Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([F:24])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH2:25]([O:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37](OS(C(F)(F)F)(=O)=O)=[CH:38][CH:39]=[N:40]2)=[CH:35][C:34]=1[O:51][CH3:52])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1C(C)=CC=CC=1C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:37]4[C:36]5[C:41](=[CH:42][C:33]([O:32][CH2:25][C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[C:34]([O:51][CH3:52])[CH:35]=5)[N:40]=[CH:39][CH:38]=4)=[C:19]([F:24])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(O)c(F)c2)CC1
Reactant: COc1cc2c(OS(=O)(=O)C(F)(F)F)ccnc2cc1OCc1ccccc1
Solvent: Cc1cccc(C)n1
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1OCc1ccccc1
Temperature: 143 °C
Yield: 48 %

Procedure:
To a flask containing cyclopropane-1,1-dicarboxylic acid (3-fluoro-4-hydroxy-phenyl)-amide (4-fluoro-phenyl)-amide (2.25 g, 6.7 mmol) and trifluoromethanesulfonic acid 7-benzyloxy-6-methoxy-quinolin-4-yl ester (1.87 g, 4.5 mmol) was added dry 2,6-lutidine (9 mL). The reaction mixture was heated to reflux (143° C.) with vigorous stirring. The reaction progress was monitored by LC-MS. 2,6-Lutidine was removed under reduced pressure when the reaction was complete (about 6 h). The residue was treated with charcoal (1.5 g) in refluxing EtOAc (50 mL) for 15 min, and filtered through celite. The volume of the filtrate was reduced to about 20 mL and was added 20 mL of 1 N HCl. The crude product precipitated as the HCl salt, which was filtered and washed with EtOAc and H2O (88% purity by analytical HPLC). The HCl salt was free-based with saturated aqueous NaHCO3 solution. Further purification by column chromatography (hexans:EtOAc=1:4) gave cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide (4-fluoro-phenyl)-amide as an off-white solid (1.3 g, 48% yield. 1H NMR (400 MHz, DMSO, d6): 10.41 (s, 1H), 10.02 (s, 1H), 8.48 (d, 1H), 7.92 (dd, 1H), 7.65 (m, 2H), 7.54 (m, 5H), 7.41 (m, 4H), 7.17 (m, 2H), 6.43 (d, 1H), 5.32 (s, 2H), 3.97 (s, 3H), 1.48 (m, 4H). LC/MS Calcd for [M+H]+ 596.2, found 596.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([NH:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([NH:30][CH2:31][C:32]([CH3:34])([CH3:33])[CH3:35])(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)NCC(C)(C)C)cc1Br
Product: Cc1ccc(S(=O)(=O)NCC(C)(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-N-(2,2-dimethyl-propyl)-4-methyl-benzenesulfonamide (Intermediate 145), the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=1[Cl:27])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>CO.[Zn]>[C:1]([O:5][C:6](=[O:28])[N:7]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[Cl:27])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc([N+](=O)[O-])cc1Cl)Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(N)cc1Cl)Cc1ccc(F)cc1
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
To a solution of [2-(2-chloro-4-nitro-phenyl)ethyl]-(4-fluoro-benzyl)-carbamic acid tert-butyl ester (0.6 g, 1.4 mmol) in methanol (18 mL) was added a saturated solution of NH4Cl (18 mL), followed by zinc powder (0.41 g, 7.3 mmol) and the reaction mixture was heated at 45° C. for 1 hour. The reaction mixture was cooled to RT, filtered and EtOAc (60 mL) and water (100 mL) were added to the filtrate and the mixture was stirred for 15 minutes. The separated organic phase was washed with water (80 mL), brine (80 mL), dried (Na2SO4) and the solvents removed under reduced pressure to afford the title compound (0.49 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[Li][CH3:10].[NH4+].[Cl-].O>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([OH:8])[CH3:10])[S:5][CH:6]=1
Reactant: [Li]C
Reactant: O=Cc1cc(Br)cs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CC(O)c1cc(Br)cs1
Yield: 98.5 %

