Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)C(O)=O.C([Zn]CC)C.ICI.[C:16]([NH:19][C@@:20]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][C:24](=[CH2:26])[C@@H:23]2[C@H:21]1[C@H:22]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:18])[CH3:17]>ClCCl>[C:16]([NH:19][C@@:20]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][C:24]2([CH2:2][CH2:26]2)[C@@H:23]2[C@H:21]1[C@H:22]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:18])[CH3:17]
Reactant: O=C(O)C(F)(F)F
Reactant: C=C1C[C@@](NC(C)=O)(C(=O)OCC)[C@H]2[C@@H]1[C@@H]2C(=O)OCC
Agent: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(C)=O)(C(=O)OCC)CC21CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under nitrogen, add a solution of trifluoroacetic acid (1.9 mL, 25 mmol) in dichloromethane (12.5 mL) dropwise very slowly to a cooled (ice bath) stirred solution of diethylzinc (1M in heptanes) (25 mL, 25 mmol) in dichloromethane (12.5 mL). After 10 minutes, add a solution of diiodomethane (2.01 mL, 25 mmol) in dichloromethane (12.5 mL). After 10 minutes, add a solution of diethyl (1S,2S,5R,6S)-2-acetamido-4-methylene-bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.46 g, 8.3 mmol) in dichloromethane (12.5 mL). After 60 minutes remove the ice bath and leave the reaction mixture to stir overnight at room temperature. Quench the clear reaction solution by dropwise addition of the reaction mixture to 0.2M aqueous hydrochloric acid (200 mL) under vigorous stirring. After 1 hour separate the dichloromethane layer, wash with brine, dry over magnesium sulfate, filter and concentrate in vacuum to yield the required product contaminated with unreacted starting material (4.4 g). Purify by flash chromatography eluting with ethyl acetate:cyclohexane (50:50 to 100:0) to give a colorless oil (3.1 g). Purify by SFC(RT=2.48 minutes (UV, 200 nm); HPLC Column: AD-H 30 mm×250 mm 5 μm; CO2 gradient: 5% iso-propyl alcohol w/0.2% dimethylethylamine for 0.5 minutes, then 5%-27% in 2.2 minutes. Column temperature: 35° C.; pressure: 100000 kPa; flow rate: 210 mL/minute) to yield unreacted diethyl (1S,2S,5R,6S)-2-acetamido-4-methylene-bicyclo[3.1.0]hexane-2,6-dicarboxylate. (580 mg, 2.0 mmol) and title compound (1.82 g, 5.9 mmol). MS (m/z): 310 (M+1), 332 (M+23).
Reaction SMILES: Cl.Cl.[C:3]1([C:9]2[C:10]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]([C@@H:35]2[CH2:39][CH2:38][C:37]([CH3:41])([CH3:40])[N:36]2[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:32](O)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([C@@H:31]([C@H:35]2[N:36]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:37]([CH3:41])([CH3:40])[CH2:38][CH2:39]2)[C:32](=[O:33])[N:21]2[CH2:20][CH2:19][N:18]([C:10]3[C:9]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:14][N:13]=[C:12]4[NH:15][CH:16]=[CH:17][C:11]=34)[CH2:23][CH2:22]2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Br)cc2)CCC1(C)C
Reactant: c1ccc(-c2cnc3[nH]ccc3c2N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2CCN(c3c(-c4ccccc4)cnc4[nH]ccc34)CC2)c2ccc(Br)cc2)CCC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Phenyl-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyri dine dihydrochloride (0.0159 g, 0.0454 mmol, see Example 19), (S)-2-(4-bromophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (0.017 g, 0.0412 mmol, see Example C) and TBTU (0.0159 g, 0.0495 mmol) in DCM (1 mL) were added to DIEA (0.0287 mL, 0.165 mmol) and stirred at room temperature for 1 hour. The mixture was directly loaded to column and purified by chromatography (1:1 hexane:ethyl acetate) to give (S)-tert-butyl 5-((S)-1-(4-bromophenyl)-2-oxo-2-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)ethyl)-2,2-dimethylpyrrolidine-1-carboxylate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (0.5 mL) and 2M HCl in ether (1 mL) was added. The resulting solid was collected by filtration to give (S)-2-(4-bromophenyl)-2-((S)-5,5-dimethylpyrrolidin-2-yl)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)ethanone dihydrochloride (0.025 g, 95%). MS APCI (+) m/z 574 detected.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.C(Cl)(Cl)Cl>C(O)C.O=[Mn]=O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OCc1ccc(Oc2ccc3[nH]cnc3c2)cc1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=Cc1ccc(Oc2ccc3[nH]cnc3c2)cc1
Yield: 100.8 %

