Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]([CH3:45])([CH3:44])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[C:27]3[N:26]=[C:25]([C:28]4[C:33]([Br:34])=[CH:32][CH:31]=[CH:30][C:29]=4[Br:35])[NH:24][C:23]=3[C:22]3[C:17](=[CH:18][C:19]([O:36][CH2:37][CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:20][CH:21]=3)[C:15]=2[CH:16]=1)(C(C)(C)C)(C)C.[Si](OC(C)(C)CC1C=CC2C3N=C(C4C(Br)=CC=CC=4Br)NC=3C3C(=CC(OCC4CC4)=CC=3)C=2C=1)(C(C)(C)C)(C)C>>[Br:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([Br:34])[C:28]=1[C:25]1[NH:24][C:23]2[C:22]3[C:17]([C:15]4[CH:16]=[C:11]([CH2:10][C:9]([CH3:45])([OH:8])[CH3:44])[CH:12]=[CH:13][C:14]=4[C:27]=2[N:26]=1)=[CH:18][C:19]([O:36][CH2:37][CH2:38][CH2:39][C:40]([F:43])([F:41])[F:42])=[CH:20][CH:21]=3
Reactant: CC(C)(Cc1ccc2c(c1)c1cc(OCCCC(F)(F)F)ccc1c1[nH]c(-c3c(Br)cccc3Br)nc21)O[Si](C)(C)C(C)(C)C
Agent: CC(C)(Cc1ccc2c(c1)c1cc(OCC3CC3)ccc1c1[nH]c(-c3c(Br)cccc3Br)nc21)O[Si](C)(C)C(C)(C)C
Product: CC(C)(O)Cc1ccc2c(c1)c1cc(OCCCC(F)(F)F)ccc1c1[nH]c(-c3c(Br)cccc3Br)nc21

Procedure:
This imidazole was prepared as described in Step 8 of Route A of Example 168, substituting 6-(2-([tert-butyl(dimethyl)silyl]oxy)-2-methylpropyl)-2-(2,6-dibromophenyl)-9-(4,4,4-trifluorobutoxy)-1H-phenanthro[9,10-d]imidazole from Step 5 above for 6-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-9-(cyclopropylmethoxy)-2-(2,6-dibromophenyl)-1H-phenanthro[9,10-d]imidazole.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1([O:13][C:14](=O)[O:15][C:16]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]([S:26]([C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:38]=3[N:37]=[CH:36][CH:35]=[CH:34]4)(=[O:28])=[O:27])[C:17]2=[O:39])C=CC=CC=1.[OH-].[Na+]>C1COCC1>[Cl:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:26]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]3[C:38]=1[N:37]=[CH:36][CH:35]=[CH:34]3)(=[O:28])=[O:27])[C:17](=[O:39])[C:16]2([O:15][C:14]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:46][CH3:47]
Reactant: COc1ccccc1C1(OC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2cccc3cccnc23)c2ccc(Cl)cc21
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccccc1C1(OC(=O)N2CCCCC2)C(=O)N(S(=O)(=O)c2cccc3cccnc23)c2ccc(Cl)cc21
Reaction time: 8 h
Yield: 57.3 %