Procedure:
A solution of 4-bromo-2-thiophenecarboxaldehyde (Aldrich, 1.20 g, 6.28 mmol) in 15 ml of anhydrous ethyl ether is brought to −70° C. in a flask fitted with a thermometer, under an atmosphere of argon and with magnetic stirring. Then a 1.6 M solution of MeLi in ether (4.12 ml, 6.59 mmol) is added drop by drop between −70° C. and −60° C. The reaction is followed by CCM (eluent ether:petroleum ether=20:80). The mixture is hydrolysed in the cold with 5 ml of saturated NH4Cl solution, 20 ml of distilled water is added and the mixture is extracted with ether (3×40 ml). The ether phase is dried over MgSO4, filtered and evaporated to obtain 1.28 g of a slightly yellowish oil, 4-bromo-2-(1′-hydroxyethyl)thiophene (gross yield=98.5%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>>[Cl:13][C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: NCc1cccc(Cl)c1Cl
Reactant: Cc1cc(Cl)c2ccccc2n1
Product: Cc1cc(NCc2cccc(Cl)c2Cl)c2ccccc2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methylquinoline and 2,3-dichlorobenzylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[C:8]([F:11])=[CH:9][CH:10]=1.[CH2:25]([NH2:27])[CH3:26]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[CH2:22][NH:27][CH2:25][CH3:26])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CCN
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1F

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (6-fluoro-2′-formyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and ethylamine (2M in THF).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2.[Br-:13].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[NH:9][CH2:8][CH2:7][CH2:6]2
Reactant: [Br-]
Reactant: COc1ccc2c(c1)CCCN2
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cc(Br)c2c(c1)CCCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.9 %

Procedure:
Part A: A solution of 6-methoxy-1,2,3,4-tetrahydroquinoline (6.19 g, 37.9 mmol) in CH2Cl2 (76 mL) was treated with pyridinium tribromide (25.42 g, 79.7 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with sat NaHSO3 (50 mL) and water (50 mL). The dichloromethane was separated, dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel using 20% ethyl acetate/hexanes as eluent to give 8-bromo-6-methoxy-1,2,3,4-tetrahydroquinoline (2.93 g, 32% yield): 1H NMR (300 MHz, CDCl3): δ 6.88 (s 1 H), 6.55 (s, 1 H), 3.71 (s, 3 H), 3.37–3.33 (t, J=6.6, 2 H), 2.78–2.74 (t, 2 H), 1.97–1.89 (m, 2 H); LRMS (AP+) for (M+H)+: for C10H12NOBr Calculated: 241.1 found : 241.0.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:27])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10](Br)[C:9]1=[O:26])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.[N-:33]=[N+:34]=[N-:35].[Na+].O>C(OCC)(=O)C>[C:1]([NH:5][C:6](=[O:27])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([N:33]=[N+:34]=[N-:35])[C:9]1=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)NC(=O)CN1C(=O)C(Br)CC(c2ccccc2)c2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)CN1C(=O)C(N=[N+]=[N-])CC(c2ccccc2)c2ccccc21
Temperature: 75 °C

Procedure:
To a 250 ml round-bottomed flask equipped with N2 inlet were added N-tert-butyl-2-[3-bromo-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide, (8.317 g, 19.37 mmoles), 90 ml dimethylformamide (DMF), and sodium azide (5.25 g, 80 mmoles, under nitrogen), and the mixture was heated at 75° C. for 20 hours with stirring. The reaction mixture was then cooled and distributed between water and ethyl acetate, separated, and the aqueous phase was again extracted. The combined extracts were washed with water three times, with bicarbonate solution once, and then dried with brine and sodium sulfate and filtered and evaporated, leaving a gummy residue, 8.58 g (100%), containing some solvent.
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:20]1(=[N:34]O)[C:33]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH2:23][CH2:22][CH2:21]1.[OH2:36]>ClCCl>[O:36]=[C:20]1[NH:34][C:33]2[CH:32]=[CH:31][C:30]3[C:25]([C:24]=2[CH2:23][CH2:22][CH2:21]1)=[CH:26][CH:27]=[CH:28][CH:29]=3
Reactant: O
Reactant: ON=C1CCCc2c1ccc1ccccc21
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: O=C1CCCc2c(ccc3ccccc23)N1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
A solution of methanesulfonic acid (25 ml) and phosphorus pentaoxide (5.2 g, 37 mmol) was heated at 90° C. for 3.5 h. The solution was cooled to 50° C. and 3,4-dihydro-2H-phenanthren-1-one-oxime (4.8 g, 23 mmol) was added. The solution was heated at 60° C. for 10 minutes and then at 80° C. for 3.5 hr. The hot reaction mixture was added to a mixture of ice (300 g) and water (100 ml). The precipitated solid was isolated by filtration, redissolved in dichloromethane (50 ml), dried (MgSO4) and evaporated in vacuo to afford a white product. Purification was achieved using column chromatography with silica gel (200 g) and a mixture of heptane and ethyl acetate (1:2) to afford 4.8 g of 4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepine.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC.[CH2:23]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CO>[CH2:23]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:1][CH2:2][CH:3]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:4][PH:5](=[O:9])[OH:6])=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCOC(OCC)P(=O)(CC(CN)c1ccccc1)OCC
Reactant: CCCCCCCCc1ccc(C=O)cc1
Solvent: CO
Product: CCCCCCCCc1ccc(CNCC(C[PH](=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.1 %

