Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([CH:8]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[C:9]2[N:10]=[N:11][NH:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>ClCCl>[C:2]1(=[C:8]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[C:9]2[N:10]=[N:11][NH:12][CH:13]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: N#Cc1ccc(C(c2c[nH]nn2)C2(O)CCCCC2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(C(=C2CCCCC2)c2c[nH]nn2)cc1
Reaction time: 2 h
Yield: 36.5 %

Procedure:
7.6 g of crude 4-[1-hydroxycyclohex-1-yl-1-(1,2,3-triazolyl)methyl]benzonitrile is dissolved at 0° in 50 ml of dichloromethane and stirred at 0° for 1 hour with 22.7 ml of thionyl chloride. Then the mixture is concentrated to dryness under vacuum, dissolved in 50 ml of dichloromethane, stirred with 30 ml of triethylamine for 2 hours, diluted with water, extracted three times with ethyl acetate, washed with water, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus obtaining 2.6 g of 4-[1-cyclohexylidene-1-(1,2,3-triazolyl)methyl]benzonitrile as the free base. 132-133° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH2:11][O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)[CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[C:14]3[C:15]([F:20])=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][CH2:11][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1COc1cc(F)cc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2ccc(Br)cc2COc2cc(F)cc(F)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
[step 2] 4-Bromo-2-[(3,5-difluorophenoxy)methyl]benzoic acid (11.4 g, 33.2 mmol) obtained in step 1 was dissolved in dichloromethane (111 mL), trifluoroacetic anhydride (9.4 mL, 66.4 mmol) and trifluoroborane diethyl ether complex (4.2 mL, 33.2 mmol) were added, and the mixture was stirred at room temperature for 4 hr. To the mixture were added 2 mol/L aqueous sodium hydroxide solution (100 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted 3 times with dichloromethane (300 mL). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained brown solid (12.6 g) was suspended in isopropylalcohol (100 mL), and the suspension was stirred at room temperature for 13 hr. The suspension was suction filtered, and the obtained solid was dried under reduced pressure to give 8-bromo-1,3-difluorodibenzo[b,e]oxepin-11(6H)-one (9.3 g, 86%).
Reaction SMILES: [F:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([OH:15])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]1[O:24][C@H:23]1[CH2:25]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O>CC(C)=O>[CH2:25]([O:15][C:5]1[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:13][C:14]=2[C:2]([F:1])=[CH:3][CH:4]=1)[CH:23]1[O:24][CH2:22]1
Reactant: Oc1ccc(F)c2[nH]c3ccccc3c12
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(OCC2CO2)c2c1[nH]c1ccccc12
Yield: 48 %

Procedure:
A mixture of 1-fluoro-4-hydroxycarbazole (470 mg, 2 mmol), potassium carbonate (345 mg, 2.5 mmol), (2R)-(−)-glycidyl 3-nitrobenzenesulfonate, (518 mg, 2 mmol), and 20 mL of acetone was heated to reflux for about 18 hours. The reaction was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via flash silica gel chromatography eluting with 10% ethyl acetate/hexanes to give 247 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:36])[C:20]=3[C:24](=[O:35])[NH:25][CH2:26][CH:27]3[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:36])[C:20]=3[C:24](=[O:35])[NH:25][CH2:26][CH:27]3[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)CC1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)CC1

Procedure:
The title compound was synthesized according to the procedure described in example 126 using 4-{6-chloro-5-[(4,4-difluoro-cyclohexylmethyl)-carbamoyl]-quinolin-2-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester, palladium on carbon and triethylsilane. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.80 (t, J=5.71 Hz, 1H), 8.00 (dd, J=10.82, 9.12 Hz, 2H), 7.77 (d, J=9.04 Hz, 1H), 7.61 (d, J=8.80 Hz, 1H), 4.07-4.10 (m, 2H), 3.05-3.11 (m, 2H), 2.87 (s, 3H), 2.01-2.04 (m, 2H), 1.83-1.91 (m, 5H), 1.62-1.77 (m, 4H), 1.41 (s, 9H), 1.22-1.29 (m, 2H). m/z: 522.0 [M+H]+
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2].I[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)C>[CH2:15]([O:11][C:9]1[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]([CH:5]=[O:6])=[C:3]([CH2:1][CH3:2])[CH:10]=1)[CH3:16]
Reactant: CCc1cc(O)cc(CC)c1C=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cc(CC)c(C=O)c(CC)c1
Temperature: 50 °C
Yield: 89.5 %

