Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1O
Product: O=C(O)c1cc([N+](=O)[O-])cnc1Cl

Procedure:
A solution of 2-hydroxy-5-nitronicotinic acid (9.2 g, 0.05 mol) in phosphorus oxychloride (25 ml) was refluxed for 5 hours. The solvent was removed in vacuo and the residue dissolved in a mixture of tetrahydrofuran and ether. After cooling the solution in an ice bath, water was cautiously added dropwise with stirring until a clean separation of layers was obtained. The organic layer was washed with water and a saturated sodium chloride solution, dried (anhydrous magnesium sulfate) and concentrated. Recrystallization from ether gave 6.94 g (69% of theory) of pure product, m.p. 135° C. (dec).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:13][CH3:14])[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:11]C1)=[O:7].N[C@@H:16](CCC)CO.[N+](CC)#[C-]>>[ClH:1].[ClH:1].[NH2:3][C@@H:4]([CH2:13][CH2:14][CH3:16])[C@H:5]([OH:12])[C:6]([NH:8][CH2:9][CH3:11])=[O:7]
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: CCC[C@H](N)CO
Agent: Cl
Agent: [C-]#[N+]CC
Product: CCC[C@H](N)[C@H](O)C(=O)NCC

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, starting with (S)-2-aminopentan-1-ol in the first step (A1), and using isocyanoethane in the third step (A3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.Cl[S:28]([OH:31])(=[O:30])=[O:29].C(=O)([O-])[O-].[K+:36].[K+]>N1C=CC=CC=1>[S:28]([O-:31])([O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1)(=[O:30])=[O:29].[K+:36]
Reactant: COc1ccc(S(=O)(=O)Nc2cccnc2Nc2ccc(O)cc2)cc1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cccnc2Nc2ccc(OS(=O)(=O)[O-])cc2)cc1
Reaction time: 72 h

Procedure:
2.0 g (5.38 mmol) of the compound of Example 6 was dissolved in 20 ml of pyridine. 800 mg (6.87 mmol) of chlorosulfonic acid (95%) was added dropwise thereto at -15° to -10° C. The temperature was slowly elevated to room temperature and the mixture was stirred for 3 days. A 1N aqueous potassium carbonate solution was added to the reaction mixture to adjust the pH to 8 to 9. The solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the residue and an aqueous layer thus formed was separated, concentrated, purified by silica gel column chromatography and precipitated with methanol/dichloromethane to obtain 1.58 g of the title compound.
Reaction SMILES: C[C:2]1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[S:21]([CH3:23])=[O:22])[O:11][CH3:12])=[O:9])[C:4](=[O:24])[O:3]1>CO>[CH3:2][O:3][C:4](=[O:24])[C:5]([OH:6])=[CH:7][C:8](=[O:9])[N:10]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[S:21]([CH3:23])=[O:22])[O:11][CH3:12]
Reactant: CON(Cc1ccc(F)cc1S(C)=O)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1S(C)=O)OC
Yield: 100 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfinyl-benzyl)-N-methoxy-acetamide was reacted with methanol using the procedure described for the synthesis of compound 90-C to yield 3-[(4-fluoro-2-methanesulfinyl-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester as a white sticky solid (0.1020 g, 100% yield). This crude was reacted with paraformaldehyde and 4-amino-butyric acid using the procedure described for Compound 810 to give the title compound as an orange solid (0.0360 g, 64% yield). 1HNMR (300 MHz, CDCl3) δ: 7.75 (1H, dd, J=8.05, 2.56 Hz), 7.48 (1H, dd, J=8.42, 4.76 Hz), 7.21 (1H, td, J=8.05, 2.56 Hz), 4.96 (2H, q), 4.19 (2H, s), 3.78 (3H, s), 3.58 (2H, td, J=6.95, 1.83 Hz), 2.82 (3H, s), 2.39 (2H, t, J=6.95 Hz), 1.97–1.92 (2H, m).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:48])[CH2:30][CH2:31][N:32]([C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1)[C:33]([C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)=[O:34]>>[CH3:28][N:29]([CH3:48])[CH2:30][CH2:31][N:32]([C:41]1[CH:42]=[CH:43][C:44]([NH:45]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:46][CH:47]=1)[C:33]([C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)=[O:34]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C)CCN(C(=O)c1cccnc1)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)C(=O)c2cccnc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-(pyridine-3-carbonyl)-amino)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C33H31N5O4
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:32]=[CH:31][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([N:19]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:20](=[O:22])[CH3:21])[CH2:11][C@@H:10]2[CH3:30])=[O:8])=[CH:5][CH:4]=1.FC(F)(F)C1C=CC(CCl)=CN=1>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([N:19]([C@H:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([C:2]#[N:1])=[CH:32][CH:31]=3)[C@@H:10]([CH3:30])[CH2:11]2)[C:20](=[O:22])[CH3:21])=[CH:28][CH:27]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CN)cc2)c2ccccc21
Agent: FC(F)(F)c1ccc(CCl)cn1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C#N)cc2)c2ccccc21