Procedure:
A mixture of 69.2 mg (0.210 mmol) of ethyl 3-amino-2-phenylpropyl(diethoxymethyl)phosphinate (Tetrahedron, 1989, 3787-3808) and 48.2 mg (0.221 mmol) of 4-octylbenzaldehyde in 1 mL of MeOH at rt was treated with 6.7 mg (0.105 mmol) of Na(CN)BH3. The resulting reaction mixture was stirred at rt for 16 hr. The reaction was quenched with 0.3 mL of 12 N HCl, then heated up to 60° C. for 5 hr. The mixture was cooled and concentrated. HPLC purification (LC-2) afforded 22 mg (26%) of the title compound. 1H NMR (500 MHz) (CD3OD) δ 0.88 (t, J=7.1, 3H), 1.26-1.30 (m, 10H), 1.58-1.61 (m, 2H), 2.01-2.17 (m, 2H), 2.62 (t, J=7.8, 2H), 3.20-3.23 (m, 1H),3.35-3.46 (m, 2H), 4.11 (s, 2H), 6.92 (d, J=535.4, 1H), 7.23-7.37 (m, 9H); LC-1: 3.31 min; ESI-MS 402 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[OH:24].C(S(C1C=C(C2C=C[C:44]([O:47]CCO)=[C:43]3[C:39]=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[O:24][CH2:39][CH2:43][CH2:44][OH:47]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(Cl)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCO)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCCO)c3[nH]c4ncc(Cl)cc4c23)c1

Procedure:
The title compound was prepared from Compound 218 by using an analogous procedure to that outlined in the preparation of Compound 215. 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1 H) 8.06 (m, 1 H) 8.01 (m, 2 H) 7.87 (t, J=8.0 Hz, 1 H) 7.63 (s, 1 H) 7.23 (d, J=8.32 Hz, 1 H) 7.16 (d, J=8.32 Hz, 1 H) 4.34 (t, J=6.32 Hz, 2 H) 3.72 (t, J=6.32 Hz, 2 H) 3.43 (q, J=7.32 Hz, 2 H) 2.02 (m, 2 H) 1.18 (t, J=7.32 Hz, 3 H). [M+H] calc'd for C22H22ClN2O4S, 445; found, 445.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)CCC.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](Br)[CH:27]=1.[Cl-].[Li+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Br:25][C:26]1[CH:27]=[C:28]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:29]=[CH:30][CH:31]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1-n1cncn1
Reactant: Brc1cccc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(-c2ccccc2-n2cncn2)c1
Temperature: 25 °C

