Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[C:42]([O:46][C:47](=[O:56])[CH:48](N1C=CC(N)=N1)C)([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[C:42]([O:46][C:47](=[O:56])[CH2:48][CH2:21][N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[N:17]1)([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C(=O)OC(C)(C)C)n1ccc(N)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 2.66 g, 8.04 mmol) in methylene chloride (20 mL), a 2.0 M solution of oxalylchloride in methylene chloride (4.42 mL, 8.84 mmol) was added and allowed to stir for 1 h at 0° C. then for 1 h at 25° C. 2,6-lutidine (1.12 g, 10.0 mmol) was then added dropwise at 0° C., turning the solution light brown and resulting in effervescence. To this solution was added (3-amino-pyrazol-1-yl)-propionic acid tert-butyl ester (1.87 g, 8.84 mmol) dissolved in methylene chloride (5 mL). The reaction was allowed to proceed at 0° C. for 1 h and then overnight at 25° C. The reaction was washed with 1.0 M aqueous hydrochloric acid solution (20 mL) and the organic layer was dried with anhydrous sodium sulfate. The solvent was then removed in vacuo and was purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 120 g; 10% ethyl acetate/methylene chloride) to afford 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid tert-butyl ester (3.06 g, 73%) as a white solid: ESI-LRMS m/e calcd for C25H34ClN3O5S [M+] 523.2, found 524.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.20 (m, 2H, CH2), 1.40 (s, 9H, 3×CH3), 1.39-1.92 (m, 8H, 4×CH2), 2.10-2.31 (m, 1H, CH), 2.70 (t, J=6.6 Hz, 2H, COCH2), 3.25 (s, 3H, SO2CH3), 3.57 (t, J=7.6 Hz, 1H, CH), 4.21 (t, J=6.6 Hz, 2H, NCH2), 6.60 (d, J=2.3 Hz, 1H, Ar), 7.28 (d, J=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.58 (d, Jm=1.7 Hz, 1H, Ar), 8.06 (d, Jo=8.2 Hz, 1H, Ar), 8.17 (s, 1H, NH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH:24]=1)[C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CCCCC1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Product: CC(C)c1ccc(N(Cc2cnn(CC3CCCCC3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) and (bromomethyl)cyclohexane (0.142 mL) as starting materials, 5-benzyloxy-N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.26 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 105, N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.18 g) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[ClH:17].[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH3:19])[CH2:9][NH:8][CH2:16]2
Reactant: COc1cc2c(cc1Cl)CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: COc1cc2c(cc1Cl)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-chloro-6-methoxy-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and HCl. Off-white solid. MS (m/e): 186.1 ({37Cl}M+H+, 30%), 184.1 ({35Cl}M+H+, 100%).
Reaction SMILES: [N:1]1([C:6]2([C:9]#[N:10])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH:9]([NH2:10])[C:6]2([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:8][CH2:7]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CC1(N2CCCC2)CC1
Reactant: [Li]c1ccccc1
Product: NC(c1ccccc1)C1(N2CCCC2)CC1

Procedure:
The title compound, light yellow liquid, MS: m/e=200.3 [(M−NH2)+], was prepared in accordance with the general method of intermediate B from 1-pyrrolidin-1-yl-cyclopropanecarbonitrile (intermediate C) and phenyllithium.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][N:5]([C:10]1[N:15]=[N:14][C:13]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)=[CH:12][CH:11]=1)[CH2:6]2.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>>[CH2:25]([NH:27][C:28]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]#[C:16][C:13]2[N:14]=[N:15][C:10]([N:5]3[CH2:6][CH:7]4[N:2]([CH3:1])[CH:3]([CH2:9][CH2:8]4)[CH2:4]3)=[CH:11][CH:12]=2)=[CH:23][CH:22]=1)=[O:29])[CH3:26]
Reactant: CCN=C=O
Reactant: CN1C2CCC1CN(c1ccc(C#Cc3ccc(N)cc3)nn1)C2
Product: CCNC(=O)Nc1ccc(C#Cc2ccc(N3CC4CCC(C3)N4C)nn2)cc1