Procedure:
[4-(1H-benzimidazol-5-yloxy)phenyl]methanol (1.26 g) was dissolved in 70 ml of ethanol and 70 ml of chloroform and heated with MnO2 (4.56 g, 52.5 mmol) in a 75 degrees Centigrade oil bath for 14 hrs. An additional 1 g of MNO2 was added and the reaction continued heating for 3 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure to afford 1.26 g of 4-(1H-benzimidazol-5-yloxy)benzaldehyde.
Reaction SMILES: CN(C)CCO.[CH3:7][N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[Cl:19]C(Cl)(Cl)C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH3:7])=[CH:14][N:15]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CN1CCC[C@H]1c1cccnc1
Agent: CN(C)CCO
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 100 mL RB flask was placed under an argon atmosphere and degassed with argon by vacuum. The solvents (hexanes (4 ml) and toluene 12 ml)) were added to the flask. N,N-dimethylethanolamine (1.07 g, 1.21 ml, 12.0 mmol) was added. The reaction mixture was cooled to 0° C. N-butyl lithium (8.66 ml of 2.5M in hexanes, 21.6 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was cooled to −20° C. (S)-3-(1-methylpyrrolidin-2-yl)pyridine (650 mg, 0.64 ml, 4.01 mmol) was added. The reaction mixture was stirred −20° C. for 1 h. The reaction mixture was cooled to −78° C. and hexachloroethane (3.8 g, 16.0 mmol) was added in toluene (8 ml). The reaction mixture was stirred at −78° C. for 1 h. The reaction was quenched cold with satd. NaHCO3 (4 mL). LCMS showed that the reaction gave the desired regioisomer in a 6:1 ratio over the undesired 6-chloro pyridine product. The reaction mixture was poured into 50 mL H2O and extracted with DCM (3×125 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 55% EtOAc in hexanes) to afford the desired product (467 mg, 59%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.56-2.05 (m, 3H) 2.16-2.40 (m and overlapping s, 5H) 3.09 (t, J=8.31 Hz, 1H) 3.17-3.29 (m, 1H) 7.23-7.32 (m, 1H) 7.68 (dd, J=8.12, 2.45 Hz, 1H) 8.30 (d, J=2.27 Hz, 1H)
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20](C(O)=O)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1.C([N:30](CC)CC)C.C1C=CC(OP(OC2C=CC=CC=2)(N=[N+]=[N-])=O)=CC=1.O>CN(C=O)C.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[F:26][C:2]([F:27])([F:1])[CH2:3][N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([NH2:30])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Temperature: 100 °C
Reaction time: 3 h
Yield: 53.9 %

Procedure:
To a mixture of 2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (170 mg, 0.45 mmol) and triethylamine (95 uL, 0.68 mmol), in DMF (3.5 mL), was added diphenylphosphonic azide (146 uL, 0.68 mmol) at ambient temperature. After 3 h, water (0.45 mL) was added and the reaction mixture was heated at 100° C. After 1 h, the mixture was diluted with ethyl acetate and sat. NaHCO3. The aqueous layer was extracted into ethyl acetate (3×), and the combined organics were filtered through a plug of celite and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 493 as a white solid (85 mg, 54%). LC/MS (ESI+): m/z 351 (M+H). 1H NMR (400 MHz, DMSO) δ 8.05 (s, 1H), 8.01 (d, J=8.7 Hz, 1H), 7.89 (s, 1H), 6.38 (dd, J=8.7, 2.2 Hz, 1H), 6.18 (d, J=2.2 Hz, 1H), 5.92 (q, J=8.9 Hz, 2H), 5.56 (s, 2H), 4.41 (dd, J=12.3, 5.6 Hz, 4H)
Reaction SMILES: C([C:6]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])(OCC)=O.S(=O)(=O)(O)O.C(O)(=O)C>O>[C:7]1(=[O:12])[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)C1(CCCCCCC(=O)[O-])CCCCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCCCCCC1CCCCC1=O

Procedure:
A stirred mixture of 380 g. of mixed methyl and ethyl esters of 7-(2-carbethoxycyclohexan-1-on-2-yl)heptanoate (Example 10), 202 ml. of concentrated sulfuric acid, 970 ml. of glacial acetic acid, and 970 ml. of water is refluxed for 22.5 hours. The cooled reaction mixture is treated with 380 g. of sodium carbonate and 2 liters of water and is extracted with ether. Acidic material is partitioned from the ether extract with 1.0 M sodium carbonate. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ether. The extract is washed successively with water and saturated sodium chloride, dried, and evaporated to give an oil.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:21])[CH2:8][O:9][C:10]1[C:19]2[CH2:18][CH2:17][CH2:16][C@@H:15]([NH2:20])[C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:5])([CH3:4])[CH3:3].[Cl:22][C:23]1[CH:24]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:26]=[CH:27][C:28]=1[F:29]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:2]([O:6][C:7](=[O:21])[CH2:8][O:9][C:10]1[C:19]2[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:20][S:30]([C:25]3[CH:26]=[CH:27][C:28]([F:29])=[C:23]([Cl:22])[CH:24]=3)(=[O:32])=[O:31])[C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2N
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2NS(=O)(=O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
A solution of dimethyl-pyridin-4-yl-amine (1.17 g, 9.60 mmol) in tetrahydrofuran (10 mL) was added dropwise to a solution of (R)-(5-amino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester hydrochloride salt (1 g, 3.18 mmol) and 3-chloro-4-fluoro-benzenesulfonyl chloride (0.68 mL, 4.77 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature overnight, and then concentrated. The residue was purified by column chromatography (gradient elution, 0-5% methanol in dichloromethane) to afford (R)-[5-(3-chloro-4-fluoro-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (1.4 g, 93.8%) as a white solid. MS calcd. for C22H25ClFNO5S 469, obsd 470 (ESI+) [(M+H)+].
Reaction SMILES: C(OC(=O)C[C:6]([CH2:8][CH:9]([CH2:18][C:19](=[O:26])CC(OCC)=O)[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)=[O:7])C.[OH-:28].[Na+].[OH2:30]>C(O)C>[Cl:17][C:12]1[CH:11]=[C:10]([CH:9]([CH2:8][C:6]([OH:7])=[O:30])[CH2:18][C:19]([OH:26])=[O:28])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CCOC(=O)CC(=O)CC(CC(=O)CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1