Procedure:
To a degassed solution of 1-(2-tributylstannylphenyl)-1H-[1,2,4]triazole (300 mg, 0.7 mmol) in N,N-dimethylformamide (5 ml) was added 1,3-dibromobenzene (0.17 ml, 1.4 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 35 μmol), lithium chloride (293 mg, 6.9 mmol), then copper(I) iodide (13 mg, 69 μmol), and the mixture was heated at 80° C. for 5 h. The reaction was cooled to ambient temperature then poured into water (20 ml) and extracted with dichloromethane (3×20 ml). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. Purification by chromatography on silica gel eluting with dichloromethane on a gradient of methanol (0-1%), then by preparative thin-layer chromatography on silica gel using 5% methanol in dichloromethane as eluent, gave 1-(3′-bromobiphenyl-2-yl)-1H-[1,2,4]triazole as a colourless gel: m/z (ES+) 300, 302 (M++H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Ni]>[NH2:11][CH2:10][C:9]1[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([F:17])([F:18])[F:19])[C:8]=1[NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1cccc(C(F)(F)F)c1NC1CCCCC1
Agent: [Ni]
Solvent: CCO
Product: NCc1cccc(C(F)(F)F)c1NC1CCCCC1

Procedure:
Under an atmosphere of hydrogen and in ethanol, catalytic hydrogenation reaction of 2-(cyclohexylamino)-3-(trifluoromethyl)benzonitrile was carried out in the presence of Raney nickel to obtain 2-(aminomethyl)-N-cyclohexyl-6-(trifluoromethyl)aniline.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:38])[C@@H:5]([NH:10][C:11]([N:13]1[CH2:19][CH:18]([OH:20])[C@@H:17]([NH:21][C:22](=[O:36])[C@@H:23]([NH:28]C(OC(C)(C)C)=O)[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:15][C@H:14]1[CH3:37])=[O:12])[CH2:6][CH:7]([CH3:9])[CH3:8]>O1CCOCC1.CO>[CH3:2][O:3][C:4](=[O:38])[C@@H:5]([NH:10][C:11]([N:13]1[CH2:19][CH:18]([OH:20])[C@@H:17]([NH:21][C:22](=[O:36])[C@@H:23]([NH2:28])[CH2:24][CH:25]([CH3:26])[CH3:27])[CH2:16][CH2:15][C@H:14]1[CH3:37])=[O:12])[CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)N1CC(O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)CC[C@H]1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)N1CC(O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC[C@H]1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4.0 M HCl in dioxane (8 ml) was added to a stirred solution (S)-2-({1-[(2R,5S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-2-methyl-6-hydroxy-azepan-1-yl]-methanoyl}-amino)-4-methyl-pentanoic acid methyl ester (490 mg, 0.93 mmol) in MeOH (8 ml). The reaction mixture was stirred for 2.5 h at RT, then was concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (430 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].[CH:17]1(Br)[CH2:19][CH2:18]1>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH:17]2[CH2:19][CH2:18]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(O)ccc1Br
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(OC2CC2)ccc1Br
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 2.50 g (13 mmol) 2-bromo-5-hydroxy-benzonitrile in 100 mL DMF are added 5.23 g (38 mmol) K2CO3 and 3.05 g (25 mmol) cyclopropylbromide. The reaction mixture is stirred for 16 h at 120° C. Afterwards the reaction is quenched by the addition of ice water and extracted with EtOAc. The org. layers are combined, washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE/EtOAc).
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1)C.Cl.Cl[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[N:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH2:30][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]([CH:15]3[CH2:14][CH2:13][N:12]([CH2:11][C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:5]=4[C:4]([OH:3])=[O:27])[CH2:17][CH2:16]3)=[CH:19]2)[CH:32]=1
Reactant: ClCc1cccnc1
Reactant: CCOC(=O)c1cccnc1CN1CCC(c2c[nH]c3ccccc23)CC1
Agent: Cl
Product: O=C(O)c1cccnc1CN1CCC(c2cn(Cc3cccnc3)c3ccccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 1 (part E) starting with 0.76 g (0.21 mmol) of 2-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-nicotinic acid ethyl ester and 0.04 g (0.25 mmol) of 3-chloromethyl-pyridine hydrochloride. After standard purification, 0.040 g (45% of yield) of the expected acid were obtained.
Reaction SMILES: Br[CH:2](Br)C.[CH3:5][O:6][C:7]([C:9]1[S:10][C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:12][C:13]=1[N:14]([C:22]([CH:24]1[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])[CH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:8].C(=O)(O)[O-].[Na+]>O1CCCC1.ClCCl.[Zn]>[CH3:5][O:6][C:7]([C:9]1[S:10][C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:12][C:13]=1[N:14]([C:22]([CH:24]1[CH2:25][CH2:26][CH:27]([CH3:30])[CH2:28][CH2:29]1)=[O:23])[CH:15]1[CH2:20][CH2:19][C:18](=[CH2:2])[CH2:17][CH2:16]1)=[O:8]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1
Reactant: CC(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C1CCC(N(C(=O)C2CCC(C)CC2)c2cc(-c3ccccc3)sc2C(=O)OC)CC1
Temperature: -40 °C
Yield: 80.5 %