Procedure:
Was prepared according to Method F from 4-[6-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridazin-3-ylethynyl]-phenylamine and ethylisocyanate. Mp 269° C. LC-ESI-HRMS of [M+H]+ shows 391.2253 Da. Calc. 391.224634 Da, dev. 1.7 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][C:10]([F:13])([F:12])[F:11].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([O:9][C:10]([F:12])([F:11])[F:13])[CH:4]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc(Br)c(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1cc(OCc2ccccc2)ccc1Br
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a mixture of 4-bromo-3-(trifluoromethoxy)phenol (2.97 g, 11.6 mmol) in DMF (10 mL) was added Cs2CO3 (5.65 g, 17.3 mmol) and benzyl chloride (1.46 mL, 12.7 mmol) at RT. The reaction mixture was stirred overnight then quenched with water and diluted with EtOAc. The organic phase was washed with water (3×), brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Heptane) to afford the title compound as a colorless oil (3.92 g, 98% yield). 1H NMR (METHANOL-d4) δ 7.51 (d, J=9.1 Hz, 1H), 7.40-7.45 (m, 4H), 7.34-7.40 (m, 1H), 6.97 (dd, J=2.5, 1.5 Hz, 1H), 6.82 (dd, J=9.1, 3.0 Hz, 1H), 5.06 (s, 2H).
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([OH:17])=[C:10]([C:14]([NH2:16])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][F:30].Cl>CN(C=O)C>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:17][CH2:28][CH2:29][F:30])=[C:10]([C:14]([NH2:16])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:19][CH3:20]
Reactant: FCCBr
Reactant: CCCN(CCC)C1Cc2cc(O)c(C(N)=O)cc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN(CCC)C1Cc2cc(OCCF)c(C(N)=O)cc2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(Dipropylamino)-2,3-dihydro-6-hydroxy-1H-indene-5-carboxamide (87, 0.14 g, 0.5 mmol), potassium carbonate (0.2 g, 1.5 mmol), 1-bromo-2-fluoroethane (0.19 g, 1.5 mmol) in DMF (10 mL) was stirred at room temperature for 5 h. The mixture was quenched with water, and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. Chromatographic purification yielded a pale yellow solid which was converted into the HCl salt and crystallized from EtOAc/MeOH to give the title compound 88 as an off-white solid (m.p. 232-233° C.).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Br)C(Cl)(Cl)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][Br:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: OCc1cccc(Cc2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: BrCc1cccc(Cc2ccccc2)c1
Reaction time: 0.17 h
Yield: 100.5 %

Procedure:
A solution of 3-benzylbenzyl alcohol (1.98 g) in diethyl ether (60 cm3) was cooled in an ice bath, and 1,1,2,2-tetrachloro-1,2-dibromoethane (3.90 g) added. When the addition was complete, triphenyl phosphine (3.14 g) was added to the cooled mixture. The reaction mixture was stirred for 10 minutes, then filtered and the solvent evaporated under reduced pressure. The resultant yellow oil was purified by column chromatography on a silica gel support, eluting with petroleum ether (boiling range 60°-80° C.) containing 10% by volume diethyl ether, to give 3-benzylbenzyl bromide (2.62 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[F:21][CH2:22][CH2:23][NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:23][CH2:22][F:21])[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: FCCNCC1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(CNCCF)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A suspension of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-(2-fluoroethylaminomethyl)pyrrolidine (165 mg) and 1,8-diazabicyclo[5,4,0]-7-undecene (100 mg) in absolute acetonitrile (2 ml) was refluxed for an hour. After cooling, the reaction mixture was concentrated and to the residue was added acetonitrile-ether (1:1, 5 ml). The solution was allowed to stand overnight at 5° C., then the resulting precipitate was collected by filtration and recrystallized from chloroform-methanol-ether to give the title compound (140 mg), mp 134°-138° C.
Reaction SMILES: Cl.[C:2]([C:4]1([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][CH:8](C(OCC)=O)[C:7](=[O:15])[CH2:6][CH2:5]1)#[N:3].[OH-].[Na+]>C(O)(=O)C>[C:2]([C:4]1([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][CH2:8][C:7](=[O:15])[CH2:6][CH2:5]1)#[N:3]
Reactant: CCOC(=O)C1CC(C#N)(c2cccs2)CCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N#CC1(c2cccs2)CCC(=O)CC1
Temperature: 0 °C

Procedure:
Conc. HCl (60 ml) was added to ethyl 5-cyano-2-oxo-5-(thiophen-2-yl)cyclohexanecarboxylate (12 g) in acetic acid (120 ml). The reaction mixture was refluxed for 3 hours (110° C.-120° C.). The mixture was cooled to 0° C. and adjusted with 2N NaOH-solution (200 ml) until it was neutral (pH ˜7).
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3]1.Br[CH2:17][C:18]1[CH:41]=[CH:40][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C@@H:30]([C:37]#[C:38][CH3:39])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]2([CH2:5][CH2:6][N:7]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:22][O:23][C:24]4[CH:29]=[CH:28][C:27]([C@@H:30]([C:37]#[C:38][CH3:39])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=4)=[CH:40][CH:41]=3)[CH2:8][CH2:9]2)[CH2:3]1
Reactant: CN1CC2(CCNCC2)c2ccccc21
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc(CN3CCC4(CC3)CN(C)c3ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.8 %

