then twice from an ethanol-water mixture to give flakes, mp 111°-112° C., 3-{2-[4-(2-toluyl)piperidyl]ethyl}indole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([OH:10])[N:7]([CH3:11])[N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH:19]([F:21])[F:20].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH:19]([F:21])[F:20])[N:7]([CH3:11])[N:6]=1)=[O:4]
Reactant: FC(F)Cl
Reactant: COC(=O)c1cc(O)n(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(OC(F)F)n(C)n1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
67.6 g (0.43 mol) 3-Methoxycarbonyl-5-hydroxy-1-methylpyrazole and 299.2 g (2.17 mol) potassium carbonate were dissolved in 1500 ml dimethylformamide and warmed to 70° C. At this temperature, chlorodifluoromethane was passed through for 2 hours and then stirred for 1.5 hours at 80° C. The reaction mixture was added to water and shaken 6 times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride and dried over magnesium sulfate. The reaction solution was concentrated.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH2:4][S:5]([Cl:8])(=[O:7])=[O:6].Cl.Cl.[CH2:16]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:8].[CH2:16]([N:25]1[CH2:30][CH2:29][N:28]([S:5]([CH2:4][C:3]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:2]=2[F:1])(=[O:7])=[O:6])[CH2:27][CH2:26]1)[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18]
Reactant: O=C(CN1CCNCC1)c1ccccc1
Reactant: O=S(=O)(Cl)Cc1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCN(S(=O)(=O)Cc2ccc(F)cc2F)CC1)c1ccccc1

Procedure:
A mixture of 2,4-difluorobenzylsulfonylchloride (3.5 mmol), N-phenacyl piperazine dihydrochloride (3 mmol), and K2CO3 (10.5 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-22), 0.81 g (71%), M+ 412.
Reaction SMILES: CO.C([O:5][C:6]([C:8]1[C:9]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[CH:20]3)=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=[O:7])C.[OH-].[Na+].Cl>O>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][C:9]3[C:8]([C:6]([OH:7])=[O:5])=[CH:13][N:12]=[C:11]([S:14][CH3:15])[N:10]=3)=[CH:25][CH:24]=2)[CH:20]=[N:21]1
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1ncc(C(=O)O)c(Nc2ccc3[nH]ncc3c2)n1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To the solution of methanol (80 ml) was added the 4-(1H-5-indazolylamino)-2-methylthio-5-pyrimidinecarboxylic acid ethyl ester (5 g) obtained by the preparation example 1, and the solution was hydrolyzed at 40-50° C. for 1 hr, adding H2O (30 ml) and3N aq. NaOH (15 ml). The reaction mixture was cooled, measured pH 5 at 20° C., slowly adding 3 N aq. HCl. And then the reaction mixture was slowly added H2O (100 ml),stirred at 20° C. for 1 hr, filtered, washed with H2O (30 ml), and obtained a solid product. The solid product was dried at 50° C. in vacuo to obtain the desired compound (4.44 g, 97%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:6]2[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:3]=[C:2]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[CH:7]=2)[CH:9]=1
Reactant: NCCc1ccc(O)cc1
Reactant: Clc1cc(-c2cccnc2)nc(-c2ccccn2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc(CCNc2cc(-c3cccnc3)nc(-c3ccccn3)n2)cc1

Procedure:
4-Chloro-6-pyridin-3-yl-2-pyridin-2-yl-pyrimidine (Intermediate A) (1 eq, 0.74 mmol, 200 mg) and 4-(2-amino-ethyl)-phenol (1.2 eq, 0.89 mmol, 123 mg) are dissolved in iPrOH (3 ml). Then DIPEA (2 eq, 1.49 mmol, 196 mg) is added and the resulting mixture is heated using microwave radiation at 130° C. for 20 min. The solvent is removed in vacuo and the crude residue is purified by flash chromatography eluting with 0-5% MeOH in DCM yielding the title compound [M+H]+=370.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:7])[N:6]=1.N[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH2:8]([CH:4]1[O:3][C:2]([NH:1][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:6][C:5]1=[O:7])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NCC1CCCCC1
Reactant: NC1=NC(=O)C(Cc2ccccc2)O1
Product: O=C1N=C(NCC2CCCCC2)OC1Cc1ccccc1

