Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:11](=[O:25])[CH2:12][N:13](C)[C:14](=O)OCC1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:33]>C(O)C.[C].[Pd]>[ClH:33].[CH3:14][NH:13][CH2:12][C:11](=[O:25])[CH:10]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN(CC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNCC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
[3-(Benzoylamino)-2-oxo-4-phenylbutyl]methylcarbamic acid, phenylmethyl ester (0.5 g.) is dissolved in ethanol (50 ml.) containing 1N hydrochloric acid (2 ml.). Palladium carbon catalyst (10%, 100 mg.) is added and hydrogenation is continued overnight. The reaction mixture is then filtered, evaporated, dissolved in water, and lyophilized to 300 mg. of (±)-N-[3-(methylamino)-2-oxo-1-(phenylmethyl)propyl]benzamide, hydrochloride as a homogeneous white powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=O.S(Cl)([Cl:23])=O>>[CH3:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([Cl:23])=[O:20]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Product: Cc1c(CC(=O)Cl)cccc1C(=O)c1ccc(Cl)cc1

Procedure:
A solution of 5.8 g of 2-methyl-3-(p-chlorobenzoyl)-phenylacetic acid in 25 ml of thionyl chloride was refluxed for 11/2 hours and excess thionyl chloride was removed to obtain 2-methyl-3-(p-chlorobenzoyl)-phenylacetic acid chloride melting at 62°-63°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13]OCC)=[O:10])=[CH:5][CH:4]=1.CCOCCO[C:25](/[CH:27]=[CH:28]/[C:29]1C=CC(OC)=CC=1)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:8][C:9]([O:11][CH:12]2[CH2:13][CH2:29][CH2:28][CH2:27][CH2:25]2)=[O:10])=[CH:17][CH:18]=1
Reactant: CCOCCOC(=O)C=Cc1ccc(OC)cc1
Reactant: CCOCCOC(=O)/C=C/c1ccc(OC)cc1
Product: COc1ccc(C=CC(=O)OC2CCCCC2)cc1

Procedure:
2-ethoxyethyl p-methoxycinnamate or "Cinoxate" according to the common international name, sold under the trade name Giv-Tan F;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[C:20]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21]>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:34](=[O:35])[NH:33][C:30]2[CH:29]=[CH:28][C:27]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])=[CH:32][CH:31]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCCCOC(=O)c1ccc(N=C=O)cc1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Product: CCCCOC(=O)c1ccc(NC(=O)N2C=C(C(=O)OCC)c3[nH]c4ccccc4c3CC2)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 72 by using ethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 4-(carbobutoxy)phenyl isocyanate (˜2.0 mg); MS (ES): 476 (MH+).
Reaction SMILES: [K].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:14])=[C:7]([C:9]([CH:11]2[CH2:13][CH2:12]2)=O)[CH:8]=1.[C:15]1(C)C=CC=CC=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:14])=[C:7]([C:9]([CH:11]2[CH2:13][CH2:12]2)=[CH2:15])[CH:8]=1
Reactant: Cc1ccccc1
Reactant: O=C(c1cc(Br)ccc1F)C1CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K]
Product: C=C(c1cc(Br)ccc1F)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (7.142 g, 20 mmol) in toluene (50 ml) was treated with potassium amylate (1.7 M in toluene, 11.76 ml, 20 mmol), and the mixture was stirred at 0° C. for 30 minutes. A solution of (5-bromo-2-fluoro-phenyl)-cyclopropyl-methanone (4.05 g, 17 mmol) in toluene (17 ml) was added and the mixture stirred at room temperature for 2 hours. For the workup, the mixture was extracted with water and ethyl acetate, the organic layer separated, dried and evaporated at reduced pressure. After chromatography on silica gel using a mixture of hexane and ethyl acetate as the eluent, the 4-bromo-2-(1-cyclopropyl-vinyl)-1-fluoro-benzene was obtained as yellow oil (3.816 g, 95% of theory). Mass (calculated) C11H10BrF [241.102]; (found) [M+H]+=241, [M+2-H]+=243.
Reaction SMILES: C[O:2][C:3](=[O:45])[CH2:4][NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[C:35]=2[Cl:44])[CH2:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[ClH:44].[Cl:44][C:35]1[C:36]([C:40]([F:41])([F:42])[F:43])=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][N:18]([CH2:19][CH:20]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:17][CH2:16][CH2:15][O:14][C:10]1[CH:9]=[C:8]([CH2:7][CH2:6][NH:5][CH2:4][C:3]([OH:45])=[O:2])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CNCCc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNCCc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of [2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-acetic acid methyl ester (70 mg, 0.11 mmol) in THF (10 ml) and water (3.3 ml) was added lithium hydroxide monohydrate (12 mg, 0.28 mmol). The resulting mixture was stirred at room temperature for 18 hours and acidified with HCl (0.5 ml, 1 M in water). The crude mixture was concentrated in vacuo and then extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried over sodium sulfate, filtered and concentrated in vacuo. Preparative HPLC (YMC 75×30 mm, 25 ml/min, 25-100% CH3CN) afforded the title compound as the free base. The diamine was treated with 1 M HCl in Et2O (0.11 ml, 0.11 mmol), and the Et2O was evaporated to afford the title compound as an off-white solid, 31 mg (45%). MS(ES) m/e 625.4 (M+).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:27])=[CH:24][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:15]1([N:7]2[CH2:8][C:9]([F:14])([F:13])[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[O:27])=[CH:35][CH:36]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1ccc(C(=O)NC2CCOCC2)cc1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: O=C(NC1CCOCC1)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3)cc1
Yield: 84.6 %

