Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[C:27]([CH3:28])=[N:26][C:25]([NH2:29])=[N:24]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:29][C:25]2[N:26]=[C:27]([CH3:28])[N:23]([C:17]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=3[Cl:15])[N:24]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(N)nn1-c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: Cc1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nn1-c1ccc(Cl)cc1Cl

Procedure:
Prepared in analogy to example 1 step h) starting from 4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 1-(2,4-dichloro-phenyl)-5-methyl-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a light yellow solid (yield=34%).
Reaction SMILES: [OH:1][C:2]1([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C1C(=O)N([Br:26])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+].O>CC(O)=O.C(Cl)(Cl)Cl>[Br:26][C:15]1[S:16][CH:17]=[CH:18][C:14]=1[C:2]1([OH:1])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccsc2)C1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccsc2Br)C1
Reaction time: 3 h
Yield: 83.4 %

Procedure:
To a solution of tert-butyl 3-hydroxy-3-(thiophen-3-yl)pyrrolidine-1-carboxylate (5 g, 18.6 mmol) in AcOH (10 mL) and CHCl3 (10 mL) at 0° C. was added NBS (5.0 g, 27.9 mmol) in portions. After stirring for 3 h, the reaction mixture was treated with Na2SO3 and water, followed by extraction with EtOAc. The combined organic layer was washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (5.4 g, 84%).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([N:9]([CH3:11])[CH3:10])[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[Cl:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:19][CH2:20][CH2:21][CH2:22][C:23]([N:5]1[CH2:6][CH2:7][C@H:8]([N:9]([CH3:10])[CH3:11])[C@H:3]([O:2][CH3:1])[CH2:4]1)=[O:24]
Reactant: O=C(Cl)CCCCl
Reactant: CO[C@@H]1CNCC[C@@H]1N(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@@H]1CN(C(=O)CCCCl)CC[C@@H]1N(C)C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred and cooled (ice/bath) mixture of 7.9 parts of cis-3-methoxy-N,N-dimethyl-4-piperidinamine, 7 parts of N,N-diethylethanamine, 195 parts of dichloromethane were added dropwise 6.16 parts of 4-chlorobutanoyl chloride (temperature <5° C.). Upon completion, stirring was continued for 30 minutes. The organic layer was washed twice with a saturated sodium chloride solution, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 13.7 parts (100%) of cis-1-(4-chloro-1-oxobutyl)-3-methoxy-N,N-dimethyl-4-piperidinamine (int. 29).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][CH2:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[N:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9])[CH3:2]>[Pd].CO>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][CH2:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[CH2:28][CH2:27][CH2:26][NH:25][C:24]=4[N:23]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(CC(=O)OCC)n1ccc2cc(CCCc3ccc4cccnc4n3)ccc21
Agent: [Pd]
Solvent: CO
Product: CCCC(CC(=O)OCC)n1ccc2cc(CCCc3ccc4c(n3)NCCC4)ccc21
Reaction time: 48 h
Yield: 80 %