Procedure:
Synthesis was performed from 2-amino-5-benzyl-1,3-oxazol-4(5H)-one and aminomethylcyclohexane according to Method G+H.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>C(Cl)(Cl)Cl>[C:17]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:19])[CH3:18]
Reactant: c1ccc2c(c1)CCN2
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 11.9 g of indoline in 100 ml of chloroform is cooled to 0° C., 13.9 ml of triethylamine are added and a solution of 10.4 ml of acetic anhydride in 10 ml of chloroform is then added dropwise, followed by 0.1 g of 4-dimethylaminopyride. After stirring for two hours at RT, water is added to the reaction mixture, extraction is carried out with chloroform, the organic phase is dried over sodium sulfate and the solvent is evaporated off under vacuum to give 15.44 g of the expected product, which is used as such.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]3[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:18]=3[NH:19]2)=[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH:28]=2)[CH:14]=1)=[O:12]>C(Cl)Cl>[CH3:9][O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]3[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:18]=3[NH:19]2)=[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH:28]=2)[C:14]=1[Br:1])=[O:12]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(=O)OC)cc3[nH]c4ncc(C)cc4c23)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCS(=O)(=O)c1cccc(-c2c(Br)c(C(=O)OC)cc3[nH]c4ncc(C)cc4c23)c1
Temperature: 30 °C
Reaction time: 18 h
Yield: 23.8 %

Procedure:
N-Bromosuccinimide (59 mg, 0.33 mmol) was added to a solution of Compound 132 (128 mg, 0.31 mmol) in CH2Cl2 (3 mL) at r.t. The reaction was stirred for 18 h at 30° C and was then concentrated in vacuo. Purification by prep-HPLC gave 36 mg (24%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 12.28 (br s, 1H), 8.23 (s, 1H), 8.15-8.19 (m, 2H), 7.98 (s, 1H), 7.87 (t, 1H, J=7.6 Hz), 7.72 (d, 1H, J=7.6 Hz), 7.08 (s, 1H), 4.03 (s, 3H), 3.22 (q, 2H, J=7.2 Hz), 2.34 (s, 3H), 1.33 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C22H19BrN2O4S, 487, 489; found 487, 489.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:23]([CH2:28][C:29]([NH2:31])=[O:30])=[N:24][CH:25]=[CH:26][N:27]=4)[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:38][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:23]([CH2:28][C:29]([NH2:31])=[O:30])=[N:24][CH:25]=[CH:26][N:27]=4)[C:17]([C:32]([F:33])([F:35])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1nccnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4nccnc4CC(N)=O)n3)cc2)CC1
Reaction time: 3 h
Yield: 78.2 %

Procedure:
2-(3-(2-(2-((4-(Piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyrazin-2-yl)acetamide (26) (42 mg, 0.087 mmol) was dissolved in methanol (4 mL) and 37% formaldehyde (26 μL, 0.35 mmol) was added. After five minutes sodium tri(acetoxy)borohydride (92 mg, 0.44 mmol) was added and the mixture stirred for three hours. The solution was concentrated, and the residue suspended in 10% sodium hydroxide (1 mL). After five minutes brine (2 mL) was added, and the mixture extracted with ethyl acetate (5×3 mL). The combined ethyl acetate phases were washed with brine, dried (sodium sulphate) and evaporated to give the title compound (27) (34 mg, 77% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.07 (s, 1H), 8.64 (s, 1H), 8.42 (d, J=2.6 Hz, 1H), 8.38 (d, J=2.6 Hz, 1H), 7.61 (s, 1H), 7.55 (d, J=7.3 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 7.08 (s, 1H), 4.09 (d, J=4.7 Hz, 1H), 3.77 (s, 2H), 3.17 (d, J=4.3 Hz, 2H), 3.05-2.92 (m, 2H), 2.33 (s, 3H), 2.20 (s, 2H), 1.82-1.61 (m, 4H). LCMS Method C: rt 4.53 min; m/z 500.1 [M+H]+; m/z 498.2 [M−H]−.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]1([NH:13][NH:14][C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(O)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:7]1([NH:13][N:14]=[C:15]([Cl:2])[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CSc1ccc(C(=O)NNc2ccccc2)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: Oc1ccccc1
Product: CSc1ccc(C(Cl)=NNc2ccccc2)cc1
Yield: 44.9 %