Procedure:
To a solution of 0.30 g (1.68 mmol) 2,6-diethyl-4-hydroxy-benzaldehyde in 8 ml N,N-dimethylformamide in a pressure tube were added 0.16 ml (2.02 mmol) iodoethane and 0.35 g (2.52 mmol) potassium carbonate. The tube was sealed and the reaction mixture was heated at 50° C. for 16 h. The reaction mixture was then cooled to room temperature, diluted with diethyl ether, and washed sequentially with water and saturated brine. The phases were separated, and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane 1:30) to afford 0.31 g (88%) of the title compound as a yellow oil. MS (ISP): 207.3 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:8][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=1)(=[O:22])=[O:21]
Reactant: OCCOc1cccc(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold mixture of 2-(3-bromophenoxy)ethanol (15) (16.06 g, 74.0 mmol) and triethylamine (9.12 g, 90.13 ml) in anhydrous CH2Cl2 (120 ml) under argon was slowly added neat methanesulfonyl chloride (6 ml, 77.2 mmol) and the reaction mixture stirred at 0° C. for 15 min A precipitate formed after the addition was complete. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc, washed twice with water, once with brine, dried over MgSO4 and concentrated under reduced pressure. 2-(3-Bromophenoxy)ethyl methanesulfonate (16) was isolated as a brown oil and used in the next synthetic step without further purification. Yield (21.32 g, 98%): 1H NMR (400 MHz, CDCl3) δ 7.16 (t, J=7.8 Hz, 1H), 7.11-7.14 (m, 1H), 7.07 (m, 1H), 6.39 (ddd, J=7.6, 2.5, 1.8 Hz, 1H), 4.56 (m, 2H), 4.22 (m, 2H), 3.08 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH2:7][OH:8]>C1C=CC=CC=1.O=[Mn]=O>[Cl:1][C:2]1[C:3]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=[O:8]
Reactant: OCc1sc2cccc(F)c2c1Cl
Agent: O=[Mn]=O
Solvent: c1ccccc1
Product: O=Cc1sc2cccc(F)c2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A suspension of (3-chloro-4-fluoro-benzo[b]thiophen-2-yl)methanol (1.00 g, 4.63 mmol) and MnO2 (3.10 g, 35.2 mmol) in benzene (50 mL) was stirred at room temperature overnight. The solution was filtered through diatomaceous earth and the was filtrate was concentrated to give the title compound (880 mg, 87%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 10.32 (s, 1H), 7.63 (dd, J=8.2, 0.4 Hz, 1H), 7.50 (ddd, J=8.1, 8.1, 4.7 Hz, 1H), 7.13 (ddd, J=11.0, 7.9, 0.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[CH3:24][CH:25]([CH3:30])[CH2:26][C:27](O)=[O:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:16])([NH:17][C:27](=[O:28])[CH2:26][CH:25]([CH3:30])[CH3:24])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Reactant: CC(C)CC(=O)O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)CC(C)C)c2c1N