Procedure:
A mixture of 1-methylspiro[indoline-3,4′-piperidine] (0.0486 g, 0.204 mmol), ethyl (3S)-3-(4-{[4-(bromomethyl)benzyl]oxy}phenyl)hex-4-ynoate (0.100 g, 0.24 mmol), and Cs2CO3 (0.156 g, 0.48 mmol) in DMF (5 mL) is stirred at room temperature for 16 hours. The reaction mixture is diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic layer is washed with water (3×25 mL) and saturated brine solution (25 mL), dried with a drying agent, filtered, and evaporated to dryness to give a liquid. The crude product is purified by silica gel chromatography (gradient EtOAc/hexane 30%) to give the title compound as a colourless liquid (0.095 g, 73.3%). ESI/MS m/z 537 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2Br)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2Br)CC1
Reactant: C1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2N2CCNCC2)CC1
Temperature: 95 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of N-boc-4-(2-bromo-phenoxy)-piperidine (13.4 g, 39.6 mmol, 1.0 eq.), piperazine (9.73 g, 113 mmol, 3.0 eq.), Pd2dba3 (1.72 g, 1.88 mmol, 0.05 eq.), BINAP (3.5 g, 5.65 mmol, 0.15 eq.) in toluene (150 mL) was added NaOtBu (5.1 g, 52.6 mmol, 1.4 eq.). The mixture was heated to 95° C. and stirred at that temperature overnight. The slurry was diluted with EtOAc and filtered through a pad of celite. The filtrate was concentrated and purified by ion exchange (SCX, 10 g) column. Further purification by flash chromatography (250 g SiO2, 40 ml/min, linear gradient 0–10% 2.0 M NH3 in MeOH/CH2Cl2 for 20 minutes and 10% 2.0 M NH3 in MeOH/CH2Cl2 for 73 minutes) afforded the final compound (12.65 g, 93%). LRMS (electrospray): 362.7 (M+1).
Reaction SMILES: [CH:1]12[C@@H:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]1[S:4][CH:3]=[CH:2]2.B(O[O-])=[O:13].O.[Na+].O>O1CCCC1>[OH:13][C@H:2]1[CH:1]2[CH:5]([C@@H:6]2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:4][CH2:3]1
Reactant: CCOC(=O)[C@@H]1C2C=CSC21
Reactant: O=BO[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H]1C2SC[C@@H](O)C21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (6S)-4-thiabicyclo[3.1.0]hex-2-ene-6-carboxylate (22.2 g, 131 mmol) in 136 mL of tetrahydrofuran under nitrogen at 0° C. is added borane-THF complex (98 mL, 98 mmol) over 15-20 minutes. After stirring at 0° C. for 30 minutes, the reaction is allowed to warm to 15° C. and stir until complete by HPLC (1.5-2 hours). The reaction is cooled to 0° C. and transferred over 10-15 minutes to 111 mL of a pre-cooled (0° C.) 1 N pH 7 buffer solution while maintaining the temperature at 0° C. To the mixture is added sodium perborate monohydrate (15.6 g, 157 mmol) as a solid in five portions such that the temperature is maintained below 20° C. The solution is allowed to warm to room temperature and stir for 1 hour followed by the addition of 222 mL of water. After stirring for 2 hours, the peroxides are quenched by adding sodium thiosulfate pentahydrate (9.7 g) dissolved in 24 mL of water followed by stirring for 10 minutes. The mixture is extracted with ethyl acetate (2×222 mL). The combined organic extracts are washed with saturated aqueous sodium bicarbonate (1×222 mL) followed by brine (1×222 mL) and concentration in vacuo to dryness. The crude product is dissolved in 1,2-dichloroethane (1 mL per 1 g of crude oil) and loaded onto a silica gel column (4 g of silica gel per 1 g of crude oil slurried and packed in 15% ethyl acetate-heptane). The column is eluted with 15% ethyl acetate-heptane until product is visible by TLC, at which time the solvent is switched to 50% ethyl acetate-heptane. All fractions containing the title product are combined and concentrated in vacuo to an oil. Overall yield is in the 55-65% range.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[N:6][CH:7]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:14]1([S:20]([NH:1][C:2]2[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[N:6][CH:7]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(N)cnc1CCCC#N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(NS(=O)(=O)c2ccccc2)cnc1CCCC#N