Procedure:
N-{(2S,4R)-1-[4-(aminomethyl)benzoyl]-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl}-N-(4-chlorophenyl)acetamide was made following general procedure H, substituting 4-cyanobenzoyl chloride for 6-trifluoromethyl nicotinyl chloride. The rest of the procedure is followed as indicated in general procedure H to yield the corresponding nitrile, N-(4-chloro-phenyl)-N-[(2S,4R)-1-(4-cyano-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide. N-(4-Chloro-phenyl)-N-[(2S,4R)-1-(4-cyano-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (225 mg, 0.51 mmol) was dissolved in ethanol (7 mL) and cobalt dichloride (0.079 g, 0.61 mmol) and NaBH4 (0.059 g, 1.57 mmol) were added and the mixture was stirred at room temperature for 2 h. The slurry was filtered, concentrated, and subjected to flash chromatography (1% NH4OH, 15% MeOH, EtOAc) to yield the title compound (188 mg, 83%) as a white solid. 1H-NMR (CDCl3) δ: 1.00-1.20 (m, 1H), 1.14 (s, 3H), 1.48 (bs, 2H), 2.02 (s, 3H), 2.20-2.36 (m, 1H), 3.79 (s, 2H), 4.73-4.83 (m, 1H), 5.35-5.70 (m, 1H), 6.49 (d, 1H), 6.89 (t, 1H), 7.11-7.29 (m, 8H), 7.37 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:38])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[CH:32]=[CH:31][N:30]=[C:29]([O:33]C(C)(C)C)[N:28]=3)[CH2:16][CH2:15]1)(=[O:13])=[O:12])=[CH:5]2.Cl>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:15][CH2:16][N:17]([C:20](=[O:38])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[CH:32]=[CH:31][N:30]=[C:29]([OH:33])[N:28]=3)[CH2:18][CH2:19]1)(=[O:13])=[O:12])=[CH:5]2
Reactant: CC(C)(C)Oc1nccc(-c2ccccc2C(=O)N2CCN(S(=O)(=O)c3cc4cc(Cl)ccc4[nH]3)CC2)n1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccccc1-c1ccnc(O)n1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(5-chloroindol-2-ylsulphonyl)-4-[(2-tert-butyloxypyrimidin-4-yl)benzoyl]piperazine (200 mg, 0.361 mmol) in dichloromethane and methanol (10 ml of a 4:1 mixture) was added a solution of hydrogen chloride in methanol (0.40 ml of ˜4.5 M, 1.8 mmol), and the reaction stirred at ambient temperature for 1 hr. The solvent was removed in vacuo and the residue crystallised from ethanol to give 1-(5-chloroindol-2-ylsulphonyl)-4-[(2-hydroxypyrimidin-4-yl)benzoyl]piperazine as a colourless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH2:25][O:26]C4CCCCO4)=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[C:5]([F:33])=[CH:4][N:3]=1.[N:34]1([CH2:39][CH2:40][NH2:41])[CH:38]=[CH:37][N:36]=[N:35]1.O1CCOCC1.C(O)CCC>C(O)(C)(C)C.C(Cl)(Cl)Cl.C(O)(C)C.CN1C(=O)CCC1.O1CCOCC1.CN1C(=O)CCC1>[N:34]1([CH2:39][CH2:40][NH:41][C:2]2[N:7]=[C:6]([C:8]3[S:12][C:11]4[C:13]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[O:23][CH2:24][CH2:25][OH:26])=[CH:14][CH:15]=[CH:16][C:10]=4[CH:9]=3)[C:5]([F:33])=[CH:4][N:3]=2)[CH:38]=[CH:37][N:36]=[N:35]1
Reactant: NCCn1ccnn1
Reactant: Fc1cnc(Cl)nc1-c1cc2cccc(-c3ccccc3OCCOC3CCCCO3)c2s1
Solvent: CC(C)(C)O
Solvent: CCCCO
Solvent: CC(C)O
Product: OCCOc1ccccc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 135 °C
Yield: 64.6 %