Procedure:
A mixture of 0.05 g (0.17 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20), 0.04 g (0.20 mmole) of 4-amino-N-(tetrahydro-pyran-4-yl)-benzamide and 0.05 g (0.25 mmole) of p-toluenesulfonic acid monohydrate in 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled mixture was then concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane, and the combined organic layers washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was washed with water and dried to give 0.070 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-benzamide (I-136).
Reaction SMILES: [O:1]=[C:2]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:3]=[CH:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1>C(O)C.[H][H]>[O:1]=[C:2]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: CCOC(=O)COc1ccc(C=CC(=O)c2cccnc2)cc1
Solvent: CCO
Product: CCOC(=O)COc1ccc(CCC(=O)c2cccnc2)cc1
Reaction time: 3 h
Yield: 50.3 %

Procedure:
Ethyl 4-[3-oxo-3-(3-pyridyl)-1-propenyl]phenoxyacetate (3.85 g) and 1.15 g of 10% Pd--C were suspended in 300 ml of ethanol, and stirred in hydrogen atmosphere at ambient temperature and pressure for three hours. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue obtained was subjected to chromatography on a silica gel column, and from a fraction eluted with methylene chloride was obtained 1.95 g of ethyl 4-[3-oxo-3-(3-pyridyl)propyl]phenoxyacetate.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@@H:12]1[CH2:14][O:13]1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][C:16]1=[O:21]>C(Cl)Cl>[OH:13][C@H:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:18]1[CH2:19][CH2:20][NH:15][C:16](=[O:21])[CH2:17]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: O=C1CNCCN1
Solvent: ClCCl
Product: Cc1c([C@@H](O)CN2CCNC(=O)C2)ccc2c1COC2=O
Temperature: 145 °C

Procedure:
A mixture of 4-Methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (0.46 g, 2.4 mmol) and piperazin-2-one (0.20 g, 2.0 mmol) was heated to 145° C. in a microwave tube for 1 hour. The crude reaction was diluted with DCM, adsorbed onto silica gel, and purified by silica gel chromatography to provide the title product. LC-MS (IE, m/z): 291 (M+1)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)[CH:17]=3)[S:12][C:11]([CH3:33])([CH3:32])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=4)[CH:17]=3)[S:12][C:11]([CH3:32])([CH3:33])[CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(C2=CC(C)(C)Sc3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of ethyl 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate (940.0 mg, 2.08 mmol) in 10.0 mL THF and 5.0 mL ethanol (EtOH) was added NaOH (416.0 mg, 10.4 mmol, 5.2 mL of a 2M aqueous solution). The resulting solution was stirred overnight at room temperature. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 786.0 mg (89%) of 4[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoic acid as a colorless solid. 1H NMR (300 MHz, d6-acetone) δ: 8.01 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.5 Hz), 7.42 (2H, m), 7.29 (2H, m), 7.22 (3H, m), 5.94 (1H, s), 2.69 (2H, q, J=7.7 Hz), 1.47 (6H, s), 1.25 (3H, t, J=7.7 Hz). This compound, the final desired product, was termed Compound 1.
Reaction SMILES: C1C2C3C=[C:11]4[C:16](=CC=3SC=2C=CC=1)[CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=[CH:12]4.[CH2:20]([N:22]1[C:34]2[CH:33]=[CH:32][C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[C:29]=2C2C=CC=C(C)C1=2)[CH3:21]>C(Cl)Cl.CCCCCC>[CH2:20]([N:22]1[C:34]2[CH:33]=[CH:32][C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[C:29]=2[C:16]2[C:15]1=[C:14]([CH:18]=[O:19])[CH:13]=[CH:12][CH:11]=2)[CH3:21]
Reactant: CCn1c2ccc3ccccc3c2c2cccc(C)c21
Reactant: O=Cc1ccc2cc3c(cc2c1)sc1ccccc13
Solvent: ClCCl
Solvent: CCCCCC
Product: CCn1c2ccc3ccccc3c2c2cccc(C=O)c21
Yield: 17.2 %