Procedure:
A mixture consisting of 14.2 g. (0.068 mole) phosphorus pentachloride, 100 ml. carbon tetrachloride, and 16.78 g. (0.065 mole) p-(methylthio)benzoic acid 2-phenylhydrazide (prepared in Part A above) was reacted at 25° C. until evolution of gas ceased. The reaction mixture was then heated to the reflux temperature and a clear solution resulted. The solution was chilled in ice and a suspension of 20.7 g. (0.22 mole) phenol in 50 ml. carbon tetrachloride was added. After removing the carbon tetrachloride by evaporation on a rotary evaporator at 31° C. the resulting suspension of product in triphenylphosphate was filtered. The filter cake was washed with technical hexane (Skellysolve B, a mixture of isomeric hexanes having a boiling range between 146° and 156° Fahrenheit), and then was washed with diethyl ether. Crystallization from 75 ml. ethyl acetate gave 8.10 g. (44.9% yield) of p-(methylthio)benzoyl chloride phenylhydrazone having a melting point of 138.5° to 142.5° C. Recrystallization from a mixture of ethyl acetate and the Skellysolve B gave the compound with the same melting point.
Reaction SMILES: Br[C:2]1[C:3]([O:7][CH3:8])=[N:4][S:5][CH:6]=1.[CH3:9][N:10](C)C=O.[C-]#N.[Na+]>O>[C:9]([C:2]1[C:3]([O:7][CH3:8])=[N:4][S:5][CH:6]=1)#[N:10]
Reactant: COc1nscc1Br
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: COc1nscc1C#N
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of 38.8 g. (0.2 mole) of 4-bromo-3-methoxyisothiazole prepared as in Example 15 in 80 ml. of dimethylformamide was added 54 g. (0.6 mole) of cuprous cyanide. The mixture was stirred and heated at reflux for 1 hour. Then the reaction mixture was cooled to 25° C., and 40 g. (0.81 mole) of sodium cyanide in 120 ml. of water was added in portions. The mixture exothermed to 60°-70° C. and was allowed again to cool to 25° C. The reaction solution was then extracted thoroughly with ether. The ether extracts were washed with 10% sodium cyanide solution and then water. After drying over anhydrous magnesium sulfate and evaporation 23.4 g. (83%) of 4-cyano-3-methoxyisothiazole was obtained as a white solid, m.p. 60°-62° C. after crystallization from ligroin (90°-120°).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][N:9]2[C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:4][CH:3]=1.C(O)C.Cl.[OH:26][NH2:27].N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[N:27][OH:26])[CH2:7][CH2:8][N:9]2[C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(=O)N1CCC(=O)c2ccc(Cl)cc21
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)N1CCC(=NO)c2ccc(Cl)cc21
Yield: 86.9 %

Procedure:
To a mixture of 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone (14.9 g), obtained in example 1, and ethanol (250 ml) were added hydroxyl amine hydrochloride (7 g) and pyridine (8.5 g), and the mixture was heated under reflux for 1.5 hours. After cooling, the reaction mixture was poured into 1000 ml of water, and precipitated crystals were separated by filtration, washed, dried and recrystallized with ethanol to obtain 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone-4-oxime (yield 13.6 g) as white crystal.