Procedure:
A mixture of 3-[5-(3-[1,8]naphthyridin-2-yl-propyl)-indol-1-yl]-hexanoic acid ethyl ester (100 mg, 0.665 mmol) and 10% palladium on carbon (30 mg) in methanol (5 mL) was stirred under hydrogen for 2 days. The reaction solution was filtered through celite and dried to give the crude product, which was purified via column chromatography eluting with hexane/ethyl acetate (4/1), to give the title compound (80% yield). 1H NMR (CDCl3) δ 7.39 (d, J=0.9 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.02–7.10 (m, 3H), 6.44 (dd, J=3.6, 6.3 Hz, 1H), 6.33 (d, J=7.3 Hz, 1H), 5.60 (br, 1H), 4.82 (m, 1H), 3.97 (q, 2H), 3.35 (t, 2H), 2.60–2.80 (m, 8H), 1.80–2.10 (m, 6H), 1.20 (m, 2H), 1.11 (m, 3H), 0.87 (m, 3H). Mass Spectrum (LCMS, ESI) calculated for C27H36N3O2 434.3 (M+H); found 434.4.
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][CH:19]=3)=[O:16])=[N:11]2)=[CH:6][CH:5]=1.[ClH:38].CCOCC>O1CCOCC1>[ClH:38].[F:37][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[CH:22][CH:23]=3)=[O:16])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3ncn(-c4ccc(OC(F)F)cc4)n3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1)c1ncn(-c2ccc(OC(F)F)cc2)n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
(S)-tert-Butyl 2-(4-(1-(4-(difluoromethoxy)phenyl)-1H-1,2,4-triazole-3-carboxamido)phenyl)morpholine-4-carboxylate (180 mg, 0.35 mmol) was dissolved in dioxane (1.3 ml) and a solution of HCl in dioxane (4M, 1.3 ml, 5.2 mmol) was added. The reaction mixture was stirred for 90 min at 60° C. After cooling ether was added, the solid was filtered off, washed with ether and dried in vacuo at 60° C. to afford (S)-1-(4-(difluoromethoxy)phenyl)-N-(4-(morpholin-2-yl)phenyl)-1H-1,2,4-triazole-3-carboxamide hydrochloride (123 mg, 78%) as a white solid. MS (ISP): 416.4 ([M+H]+).
Reaction SMILES: OCC(CO)O.[O:7]=[C:8]([CH3:20])[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[O:15]>O>[O:7]=[C:8]([CH3:20])[CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[O:15]
Reactant: CCC[C@H](CCCCC(C)=O)C(=O)O
Solvent: OCC(O)CO
Solvent: O
Product: CCC[C@@H](CCCCC(C)=O)C(=O)O

Procedure:
Gelatin (20 kg) and concentrated glycerin (6 kg) were admixed in the presence of purified water (20 kg) at 70° C. to give homogeneous solution. (2R)-7-oxo-2-propyloctanoic acid (0.9 kg) was injected into soft capsule filling machine (rotary-type soft capsule filling machine (TYPE-H1 manufactured by KAMATA CO., LTD.)) to give wet soft capsules each containing (2S)-7-oxo-2-propyloctanoic acid. The obtained wet soft capsules were dried by tumble-dry and rack-dry sequentially, thereby obtaining above captioned soft capsules (2200 capsules) each containing 300 mg of (2S)-7-oxo-2-propyloctanoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[CH3:15][CH:16]([CH3:44])[CH2:17][CH2:18][N:19]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]O)=[CH:38][CH:37]=1)[C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[N:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:15][CH:16]([CH3:44])[CH2:17][CH2:18][N:19]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:42][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[CH2:10][CH:9]3[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=2)=[CH:40][CH:41]=1)[C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=2)[N:24]=1
Reactant: CC(C)CCN(Cc1ccc(CO)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C1CC1c1ccc(OCc2ccc(CN(CCC(C)C)c3nc(-c4ccc(C(F)(F)F)cc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 46.2 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.152 g, 0.790 mmol), {4-[((3-methylbutyl){4-[4-(trifluoromethyl)phenyl]-1,3- thiazol-2-yl}amino)methyl]phenyl}methanol (0.312 g, 0.718 mmol) and tributylphosphine (0.291 g, 1.44 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.363 g, 1.44 mmol) was added, and the mixture was stirred at room temperature for 60 hr. Hexane (15 mL) was added to the reaction mixture, and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-30:70) to give the title compound (0.202 g, yield 42%) as a colorless oil.
Reaction SMILES: C([Li:5])CCC.Br[C:7]1[CH:27]=[CH:26][C:10]2[O:11][C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:9]=2[CH:8]=1.[C:28](=[O:30])=[O:29]>O1CCCC1>[Li+:5].[C:14]1([C:12]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:11][C:10]3[CH:26]=[CH:27][C:7]([C:28]([O-:30])=[O:29])=[CH:8][C:9]=3[O:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=O
Reactant: [Li]CCCC
Reactant: Brc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Solvent: C1CCOC1
Product: O=C([O-])c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Product: [Li+]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 6.25 ml of n-butyllithium (1.6M in n-hexane) in 50 ml of tetrahydrofuran is treated at -78° C. with 3.5 g of 5-bromo-2,2-diphenyl-1,3-benzodioxol and stirred for 10 minutes. The resulting solution is treated with about 10 g of solid carbon dioxide and subsequently warmed to room temperature. The precipitate formed is filtered off and dried. There are obtained 2.66 g of 2,2-diphenyl-1,3-benzodioxol-5-carboxylic acid lithium salt (1:1) as a white powder. This is dissolved in 20 ml of dimethylformamide and stirred at room temperature for 1 hour with 3.03 g of O-benzotriazol-1-yl-N,N,N',N'-tetra-methyluronium hexafluorophosphate (HBTU). The solvent is evaporated in a high vacuum, the residue is taken up in 15 ml of water and 15 ml of ethyl acetate and stirred in an ice bath for 45 minutes. The solid formed is filtered off under suction and dissolved in 40 ml of boiling ethyl acetate. A small amount of insoluble material is filtered off and the mother liquor is treated with n-hexane. The mixture is now concentrated until a suspension, which can still be filtered well, is obtained. The product is filtered off under suction and dried in a vacuum at 40° C. There are obtained 2.55 g of 1H-benzotriazol-1-yl 2,2-diphenyl-1,3-benzodioxol-5-carboxylate as white crystals of melting point 158°-160° C.
Reaction SMILES: C(O)(=O)C.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C@H:15]([NH:17][CH2:18][C@H:19]([CH3:22])[CH2:20][F:21])[CH3:16])=[CH:6]1.[F:23][C:24]1[CH:25]=[C:26](/[CH:33]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36])[CH:27]=[C:28]([F:32])[C:29]=1[CH:30]=O>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26](/[CH:33]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36])[CH:27]=[C:28]([F:32])[C:29]=1[C@@H:30]1[C:6]2[NH:5][C:13]3[C:8]([C:7]=2[CH2:14][C@@H:15]([CH3:16])[N:17]1[CH2:18][C@H:19]([CH3:22])[CH2:20][F:21])=[CH:9][CH:10]=[CH:11][CH:12]=3
Reactant: COC(=O)/C=C/c1cc(F)c(C=O)c(F)c1
Reactant: C[C@H](CF)CN[C@H](C)Cc1c[nH]c2ccccc12
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1cc(F)c([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2C[C@H](C)CF)c(F)c1
Temperature: 95 °C
Yield: 61.8 %