Procedure:
Combine 2-chloro-5-fluoro-4-(7-{2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-benzo[b]thiophen-2-yl)-pyrimidine (250 mg, 0.52 mmol) and 2-[1,2,3]triazol-1-yl-ethylamine (140 mg, 1.29 mmol) in tert-butanol (2.6 mL, alternative dioxane, n-butanol, dioxane-NMP, NMP alone as solvent) and NMP (1.3 mL) in a pressure vessel. Heat the mixture in an oil bath at 120-150° C. overnight (or in microwave reactor for a certain period of time). Dilute the mixture with chloroform/IPA (3/1). Wash the solution with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (DCM to 10% methanol in DCM) to give the title compound as a yellow solid (160 mg, 65%). MS (ES) m/z 477 [M+1]+.
Reaction SMILES: [CH:1]([NH:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])([CH2:3][CH3:4])[CH3:2].CN(C)CCN(C)C.[H-].[K+].C(S([C:27]1[O:28][CH:29]=[C:30]([CH3:32])[N:31]=1)=O)CCC>S1(CCCC1)(=O)=O.O>[CH:1]([N:5]([C:27]1[O:28][CH:29]=[C:30]([CH3:32])[N:31]=1)[C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])([CH2:3][CH3:4])[CH3:2]
Reactant: CCCCS(=O)c1nc(C)co1
Reactant: CCC(C)NC(=O)C(C)C
Agent: CN(C)CCN(C)C
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CCC(C)N(C(=O)C(C)C)c1nc(C)co1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
N-s-Butyl-isobutyramide (2.30 g, 0.016 m) and tetramethylethylenediamine (1.87 g, 0.016 m) were stirred at 40° C. in sulpholane (20 ml) under nitrogen during the portionwise addition of a 50% potassium hydride/oil dispersion (1.29 g, 0.016 m). After the addition, the mixture was warmed to 70° C. and 2-n-butylsulphinyl-4-methyloxazole (3.0 g, 0.016 m) in sulpholane (20 ml) was added. The mixture was stirred at 70° C. for 6 hours and then hydrolysed with water. Removal of the solvent in vacuo and column chromatography on silica using diethyl ether gave the title compound, which was a colourless oil after distillation in vacuo, b.p. 82° C./0.8 mm.
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13]OS(C)(=O)=O)=[CH:7][CH:6]=2)#[N:2].[CH3:25][NH2:26]>>[CH3:25][NH:26][CH2:13][CH:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3]([C:1]#[N:2])=[CH:11]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN
Reactant: CS(=O)(=O)OCC(c1ccccc1)c1ccc2[nH]c(C#N)cc2c1
Product: CNCC(c1ccccc1)c1ccc2[nH]c(C#N)cc2c1

Procedure:
A mixture of methanesulfonic acid 2-(2-cyano-1H-indol-5-yl)-2-phenyl-ethyl ester CCLXXI (0.24 g) and a solution of methylamine (33% in EtOH, 15 mL) was heated at reflux for 2 hours. The resulting mixture was evaporated under reduced pressure and the residue was purified by flash chromatography (DCM/(DCM+MeOH+NH4OH 60/10/1), 70/30 to 50/50) to give 80 mg of 5-(2-methylamino-1-phenyl-ethyl)-1H-indole-2-carbonitrile CCLXXII as a light yellow foam. MS=290 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccn1)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(Cc1ccccn1)c1ccc(Br)cc1
Reaction time: 3 h

