Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].CCN(C(C)C)C(C)C>ClCCl>[F:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:2](=[O:3])[O:4][CH3:5])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: COC(=O)Cl
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl chloroformate (13.2 mL, 170.2 mmol) was added dropwise to a cold (0° C.) dichloromethane (200 mL) solution of 4-fluoro-3-nitro aniline (24.15 g, 154.7 mmol) and DIPEA (35 mL, 201 mmol). The reaction mixture was stirred at rt overnight. The solution was then diluted with 200 mL of dichloromethane and washed with 2M HCl, brine and dried over anhydrous MgSO4. The solvent was concentrated and the product was directly used for next step without further purification. Yield: 35.5 g (99%). 1H NMR (400 MHz, CHLOROFORM-D): δ 3.81 (s, 3H), 7.02 (s, 1H), 7.23 (m, 1H), 7.72 (d, J=8.59 Hz, 1H), 8.17 (dd, J=6.35, 2.64 Hz, 1H).
Reaction SMILES: CN(C=O)C.[C:6]1([N:12]=[C:13]([O:23][C:24]2[CH:29]=CC=CC=2)[CH:14]=[CH:15]OC2C=CC=CC=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Na].[CH2:31]([SH:33])[CH3:32]>C(OCC)(=O)C>[C:6]1([N:12]=[C:13]([O:23][CH2:24][CH3:29])[CH:14]=[CH:15][S:33][CH2:31][CH3:32])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C(=CC(=Nc1ccccc1)Oc1ccccc1)Oc1ccccc1
Reactant: CCS
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(C=CSCC)=Nc1ccccc1
Reaction time: 3 h
Yield: 62.5 %

Procedure:
To DMF (5 ml) solution of phenyl N-phenyl-3-phenoxyacrylimidate (0.30 g) was added sodium salt of ethyl mercaptan (0.10 g) under ice-cooling, and stirred for three hours at the same temperature. Ethyl acetate (80 ml) was added to the reaction solution, and it was successively washed with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. DMF (5 ml) and sodium salt of ethyl mercaptan (0.1 g) were added to the residue, and stirred for three hours at room temperature. Ethyl acetate (80 ml) was added to the reaction solution and it was successively washed with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain ethyl N-phenyl-3-(ethylthio)acrylimidate (0.14 g) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:42][S:43]([C:46]1[CH:58]=[CH:57][C:49](CN2C=CC(N)=N2)=[CH:48][CH:47]=1)(=[O:45])=[O:44]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:49]3[CH:57]=[CH:58][C:46]([S:43]([CH3:42])(=[O:45])=[O:44])=[CH:47][CH:48]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(Cn2ccc(N)n2)cc1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (166 μL, 0.33 mmol) at 0+ C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (46 μL, 0.39 mmol) was added to the solution at 0° C. After 1 h, 1-(4-methanesulfonyl-benzyl)-1H-pyrazol-3-ylamine (0.30 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-methanesulfonyl-benzyl)-1H-pyrazol-3-yl]-propionamide (150 mg, 88%) as a white solid: ESI-LRMS m/e calcd for C26H30ClN3O5S2 [M+] 563.13, found 564.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.21 (m, 2H, CH2), 1.34-1.88 (m, 8H, 4×CH2), 2.09-2.29 (m, 1H, CH), 2.98 (s, 3 H, SO2CH3), 3.22 (s, 3H, SO2CH3), 3.56 (t, J=7.5 Hz, 1H, CH), 5.24 (AB, Jgem=15.9 Hz, 2H, NCH2), 6.76 (d, J=2.3 Hz, 1H, Ar), 7.14 (d, Jo=8.3 Hz, 2H, Ar), 7.38 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.44 (d, J=2.3 Hz, 1H, Ar), 7.53 (d, Jm=1.7 Hz, 1H, Ar), 7.75 (d, Jo=8.3 Hz, 2H, Ar), 7.91 (d, Jo=8.2 Hz, 1H, Ar), 8.34 (s, 1H, NH).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1B(O)O>>[CH:19]1[C:20]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:18]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Brc1cccc2cc[nH]c12
Product: c1ccc2cc(-c3cccc4cc[nH]c34)ccc2c1

