Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]=[CH:8][NH:7][N:6]=1)[CH2:2][CH3:3].[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14](Cl)=[O:15])[CH:11]=[CH2:12].O1CCCC1>C(N(CC)CC)C>[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14]([N:7]1[CH:8]=[N:9][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:6]1)=[O:15])[CH:11]=[CH2:12]
Reactant: CCCSc1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(SCCC)n1

Procedure:
A mixture of 5.75 g. 3-propylthio-1,2,4-triazole, 6.8 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 3 hours. The reaction mixture was worked up as described in Example 1 to produce an oil which was distilled under reduced pressure to give 1-diallylcarbamoyl-3-propylthio-1,2,4-triazole, b.p. 134° - 135° C./0.1 mm. Gas-liquid chromatographic (GLC) assay indicated a content of 1-isomer of 94.2%. Elemental analysis satisfactory.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:34][C:35]([F:41])([F:40])[S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:23][CH:21]([S:18]([NH:17][CH2:16][CH:15]([O:14][C:13]1[CH:25]=[CH:26][C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][NH:2][S:36]([C:35]([F:41])([F:40])[F:34])(=[O:38])=[O:37])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)[CH3:24])(=[O:20])=[O:19])[CH3:22]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CN)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CNS(=O)(=O)C(F)(F)F)cc2)cc1
Yield: 10.8 %

Procedure:
The final title compound (23 mg, 11%) was prepared from (2-{4-[4-(aminomethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (150 mg, 0.430 mmol, prepared in example 32) methylene chloride 2.5 mL, anhydrous) triethylamine (0.07 mL, 0.471 mmol) and trifluoromethylsulfonyl chloride (9.06 mL, 0.565 mmol), in a manner analogous to Example 29.
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([OH:21])=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:28][O:29][C:30]([CH:32]1[NH:37][CH2:36][C:35]2[N:38]=[CH:39][N:40]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[C:44]([CH3:51])[CH:43]=3)[C:34]=2[CH2:33]1)=[O:31]>C(#N)C>[CH3:28][O:29][C:30]([CH:32]1[N:37]([C:19](=[O:21])[CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:36][C:35]2[N:38]=[CH:39][N:40]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[C:44]([CH3:51])[CH:43]=3)[C:34]=2[CH2:33]1)=[O:31]
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1Cc2c(ncn2Cc2ccc([N+](=O)[O-])c(C)c2)CN1
Agent: Oc1cccc2[nH]nnc12
Solvent: CC#N
Solvent: O
Product: COC(=O)C1Cc2c(ncn2Cc2ccc([N+](=O)[O-])c(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 16.7 g dicyclohexycarbodiimide, 10.9 g hydroxybenzotriazole hydrate, 17.2 g diphenylacetic acid and 150 mL acetonitrile is stirred at 25° C. for 15 min then treated with a solution of 25.4 g methyl-1-(3-methyl-4-nitrophenyl)methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate in 125 mL acetonitrile. The resulting suspension is stirred 48 hr at 25° C., filtered and the filtrate is evaporated, dissolved in dichloromethane, washed with 10% Na2CO3, dried and evaporated. Chromatography on silica gel (chloroform-methanol, 99:1) gives a crisp foam which crystallizes when triturated with methanol. MS (FAB) 525 (M+1).
Reaction SMILES: Br[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].O.[NH2:11][NH2:12]>C1COCC1>[C:4]1([CH:2]([NH:11][NH2:12])[CH3:3])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(Br)c1ccccc1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: CC(NN)c1ccccc1

Procedure:
1-bromoethylbenzene Compound 3a (8.0 mL, 58.0 mMol) was added to a solution of hydrazine hydrate Compound 3b (20 mL) in THF (80 mL) which was then heated to reflux for 8 hrs. The solvent was removed in vacito and Et2O (100 mL) was added. The organic layer was washed with brine, separated and dried over Na2SO4. The solvent was removed in vacuo to yield (1-phenyl-ethyl)-hydrazine Compound 3c as a pale yellow oil (5.8 g), used in the next step without purification. MS m/z 137 (M+H, 70%), 105 (M-NHNH2, 100%).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)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>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Br)o1
Reactant: OB(O)c1cccs1
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: [Na+]
Product: COC(=O)c1ccc(-c2cccs2)o1
Reaction time: 26 h
Yield: 90.8 %