Procedure:
1 mmol of the compound obtained in Step A is dissolved in 15 ml of ethanol, and 1.5 mmol of NaBH4 are added in two portions. The reaction mixture is stirred for 3 hours; the reaction is then quenched using 0.5 ml of acetic acid; the mixture is rendered basic with 10% NaOH, and extracted with dichloromethane (3×15 ml). The organic phase is dried over MgSO4, evaporated and the solid obtained is recrystallised from ethanol.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[C:10]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][CH2:22][C:23](O)=[O:24])[CH:11]=[CH:12][CH:13]=1.O.Cl>CCOCC>[F:7][C:8]1[CH:9]=[C:10]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][CH2:22][CH2:23][OH:24])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)CCc1ccccc1Sc1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: OCCCc1ccccc1Sc1cccc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
LiAlH4 (46 mg, 1.22 mmol) was suspended in ether (1.7 mL). A solution of 3-[2-(3-fluoro-phenylsulfanyl)-phenyl]-propionic acid (2.6 g, 0.94 mmol) in ether (1.7 mL) was added slowly. The reaction was stirred for 4 h at room temperature. Excess LiAlH4 was hydrolysed with water. The mixture was made acidic using HCl (4N). Ether (20 mL) was added. The two phases were separated and the organic phase was washed with NaOH (2N) and then with water. The organic phase was dried (MgSO4), filtered and evaporated. Yield: 0.14 g, 55%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=C)=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:18].[Na+]>CC(O)CC.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=[O:18])=[CH:5][CH:4]=1
Reactant: C=CCn1c(=O)cnc2ccc(OC)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCC(C)O
Product: COc1ccc2ncc(=O)n(CC=O)c2c1
Reaction time: 3.75 h
Yield: 65.6 %

Procedure:
A mixture of 7-(methyloxy)-1-(2-propen-1-yl)-2(1H)-quinoxalinone (1.03 g, 4.75 mmol) and sodium periodate (4.68 g, 21.8 mmol) in 2-butanol (20 mL) and water (40 mL) was treated with osmium tetroxide (4% solution in water, 1.1 mL) and the mixture was stirred for 3.75 h. The butanol was evaporated and the residue was diluted with water and extracted with dichloromethane, then with dichloromethane/THF. The extracts were dried and evaporated, and the residue was chromatographed on silica eluted with 50-100% ethyl acetate/hexane to give the aldehyde (0.68 g, 66%).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]=[CH:13][CH:14]=1)([O-])=O.[Cl-].[NH4+:29].C(O)C>O>[NH2:29][C:25]1[CH:26]=[CH:27][CH:4]=[CH:5][C:6]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1occc1-c1cccc(OCc2cccc([N+](=O)[O-])c2)c1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1occc1-c1cccc(OCc2ccccc2N)c1
Yield: 78.8 %

Procedure:
A mixture of ethyl 3-[3-(3-nitrobenzyloxy)phenyl]-2-furancarboxylate (2.21 g), reduced iron (1.75 g), ammonium chloride (0.67 g), ethanol (30 ml) and water (10 ml) was heated at reflux for 1 hour. After filtering the reaction solution through celite, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/3), thereby giving 1.60 g of ethyl 3-[3-(2-aminobenzyloxy)phenyl)-2-furancarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21]I.[CH3:23][CH:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][C:24]([CH3:23])([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: FC(F)(F)c1cccc(Sc2ccc(CCCI)c(Cl)c2)c1
Product: CCOC(=O)C(C)(CCCc1ccc(Sc2cccc(C(F)(F)F)c2)cc1Cl)C(=O)OCC

Procedure:
2-Chloro-1-(3-iodopropyl)-4-(3-trifluoromethylphenylthio) benzene and diethyl 2-methylmalonate were reacted according to the same procedures as in Example 152 of WO 04026817 to obtain the target product as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[C:11](OCC)=[O:12].[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.[O-2].[O-2].[Mn+4].C(O)C>[CH3:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[CH:11]=[O:12]
Reactant: CCOC(=O)c1sc2ccncc2c1C
Agent: [Mn+4]
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C=O)sc2ccncc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.6 %