Procedure:
Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 2-naphthylboronic acid: ESMS m/e: 244.0 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[F:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: COc1ccccc1-c1cc(F)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(F)cc(-c3ccccc3OC)c2O1

Procedure:
The title compound was prepared (0.075 g, 37%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.27 g, 0.6 mmol) and methylamine (0.198 g, 6.0 mmol). mp 175-176° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=O)=[O:4].C(O)(=O)C>CO>[O:4]=[C:3]1[NH:5][C:6]2[S:7][CH:8]=[CH:9][C:10]=2[C:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[N:1][CH2:2]1
Reactant: COC(=O)c1ccc(C(=O)c2ccsc2NC(=O)CN)cc1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C2=NCC(=O)Nc3sccc32)cc1
Temperature: 100 °C
Yield: 100 %

Procedure:
In a 75 mL pressure flask was suspended compound 492 (0.265 g, 0.832 mmol) and acetic acid (0.071 mL, 1.249 mmol) in methanol (20 mL) to give a yellow suspension. The reaction mixture was heated at 100° C. overnight. The solvent was removed to afford title compound 493 (250 mg, 100%) as a tan powder. MS (m/z): 301.3 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2([CH3:27])[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CO>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2([CH3:27])[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cccc(C(C)(C)C)c2)CC1
Agent: Cl
Solvent: CO
Product: CC1(C(=O)Nc2cccc(C(C)(C)C)c2)CCNCC1

Procedure:
tert-Butyl 4-(3-tert-butylphenylcarbamoyl)-4-methylpiperidine-1-carboxylate from step A (0.4 g, 1.07 mmol) was treated with HCl (4.0 N in dioxane, 1.3 mL, 5.34 mmol) in methanol (5.0 mL) at 50° C. for 30 minutes. The mixture was concentrated to give the title compound as the hydrochloride salt in quantitative yield. MS (ES+) [M+H]+=275.
Reaction SMILES: C[O:2][CH:3]([O:10][CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12](N(CC)CC)C>CC(C)=O.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:2][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:12][CH2:11][O:10]1
Reactant: COC(OC)c1ccccc1
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: OC1OCCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 605.4 %