Procedure:
Methyl 5-bromofuran-2-carboxylate (150 mg, 0.73 mmol), Pd(PPh3)4 (42 mg, 0.04 mmol), 2M Na2CO3 (0.73 ml, 1.46 mmol) and thiophen-2-ylboronic acid (121 mg, 0.95 mmol) in 1,4-dioxanes (7 ml) and was warmed to 90° C. The solution was then held at this temperature for 26 hours then cooled and washed with 1M HCl (2×20 mL), brine (2×20 mL) then dried (MgSO4) followed by filtration and evaporation to dryness. The resulting residue was then purified by flash column chromatography (5% EtOAc/hexanes) to obtain methyl 5-(thiophen-2-yl)furan-2-carboxylate (138 mg, 91%) as a yellow oil. 1H NMR (500 MHz, DMSO-d6) δ 7.69 (dt, J=5.0, 0.9 Hz, 1H), 7.59 (dt, J=3.6, 0.8 Hz, 1H), 7.40 (dd, J=3.7, 0.6 Hz, 1H), 7.23-7.15 (m, 1H), 6.99 (d, J=3.7 Hz, 1H), 3.83 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 158.1, 152.5, 142.3, 131.2, 128.5, 127.7, 125.8, 120.7, 107.5, 51.8; HRMS (ESI) calcd for [C10H8O3S+H]+ 209.0267. found 209.0272. Method D with methyl 5-(thiophen-2-yl)furan-2-carboxylate (100 mg, 0.48 mmol) afforded 5-(thiophen-2-yl)furan-2-carboxylic acid (92 mg, 99%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.16 (bs, 1H), 7.68 (dd, J=5.0, 1.1 Hz, 1H), 7.56 (dd, J=3.6, 1.1 Hz, 1H), 7.30 (d, J=3.6 Hz, 1H), 7.18 (dd, J=5.0, 3.7 Hz, 1H), 6.95 (d, J=3.6 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 159.1, 152.0, 143.5, 131.5, 128.5, 127.4, 125.5, 120.0, 107.4; HRMS (ESI) calcd for [C9H6O3S+H]+ 195.0110. found 195.0112. Method B with 5-(thiophen-2-yl)furan-2-carboxylic acid (75 mg, 0.39 mmol) afforded the title compound VPC16b1145 (46 mg, 37%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.69 (bs, 1H), 8.72 (s, 1H), 7.81 (d, J=3.8 Hz, 1H), 7.73 (t, J=4.4 Hz, 2H), 7.22 (dd, J=4.9, 3.7 Hz, 1H), 7.07 (d, J=3.8 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 162.2, 156.0, 153.2, 143.2, 142.5, 141.9, 131.1, 128.4, 128.1, 126.5, 120.7, 107.8; HRMS (ESI) calcd for [C12H7N3O4S2+H]+ 321.9951. found 321.9963.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8]O)[CH:7]=1.S(Cl)([Cl:14])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][Cl:14])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cl)cc1CO
Solvent: ClCCl
Product: COc1ccc(Cl)cc1CCl
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To a solution of (5-chloro-2-methoxy-phenyl)-methanol (17.1 g, 99.1 mmol) in methylene chloride (100 mL) was added thionyl chloride (14.5 mL, 198 mmol). The reaction was stirred at reflux for 3 hours, cooled to room temperature and concentrated in vacuo. The crude product was dissolved in methylene chloride and washed with saturated aqueous sodium hydrogen carbonate then dried over magnesium sulfate. Concentration in vacuo gave 4-chloro-2-chloromethyl-1-methoxy-benzene (18.4 g). To a solution of 4-chloro-2-chloromethyl-1-methoxy-benzene (18.4 g, 96.4 mmol) in acetonitrile (100 mL) was added potassium cyanide (12.5 g, 193 mmol) and 18-crown-6 (2.54 g, 9.64 mmol). The reaction was stirred 12 hours at ambient temperature, diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by passing it through a pad of silica gel, eluting with methylene chloride to give the title compound (17.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][CH2:26][CH2:27][OH:28])=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:24]=[N:23][C:22]([NH:25][CH2:26][CH2:27][OH:28])=[CH:21][CH:20]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: Nc1ccc(NCCO)nc1
Product: O=C(c1cnc2ccc(Br)cc2c1Nc1ccc(NCCO)nc1)C1CC1
Yield: 67.2 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with 2-(5-aminopyridin-2-ylamino)ethanol (230 mg, 1.5 mmol) to afford the desired product (287 mg, 67%) as a yellow solid: ESI MS m/z 427 [C20H19BrN4O2+H]+.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.[NH:16]1[CH:20]=[C:19]([C:21]2[C:22]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:18]=[N:17]1.C1CCN2C(=NCCC2)CC1>>[C:1]1([CH:7]([N:16]2[CH:20]=[C:19]([C:21]3[C:22]4[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH:18]=[N:17]2)[CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)/C=C/c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)CC(c1ccccc1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A solution of methyl (2E)-3-phenylacrylate (500 mg, 0.003 mol) in ACN (2 mL, 0.04 mol) was slowly added to a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.5 g, 0.002 mol) in ACN (2 mL, 0.04 mol) and DBU (500 μL, 0.003 mol). The reaction was stirred at room temperature over the weekend. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated sodium chloride, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC on silica gel using EtOAc/Hexane (1:2 to 1:1) gave methyl 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoate (500 mg, 70%) as a semisolid residue.
Reaction SMILES: [OH:1][C:2]1([C:29]2[S:33][C:32](S(C)(=O)=O)=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[OH:1][C:2]1([C:29]2[S:33][C:32]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:9][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[O:14])[CH2:11]2)[CH2:4][CH2:3]1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cnc(N4CCCC4)s3)CC2)C1