Procedure:
To a mixture of ethyl 3-methylthieno[3,2-c]pyridine-2-carboxylate (3.40 g) synthesized above, calcium chloride (3.42 g), ethanol (30 mL) and tetrahydrofuran (30 mL) was added sodium borohydride (2.33 g) at 0° C., and the mixture was stirred at room temperature for 3 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a pale-yellow oil. To a solution (60 mL) of the obtained oil in tetrahydrofuran was added active manganese dioxide (14.4 g) and the mixture was stirred at 50° C. overnight. Manganese dioxide was filtered off, and the filtrate was concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (1.54 g, 56%) as a pale-brown solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1)=[O:4].[I-].[K+].C(N(CC)CC)C.Cl.[F:26][C:27]1[CH:39]=[CH:38][C:30]([CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:29][CH:28]=1>C(#N)C>[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][CH:32]2[CH2:33][CH2:34][N:35]([CH2:2][C:3]([NH:5][C:6]3[CH:15]=[CH:14][C:9]4[NH:10][C:11](=[O:13])[O:12][C:8]=4[CH:7]=3)=[O:4])[CH2:36][CH2:37]2)=[CH:38][CH:39]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)oc2c1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc2[nH]c(=O)oc2c1
Yield: 26.1 %

Procedure:
A mixture of 0.91 g (4 mmol) of 2-chloro-N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-acetamide, 0.7 g (4 mmol) of potassium iodide, 1.2 ml (8 mmol) of triethylamine, 0.7 g (3 mmol) of 4-(4-fluoro-benzyl)-piperidine hydrochloride and 50 ml of acetonitrile is refluxed for 20 hours. The reaction mixture is concentrated and 30 ml of water and 30 ml of chloroform are added to the residue. The organic layer is separated and the water phase is extracted three times with 10 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated and the residue is purified by column chromatography using Kieselgel 60 adsorbent (Merck) and chloroform methanol=97:3 as eluent to yield 0.3 g (26%) of the title compound. Melting Point: 232-234° C. (diethylether)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[CH:10][N:9]=1.[CH3:15][C:16]1[NH:17][C:18]2[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([C:26]([F:29])([F:28])[F:27])[C:19]=2[N:20]=1>CN(C=O)C>[Cl:14][C:12]1[N:11]=[CH:10][N:9]=[C:8]([O:25][C:23]2[CH:22]=[C:21]([C:26]([F:29])([F:28])[F:27])[C:19]3[N:20]=[C:16]([CH3:15])[NH:17][C:18]=3[CH:24]=2)[CH:13]=1
Reactant: Cc1nc2c(C(F)(F)F)cc(O)cc2[nH]1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2c(C(F)(F)F)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
221 mg (1.60 mmol) potassium carbonate were added at RT to 245 mg (1.60 mmol) 4,6-dichloropyrimidine and 330 mg (1.52 mmol) 2-methyl-7-trifluoromethyl-3H-benzimidazole-5-ol in 5.0 mL DMF and the mixture was stirred overnight at RT. The reaction mixture was poured onto water. The precipitate formed was filtered off, washed with water and dried.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]C(=O)C)=[CH:9][CH:8]=1)[CH3:5]>Cl>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH:4]([CH3:5])[C:3]([OH:17])=[O:2])=[CH:12][CH:11]=1
Reactant: COC(=O)C(C)Oc1ccc(NC(C)=O)cc1
Agent: Cl
Product: CC(Oc1ccc(N)cc1)C(=O)O
Temperature: 10 °C
Yield: 98.1 %

Procedure:
A mixture of 2-(4-Acetylaminophenoxy)propionic acid methyl ester 16 (320 grams, 1.35 mol) in concentrated hydrochloric acid (8 liters) was refluxed for 48 hours. Excess concentrated hydrochloric acid was distilled off in vacuum and filtered hot. The mixture was cooled to 10° C., filtered and dried to give pure 17 (240 g, 81.7%) as a brown powder. The melting point was found to be 175-180° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[C:13]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.C(=O)(O)[O-].[Na+]>>[Cl:3][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[C:13]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(-c2cccnc2)n(CCCCCCO)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(-c2cccnc2)n(CCCCCCCl)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.36 ml) is combined with 1-(6-hydroxyhexyl)-3-methyl-2-(3-pyridyl)indole (1.37 g) at 0° . The mixture is then stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate is added and the mixture is extracted with dichloromethane. The extract is washed with brine and dried over anhydrous magnesium sulfate. Concentration in vacuo yields the crude chloride as an oil. Purification by silica gel chromatography (CH2Cl2 /EtOAc 9.5:0.5) gives 1-(6-chlorohexyl)-3-methyl-2-(3-pyridyl)indole as a light yellow oil; NMR (CDCl3) δ3.30 (t, 2H), 3.92 (t, 2H).