Procedure:
To a stirred solution of crude product from step 5 (1.89 g; 5.49 mmol) in a mixture of acetone (80 ml) and water (25 ml) was added p-toluene sulfonic acid monohydrate (70 mg; 0.37 mmol). After stirring at room temperature for 3 hours, triethylamine (2 ml; 1.43 mmol) was added and stirred for 5 minutes. The mixture was evaporated until volume went down to 10 ml. A mixture of acetone (80 ml) and water (15 ml) was added followed by addition of p-toluene sulfonic acid monohydrate (70 mg; 0.37 mmol). After 3.5 hours, triethylamine (3 ml; 2.15 mmol) was added, evaporated to a small volume, extracted with ether (3×100 ml). The extract was washed with brine (50 ml), dried over MgSO4 and evaporated yielding quite pure 1-hydroxyisochroman (1.3 g; 94%), (MP. 136°-138° C.). NMR (CDCl3 ; 300 MHz) δ:2.32 (3H, s, CH3O), 2.51 (1H, dd, J=12.4, 17.5 Hz, H-4), 2.97 (1H, d, J=3.5 Hz; --OH), 3.06 (1H, dd, J=4.1, 17.5 Hz, H-4), 3.77, 3.82 (3H, s each, ArOCH3), 4.70 (1H, dd, J=4.1, 12.4 Hz, H-3), 6.22 (1H, d, J=3.4 Hz, 1H), 6.71, 6.76, (1H, d each, J=9.0 Hz, ArH).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH:18]=[CH:19][C:20]=1[Cl:21].CCN(CC)CC>C(#N)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:2]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])=[CH:30][CH:31]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Nc1ccc(CCCCc2ccc(Cl)c(Cl)c2)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)c1cc([N+](=O)[O-])ccc1Nc1ccc(CCCCc2ccc(Cl)c(Cl)c2)cc1
Yield: 30 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzoic acid (1.85 g, 0.01 mol), 4-[4-(3,4-dichlorophenyl)butyl]-phenylamine (2.94 g, 0.01 mol) and Et3N (2.80 mL) in acetonitrile (110 mL) was heated to reflux for 48 hours. The reaction mixture was cooled and concentrated in vacuo to remove the solvent. The residue was dissolved in CH2C2 and washed with diluted HCl. The organic layer was dried Na2SO4), concentrated in vacuo to give a crude solid. Purification by flash chromatography (silica gel, CH2Cl2) yielded 1.40 g (0.003 mol, 30%) of the desired product.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][N:6]=1.[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[NH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[C:21]2[CH:20]=[CH:19][C:18]([C:32]3[CH:37]=[N:36][C:35]([NH2:38])=[N:34][CH:33]=3)=[C:17]([F:16])[CH:22]=2)[N:10]=1
Reactant: Nc1ccnc(Oc2ccccc2Br)n1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ccnc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)n1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)pyrimidin-4-amine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H15FN6O, 374.13; m/z found, 375.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.49-8.43 (d, J=1.4, 2H), 7.79-7.72 (d, J=5.9, 1H), 7.51-7.47 (dd, J=7.6, 1.7, 1H), 7.47-7.41 (m, 2H), 7.39-7.28 (m, 3H), 7.22-7.17 (dd, J=8.1, 1.2, 1H), 6.16-6.05 (d, J=105.9, 1H).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:7]2[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][CH3:50])[CH:42]=1.[O-]CC.[Na+].[CH3:55][N:56]1[CH:60]=[CH:59][N:58]=[C:57]1[CH2:61][CH2:62][CH:63]=O.O>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9](/[CH:16]=[CH:63]/[CH2:62][CH2:61][C:57]1[N:56]([CH3:55])[CH:60]=[CH:59][N:58]=1)[C:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:7]2[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][CH3:50])[CH:42]=1
Reactant: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: Cn1ccnc1CCC=O
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(/C=C/CCc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
[6,7-Dimethoxy-4-(3,4-dimethoxyphenyl )-3-ethoxycarbonylquinolin-2-yl]methyltriphenylphosphonium chloride (3.0 g) was added at room temperature to a solution of sodium ethoxide in ethanol (prepared from Na (0.13 g) and ethanol (45 ml)). Then 3-(1-methylimidazol-2-yl)propionaldehyde (0.787 g) was added. The mixture was stirred at room temperature for 3 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate/methanol (30/1, v/v) gave ethyl (E)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[2-[2-(1-methylimidazol-2-yl)ethyl]vinyl]quinoline-3-carboxylate (0.36 g, 15%) as an oil.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([CH:32]=[C:33]([F:36])[CH2:34]O)[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>C(Cl)(Cl)(Cl)Cl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([CH:32]=[C:33]([F:36])[CH2:34][Br:1])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1
Reactant: BrBr
Reactant: OCC(F)=CC1(c2ccc(Cl)cc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(=CC1(c2ccc(Cl)cc2)CC1)CBr
Temperature: 25 °C
Yield: 63 %