Procedure:
To a suspension of zinc dust (2.87 g, 44.0 mmol) and dibromoethane (1.00 mL, 14.4 mmol) in tetrahydrofuran (20 mL) stirred under a nitrogen atmosphere at −40° C. was added titane tetrachloride (10 mL of a solution 1M in dichloromethane, 10 mmol). The mixture was then allowed to warm to room temperature and was stirred for two days at this temperature. This methylation reagent (2.5 eq) was added to a solution of 3-[(4-Methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.200 g, 0.440 mmol, 1 eq) in dichloromethane (2 mL) and the resulting mixture was stirred 3 h at room temperature. A saturated solution of sodium bicarbonate was then added and reaction mixture was extracted with dichloromethane (3×30 mL). Organic phases were combined, dried over sodium sulfate and concentrated. The crude was purified by chromatography (30% ethyl acetate/hexanes) to give 160 mg (81%) of 3-[(4-Methyl-cyclohexanecarbonyl)-(4-methylene-cyclohexyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester as a white solid. NMR 1H (CDCl3, 400 MHz) 7.63 ppm (d, 2H); 7.40 ppm (m, 3H); 6.98 ppm (s, 1H); 4.82 ppm (tt, 1H); 4.78 ppm (d, 2H); 3.85 ppm (s, 3H); 2.20 ppm (m, 4H); 2.05 ppm (m, 2H); 1.90 ppm (d, 1H); 1.65 ppm (m, 4H); 1.42 ppm (m, 1H); 1.30 ppm (m, 2H); 1.00 ppm (m, 2H); 0.78 ppm (d, 3H); 0.64 ppm (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]([CH3:17])[C:7]2[CH:18]=[CH:19][CH:20]=[N:21][C:6]1=2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:28]1[O:43][C:42]2[CH:41]=[CH:40][C:32]([CH2:33][N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[CH:31][C:30]=2[O:29]1>C(O)C>[CH3:17][N:8]1[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:5]([C:3](=[O:4])[CH2:2][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][C:32]3[CH:40]=[CH:41][C:42]4[O:43][CH2:28][O:29][C:30]=4[CH:31]=3)[CH2:35][CH2:36]2)[C:6]2[N:21]=[CH:20][CH:19]=[CH:18][C:7]1=2
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: CN1C(=O)c2ccccc2N(C(=O)CCl)c2ncccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CN1C(=O)c2ccccc2N(C(=O)CN2CCN(Cc3ccc4c(c3)OCO4)CC2)c2ncccc21

Procedure:
10.5 gm of 11-chloroacetyl-5,11-dihydro-5-methyl-6H-pyrido[2,3-b]-[1,4]benzodiazepine-6-one, 3.8 gm of sodium carbonate and 8 gm of 1-[(3,4-methylenedioxy)benzyl]-piperazine were reacted in 200 ml of absolute ethanol and worked up in analogy to Example 1.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[S:11][CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH2:3]>C1C=CC=CC=1>[CH3:3][C:2]1[CH2:4][S:11][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:1]=1
Reactant: C=C(C)C1SC1CCCCC
Solvent: c1ccccc1
Product: CCCCCC1C=C(C)CS1
Yield: 93.1 %

Procedure:
A solution of 2-methyl-3,4-epithio-1-nonene (50 mg, 0.29 mmol) and Cu(hfacac)2 (14.5 mg, 29 μmol) in benzene (29 mL) was heated to 80° C. for 20 h under N2. After cooling, concentration of the solvent in vacuo afforded a residue, which was purified by column chromatography (n-pentane) to give 4-Methyl-2-pentyl-2,5-dihydrothiophene (46 mg, 92%) as a colorless oil.