Procedure:
The title compound was prepared as a white solid from N-({1-[4-hydroxy-4-(2-methanesulfonyl-thiazol-5-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (less polar isomer, 47a), and pyrrolidine (Aldrich) using the procedure described in Example 50.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C[Si]([C:17]#[CH:18])(C)C>N1C=CC=CC=1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)#[CH:18]
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CCc2cc(Br)ccc2N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: C#Cc1ccc2c(c1)CCC(=O)N2
Reaction time: 18 h

Procedure:
A mixture of 8.0 g of 6-bromo-3,4-dihydrocarbostyril, 6.95 g of trimethylsilylacetylene, 460 mg of bis(triphenylphosphine)palladium dichloride and 62 mg of cuprous iodide in 53 ml of pyridine and 11 ml of triethylamine was refluxed for 3 days. The solvent was removed under reduced pressure, 50 ml of methanol added along with 300 mg of potassium carbonate, and the mixture stirred under nitrogen for 18 hours. The solvent was removed under reduced pressure and the residue chromatographed on silica gel, eluting with 3% methanol in methylene chloride, giving a product of 6-ethynyl-3,4-dihydrocarbostyril, m.p. 182°-184° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:11](=O)[CH2:12][O:13][CH3:14])=[C:5](OC)[CH2:6][O:7][CH3:8].[Br:17][C:18]1[CH:19]=[C:20]([NH:24][NH2:25])[CH:21]=[CH:22][CH:23]=1>>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH2:6][O:7][CH3:8])=[N:25][N:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Br:17])[CH:19]=2)[C:11]=1[CH2:12][O:13][CH3:14])=[O:16]
Reactant: COCC(=O)C(C(=O)OC)=C(COC)OC
Reactant: NNc1cccc(Br)c1
Product: COCc1nn(-c2cccc(Br)c2)c(COC)c1C(=O)OC