Procedure:
Piperidine (0.132 ml, 1.33 mmol) was added to a solution of the intermediate from Step A (200 mg, 0.33 mmol) in THF (10 ml), and the reaction solution was stirred overnight. 2 M sodium hydroxide solution was added to the reaction mixture, which was then extracted with dichloromethane. The organic phase was washed three times with water and concentrated under reduced pressure. Recrystallization from dichloromethane/diethyl ether resulted in 112 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:16])[CH2:14][OH:15])=[CH:9][CH:8]=1.N1C=CN=C1.[C:26]([Si:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)Cl)([CH3:29])([CH3:28])[CH3:27]>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:26]([Si:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[O:15][CH2:14][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:2]([Cl:1])[CH:3]=2)=[CH:12][CH:11]=1)[OH:16])([CH3:29])([CH3:27])[CH3:28]
Reactant: OCC(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCC(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-[4-(3,4-Dichloro-benzyloxy)-phenyl]-ethane-1,2-diol (18.8 g), imidazole (8.17 g), and a catalytic amount of DMAP were dissolved in 60 mL of anhydrous DMF. tert-Butyldiphenylchlorosilane (18.7 mL) was added drop-wise and the mixture stirred at rt for 16 h. The reaction mixture was poured into 1 L of a mixture of water-ethyl acetate-hexanes (2:2:1) and the layers were separated. After an additional extraction with 0.5 L 3:1 EtOAc/hexanes, the organic extracts were dried over sodium sulfate and concentrated. The yellow oil was purified by silica gel flash chromatography (ethyl acetate/hexanes) to give 14.0 g of the desired product. 1H NMR (400 MHz, CDCl3): 7.65 (m, 4H), 7.52 (m, 1H), 7.34-7.46 (m, 7H), 7.22 (m, 3H), 6.88 (d, 2H), 5.0 (s, 2H), 4.78 (m, 1H), 3.6-3.8 (m, 2H), 3.05 (m, 1H), 1.10 (s, 9H).
Reaction SMILES: FC1C=C(F)C=CC=1N[S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=O)=O.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH2:32]S>>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH2:32][S:10][CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1
Reactant: Fc1ccc(CS)c(F)c1
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Product: CCOC(=O)C1=CCCCC1SCc1ccc(F)cc1F
Yield: 45 %

Procedure:
In the same manner as in Reference Example 1, ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (455 mg) and (2,4-difluorophenyl)-methanethiol (421 mg) were reacted to give ethyl 6-[(2,4-difluorobenzyl)sulfanyl]-1-cyclohexene-1-carboxylate (185 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([C:6]1[CH:38]=[CH:37][C:9]([CH2:10][N:11]([C:23](=[O:36])[CH:24]=[CH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:70]([N:72]1[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]1)=[O:71]>C(#N)C>[CH2:16]([C@H:12]([N:11]([CH2:10][C:9]1[CH:37]=[CH:38][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=1)[C:23](=[O:36])[CH:24]=[CH:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=1)[C:13]([N:75]1[CH2:76][CH2:77][N:72]([CH:70]=[O:71])[CH2:73][CH2:74]1)=[O:15])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=CN1CCNCC1
Reactant: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(C=O)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
2-{(4-pentyl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}-(S)-3-phenyl-propionic acid (50 mg, 0.095 mmol) was dissolved in acetonitrile (1.0 ml), TBTU (37 mg, 0.115 mmol), DIPEA (37 mg, 0.29 mmol) and 1-formylpiperazine (12.23 mg, 0.105 mmol) was added and the mixture was stirred for 16 h at rt, filtered and directly purified by prep. HPLC to give 32 mg of N—[(S)-1-benzyl-2-(4-formyl-piperazin-1-yl)-2-oxo-ethyl]-N-(4-pentyl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=1.17 min; [M+H]+=620.50.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[O:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].[Br:16]N1C(=O)CCC1=O.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][Br:16])[O:8][C:7]=1[C:12]([F:15])([F:13])[F:14])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(C)oc1C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(CBr)oc1C(F)(F)F
Temperature: 25 °C
Yield: 37.6 %

Procedure:
To a solution of 5-methyl-2-trifluoromethyl-furan-3-carboxylic acid ethyl ester (0.95 g, 4.5 mmol) in CCl4 (12 mL) was added N-bromosuccinimide (0.84 g, 4.8 mmol) followed by AIBN (0.004 g, 0.01 mmol). After refluxing for 2 h, analytical HPLC analysis confirmed the reaction was complete. The reaction was cooled to rt, then CH2Cl2 and sat'd NaHCO3 (aq.) were added. The organic portion was separated and dried to provide the crude residue as a yellow oil. This material was purified by RP HPLC to provide the title compound (510 mg, 38%). MS (ESI): mass calcd. for C9H8BrF3O3, 300.0; m/z found, 302.9 [M+H]+. 1H NMR (CDCl3): 6.84 (s, 1H), 4.44 (s, 2H), 4.34 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:33]=[C:34]([CH:36]=[CH:37][C:38]=2[O:39][CH3:40])[NH2:35])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:33]=[C:34]([NH:35][C:20]([C:17]3[CH:16]=[CH:15][C:14]([C:3]4[CH:4]=[CH:5][C:6]([C:8]5[N:12]=[C:11]([CH3:13])[O:10][N:9]=5)=[CH:7][C:2]=4[CH3:1])=[CH:19][CH:18]=3)=[O:21])[CH:36]=[CH:37][C:38]=2[O:39][CH3:40])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(N)cc1OCCN1CCCCC1
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1OCCN1CCCCC1