Procedure:
Prepared as in Example 24a from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b) and 3-methylbutanoic acid as an off-white solid (100%). MS 402 (MH+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C:16]1[CH:15]=[CH:14][C:13]([O:20]C)=[CH:12][C:11]=1[CH2:10][C@H:9]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([CH2:37][CH2:38][CH2:39][C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42])[C:32]([O:34][CH2:35][CH3:36])=[O:33].[Br-].[Br-].[Br-].B.O>ClCCl>[OH:20][C:13]1[CH:14]=[CH:15][C:16]2[C@@H:17]3[C@H:8]([C@H:5]4[C@@:3]([CH2:19][CH2:18]3)([CH3:4])[C@@H:2]([OH:1])[CH2:7][CH2:6]4)[C@H:9]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([CH2:37][CH2:38][CH2:39][C:40]([F:45])([F:46])[C:41]([F:42])([F:43])[F:44])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:10][C:11]=2[CH:12]=1
Reactant: CCOC(=O)C(CCCCCCCCC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12)CCCC(F)(F)C(F)(F)F
Agent: B
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(CCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12)CCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
Ethyl 11-[17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoate (946 mg, 1.43 mmol) was dissolved in dichloromethane (18 ml). To this solution, a 1M solution of borane tribromide in dichloromethane (4.3 ml, 4.3 mmol) was added dropwise at −78° C. The reaction mixture was warmed slowly and stirred for 3 hours at 0° C. Water was added to stop the reaction and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then filtered. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to give ethyl 11-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoro-pentyl)undecanoate (663 mg, Yield 72%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10](C)[CH2:11][CH2:12][C:6]=2[C:5]([C:14]#N)=[CH:4][CH:3]=1.[OH2:16].[OH2:17].O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C(O)C.O.CO.C(=O)=O>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[C:5]([C:14]([OH:17])=[O:16])=[CH:4][CH:3]=1
Reactant: CN1CCc2c(Cl)ccc(C#N)c2CC1
Reactant: O
Agent: O=C=O
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: O=C(O)c1ccc(Cl)c2c1CCNCC2

Procedure:
A solution of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carbonitrile, prepared as in Example 12, (1.5 g, 6.8 mmol) in ethanol (25 ml) was treated with barium hydroxide octahydrate (2.6 g, 8.1 mmol) and water (25 ml) and heated to reflux for 94 hours. The mixture was cooled, diluted with water, ethanol and methanol, saturated with carbon dioxide and filtered. The filtrate was treated with Dry Ice to pH 5-6 and filtered. The filtrate was concentrated and extracted with ethyl acetate-ethyl ether and ethyl ether. The aqueous phase was treated with toluene, concentrated and the residue triturated with ethyl ether to give 9-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine-6-carboxylic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:19]([NH:29][CH2:30][C:31](=[O:37])[CH2:32][CH2:33][C:34]([O-:36])=[O:35])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].[Cs+]>>[C:19]([NH:29][CH2:30][C:31](=[O:37])[CH2:32][CH2:33][C:34]([O:36][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:35])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: O=C(CCCCCCCBr)OCc1ccccc1
Reactant: O=C([O-])CCC(=O)CNC(=O)OCc1ccccc1
Agent: [Cs+]
Product: O=C(CCC(=O)OCCCCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
This compound was prepared from the product of 10a (0.79 g; 2.5 mmol) and 8b (1.0 g; 2.5 mmol) according to Procedure C. The reaction time was 2 days. The crude product was purified on a 80×45 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (1000 mL) collecting 13×50 mL fractions. Fractions containing the product (3-6) were collected, and after evaporation 0.83 g (67%) product was obtained (amber oil that solidified to a waxy solid on standing in the freezer, mp 52-54° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[OH:12]O>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:12])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cc2c([n+]([O-])c1)CCCC2
Temperature: 80 °C