Procedure:
In analogy to the procedures described for intermediates 1A-E, the title compound has been obtained by i) condensation of methyl 4-methoxyacetoacetate with methoxyacetyl chloride to give 4-methoxy-2-(2-methoxy-acetyl)-3-oxo-butyric acid methyl ester; ii) methylation of 4-methoxy-2-(2-methoxy-acetyl)-3-oxo-butyric acid methyl ester with methyl trifluoromethanesulfonate to give (E and/or Z)-3,4-dimethoxy-2-(2-methoxy-acetyl)-but-2-enoic acid methyl ester; iii) condensation of (E and/or Z)-3,4-dimethoxy-2-(2-methoxy-acetyl)-but-2-enoic acid methyl ester with (3-bromo-phenyl)-hydrazine to give 1-(3-bromo-phenyl)-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester; iv) reaction of 1-(3-bromo-phenyl)-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester with (E)-2-(4-chlorophenyl)vinyl boronic acid to give 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester; v) saponification of 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester to give the title compound as light brown solid. MS: 411.2 ([M−H]−, 1 Cl).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:20]#[N:21]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([C:20](=[NH:21])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: COc1ccc(C#N)cc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (2.82 g, 16.5 mmol) in toluene (150 mL), trimethylaluminum (2M solution in toluene, 12.5 mL, 24.7 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 3-fluoro-4-methoxybenzonitrile (5 g, 33 mmol) in toluene (100 mL) was added over 10 minutes and the reaction mixture was heated to 80-85° C. After 20 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates were concentrated in vacuo and the resulting yellowish solid was stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate was filtered and washed with more hexane/ether (2/1). The pale yellow solid 3-fluoro-4-methoxy-N-(4-(methylsulfonyl)phenyl]benzenecarboximidamide (3.95 g, 74%) was used in the next reaction without further purification: mp (DSC) 195C. Anal. Calc'd. for C15H15N2SO3F: C, 55.89, H, 4.69, N, 8.69. Found: C, 55.92, H, 4.74, N, 8.53.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:5].[CH2:34]([N:38]=[C:39]=[O:40])[CH2:35][CH2:36][CH3:37]>C(Cl)(Cl)Cl>[N+:31]([C:28]1[CH:29]=[CH:30][C:2]([NH:1][C:39]([NH:38][CH2:34][CH2:35][CH2:36][CH3:37])=[O:40])=[C:3]([CH:27]=1)[C:4]([NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:10][CH2:9]1)=[O:5])([O-:33])=[O:32]
Reactant: CCCCN=C=O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Step 1): To a solution of 2amino-5nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (Preparation 28) (1.2 g, 2.69 mmol) in CHCl3 (15 ml) was added n-butylisocyanate (802 mg, 8.09 mmol). After the solution was refluxed for 24 hours, the solvent was evaporated. The residue was purified by column chromatography on silica gel to give 5-nitro-2-(N'-n-butylureido)-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide, 1.1 g (75%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C@H:10]([NH:25][C:26](=[O:43])[C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34](=[O:42])[C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)[CH2:9]1)=O)(C)(C)C.[ClH:44]>C(COC)OC.C(O)(C)C>[ClH:44].[F:41][C:38]1[CH:37]=[CH:36][C:35]([C:34]([O:33][C:30]2[CH:31]=[CH:32][C:27]([C:26]([NH:25][C@H:10]3[C@H:11]([O:15][C:16](=[O:24])[C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9]3)=[O:43])=[CH:28][CH:29]=2)=[O:42])=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OC(=O)c2ccc(O)cc2)[C@H](NC(=O)c2ccc(OC(=O)c3ccc(F)cc3)cc2)C1
Agent: Cl
Solvent: CC(C)O
Solvent: COCCOC
Product: O=C(N[C@@H]1CNCCC[C@H]1OC(=O)c1ccc(O)cc1)c1ccc(OC(=O)c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
56 mg (3R,4R)-3-[4-(4-Fluoro-benzoyloxy)-benzoylamino]-4-(4-hydroxy-benzoyloxy)-azepane-1-carboxylic acid tert-butyl ester was dissolved in 2 ml dimethoxyethane and 2 ml isopropanol (i-Pr-OH); after cooling to 0° C. the solution was slowly saturated with HCl-gas and stored in a refrigerator for 24 h. The solvent was completely removed in vacuo; the product was triturated with diethylether; the resulting suspension was stirred for several hours. The solvent was decanted and stirring was continued overnight after addition of another portion of fresh solvent. The product was filtered, washed with several portions of diethylether and dried in vacuo (0.1 mbar) at 50° C. 40 mg (85% yield) 4-Hydroxy-benzoic acid (3R,4R)-3-[4-(4-fluoro-benzoyloxy)-benzoylamino]-azepan-4-yl ester hydrochloride (1:1) was obtained as a yellow powder
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH:17]1[C:22]([S:23](Cl)(=[O:25])=[O:24])=[CH:21][CH:20]=[C:19]([I:27])[CH:18]=1.Cl>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][S:23]([C:22]1[CH:17]=[CH:18][C:19]([I:27])=[CH:20][CH:21]=1)(=[O:25])=[O:24])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
To a magnetically stirred solution of 2-amino-5-chlorobenzophenone (1.62 g, 7.0 mmol) in dry pyridine (30 mL) was added dropwise a solution of pipsyl chloride in toluene (12 mL) and the reaction was stirred at ambient temperature. The reaction was added to cold (ice bath) 6M hydrochloric acid with stirring and the mixture was extracted with ethyl acetate (3×50 mL). The extracts were washed with water and with saturated aqueous NaCl. The organic layer was dried (MgSO4), filtered and concentrated to give a crystalline solid. The product was filtered, washed with hexane and dried (vacuum) to get white crystalline solid. 1H NMR (CDCl3) δ 9.63 (br s, 1H, NH), 7.75 (dm, 1H, J=8.8 Hz), 7.62 (tm, 1H, J=7.6 Hz), 7.56 (dm, 1H, J=7.6 Hz), 7.48 (m, 3H), 7.32 (m, 5H). MS: m/z 498.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:8]2)([O-:3])=[O:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[C:7]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cc2c([N+](=O)[O-])cccc2[nH]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c([N+](=O)[O-])cccc2n1Cc1ccc(Cl)c(Cl)c1
Yield: 89 %