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) and 3-(2-piperidin-1-ylethoxy)-4-methoxyaniline (D12) using a similar procedure to Example 1, as a light brown solid (30%) mp 96°-99° C.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:16])[CH:6]=[CH:5][C:4]1=2.C([Li])CCC.[CH3:42][O:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=1.CO.O>O1CCCC1>[CH3:42][O:43][C:44]1[CH:51]=[CH:50][C:47](/[CH:48]=[C:15](/[C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[C:3]([CH3:36])([CH3:2])[CH2:12][CH2:11][C:10]3([CH3:13])[CH3:14])\[CH3:16])=[CH:46][CH:45]=1
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
358 g of [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphonium bromide are suspended in 600 ml of tetrahydrofuran and treated at 0° with 400 ml of n-butyllithium (1.6 molar in hexane). After stirring at 0° for 30 minutes a solution of 78.5 g of p-methoxybenzaldehyde in 200 ml of tetrahydrofuran is added dropwise thereto and the mixture is stirred at room temperature for a further 2 hours. The reaction mixture is subsequently poured into 2 l of methanol/water (6:4) and extracted repeatedly with hexane. The organic phase is washed three times with water and, after drying with sodium sulphate, evaporated. The crystalline residue can be recrystallized from hexane and gives 138 g of 1,2,3,4-tetrahydro-6-[(E)-p-methoxy-α-methylstyryl]-1,1,4,4-tetramethylnaphthalene, melting point 108°-110°.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C(Cl)=O.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([CH3:47])[C:41]=1[CH3:48].C1(C)C=CC=CC=1>C(O)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[C:41]([CH3:48])[C:42]=1[CH3:47])=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C(N=C=S)c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4Cl)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
2,4-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,4-Dichloro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 69%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH:13]([C:20]1[NH:21][C:22](=[O:33])[C:23]2[N:28]([CH3:29])[N:27]=[C:26]([CH2:30][CH2:31][CH3:32])[C:24]=2[N:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[CH3:29][N:28]1[C:23]2[C:22](=[O:33])[NH:21][C:20]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])=[N:25][C:24]=2[C:26]([CH2:30][CH2:31][CH3:32])=[N:27]1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(C(O)c3ccccc3)nc12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCc1nn(C)c2c(=O)[nH]c(C(=O)c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyridinium chlorochromate (400 mg, 0.00186 mol) was added to a solution of 5-[α-hydroxybenzyl]-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (200 mg, 0.00068 mol) in dichloromethane (50 ml) and the reaction stirred at room temperature for 3 hours.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C([Li])CCC.IN1C(=O)CCC1=O.C(=O)([O-])O.[Na+].[OH:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[N:34][CH:35]=1.IC1(SC2C=CC=CC=2)CC1>O1CCCC1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2].C(O)(=O)C>[CH3:36][C:33]1[CH:32]=[CH:31][C:30]([O:29][C:1]2([S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:3][CH2:2]2)=[CH:35][N:34]=1
Reactant: Cc1ccc(O)cn1
Reactant: c1ccc(SC2CC2)cc1
Agent: [Ag+2]
Agent: IC1(Sc2ccccc2)CC1
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(OC2(Sc3ccccc3)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
Cyclopropylphenylthioether (5.0 g, 33.3 mmol) was dissolved in tetrahydrofuran (50 mL), and n-butyllithium (25.1 mL, 39.9 mmol) was dropped for 5 minutes under an argon atmosphere at 0° C. Then, at −78° C., a solution of N-iodosuccinimide (8.99 g, 39.9 mmol) in tetrahydrofuran (100 mL) was dropped. The mixture was stirred overnight and allowed to warm gradually to room temperature. The reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and extracted with hexane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica-gel column chromatography (hexane). A crude product (5.64 g) ((1-iodocyclopropyl)(phenyl)sulfane:cyclopropylphenylthioether=2.4:1) was obtained. Then, 5-hydroxy-2-methylpyridine (1.82 g, 16.7 mmol) was dissolved in toluene (150 mL), added silver carbonate (9.19 g, 33.3 mmol), and a mixture of (1-iodocyclopropyl)(phenyl)sulfane:cyclopropylphenylthioether (=2.4:1) (5.64 g, 16.7 mmol (*converted in terms of the amount of (1-iodocyclopropyl)(phenyl) sulfane), and the mixture was stirred at room temperature overnight. Then, acetic acid (200 mL) was added and stirred for 10 minutes. The reaction solution was filtered through a pad of celite, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (1.88 g (yield 44%)) was obtained as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]O)=[CH:3][CH:2]=1.CC1C=CC(S([Cl:21])(=O)=O)=CC=1>N1C=CC=CC=1>[Cl:21][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCc1ccncc1
Solvent: c1ccncc1
Product: ClCCCc1ccncc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
To a solution of 3-pyridin-4-yl-propan-1-ol (3.1 g) in pyridine (8 mL) was added 4-methylbenzenesulfonyl chloride (5.0 g) at 0° C. The reaction mixture was stirred at RT for 12 hr. The reaction mixture was concentrated in vacuo. Saturated aqueous NaHCO3 was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: hexane/ethyl acetate=1/2) to give the title compound (2.1 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]([C:17]3[C:18](=O)[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:10]3[N:11]=[C:12]([CH3:15])[N:13]([CH3:14])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:26]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]([C:17]3[C:18](=[S:28])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:10]3[N:11]=[C:12]([CH3:15])[N:13]([CH3:14])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:26]=1
Reactant: Cc1nc2c(n1C)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Product: Cc1nc2c(n1C)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=S
Temperature: 100 °C