Procedure:
Acetic acid (2.0 ml) was added to a solution of (S)—N—((R)-1-(1H-indol-3-yl)propan-2-yl)-3-fluoro-2-methylpropan-1-amine (273 mg, 1.10 mmol) and (E)-methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (obtained as described in Example 1, preparation of starting materials) (226 mg, 1 mmol) in toluene (8.0 ml). The reaction was warmed to 95° C. for 2.5 h. The volatiles were removed under vacuum, then the residue was passed through an SCX-2 column. The column was then eluted with 7M NH3/methanol to liberate the product. The filtrate was concentrated and the crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanol in DCM. Pure fractious were evaporated to dryness to afford (E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-((S)-3-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (282 mg, 61.8%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, 30° C.) δ 0.82 (3H, d), 1.12 (3H, d), 1.81-1.99 (1H, m), 2.24 (1H, ddd), 2.64 (1H, ddd), 2.71 (1H, dd), 2.93-3.01 (1H, ddd), 3.42 (1H, dq), 3.81 (3H, s), 4.25-4.39 (1H, m), 4.38-4.53 (1H, m), 5.20 (1H, s), 6.39 (1H, d), 6.99 (2H, m), 7.06-7.16 (2H, m), 7.21-7.25 (1H, m), 7.52 (3H, m). m/z: ES+ [M+H]+ 457.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH:30]=O>>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][N:14]([CH2:30][C:29]3[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:27]([O:26][CH3:25])[CH:28]=3)[CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(CN2CCc3c(-c4ccc(Cl)cc4)nn(Cc4ccccc4)c3CC2)cc1OC