Procedure:
Using the procedure outlined in 8A, 7-ethyl-8-methyl-7H-benzo[c]carbazole gave a 17.2% of 7-ethyl-7H-benzo[c]carbazole-8-carbaldehyde, mp 148°-149°, (CH2Cl2 /hexane), (C,H,N).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:20][C:21]([OH:23])=O)=[CH:15][CH:14]=1.FC(F)(F)C([O-])=O.[NH2:31][C@@H:32]1[C:39](=[O:40])[N:38]2[C@@H:33]1[S:34][CH2:35][C:36](/[CH:44]=[C:45]1/[C:46](=[O:68])[N:47]([CH2:50][C:51]3[CH:56]=[CH:55][N+:54]([CH2:57][C:58](=[O:67])[NH:59][C:60]4[CH:65]=[CH:64][C:63]([OH:66])=[CH:62][CH:61]=4)=[CH:53][CH:52]=3)[CH2:48][CH2:49]/1)=[C:37]2[C:41]([OH:43])=[O:42]>CN(C)C(=O)C>[OH:66][C:63]1[CH:62]=[CH:61][C:60]([NH:59][C:58]([CH2:57][N+:54]2[CH:55]=[CH:56][C:51]([CH2:50][N:47]3[CH2:48][CH2:49]/[C:45](=[CH:44]\[C:36]4[CH2:35][S:34][C@H:33]5[N:38]([C:39](=[O:40])[C@H:32]5[NH:31][C:21](=[O:23])[CH2:20][S:19][C:16]5[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=5)[C:37]=4[C:41]([O-:43])=[O:42])/[C:46]3=[O:68])=[CH:52][CH:53]=2)=[O:67])=[CH:65][CH:64]=1
Reactant: O=C(O)CSc1ccncc1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)cc5)cc4)C3=O)CS[C@H]12
Agent: O=C([O-])C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CSc5ccncc5)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)cc1