Procedure:
A mixture of the product from step (iv) (0.535 g), and phosphorus pentasulphide (0.967 g) in 1,4-dioxane (10 ml) was heated at 100° C. for 3 h. The solvent evaporated and the residue dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate solution then with water, dried (MgSO4) and evaporated. Purification was by chromatography on a biotage silica column, using 3% methanol/0.1% 0.880 ammonia in dichloromethane as eluant.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(N(CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:19](=[O:20])[CH2:18][Cl:17]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C)c1NC(=O)CCl
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a 3-necked, 1-liter flask provided with a reflux condenser, an additional funnel and a magnetic stirring bar was charged 36.3 grams (0.3 mole) of 2,6-dimethyl aniline and 30.36 grams (0.3 mole) of triethylamine in 550 milliliters of methylene chloride. To the stirred solution, maintained at 0° to 5° C. by means of an ice bath, was added dropwise, over a period of 30 minutes, 33.9 grams (0.3 mole) of chloroacetyl chloride. The reaction mixture was then stirred at ambient temperature for 21 hours after which it was transferred to a separatory funnel and washed consecutively with 300 milliliter portions of 1 Normal hydrochloride acid, 10 percent aqueous sodium carbonate solution and water. The organic layer was removed, dried over magnesium sulfate and concentrated on a rotary evaporator at 55° C. leaving a bluish-gray solid. This solid was recrystallized from a hot 20:80 volume/volume ethylacetate-ligroin solution yielding 41 grams of gray, solid N-(2,6-dimethylphenyl)-α-chloroacetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([O:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=[O:19])[CH3:18]
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1cc(Cl)ccc1C(=O)O
Yield: 88.1 %