Procedure:
The title compound was prepared (12 mg) from 1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 59, Step E; 0.1 mmol) using 3,4-dimethoxy-benzaldehyde (0.2 mmol) in place of formaldehyde. MS (ESI): exact mass calculated for C29H30ClN3O2, 487.20. found, m/z 488.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.44-7.43 (m, 2H), 7.30-7.29 (m, 2H), 7.25-7.22 (m, 2H), 7.20-7.18 (m, 1H), 7.03-7.02 (m, 2H), 6.86 (d, J=1.7 Hz, 1H), 6.76-6.71 (m, 2H), 5.25 (s, 2H), 3.79 (s, 6H), 3.63 (s, 2H), 2.72 (s, 4H), 2.68-2.66 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.C(S)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8][CH2:10][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: SCCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Nc1nc(SCCc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-ylamine, phenethylmercaptan and DBU in THF. ES-MS m/e (%): 378 (M{81Br}+H+, 100), 376 (M {79Br}+H+, 99).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C:24]2[CH:36]=[CH:35][CH:34]=[CH:33][C:25]=2[C:26]([NH:28][CH2:29][CH2:30][S:31][CH3:32])=[O:27])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:10]=2)=[N:6][CH:7]=1.[OH:37][O:38][S:39]([O-:41])=O.[K+].[CH2:43]1COCC1>CO.O>[F:1][C:2]1[C:3]([NH:23][C:24]2[CH:36]=[CH:35][CH:34]=[CH:33][C:25]=2[C:26]([NH:28][CH2:29][CH2:30][S:31]([CH3:32])=[O:37])=[O:27])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[CH:10]=2)=[N:6][CH:7]=1.[F:1][C:2]1[C:3]([NH:23][C:24]2[CH:36]=[CH:35][CH:34]=[CH:33][C:25]=2[C:26]([NH:28][CH2:29][CH2:30][S:39]([CH3:43])(=[O:41])=[O:38])=[O:27])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: CSCCNC(=O)c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1F
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)CCNC(=O)c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1F
Product: CS(=O)CCNC(=O)c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-{[5-Fluoro-2-({3-[2-(4-morpholinyl)ethyl]phenyl}amino)-4-pyrimidinyl]amino}-N-[2-(methylthio)ethyl]benzamide (100 mg, 0.20 mmoles) was dissolved in 5 mL of THF and 5 mL of methanol, and treated with a solution of OXONE® reagent (a registered trademark of DuPont, 15 equivalents) in 5 mL water. The system was stirred for 48 h at room temperature, and then filtered and concentrated to dryness. The residue was immobilized onto silica gel and purified by silica gel chromatography, using a gradient of 100% A to 90% A-10% B, where “A” is chloroform and “B” is 10:90:1 methanol-chloroform-concentrated aqueous ammonium hydroxide). The title compounds 2-{[5-fluoro-2-({3-[2-(4-morpholinyl)ethyl]phenyl}amino)-4-pyrimidinyl]amino}-N-[2-(methylsulfinyl)ethyl]benzamide (Example 187) and 2-{[5-fluoro-2-({3-[2-(4-morpholinyl)ethyl]phenyl}amino)-4-pyrimidinyl]amino}-N-[2-(methylsulfonyl)ethyl]benzamide were isolated and characterized.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:14][CH2:15][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>FC(C1C=CC=CC=1)(F)F>[S:18]1[CH:19]=[CH:20][C:16]([CH2:15][NH:14][C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:17]1
Reactant: NCc1ccsc1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Solvent: CCOC(C)=O
Solvent: FC(F)(F)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(C(F)(F)F)ccc1NCc1ccsc1
Temperature: 160 °C
Yield: 85.9 %