Procedure:
With 70.0 mg (0.43 mmol) 1,1′-carbonyldiimidazole, 72.8 mg (0.43 mmol) (pyridin-4-ylsulfanyl)-acetic acid and 232.8 mg (0.36 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin- 1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3 -ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo [4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml ml N,N-dimethylacetamide. The brown solid was purified by column chromatography on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water: acetonitrile (1:0, 4:1, 3:1, 2:1, 1:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.[CH:25]([C:27]1[C:28]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:29]=2[S:30][CH:31]=1)=O.CCCCC>ClCCl.[Zn]>[Br:20][C:21]([Br:24])=[CH:25][C:27]1[C:28]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:29]=2[S:30][CH:31]=1
Reactant: Cc1cccc2c(C=O)csc12
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: ClCCl
Product: Cc1cccc2c(C=C(Br)Br)csc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.04 g of Zn dust and 4.17 g of triphenylphosphine are taken up in dichloromethane and 5.27 of tetrabromomethane dissolved in dichloromethane added dropwise under inert gas and with cooling. Following stirring for 24 hours at room temperature 1.4 g of 3-formyl-7-methylbenzo[b]thiophene dissolved in dichloromethane are added dropwise with ice-cooling and stirring continued overnight at room temperature. Pentane is added and the precipitated Ph3PO filtered off. Evaporation of the filtrate under vacuum yields a residue which is chromatographed over silica gel to yield the title compound, M.p.=75°-78°.
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][C@H:19]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:17])([CH3:14])([CH3:13])[CH3:12].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=[CH2:1])[CH2:20][C@H:19]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C[C@H]1C(=O)OCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C1CCN(C(=O)OC(C)(C)C)[C@H](C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a suspension of methyl(triphenyl)phosphonium bromide (248 g, 0.69 mol) in anhydrous toluene (1 L) was added sodium hexamethyldisilazide (258 ml, 0.69 mmol) at 0° C., after addition was completed, the reaction mixture was warmed to room temperature, and stirred at room temperature for 1 hour, then cooled to 0° C. and the solution of (S)-4-oxo-piperidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (intermediate 14, 210 g, 0.63 mol) in anhydrous toluene (0.5 L) was added. The resulting mixture was warmed to room temperature, and stirred at room temperature for 1 hour, added water (500 ml), extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 10/1 to 5/1). (S)-4-Methylene-piperidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester was obtained as colourless oil (120 g), yield:57.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[CH2:27]([NH:29][CH2:30][CH2:31][OH:32])[CH3:28]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:29]([CH2:27][CH3:28])[CH2:30][CH2:31][OH:32])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: CCNCCO
Solvent: CC(=O)N(C)C
Product: CCN(CCO)CCCCOC[C@H]1CC[C@H](CN(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was reacted with ethyl-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at 50° C. for 3 hours to yield trans-(4-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butoxymethyl}-cyclohexylmethyl)-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 455 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCN4CCOCC4)CC3)noc2c1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 2-chloroethyl morpholine hydrochloride (4.46 g, 29.7 mmol) and K2CO3 (7.3 g, 2.2 eq) in acetonitrile (60 ml) was heated at reflux for 24 hours. The crude mixture was diluted with DCM and filtered. The solvent was concentrated to an oil (~7.1 g). Purification on a silica gel column (55 g, SiO2, eluted with MeOH:DCM) yielded a solid product weighing 4 g. Recrystallization from hot ethanol yielded 2.1 g (48%), m.p.=131°-132° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH3:15])[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[C@H:11]([CH2:13][N:14]([C:40]([CH:37]2[CH2:39][CH2:38]2)=[O:41])[CH3:15])[CH2:12]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CNC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C)C(=O)C2CC2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R*,4R*)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (134 mg, 0.264 mmol) in CH2Cl2 (2 mL), cyclopropanecarbonyl chloride (29 μL, 0.317 mmol) and triethylamine (44 μL, 0.317 mmol) are added under N2 atmosphere. The mixture is stirred overnight at RT, diluted with CH2Cl2 and poured into an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous one is extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude product is used in the next step without purification. TLC, Rf (CH2Cl2/MeOH 95:5)=0.2. MS (LC-MS): 476.1 [M+H-Boc]+. tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.42 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1.[Cl-].[Ca+2].[Cl-]>C(O)C>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([S:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)=[CH:13][CH:12]=1
Reactant: Cn1ccnc1Sc1ccc([N+](=O)[O-])cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Cn1ccnc1Sc1ccc(N)cc1
Temperature: 105 °C
Reaction time: 6 h
Yield: 83.7 %

Procedure:
1-methyl-2-[(4-nitrophenyl)thio]imidazole (6.0 g), reduced iron (7.12 g) and calcium chloride (1.42 g) were added to 85% aqueous solution of ethanol (100 ml), and the mixture was stirred for 6 hours at 105° C. under nitrogen atmosphere. The mixture was allowed to be at room temperature, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. To the obtained residue was added water and the mixture extracted with ethyl acetate twice. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethyl acetate-diisopropyl ether, to give 2-[(4-aminophenyl)thio]-1-methylimidazole (4.38 g) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:10][C:11]([CH2:13][C:14](=O)[CH3:15])=[O:12]>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:13]([C:11](=[O:12])[CH3:10])=[C:14]([CH3:15])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccnc1N
Reactant: CC(=O)CC(=O)CCl
Solvent: CCO
Product: CC(=O)c1c(C)nc2c(N)cccn12
Yield: 15.7 %

Procedure:
A mixture of 2,3-diaminopyridine (7 g, 64.1 mmol), 3-chloroacetylacetone (8.6 g, 64.1 mmol) in ethyl alcohol (80 ml) was refluxed for 9 hours. The solvent was removed under reduced pressure and the residue dissolved in methylene chloride. A sodium bicarbonate solution was added and the organic layer was separated. The aqueous layer was extracted twice with methylene chloride. The combined organic layer was dried and evaporated under reduced pressure. Chromatography of the residue on silica gel (methylene chloride:methanol, 100:5) gave a product which after recrystallisation from ethyl acetate gave 1.9 g (15%) of the title compound.