Procedure:
Using 4-chlorosalicylic acid, concentrated sulfuric acid and acetic anhydride as the raw materials, the same operation as the Example 34(1) gave the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:3]1=2.[N+](=[CH2:22])=[N-]>CCOCC>[CH3:22][O:18][C:17]([C:14]1[CH:15]=[CH:16][C:3]2[CH:2]([OH:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C:4]=2[CH:13]=1)=[O:19]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2O
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)Sc1ccccc1CC2O

Procedure:
13.5 G. 10,11-dihydro-11-hydroxydibenzo[b,f]thiepin-3-carboxylic acid is suspended in ether and excess diazomethane is added in portions. A clear solution results which is filtered from small particles in suspension and the filtrate evaporated to dryness to a yellow oil weighing 14.2 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[NH:9][CH2:8][CH2:7][C:6]2=1.Br[CH:29]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH2:33]([O:32][C:30](=[O:31])[CH:29]([N:9]1[CH2:8][CH2:7][C:6]2[C:5]3[C:13](=[CH:14][CH:15]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:12][C:11]=2[CH:10]1[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:34]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: COc1ccc2[nH]c3c(c2c1)CCNC3CCc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(c1ccccc1)N1CCc2c([nH]c3ccc(OC)cc23)C1CCc1ccc(C(F)(F)F)cc1
Yield: 16.3 %

Procedure:
A mixture of 90 mg (0.24 mmol) 6-methoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-2,3,4,9-tetrahydro-1H-β-carboline, 59 mg (0.24 mmol) ethyl bromophenylacetate and 28.8 mg (0.27 mmol) Na2CO3 in 4 mL methanol was heated to reflux for 16 h. After filtration DMF was added and the mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The combined product fractions were evaporated to dryness to yield 21 mg (16%) {6-methoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-1,3,4,9-tetrahydro-β-carbolin-2-yl}-phenyl-acetic acid ethyl ester (diastereoisomer 1)
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:9][CH2:8][N:7](CC=C)[C@@H:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5]1)#[N:2].Cl[C:19]([O:21][CH:22]=[CH2:23])=[O:20].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1>ClCCl>[C:1]([CH2:3][C@H:4]1[CH2:9][CH2:8][N:7]([C:19]([O:21][CH:22]=[CH2:23])=[O:20])[C@@H:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5]1)#[N:2]
Reactant: C=CCN1CC[C@H](CC#N)C[C@@H]1C(=O)OCC
Reactant: C=COC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Product: C=COC(=O)N1CC[C@H](CC#N)C[C@@H]1C(=O)OCC
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A solution of 2.0 g of the product from step C above, 1.8 g (16.5 mmol) of vinyl chloroformate and 3.5 g (16.5 mmol) of 1,8-bis-dimethylaminonaphthalene in 40 ml of dichloromethane was heated to reflux for 6 hr. The mixture was then cooled to ambient temperature and concentrated under vacuum. The residue was dissolved in diethyl ether and was washed twice with 10% aqueous sodium hydrogen sulfate and once with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum. Preparative HPLC afforded 1.8 g (79%) of the desired intermediate, [α]D =-24.8° (c=1, dichloromethane).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1.CC(C)([O-])C.[K+].[Cl:23][C:24]1[N:25]=[N:26][C:27](Cl)=[CH:28][CH:29]=1>O>[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:27]2[N:26]=[N:25][C:24]([Cl:23])=[CH:29][CH:28]=2)[CH:10]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: Clc1ccc(Cl)nn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Oc2ccc(Cl)nn2)c1
Yield: 58.8 %

Procedure:
To a dimethylformamide (8.0 mL) solution of 3-hydroxy-benzoic acid methyl ester (928 mg, 6.1 mmol) was added potassium t-butoxide (750 mg, 6.7 mmol). Upon stirring the reaction at room temperature for 15 min, 3,6-dichloro-pyridazine (1.0 g, 6.7 mmol) was added. The reaction was stirred at room temperature for 15 h. Crude reaction mass was added to water, aqueous layer was acidified to pH 4.0 and product was extracted with ethyl acetate to give 3-(6-chloro-pyridazin-3-yloxy)-benzoic acid methyl ester (950 mg).