Procedure:
To a solution of 2-fluoro-5-trifluoromethylbenzonitrile 1A (1.11 g, 5.87 mmol) and 3-(aminomethyl)thiophene 1B (1.0 g, 8.85 mmol) in trifluoromethylbenzene (10 mL) was added diisopropylethylamine (2.3 g, 17.8 mmol). The reaction mixture was heated in a microwave reactor at 160° C. for 30 minutes. Ethyl acetate (100 mL) was added and the organic layer was washed with 1 N hydrochloric acid and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to provide 2-[(thiophen-3-yl-methyl)amino]-5-trifluoromethylbenzonitrile 1C (1.42 g, 5.04 mmol) which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:17]=[N:18][N:19]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[N:10][CH:9]=2)[CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:3]2[N:4]([CH:17]=[N:18][N:19]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[N:10][CH:9]=2)[CH:7]=1
Reactant: CC(C)Nc1ncc(-c2cc(Br)c3nncn3c2)s1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)Nc1ncc(-c2cc(-c3ccccc3F)c3nncn3c2)s1
Temperature: 100 °C
Yield: 47 %

Procedure:
A mixture of 5-(8-bromo-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-isopropylthiazol-2-amine (19.6 mg, 0.0579 mmol) and 2-fluorophenylboronic acid (12.7 mg, 0.081 mmol) in toluene (0.58 mL) was degassed via nitrogen bubble, then was added Pd(PPh3)4 (3.3 mg, 0.003 mmol), aqueous K3PO4 (2 M, 58 μL, 0.116 mmol) and ethanol (84 μL). The reaction mixture was heated to 100° C. overnight, cooled to rt, diluted with EtOH (1 mL), filtered and concentrated. The residues were purified directly by reverse phase preparative HPLC and the product containing fractions were concentrated and neutralized with aqueous NaHCO3 to precipitate the product. The solids were filtered, washed and dried to give (9.7 mg, 47% yield). LCMS 354.23, Tr 3.50 min (Conditions A).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:14])=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][N:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O.C(=O)(O)[O-].[Na+]>CCOCC>[N+:15]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:9]1[CH2:10][CH2:5][CH:18]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:7][CH2:8]1)[NH:9][CH:8]=[C:7]([C:12]#[N:13])[C:6]2=[O:14])([O-:17])=[O:16]
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1O
Reactant: CN1CCCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: N#Cc1c[nH]c2cc(N3CCC(N4CCCC4)CC3)c([N+](=O)[O-])cc2c1=O
Temperature: 25 °C

Procedure:
A mixture of 1.3 g (5.21 mmol) of 7-chloro-4-hydroxy-6-nitro-3-quinolinecarbonitrile (U.S. Pat. No. 6,297,258) and 2.6 g (16.67 mmol) of 4-(1-pyrrolidine)piperidine 17.0 ml of 1-methyl 2-pyrrolidinone is heated at 120° C. for 5 hours. The mixture is cooled to room temperature and stirred with 15 mL of saturated solution of sodium bicarbonate. Following removal of solvents in vacuo, a residue is obtained, which is stirred with ether. The solid is collected by filtration and washed with ether. The crude product is dissolved in 9:1 methylene chloride/methanol, filtered through a pad of Celite (to remove inorganic material) and further washed with 9:1 methylene chloride/methanol. Evaporation of the filtrate to dryness yields a glassy residue. Purification by silica gel chromatography (gradient 9:1 methylene chloride/methanol to 4:1 methylene chloride/methanol) gives 1.3 g of 6-nitro-4-oxo-7-(4-pyrrolidin-1-ylpiperidin-1-yl)-1,4-dihydroquinoline-3-carbonitrile as an orange solid, mp 232-235° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]([CH2:16]Cl)=[CH2:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][CH2:16][C:14]([Cl:13])=[CH2:15])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: C=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(Cl)COc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Yield: 52.8 %

Procedure:
A mixture of 2-chloro-4-fluoro-5-nitrophenol (20.3 g) and 2,3-dichloropropene (11.7 g) was dissolved in N,N-dimethylformamide (200 ml), and potassium carbonate (14.6 g) was added thereto at room temperature, and the resultant mixture was stirred at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was purified by silica gelchromatography (eluent: hexane/ethyl acetate=4/1) to give 4-chloro-5-(2-chloro-2-propenyloxy)2-fluoronitrobenzene (14.8 g; yield, 53%).
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.F[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Fc1cnccn1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2cnccn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-fluoro-pyrazine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.43 min; Mass spectrum (ESI+): m/z=390 [M+H]+.