Procedure:
Under a nitrogen atmosphere, a solution of bromine (0.767 g, 4.8 mmol) in carbon tetrachloride at ice-water bath temperature is treated sequentially with a solution of triphenylphosphine (1.26 g, 4.8 mmol) in carbon tetrachloride and a solution of 3-[1-(p-chlorophenyl)-cyclopropyl]-2-fluoro-2-propen-1-ol, (Z)- (0.907 g, 4 mmol) in carbon tetrachloride, heated to and stirred at reflux for 70 minutes, cooled to room temperature, and poured into petroleum ether. The resultant mixture is filtered, and the filtrate is concentrated in vacuo to obtain a residue: The residue is dissolved in petroleum ether and passed through a plug of silica gel (eluted with hexanes) to obtain an oil. Flash column chromatography of the oil using silica gel and a 3:20 methylene chloride/hexanes solution gives the title product as a colorless oil (0.73 g, 63% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:4][C:3]=1[F:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccc(Cl)c(F)c1
Product: O=[N+]([O-])c1cccnc1Nc1ccc(Cl)c(F)c1
Temperature: 180 °C
Reaction time: 0.17 h

Procedure:
4-Chloro-3-fluoroaniline (10.0 g, 68.7 mmol) was heated to 180° C. in an oil bath. 2-Chloro-3-nitropyridine (11.0 g, 69.4 mmol) was added, and the resulting mixture was stirred at 180° C. for 10 minutes. The reaction mixture was then cooled to 15° C. and washed with petroleum ether, providing the product as a salmon-pink solid. Yield: 15 g, 56 mmol, 82%. 1H NMR (400 MHz, CDCl3) δ 10.20 (br s, 1H), 8.57 (dd, J=8.3, 1.6 Hz, 1H), 8.54 (dd, J=4.6, 1.7 Hz, 1H), 7.90 (dd, J=11.3, 2.4 Hz, 1H), 7.38 (dd, J=8.5, 8.3 Hz, 1H), 7.23-7.28 (m, 1H, assumed; partially obscured by solvent peak), 6.94 (dd, J=8.3, 4.5 Hz, 1H).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH:1]1([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C1CCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CCC2N1CCCCC1
Reaction time: 48 h

Procedure:
A mixture of 100 g. of 1-indanone (0.758 mole) and 125 ml. of piperidine in 750 ml. of toluene is treated with 0.5 g. of p-toluenesulfonic acid and heated under reflux with a water take-off trap attached. Heating is continued for 48 hours. Solvent and excess piperidine are removed in vacuo and the residue is dissolved in 1500 ml. of absolute methanol. The resulting solution is stirred and treated portionwise with 50 g. of sodium borohydride below 30° C. After stirring several hours longer, the mixture is treated with a small amount of acetic acid then made strongly basic by the addition of sodium hydroxide solution. After 400 ml. of water is added, most of the methanol is removed in vacuo. Product is extracted into ether, dried over potassium hydroxide and distilled. 119.7 g. of 1-(1-indanyl)piperidine is collected at 101°-102° (0.2 mm.).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH:28]([OH:33])[C:29]([F:32])([F:31])[F:30])[CH2:25][CH3:26])[C:5]1=[O:34])[CH:2]=[CH2:3].O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:39]>C(Cl)Cl>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][C:28]([OH:39])([OH:33])[C:29]([F:30])([F:31])[F:32])[CH2:25][CH3:26])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(O)C(F)(F)F)C1=O
Solvent: ClCCl
Solvent: O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(O)(O)C(F)(F)F)C1=O
Reaction time: 8 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one prepared above in Step A (100 mg, 0.189 mmol) in DCM (2.1 mL) was added water (17 μL, 0.95 mmol) and Dess-Martin periodinane (161 mg, 0.378 mmol) at rt and the resulting solution was stirred overnight. The reaction was quenched (1 M aq. Na2S2O3), extracted (2×DCM), and washed (2×sat. NaHCO3 and 1×sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a colorless film. The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].CS(O[CH2:10][C@H:11]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])[CH3:12])(=O)=O>O1CCCC1>[CH2:1]([NH:4][CH2:12][C@H:11]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])[CH3:10])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: C[C@H](COS(C)(=O)=O)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: C=CCNC[C@@H](C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 16 h