Procedure:
Ethyl 4-nitroindole-2-carboxylate (26 g) [prepared according to S. M. Parmerter el. al. J. Amer. Chem. Soc., 1958, 80, 4621], 3,4-dichlorobenzyl chloride (16 ml), potassium carbonate (17 g) and potassium iodide (2 g) in DMF (250 ml) were stirred at 60° C. for 2 hours. The reaction was concentrated in vacuo and the residue partitioned between water and dichloromethane. Iso-hexane was added to the combined organic extracts resulting in crystallisation of the product as yellow needles (39 g. 89%) NMR d (CD3SOCD3) 1.30 (t, 3H), 4.32 (q, 2H), 5.93 (s, 2H), 6.88 (dd, 1H), 7.18 (d, 1H), 7.52 (d, 1H), 7.56 (dd, 1H), 7.78 (s, 1H), 8.17 (m, 2H); M/z (+) 395 (MH+), 393.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:4][N:3]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:28][CH2:27][CH2:25][OH:26])=[N:3][CH:4]=2)=[N:12][N:11]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Cl)nc2)o1
Reactant: NCCO
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(NCCO)nc2)o1
Yield: 59 %

Procedure:
As described for example 136b, 2-chloro-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (200 mg, 0.59 mmol) was converted using ethanolamine instead of morpholine to the title compound (126 mg, 59%) which was obtained as an off-white solid. MS: m/e=364.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]2([OH:26])[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:4][CH:3]=1.C[O:28][C:29](=[O:52])[C@H:30]([C@@H:49]([CH3:51])O)[NH:31]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]2([O:26][C@H:49]([CH3:51])[C@@H:30]([C:29]([OH:52])=[O:28])[NH2:31])[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:6][CH:7]=1
Reactant: OC1(c2sccc2-c2ccc(F)cc2)c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OC1(c2sccc2-c2ccc(F)cc2)c2ccccc2-c2ccccc21)[C@H](N)C(=O)O

Procedure:
from 9-[3-(4-fluorophenyl)thien-2-yl]-9H-fluoren-9-ol (Example 3v) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4 ;