Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]([F:20])([F:19])[F:18])=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]#[N:30]>CN(C)C=O>[C:29]([CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]([F:20])([F:18])[F:19])=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]2)#[N:30]
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)ccc(O)c2n1C
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCC#N)c2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A mixture of 4.00 g (13.9 mmol) of ethyl 7-hydroxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate, 4.23 g (30.6 mmol) of potassium carbonate, 1.26 g (16.7 mmol) of chloroacetonitrile and 60 ml of dimethylformamide was stirred at room temperature for 2 hours. Insoluble matters were filtered off. The filtrate was poured onto ice water followed by extraction with diethyl ether. The extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 4.50 g of ethyl 7-cyanomethoxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([N+:24]([O-])=O)=[C:13]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=2)=[CH:4][CH:3]=1>[Pd].CO>[NH2:24][C:12]1[CH:11]=[CH:10][C:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:14][C:13]=1[N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Sc2ccc(O)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(Sc2ccc(O)cc2)ccc1N
Yield: 90.7 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(4-hydroxyphenylthio)-2-nitrophenyl]-N-methylcarbamate (2.84 g), palladium on carbon (10%, 1.52 g) and methanol (50 ml) and the reaction mixture was purified to give the title compound (2.37 g).
Reaction SMILES: B.C1C[O:5]CC1.[CH2:7]([O:9][C:10]([C:12]1[C:13]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:14]([CH2:33][CH:34]=[CH2:35])[N:15]2[C:20]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:18][C:17]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[N:16]2)=[O:11])[CH3:8].[OH-].[Na+].OO>C1COCC1>[CH2:7]([O:9][C:10]([C:12]1[C:13]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:14]([CH2:33][CH2:34][CH2:35][OH:5])[N:15]2[C:20]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:18][C:17]([N:27]1[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)=[N:16]2)=[O:11])[CH3:8]
Reactant: C=CCc1c(C(=O)OCC)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn12
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Na+]
Product: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1CCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
BH3.THF (162 μL, 0.162 mmol) was added dropwise via syringe to a solution of 1 (50 mg, 0.108 mmol) in anhydrous THF (6 mL). The reaction mixture was stirred at ambient temperature for 1 h. 5% aqueous NaOH (0.5 mL) and 30% aqueous H2O2 (1 mL) were added and the reaction mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was extracted with EtOAc and the organic layers were pooled, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to provide a yellow oil. The oil was purified by flash chromatography (silica gel, 40% EtOAc/hexane) to yield a yellow oil. The oil was triturated in (1:1) Et2O/hexane to provide a white solid. 1H NMR (DMSO-d6) δ 0.89 (t, J=7.2 Hz, 3H), 1.21 (t, J=7.0 Hz, 3H), 1.78 (m, 2H), 3.18 (m, 2H), 3.40 (m, 2H), 3.50 (m, 6H), 3.72 (m, 4H), 4.16 (q, J=7.1 Hz, 2H), 4.45 (t, J=5.3 Hz, 1H), 6.77 (s, 1H), 7.41 (m, 2H), 7.46 (m, 3H). Mass Spectrum (ESI+) m/e=482.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:12]([F:13])=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[C:4]([F:14])[C:3]=1[O:15][CH:16]([F:18])[F:17].[OH-].[Na+].Cl>C(O)C>[NH2:1][C:2]1[C:12]([F:13])=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:14])[C:3]=1[O:15][CH:16]([F:17])[F:18]
Reactant: CCOC(=O)c1cc(F)c(N)c(OC(F)F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(F)cc(C(=O)O)c(F)c1OC(F)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
In 61 ml of ethanol was suspended 12.3 g of ethyl 4-amino-2,5-difluoro-3-difluoromethoxybenzoate, and 31 ml of 2N aqueous sodium hydroxide solution was added to the suspension, after which the resulting mixture was stirred at 40° C. for one hour. To the reaction mixture was added 35 ml of 2N hydrochloric acid and the precipitate formed was collected by filtration, to obtain 10.6 g of colorless, crystalline 4-amino-2,5-difluoro-3-difluoromethoxybenzoic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:17]([O-])=O)[CH:11]=1>CO.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=1
Reactant: Nc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2nc3ccccc3o2)cc1N
Reaction time: 18 h
Yield: 87.8 %

Procedure:
To a stirred solution of 226 (517 mg, 1.77 mmol) in methanol (20 mL) was added palladium on charcoal (10%, 188 mg). The reaction was stirred under hydrogen atmosphere for 18 hours, filtered through a celite pad; the filtrate was evaporated under reduced pressure to afford title compound 227 (350 mg, 87% yield). 1H NMR: (DMSO) δ 7.673-7.641 (m, 2H), 7.39 (d, J=2.0 Hz, 1H), 7.32-7.30 (m, 3H), 6.64 (d, J=8.0 Hz, 1H). MS: (calc.) 225.2; (obt.) 226.1 (MH)+.
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][O:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C@H:22]3[O:31][C@H:25]4[O:26]C(C)(C)[O:28][C@H:24]4[C@H:23]3[CH2:32][CH2:33][N:34]3[C:39](=[O:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=[N:35]3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>C(#N)C.C(OCC)(=O)C.O>[OH:28][C@@H:24]1[C@H:25]([OH:26])[O:31][C@H:22]([CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:12]=[N:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)[C@@H:23]1[CH2:32][CH2:33][N:34]1[C:39](=[O:40])[C:38]2[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=2[N:36]=[N:35]1
Reactant: COc1ccc(-c2ccc(CC[C@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCn3nnc4ccccc4c3=O)cc2)cn1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(CC[C@H]3O[C@@H](O)[C@@H](O)[C@H]3CCn3nnc4ccccc4c3=O)cc2)cn1
Temperature: 55 °C

Procedure:
Perchloric acid (4.8 mL) was added to a solution of the compound obtained from step c above (8.1 g) in acetonitrile (50 mL) and water (8 mL) at room temperature. The reaction mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched using sodium bicarbonate solution. The solvents were evaporated under reduced pressure. The residue thus obtained was taken up in ethyl acetate and water. The organic layer was separated, washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was concentrated under reduced pressure to yield the title compound (8 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7].[Mg].[CH:9]12[CH2:15][CH:12]([CH:13]=[CH:14]1)[CH2:11][CH:10]2[CH:16]=[O:17].Cl>O1CCCC1.O>[OH:17][CH:16]([CH:10]1[CH2:11][CH:12]2[CH2:15][CH:9]1[CH:14]=[CH:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7]
Reactant: O=CC1CC2C=CC1C2
Reactant: COCCCCCl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: COCCCCC(O)C1CC2C=CC1C2
Reaction time: 2 h
Yield: 75.4 %

Procedure:
In 300 g of tetrahydrofuran was dissolved 122.6 g of 1-chloro-4-methoxybutane. The solution was added dropwise to 24.3 g of metallic magnesium over 2 hours and below 60° C. Agitation was continued for 2 hours at room temperature. To the solution, 122.2 g of 5-norbornene-2-carbaldehyde was added dropwise over one hour and below 50° C. Agitation was continued for one hour at room temperature to drive the reaction to completion. Then 300 g of water and 44 g of 20% HCl were added to the solution, which was agitated. Extraction with 500 g of hexane gave the organic layer, which was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The oily matter thus obtained was distilled in vacuum, obtaining 158.6 g of 5-(1-hydroxy-5-methoxypentyl)-2-norbornene. The yield was 75.4%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:19])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
292.4 g (1 mole) of methyl β-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionate and 383.6 g (1 mole) of oleyl alcohol are initially taken in 50 ml of toluene and are heated at 120° C., so that the toluene has distilled off in the course of one hour. 2.5 g of lithium amide are then added and the methanol which is formed is distilled off at 80° C. The mixture is then heated to 120° C. and is kept at this temperature for 4 hours. The reaction is monitored by thin layer chromatography. When the reaction is complete, the reaction mixture is dissolved in 200 ml of toluene, neutralised with 12 ml of concentrated HCl and then washed with twice 200 ml of water.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][NH:11][C:12](=[O:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:44][CH2:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54](=[O:65])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[C:61]([F:64])([F:63])[F:62])[CH2:50][CH2:49]1)=[O:47].Cl>CN(C=O)C.O>[CH3:10][NH:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([NH:44][CH2:45][C:46](=[O:47])[N:48]2[CH2:49][CH2:50][N:51]([C:54](=[O:65])[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[C:61]([F:64])([F:62])[F:63])[CH2:52][CH2:53]2)=[O:17])[CH:14]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: CNC(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.18 %

Procedure:
DIPEA (330 mg, 0.44 mL, 2.6 mmol) was added drop wise to N-methyl-isophthalamic acid (145 mg, 0.8 mmol) in DMF (3 mL). EDCI (180 mg, 0.96 mmol) and HOBT (130 mg, 0.96 mmol) were added consecutively and, after 10 minutes, 2-Amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (281 mg, 0.8 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using basic alumina and 10% MeOH in CHCl3 as eluent) to afford 35 mg (9.18% yield) of N-methyl-N′-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-isophthalamide. LCMS Purity: 97.7%. 1H NMR (CDCl3): δ 8.1 (bs, 1H), 7.9 (m, 2H), 7.7 (m, 1H), 7.5 (m, 3H), 7.4 (m, 2H), 6.3 (bs, 1H), 4.2 (m, 2H), 4.0 (m, 2H), 3.6 (m, 5H), 3.4 (m, 1H), 3.2 (m, 2H), 3.0 (d, 3H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[CH:22]=[C:21]([CH3:33])[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:27]1[CH:26]=[C:25]([C:23]2[CH:22]=[C:21]([CH3:33])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:24]=2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.5 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-(3,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.41 g) in dichloromethane (5 mL) was added TFA (5 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (10 mL) was added. The mixture was stirred at room temperature for 30 min, the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (MeOH/diethyl ether) to yield the title compound as a light brown solid (0.28 g, 79%). MS (ISP) 466.1 [(M+H)+]; mp 253.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:31])[CH:9]([NH:21][C:22]([C:24]2[O:25][CH:26]=[CH:27][C:28](=[O:30])[CH:29]=2)=[O:23])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO.[Cl-].[Mn+2].[Cl-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:31])[CH:9]([NH:21][C:22]([C:24]2[O:25][CH:26]=[CH:27][C:28](=[O:30])[CH:29]=2)=[O:23])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1)c1cc(=O)cco1
Agent: [Mn+2]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cc(=O)cco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
To a solution of N-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-oxo-4H-pyran-2-carboxamide (400 mg, 0.92 mmol) in methanol (30 ml) was added manganese (II) chloride (232 mg, 1.85 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction solution was added sodium borohydride (70 mg, 1.85 mmol) under ice-cooling and the mixture was stirred for 1 hr. The reaction solution was poured into 1N hydrochloric acid (30 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). High polar fractions were collected and concentrated, and the obtained crude crystal was washed with hexane to give N-(2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-oxo-4H-pyran-2-carboxamide((1RS,2SR) form: (1RS,2RS) form=3:2, 139 mg, 35%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=1)=O.[SH:17][C:18]1[NH:19][N:20]=[CH:21][C:22](=[O:24])[N:23]=1>C(O)C>[C:13]([C:7]1[CH:6]=[C:5]([C:3]2[N:19]3[N:20]=[CH:21][C:22](=[O:24])[N:23]=[C:18]3[S:17][CH:2]=2)[CH:10]=[C:9]([CH3:11])[C:8]=1[OH:12])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: O=c1cn[nH]c(S)n1
Solvent: CCO
Product: Cc1cc(-c2csc3nc(=O)cnn23)cc(C(C)(C)C)c1O

Procedure:
A solution of 28.5 g (0.1 mol) of 2-bromo-1-(3-tert.butyl-5-methyl-4-hydroxyphenyl)-ethanone from step (a1) and 12.9 g (0.1 mol) of 3-mercapto-2H-1,2,4-triazin-5-one was refluxed for 8 hours in 250 ml of ethanol. After the solvent had been removed in vacuo, the solid residue was dissolved in 200 ml of boiling ethyl acetate and filtered while hot. On concentration of the filtrate, colorless crystals were produced which were again recrystallized from isopropanol.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([I:14])=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20]C)[C@H:17]([O:22][C:23](=O)C)[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C[O-].[Na+]>O>[CH2:1]([C:8]1[C:13]([I:14])=[CH:12][CH:11]=[C:10]([N:15]2[CH2:16][C@H:17]([O:22][CH3:23])[C@H:18]([OH:20])[CH2:19]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Yield: 98.5 %

Procedure:
To a mixture of 7.5 g of 2-benzyl-3-iodo-6-[(3R,4S)-3-acetoxy-4-methoxypyrrolidin-1-yl]pyridine and 30 ml of methanol was added 0.33 ml of 28% methanol solution of sodium methoxide and the resultant mixture was stirred under nitrogen atmosphere at room temperature for 30 minutes. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (20–50% ethyl acetate/hexane), to give 6.7 g of the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:17][S@](C(C)(C)C)=O)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)(C(C)(C)C)(C)C.[ClH:24]>CO>[ClH:24].[ClH:24].[NH2:17][C@@H:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][OH:8]
Reactant: CC(C)(C)[S@](=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1cccnc1
Agent: Cl
Solvent: CO
Product: N[C@H](CO)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.1 %

Procedure:
A mixture of (S)—N—((S)-2-(tert-butyldimethylsilyloxy)-1-(pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.2 g, 1.77 mmol) in MeOH (9 mL) was treated with 4N hydrogen chloride (2.21 mL, 8.85 mmol) at 0° C. The mixture was allowed to warm up to ambient temperature and stirred for 1 hour. The mixture was concentrated and the residue treated with aqueous saturated NaHCO3/EtOAc. The organic layer was dried (phase separator silicone treated filter paper), concentrated. The residue was purified on silica gel (2-10% 7N ammonia in MeOH in DCM) to provide (S)-2-amino-2-(pyridin-3-yl)ethanol dihydrochloride (0.060 g, 16% yield) as a beige solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[C:18]1([C:9]2[CH2:10][C:11]3[C:16]([CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C1=Cc2ccccc2C1
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: C1=C(c2ccccc2)Cc2ccccc21
Temperature: 25 °C
Yield: 41.6 %

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 4.08 g (20 mmole) of iodobenzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 ml of ethanol. The crystalline precipitate was isolated, washed with ethanol and dried under vacuum to obtain 1.6 g (46%) of 2-phenyl-indene.
Reaction SMILES: [C:1](OCC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[O:4]=[C:3]([CH3:5])[CH2:2][C:1]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([O:12][C:11]([F:20])([F:21])[F:10])=[CH:14][CH:15]=1)=[O:6]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)CC(C)=O
Product: CC(=O)CC(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(Trifluoromethoxy)aniline (10 mL) was added dropwise to ethyl acetoacetate (44 mL) at 160° C., and the mixture was stirred at the same temperature for 1 h. The mixture was left stand for cooling to room temperature and crystallized with hexane to obtain 3-oxo-N-(4-(trifluoromethoxy)phenyl)butane amide (6.5 g). (2) To concentrated sulfuric acid (32.5 mL) was added 3-oxo-N-(4-(trifluoromethoxy)phenyl)butane amide (6.5 g), and the mixture was stirred at 95° C. for 3 h. The reaction solution was added dropwise to water with ice cooling, and the precipitated crystals were collected by filtration. The resulting crystals were suspended in water, the suspension was made basic with aqueous ammonia, and the precipitated crystals were collected by filtration to obtain 4-methyl-6-(trifluoromethoxy)quinoline-2(1H)-one (1.87 g). (3) A mixture of 4-methyl-6-(trifluoromethoxy)quinoline-2(1H)-one (1.87 g) and phosphorus oxychloride (19 mL) was stirred at 105° C. for 2.5 h. The reaction solution was added dropwise to water with ice cooling, and the precipitated crystals were collected by filtration to obtain 2-chloro-4-methyl-6-trifluoromethoxyquinoline (1.98 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)[CH2:4][CH2:3]1.[Cl:22]N1C(=O)CCC1=O>C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:22][C:19]1[N:10]2[C:9]([C:8](=[C:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11]2)=[N:21][CH:20]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCC(=C2c3ccccc3CCn3ccnc32)CC1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN1CCC(=C2c3ccccc3CCn3c(Cl)cnc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
6,11-Dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine (28 g) was stirred in DCM (500 ml), until complete dissolution. Dibenzoyl peroxide (0.1 g) was added. N-chlorosuccinimide (13.4 g) was added portionwise and the resulting reaction mixture was stirred overnight at room temperature, then for 2 hours at reflux temperature. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 97/3, upgrading to 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried, yielding 23.3 g (74%) of 3-chloro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo-[2,1-b][3]benzazepine (intemediate 11).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([CH2:20][N:21]3[C@@H:25]([CH3:26])[C@@H:24]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=4)[O:23][C:22]3=[O:35])=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl.[F:37][CH:38]1[CH2:41][NH:40][CH2:39]1.CCN(CC)CC.Cl>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([CH2:20][N:21]3[C@@H:25]([CH3:26])[C@@H:24]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=4)[O:23][C:22]3=[O:35])=[N:12][C:13]([N:40]3[CH2:41][CH:38]([F:37])[CH2:39]3)=[N:14][CH:15]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: FC1CNC1
Reactant: COc1ncc(Cl)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(F)cc(F)c2)[C@@H]1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ncc(Cl)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(F)cc(F)c2)[C@@H]1C
Temperature: 100 °C

Procedure:
(4S,5R)-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-5-(3,5-difluorophenyl)-4-methyl-1,3-oxazolidin-2-one (Step A, 519 mg, 0.989 mmol) and 3-fluoroazetidine hydrochloride (331 mg, 2.97 mmol) were placed in a microwave vial and suspended in THF (3 mL). Et3N (0.689 mL, 4.94 mmol) was added, the vial was sealed and the reaction heated to 100° C. for 20 minutes in a microwave reactor. LCMS showed complete conversion to product. The reaction was diluted with ethyl acetate (50 mL) and poured into 0.1N HCl solution (50 mL). The ethyl acetate layer was washed with brine (50 mL), dried over sodium sulfate and concentrated on rotary evaporator. Silica gel purification employing a 0-50% ethyl acetate/hexanes linear gradient followed by isocratic elution at 50% ethyl acetate/hexanes gave the product as a pale yellow solid. LCMS (M+H)+: 520.3. 1H NMR (500 MHz, CDCl3): δ 8.19 (d, J=2.5 Hz, 1H), 8.14 (s, 1H), 7.48 (d, J=2.5 Hz, 1H), 6.84 (m, 3H), 5.52 (m, 1.5H), 5.42 (m, 0.5H), 4.64 (d, J=17.3 Hz, 1H), 4.49 (m, 2H), 4.35 (m, 2H), 3.98 (d, J=17.3 Hz, 1H), 4.07 (m, 4H), 3.95 (s, 3H), 0.78 (d, J=6.6 Hz, 3H). SPA IC50: 728 nM.