Procedure:
3-Methyl-5,6,7,8-tetrahydroquinoline (50 g.) dissolved in glacial acetic acid (180 ml.) and the solution treated with 30% hydrogen peroxide (70 ml.) and heated at 80° C for 20 hours. The solvent was removed in vacuo and the residual oil diluted with water (25 ml.) and re-evaporated. The resulting oil was dissolved in chloroform (100 ml.), washed with aqueous sodium carbonate (2 × 25 ml.), saturated brine (2 × 25 ml.), dried (MgSO4) and the solvent removed in vacuo to give 3-Methyl-5,6,7,8-tetrahydroquinoline -1 -oxide (60 g.) as a pale yellow solid which was used without purification. The N-oxide (60 g.) was dissolved in acetic anhydride (120 ml.) and added to boiling acetic anhydride (120 ml.) and the mixture heated at reflux for 30 minutes. The solvent was removed in vacuo and the residual oil was treated with 10% hydrochloric acid (700 ml.) and the solution heated on a steam bath for 2 hours. The cooled reaction mixture was adjusted to pH 9.0 with sodium hydroxide and extracted with ether (3 × 100 ml.). The combined etheral extracts were washed with saturated brine, dried (MgSO4) and the solvent removed in vacuo. The resultant oil was distilled at 0.15 mmHg to give a colourless oil (22 g.) b.p. 70-78° C which crystallised from n-hexane to give 8-hydroxy-3 -methyl-5,6,7,8-tetrahydroquinoline as colourless needles m.p. 58° C. (Found: C,73.7; H,8.2;N,8.3. C10H13NO requires: C,73.6; H,8.0; N,8.6%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].C[Si]([N:31]=[C:32]=[O:33])(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][CH2:23][N:24]([C:32]([NH2:31])=[O:33])[CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCNCC3)cc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCN(C(N)=O)CC3)cc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)-ethyl]-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (12.0 mg, 0.0307 mmol), trimethylsilyl isocyanate (8.32 μL, 0.0615 mmol), DIPEA (26.8 μL, 0.154 mmol) and DMF (0.5 mL) was stirred at rt for 20 min. The solution was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.87 (d, J=7.1 Hz, 3 H), 2.28-2.51 (m, 2 H), 3.60 (t, J=5.8 Hz, 2 H), 4.02 (q, J=2.5 Hz, 2 H), 5.26 (q, J=7.1 Hz, 1 H), 5.88-5.94 (m, 1 H), 7.18 (t, J=8.6 Hz, 1 H), 7.29 (d, J=2.0 Hz, 1 H), 7.32-7.55 (m, 2 H), 8.23 (br. s., 1 H). MS (ES+): m/z 433.02 (100) [MH+]. HPLC: tR=3.15 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:23]2[C:6](=[CH:7][C:8]3[O:12][C:11]([C:13]4[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=4)=[N:10][C:9]=3[CH:22]=2)[C:5]([CH3:25])([CH3:24])[CH2:4][CH2:3]1.[Cl:27]CCl>>[CH3:1][C:2]1([CH3:26])[C:23]2[C:6](=[CH:7][C:8]3[O:12][C:11]([C:13]4[CH:21]=[CH:20][C:16]([C:17]([Cl:27])=[O:18])=[CH:15][CH:14]=4)=[N:10][C:9]=3[CH:22]=2)[C:5]([CH3:25])([CH3:24])[CH2:4][CH2:3]1
Reactant: ClCCl
Reactant: CC1(C)CCC(C)(C)c2cc3oc(-c4ccc(C(=O)O)cc4)nc3cc21
Product: CC1(C)CCC(C)(C)c2cc3oc(-c4ccc(C(=O)Cl)cc4)nc3cc21

Procedure:
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid (4.57 g - 13.1 mmoles) is suspended in dichloromethane (200 ml). There is then slowly added dicyclohexylamine (2.37 g - 13.1 mmoles) and the dichloromethane is then evaporated.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[C:10]([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[C:25]([O:26][CH3:27])[CH:24]=2)[CH:11]=1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Product: COc1ccc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cc1OC

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 1 step (i) and 3,4-dimethoxyphenylboronic acid. Yield 0.86 g
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([NH2:17])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1.N1C=CC=CC=1>O1CCOCC1>[CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15](=[S:27])[NH2:17]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ccc2c(c1)Nc1ccccc1S2
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: NC(=S)c1ccc2c(c1)Nc1ccccc1S2
Temperature: 110 °C

Procedure:
A reaction mixture comprising 3.4 g (14 mmoles) of 10H-phenothiazine-2-carboxamide (J. Org. Chem. 1961, 26, 1138-1143) and 3.4 g (8.4 mmoles) of Lawesson reagent in solution in 40 ml of 1,4-dioxane to which 20 ml of pyridine has been added is heated at 110° C. for 1 h 30. The brown solution is then concentrated under vacuum and the residue is diluted in 200 ml of AcOEt and 100 ml of H2O. After stirring and decantation, the organic phase is washed successively with 100 ml of a 1N aqueous solution of HCl and 100 ml of salt water. After drying over sodium sulphate, filtration and evaporation of the solvent under vacuum, an orange powder is obtained. This powder is washed with Et2O, the filtrate is eliminated, and extracted with acetone. The acetone filtrate is then concentrated under vacuum and the evaporation residue is then purified using a silica column (eluent: Heptane/AcOEt:1/1 to 416). Orange powder. Melting point: 208-209° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=2)[CH:5]=[N:4][C:3]=1[C:22]([NH2:24])=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=2)[CH:5]=[N:4][C:3]=1[C:22]#[N:24]
Reactant: NC(=O)c1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: N#Cc1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N
Reaction time: 2 h

Procedure:
Combine 5-Amino-1-(3,5-bis-trifluoromethyl-benzyl)-1H-imidazole-4-carboxylic acid amide (0.106 g, 0.30 mmol) and p-toluenesulfonyl chloride (0.069 g, 0.36 mmol) in pyridine (0.1 M), and stir at RT. After 2 h, quench the reaction with MeOH and concentrate. Redissolve in EtOAc, wash with H2O and brine, then dry (MgSO4), filter, and concentrate. Purify by radial chromatography on silica gel to give the title compound. MS (ES) 335.1 (M+1); 1H NMR (300 MHz, CD3OD): δ 7.96 (s, 1H), 7.77 (s, 2H), 7.37 (s, 1H), 5.31 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)[N:8]=[N:7][C:6]=1[C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22].[Cl:27][CH2:28][CH2:29][N:30]=[C:31]=[O:32]>C1COCC1>[Cl:27][CH2:28][CH2:29][NH:30][C:31]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:15]=2)[N:8]=[N:7][C:6]=1[C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22])=[O:32]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCN)cc1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCNC(=O)NCCCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a solution of 5-(3-aminopropyl)-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (356 mg, 1 mmol) obtained in Example 1202 in THF (5 ml) was added 1-chloro-2-isocyanatoethane (106 mg, 1 mmol) at room temperature, and the mixture was stirred at room temperature for 30 min. The precipitated crystals were collected by filtration and dried to give the title compound as a white powder (450 mg, 97.4%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1[C:23]2[CH:22]=[CH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[CH:18]([C:28]#[N:29])[C:17]=2[CH:16]=[CH:15][CH:14]=1.Br[CH2:31][CH2:32][CH2:33][C:34]#[N:35]>C1COCC1>[C:34]([CH2:33][CH2:32][CH2:31][C:18]1([C:28]#[N:29])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:23]=2[CH:22]=[CH:21][C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]1=2)#[N:35]
Reactant: N#CCCCBr
Reactant: N#CC1c2ccccc2C=Cc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CCCCC1(C#N)c2ccccc2C=Cc2ccccc21
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 78.1 %

Procedure:
To a −5° C. solution of diisopropylamine (0.143 ml, 1 mmol) in THF (1 ml) was added dropwise nBuLi (0.67 ml, 1.06 mmol, 1.6 M in hexane). After 20 minutes stirring at −5° C., a solution of 5H-dibenzo[a,d]cycloheptene-5-carbonitrile (prepared according to: Regnier G. J. et al. J. Med. Chem. 1992, 35, 2481-2496) (0.2 g, 0.9 mmol) in THF (1 ml) was added dropwise. After 15 minutes at −5° C., a solution of 4-bromobutyronitrile (0.1 ml, 1 mmol) in THF (1 ml) was added slowly. The reaction mixture was allowed to warm up slowly to room temperature, stirred overnight and quenched with water and ether. Aqueous phase was extracted with ether and the combined organic phases were washed with water, dried with Na2SO4 and concentrated in vacuo. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1) to provide 5-(3-cyano-propyl)-5H-dibenzo[a,d]cycloheptene-5-carbonitrile (0.2 g, 76%) as a colorless oil, MS: m/e=284 (M+).