Procedure:
5.4 mL of allylamine was added to a tetrahydrofuran (100 mL) solution of 8.2 g of (R)-2-(2-nitrophenylsulfonamido)propyl methanesulfonate, and the mixture was stirred at 80° C. for 16 hours. After the completion of reaction, the reaction solution was returned to room temperature, and 100 mL of saturated saline was added thereto. From this mixed solution, two extractions were performed with 100 mL of ethyl acetate. The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 7 g of the compound of interest as a yellow oil (96%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].F[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
Glycine (5.31 g, 70.8 mmol) was added to a mixture of 1-fluoro-4-nitro-benzene (5.0 g, 35.4 mmol) and sodium bicarbonate (5.94 g, 70.8 mmol) in dioxane (10 mL) and water (60 mL) and heated at reflux for 6 h. The reaction mixture was cooled to room temperature and washed with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid to pH ˜3 and extracted with ethyl acetate. The extract was washed with water, brine, dried over anhydrous sodium sulfate and concentrated to dryness to afford (4-nitro-phenylamino)-acetic acid (5.0 g, 72%) as a yellow solid.
Reaction SMILES: [Na].[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:28])[CH:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18](=[O:28])[CH:19]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:13][CH:12]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:16]
Reactant: Oc1ccc(C2=CCCCC2)cc1
Reactant: CCCCCCCC(Br)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCCCCC(Oc1ccc(C2CCCCC2)cc1)C(=O)OCC

Procedure:
To a solution of 2.4 g of sodium in 100 ml of absolute ethanol are added initially 15 g of p-(1-cyclohexenyl)-phenol in a small amount of absolute ethanol at room temperature under anhydrous conditions and with stirring. 34 Grams of α-bromo-nonanoic acid ethyl ester are then added dropwise and the reaction mixture is stirred for 24 hours at 50° C. The ethanol is subsequently stripped off in vacuo and the residue is partitioned between water and ice-cold N sodium hydroxide solution. The organic phase is washed until neutral, dried over sodium sulphate and concentrated in vacuo. The residue yields the crude α-[p-(1-cyclohexyl)-phenoxy]-nonanoic acid ethyl ester of the formula ##STR15## in the form of an oil.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[OH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[CH2:13][CH2:14][C:15](O)=O>Cl>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:15]=1[CH2:14][CH2:13][C:12]1[CH:11]=[C:10]([OH:9])[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)CCc1cccc(O)c1
Reactant: Nc1ccccc1N
Agent: Cl
Product: Oc1cccc(CCc2nc3ccccc3[nH]2)c1
Temperature: 135 °C
Reaction time: 8 h
Yield: 803.5 %

Procedure:
A 100 mL flask fitted with a stir-bar and a condenser was charged with 1,2-phenylenediamine (3.42 g, 31.6 mmol), 3-hydroxyhydrocinnamic acid (5.25 g, 3.16 mmol), and 4M HCl (50 mL). The mixture was heated in a 135° C. bath overnight. The mixture was cooled in an ice bath, and the precipitate was filtered and rinsed with H2O (5 mL). The solid was suspended in saturated NaHCO3 (75 mL). 50% aq NaOH was added until pH 11 was attained, and then another portion of saturated NaHCO3 (75 mL) was added. The suspension was stirred overnight. The solid was filtered, pressed with rubber dam, and rinsed with H2O (2×10 mL). The resultant material was dried to give 6.05 g of 69 as a white solid (80%). 1H NMR (60 MHz, CDCl3): δ 7.6-7.4 (m, 2H), 7.4-7.0 (m, 3H), 6.9-6.6 (m, 3H), 5.2 (s, 2H), 3.1 (s, 4H) ppm. HPLC analysis (35:10:55 H2O:A1:MeOH) showed a purity of greater than 99% with a retention time of 3.1 min.