Procedure:
A solution of 5-amino-2-(3-cyanopropyl)-3-methylpyridine* (5 g) in chloroform (50 ml) was treated with benzenesulphonyl chloride (7.35 ml) and triethylamine (3 ml) for 96 hours. The chloroform layer was extracted with dilute sodium hydroxide solution (2×50 ml). The chloroform layer was discarded and the combined aqueous extracts were adjusted to pH=5 and extracted with chloroform (3×50 ml). The combined extracts were dried over magnesium sulphate, the solvent was removed and the residue was chromatographed on silica gel eluted with 2% v/v methanol in chloroform to give the title compound (3.28 g) as white prisms. m.p. 119°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:23][CH3:24])=[C:8]([S:10]([C:13]2[CH:21]=[C:20]([Br:22])[C:16]3[N:17]=[CH:18][NH:19][C:15]=3[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[N+]1([O-])C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:23][CH3:24])=[C:8]([S:10]([C:13]2[CH:21]=[C:20]([Br:22])[C:16]3[N:17]=[CH:18][N:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:15]=3[CH:14]=2)(=[O:11])=[O:12])[CH:9]=1)=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c3nc[nH]c3c2)c(SC)s1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [O-][n+]1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c3ncn(-c4ccccc4)c3c2)c(SC)s1
Yield: 51.3 %

Procedure:
4-(7-Bromo-3-phenyl-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester was prepared according to literature (Lam, P. Y. S. et al., Tetrahedron Letters, 42:3415 (2001)) using 4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (20 mg, 44.7 μmol, Example 38: step e), phenylboronic acid (11.4 mg, 93.5 μmol), Cu(OAc)2 (8.5 mg, 46.8 μmol), pyridine N-oxide (4.7 mg, 49.2 μmol), triethylamine (13 μL, 93.3 μmol), and CH2Cl2 (1.5 mL) in a loosely-capped, 1-dram vial. The reaction mixture was diluted in CH2Cl2 and washed with water and brine. The organic layer was dried over magnesium sulfate. Removal of solvents in vacuo followed by preparative TLC afforded the title compound as a brown oil (12 mg, 51%). ESI-MS (m/z): Calcd. for C20H15BrN2O4S3: 522.9 (M+1); found: 525.0.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([F:31])[CH:30]=1)[C:25](Cl)=[O:26]>>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([F:31])[CH:30]=1)[C:25]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:26]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1cc(F)cc(F)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 3,5-difluorobenzoyl chloride, there is obtained ethyl N-(3,5-difluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a solid, mass spectrum m/e: M+ 406 (4), 377 (20), 194 (100), 141 (35);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18])[CH2:6][O:7][CH3:8].[I-].[CH3:21][N:22]1[C:30]2[C:25](=[C:26]([CH3:31])[CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:32][N+](C)(C)C)=[CH:23]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:32][C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[N:22]([CH3:21])[CH:23]=2)[C:10]1=[O:18])[CH2:6][O:7][CH3:8]
Reactant: COCC(CC(=O)OC)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(CC(=O)OC)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Temperature: 100 °C
Yield: 60.8 %

Procedure:
To a solution of 4-Methoxy-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-butyric acid methyl ester (205 mg, 0.78 mmol) in DMF (10 mL) are added (1,4-Dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (470 mg, 1.4 mmol) and K2CO3 (210 mg, 1.6 mmol) at room temperature. The solution is heated to 100° C. for 5.5 hours. The solution is cooled down and 30 mL of water is added. The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, washed with water (3×100 mL), dried with MgSO4 and concentrated to give crude product. Purification by flash column chromatography affords 200 mg (61%) of 3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-4-methoxy-butyric acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27]([OH:29])=O)=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.[CH3:36][NH:37][O:38][CH3:39]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27](=[O:29])[N:37]([O:38][CH3:39])[CH3:36])[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CNOC
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)N(C)OC)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 34.9 %

Procedure:
(3S)-4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (4 g, 7.2 mmol) was reacted with N,O-dimethylhydroxylamine hydrochloride (0.84 g, 8.64 mmol) according to the procedure as described in Example 53 to give the title compound as a yellow solid (1.5 g, 35%). The compound was characterized by the following spectroscopic data: