Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[C:4]=2[CH:3]=1.Cl.[CH3:19][N:20](C)C=O>>[C:19]([C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[C:4]=2[CH:3]=1)#[N:20]
Reactant: O=C1c2ccccc2COc2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: Cl
Product: N#Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 100 °C

Procedure:
Reflux 43 gm. (0.1488 mole of 2-bromo-6,11-dihydro-11-oxodibenz[b,e]oxepin and 16 gm. (0.178 mole, 20% excess) of cuprous cyanide in 150 cc. of N,N-dimethylformamide for 24 hours. Cool to 100° C. and pour into a solution of 100 gm. of ferric chloride in 140 cc. of 5% aqueous hydrochloric acid with stirring. Keep the mixture at 70° C. for 30 minutes cool, filter and wash the solids with water. Dissolve the solids in methylene chloride and purify by filtering through a short column of silica gel (m.p. 160°-161° C.).
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:34])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[CH:20][C:21]=1[CH2:22][CH3:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:22]([C:21]1[CH:20]=[C:19]([C:24](=[O:34])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[S:18][C:17]=1[C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])[C:3]([OH:35])=[O:2])=[O:16])[CH3:23]
Reactant: CCc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)-2-{[3-Ethyl-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (74.7 mg, 0.14 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (61 mg, 1.45 mmol) in water (5 mL). The mixture was then stirred at room temperature 15 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 61.1 mg (87%). MS m/e 501.9 (M+H+).
Reaction SMILES: [O:1]([C:3]#[N:4])[Na].[CH2:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[CH3:6]>>[CH2:5]([N:7]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:3]([NH2:4])=[O:1])[CH3:6]
Reactant: CCNc1ccc2c(c1)OCO2
Reactant: N#CO[Na]
Product: CCN(C(N)=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.3 %

Procedure:
To a solution of N-ethyl-3,4-(methylenedioxy)aniline (8.1 g) AcOH (100 mL) was added NaOCN (3.0 g) at 10° C. he cold bath was removed and the mixture was stirred at rt for 24 h. The solvent was removed in vacuo and the resulting residue was neutralized with 2 N NaOH. The mixture was extracted with chloroform (3×50 mL). The combined organic phase was washed with water and brine, dried over Na2SO4. The solvent was removed in vacuo and the resulting residue was recrystallized from chloroform/hexane to yield the title compound (5.7 g, 56%). 1H NMR ((CDCl3): 6.78-6.72 (m, 3H), 6.02 (s, 2H), 4.38 (br s, 2H), 3.66 (q, J=7.0, 2H), 1.11 (t, J=7.0 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=1.C(OC(=O)C)(=[O:19])C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:19])[CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1ccc(OCc2cccc(Cl)c2)cc1
Product: O=c1cc(OCc2cccc(Cl)c2)cc[nH]1
Temperature: 25 °C

Procedure:
To 4-((3-chlorobenzyl)oxy)pyridine 1-oxide (2.0 g) was added acetic anhydride (20 ml), and the solution was heated at reflux for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with MeOH/NaOH (1:1, 150 ml) and heated at reflux for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted with DCM. The combined DCM layer was concentrated in vacuo and the crude residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (984 mg) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH3:22])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:37]([O:39][CH3:40])=[O:38]>>[CH3:40][O:39][C:37](=[O:38])[N:21]([CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13](=[O:23])[NH:12][C:10]2[S:11][C:7]3[C:6]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[CH:15][CH:16]=1)[CH3:22]
Reactant: COC(=O)Cl
Reactant: CNCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Solvent: c1ccncc1
Product: COC(=O)N(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethyl-benzamide (100 mg, 0.24 mmol), pyridine (29 μl, 0.36 mmol) and methyl chloroformate (24 μl, 0.32 mmol) were dissolved in dichloromethanel (5 ml) and stirred at ambient temperature for 18 h. Workup and purification as described in the general procedure C afforded the title compound as light yellow solid (66%), MS: m/e=471 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:32][C:11]3[C:12](=[O:31])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C@@H:23]5[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]5)=[C:18]([O:29][CH3:30])[CH:17]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C=O.[C:35](O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:32][C:11]3[C:12](=[O:31])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C@@H:23]5[CH2:28][CH2:27][CH2:26][N:25]([CH3:35])[CH2:24]5)=[C:18]([O:29][CH3:30])[CH:17]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O[C@@H]1CCCNC1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O[C@@H]1CCCN(C)C1
Yield: 34.2 %

Procedure:
Stir a solution of 2-(4-chloro-phenyl)-6-[3-methoxy-4-((R)-piperidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridine-7-one (446 mg, 0.96 mmol), formaldehyde (0.38 mL, 37% aqueous solution), and acetic acid (0.22 mL, 3.84 mmol) in methanol (34 mL) at room temperature for 5 min. Add sodium cyanoborohydride (150 mg, 2.4 mmol) to this solution and stir the reaction for 2 h. Concentrate the mixture in vacuo and partition the residue between dichloromethane (20 mL) and saturated sodium bicarbonate (20 mL). Separate the organic portion and extract the aqueous portion with dichloromethane (2×10 mL). Dry the combined organics (Na2SO4), filter, and concentrate in vacuo. Purify by chromatography (dichloromethane to 5% 2 M ammonia in methanol/dichloromethane) to afford 158 mg (34%) of 2-(4-chloro-phenyl)-6-[3-methoxy-4-((R)-1-methyl-piperidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:23])[N:9]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:10]=[C:4]2[C:3]=1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:23])[N:9]([CH2:11][C:12]4[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:16][CH:17]=4)[N:10]=[C:4]3[C:3]=2[C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(Cl)ccn2c1=O
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+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4C)nc3c2-c2ccncc2)cc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 7-chloro-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (135 mg, 0.32 mmol), 4-methoxyphenylboronic acid (190 mg, 1.29 mmol), and 2.0 M aqueous sodium carbonate (0.70 mL) in toluene (2.5 mL) was added (Ph3P)4Pd (55 mg, 0.048 mmol) in one portion, and the resulting yellow mixture was vigorously stirred under argon at 100° C. for 1.5 h. Analysis by HPLC/MS indicated the starting 7-chloro-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one had been consumed. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc layer was washed with water, then saturated aqueous NaCl twice, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (0-80%) in hexanes to afford the desired product, which was contaminated with triphenylphosphine oxide. The product was further purified by preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 90% B over 15 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue obtained was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The yellow residue was dissolved in acetonitrile, frozen and lyophilized to afford 82 mg of the title compound as a light yellow powder. HPLC/MS: retention time=2.56 min, [M+H]+=492.0.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].[H][H]>[Pd]>[CH:8]1([CH2:7][CH2:6][CH2:5][CH:2]([CH3:1])[CH2:3][OH:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(CO)CCCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: CC(CO)CCCC1CCCCC1
Reaction time: 30 h
Yield: 94.3 %

Procedure:
1200 g of 2-Methyl-5-phenyl-pentanol (Rosaphen™, supplier: Symrise) combined with 22 g Pd on activated carbon (Pd content: 5 wt. %) were hydrogenated at a hydrogen pressure of 50 bar and at a temperature of 120° C. After 30 hours the reaction was finished. The catalyst was removed and the product distilled. 1170 g (content: 99.6%) of 5-cyclohexyl-2-methyl-pentanol were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:24](O)=[O:25])[CH:4]=[N:3]1.[NH:27]1[CH2:30][CH2:29][CH2:28]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[N:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:24]([N:27]4[CH2:30][CH2:29][CH2:28]4)=[O:25])=[O:23])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Reaction time: 18 h
Yield: 81.7 %

Procedure:
A mixture of 1-methyl-5-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 422 μmol), azetidine (85.4 μl, 1.27 mmol), propylphosphonic anhydride (50% in ethyl acetate, 622 μl, 1.06 mmol) and N,N-diisopropylethylamine (287 μl, 1.69 mmol) in tetrahydrofuran (6 ml) was stirred for 18 hours at 70°. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (136 mg, 81.7%) as a light brown solid. mp: >250° C., MS: m/z=395.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Br:19][C:20]1[C:21]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][S:23][CH:24]=1>>[Br:19][C:20]1[C:21]([S:25]([NH:18][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=2[NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])(=[O:27])=[O:26])=[CH:22][S:23][CH:24]=1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=S(=O)(Cl)c1cscc1Br
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1cscc1Br

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with 4-bromothiophene-3-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.48 (br m, 2H), 7.39 (dd, J=1.8 & 10.5 Hz, 1H), 7.28 (ddd, J=2.4, 4.8 & 9.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.02 (m, 1H), 6.02 (dt, J=2.4, 8.7 & 17.4 Hz, 1H), 5.68 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH3:13])[C:9](N)=[O:10])=[CH:4][CH:3]=1.NC1C=CC(CCC[C:24](O)=[O:25])=CC=1.[S:27](=[O:31])(=[O:30])([OH:29])[OH:28]>CO>[S:27]([OH:31])([OH:30])(=[O:29])=[O:28].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH3:13])[C:9]([O:25][CH3:24])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: CCC(C(N)=O)c1ccc(N)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCC(C(=O)OC)c1ccc(N)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
The 4-aminophenylbutyramide used in this example was obtained according to patent literature WO 02/08247 A2 or WO 03/051909 A2. Procedure was as follow: Methanol (100 ml) was charged to 4-(4-Aminophenyl)-butyric acid (from Aldrich) CAS[15118-60-2] (FW=179.22, 1 eq, 15 g, 83.7 mmol). Sulphuric acid FW=98.08 (4 eq, 334.8 mmol, 33 g) was added maintaining the temperature below 20° C. The mixture was then refluxed for one hour and concentrated by distillation at atmospheric pressure until half of methanol will be removed. The reaction mixture was then cooled to 50° C. and t-butyl-methyl ether was added maintaining the temperature above 45° C. The mixture was then gradually cooled to 0-5° C. and held at this temperature for 1 hour. The resultant crystalline product was isolated by filtration and washed by cold mixture of methanol and t-butyl-methyl ether (4:10) and cold ether and then dried under vacuum and then dried under vacuum to give methyl 4-aminophenylbutyrate hydrogensulfate as a white crystal (20.0 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:24])[CH2:23][O:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[N:32]1[CH:37]=[C:36]([C:38](O)=[O:39])[CH:35]=[N:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:24][C:38]([C:36]4[CH:37]=[N:32][CH:33]=[N:34][CH:35]=4)=[O:39])[CH2:21][O:22][CH2:23]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)COC2)no1
Reactant: O=C(O)c1cncnc1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)c3cncnc3)COC2)no1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 3-amino-oxetane-3-carboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 49) was coupled with pyrimidine-5-carboxylic acid to yield the title compound as light yellow solid. MS: 549.1 (MH+, 1Cl).
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([O:13][C:14]([C:16]1[CH2:21][CH2:20][CH2:19][CH:18](Br)[C:17]=1O)=[O:15])[CH3:12]>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:11]([O:13][C:14]([CH:16]1[C:17]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:3][CH2:2][F:1])[C:18]=2[CH2:19][CH2:20][CH2:21]1)=[O:15])[CH3:12]
Reactant: FCCNc1ccccc1
Reactant: CCOC(=O)C1=C(O)C(Br)CCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCOC(=O)C1CCCc2c1c1ccccc1n2CCF
Temperature: 50 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
A mixture of (2-fluoro-ethyl)-phenyl-amine (24; prepared according to Example 4(a)) (560 mg, 4.0 mmol) and 3-bromo-2-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (29) (500 mg, 2.0 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (4 mL) and dry zinc chloride (820 mg, 6 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The product was dissolved in ethyl acetate/ether (30 mL/150 mL) and washed with 2 N HCl (40 mL), water (2×100 mL) and aqueous potassium carbonate solution (2×100 mL) then dried and concentrated to afford 447 mg (91%) of 9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (30) as a yellow oil which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 14.3, 20.4, 21.7, 26.4, 38.5, 43.1 (d, TCF=15 Hz), 60.6, 76.6, 77.0, 77.4, 82.1 (d, JCF=173 Hz), 106.9, 108.5, 118.9, 119.4, 121.1, 127.1, 136.2, 136.7, 174.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].Cl.Cl[CH2:14][CH2:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17]>ClC1C=CC=CC=1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:19][CH2:18][N:16]([CH3:17])[CH2:15][CH2:14]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: Cl
Solvent: Clc1ccccc1
Solvent: CO
Product: CN1CCN(c2cc([N+](=O)[O-])ccc2F)CC1
Yield: 30.5 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzenamine (4.06 g) and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (5.006 g) in chlorobenzene (20 ml) was heated at reflux under nitrogen for 21/2 days. The dark solid was dissolved in methanol (150 ml) and the solution was then concentrated in vacuo onto silica and purified by FCC eluting with System A (400:8:1) to give impure material (1.9 g). This was purified again by FCC eluting with System A (300:8:1) to give the title compound as a crystalline brown solid (360 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7]O.P(Br)(Br)[Br:13]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][Br:13]
Reactant: BrP(Br)Br
Reactant: COc1cccc(CCO)c1
Solvent: ClCCl
Product: COc1cccc(CCBr)c1
Temperature: 25 °C
Yield: 130.5 %

Procedure:
To a cold solution of 3-methoxyphenethyl alcohol (7.55 g, 50 mmol) in 20 ml of dry (sieves) methylene chloride, a solution of phosphorus tribromide (7 g, 26 mmol) in 20 ml of methylene chloride was slowly added under nitrogen. The reaction mixture was permitted to warm to ambient temperature overnight. The reaction was then quenched in ice/water slowly and the resulting solution neutralized with 5N NaOH and then extracted with methylene chloride. The combined extracts were washed with water and brine, dried with anhydrous magnesium sulfate and concentrated to give 7.3 g of 3-methoxyphenethyl bromide. A solution of this bromide (7.3 g) in 10 ml of dry tetrahydrofuran (THF) was slowly added to a flask containing magnesium chips (1.03 g) and a small crystal of iodine in 30 ml of THF. The reaction mixture was then heated to reflux for 1 hour. To this mixture which was cooled with ice, a solution of dry acetone (2.2 g) in 10 ml of dry THF was added and the reaction mixture stirred at ambient temperature overnight. The mixture was quenched (0° C.) with a cold solution of NH4Cl followed by 1N HCl. The mixture was extracted with ethyl acetate and dried with anhydrous magnesium sulfate. Concentration and chromatography on silica gel (10-30% ethyl acetate in hexanes) afforded 2.31 g of carbinol. This carbinol (2.3 g) in 4 ml of glacial acetic acid was slowly added to a solution of KCN (2.36 g) and H2SO4 (3.63 g) in 15 ml of acetic acid. The reaction mixture was then stirred at 90° C. (bath temperature) overnight under nitrogen. Additional KCN (3.28 g), H2SO4 (8 ml in 24 ml of acetic acid) and acetic acid (18 ml) were added and the reaction mixture heated overnight. The reaction was quenched by pouring the reaction mixture into ice/water and adjusting the pH of the solution to neutrality with 5N NaOH. The solution was repeatedly extracted with ethyl acetate and the combined extracts backwashed with water and brine and then dried with anhydrous sodium sulfate. Concentration afforded 1.64 g of formamide which was hydrolyzed to the amine in 6N HCl (40 ml) at reflux for 3 hours. The reaction mixture was partially concentrated, diluted with water and the pH of the solution adjusted with 5N NaOH to 12. The solution was extracted with ethyl acetate and the combined extracts backwashed with brine and dried with anhydrous sodium sulfate. Concentration gave 1.2 g of the titled amine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:24]([O:26]CC)=[O:25])=[C:5]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:43])=[O:42])=[CH:10][CH:9]=2)[C:5]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:6]1[C:24]([OH:26])=[O:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1C(c1ccccc1)c1ccccc1
Product: O=C(O)c1c(-c2ccccc2)c2cc(NS(=O)(=O)c3ccccc3)ccc2n1C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzhydryl-3-phenyl-1H-indole-2-carboxylate and phenylsulfonyl chloride followed the procedure of Example 1 Step 3 as a pale yellow solid: 1H NMR (DMSO-d6) δ 6.68 (d, J=9.0 Hz, 1H, 6.78 (dd, J=9.2, 2.2 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H, 7.13 (d, J=7.1 Hz, 4H, 7.25-7.30 (m, 2H, 7.30-7.40 (m, 7H, 7.40-7.55 (m, 4H, 7.58-7.68 (m, 3H, 7.84 (s, 1H, 9.93 (s, 1H, 13.19 (br s, 1H; MS (ESI) m/z 557 [M-H]−; HRMS calcd for C34H27N2O4S: 559.1689; found (ESI+): 559.1686; Anal. calcd for C34H26N2O4S.0.6H2O: C, 71.71; H, 4.81; N, 4.92. Found: C, 71.51; H, 4.77; N, 5.11.