Procedure:
Diethyl-3,4-dichlorobenzal-bis-acetoacetate (155 g) in ethanol 2 L) was treated with 50% NaOH (2 L) and heated at reflux temperature for 4 hours. Water (1 L) was added to the reaction mixture and approx. 1.5 L of solvent removed by distillation. The remaining solution was poured onto ice (1 Kg) and sufficient HCl was added to adjust the pH to 1. The resulting solution was extracted with EtOAc (3×1.5 L) and the combined extracts dried over MgSO4, filtered and concentrated to give 100 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:14])[CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1.[BH4-].[Na+]>C(O)C.C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:14])[CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1
Reactant: CCCC(=O)c1ccc(C(=O)OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of 4-butyryl-benzoic acid methyl ester (400 mg, 1.94 mmol) in ethanol (5 mL) and THF (4 mL) is added sodium borohydride (110 mg, 2.9 mmol), the mixture is stirred at room temperature for 2 h. The reaction mixture is quenched by acetic acid (0.5 mL) and water (10 mL), extracted with ethyl acetate. Combined organic layers are washed with brine and dried over sodium sulfate. Concentration and column chromatography on silica gel gives the title compound (370 mg).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:20][CH2:21][O:22][CH3:23])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.[I:32]I>C1COCC1.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][CH:16]([I:32])[C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:20][CH2:21][O:22][CH3:23])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: II
Reactant: CCCCC12CCC(=O)C(C)=C1c1ccc(OCOC)cc1C2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(I)C2
Temperature: 25 °C

Procedure:
A solution of 9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (134 mg, 0.43 mmol) in anhydrous THF (2.5 mL) was cooled in an ice bath, stirred under a nitrogen atmosphere, and treated with 0.4M LDA in THF (1.2 mL, 0.48 mmol). After stirring at 0° C. for 30 minutes, the enolate solution was cooled to −78° C. and treated with a solution of iodine (540 mg, 2.13 mmol) in THF. The resulting mixture was allowed to gradually warm to room temperature, then stirred at room temperature overnight. The mixture was diluted with EtOAc (50 mL), washed with 1N HCl, saturated aqueous Na2SO3 (2×30 mL), water, 5% NaHCO3, and brine, dried over MgSO4, filtered, and evaporated under vacuum to provide crude (2SR,9aRS)-9a-butyl-2-iodo-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as a gum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)[OH:20]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:18])=[O:20])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cnn2c(-c3cccc(F)c3)ccnc12
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cnn2c(-c3cccc(F)c3)ccnc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 131.5 g amount of 7-(m-fluorophenyl) pyrazolo[1,5-a]pyrimidine-3-carbonitrile (prepared as described in U.S. Pat. No. 4,236,005) was dissolved in 500 ml of concentrated sulfuric acid by stirring at room temperature for 18 hours. The solution was then carefully poured into ice water. The precipitate which formed was collected by filtration then washed with 1N sodium hydroxide until pH 7 was achieved, followed by washing with water to remove the excess base. The crystalline material was dried in vacuo to give 136.3 g of the desired product as yellow crystals, m.p. 247°-249° C.
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](F)[C:11]=1[C:17]([F:20])([F:19])[F:18]>>[CH2:7]([S:8][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Br:9])[C:11]=1[C:17]([F:18])([F:20])[F:19])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1cccc(Br)c1C(F)(F)F
Reactant: SCc1ccccc1
Product: FC(F)(F)c1c(Br)cccc1SCc1ccccc1

Procedure:
Phenyl-methanethiol (4.g g, 37.0 mmol) was treated with commercially available 1-bromo-3-fluoro-2-trifluoromethyl-benzene (10.0 g, 41.1 mmol) in close analogy to the procedure described in step 5.3). The crude product (10.5 g) after workup was used as such in the next reaction step without purification by chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:8][N:9]=1)[CH:5]=O.C([O-])(=O)C.[Na+].Cl.[NH2:25][OH:26]>C(O)C.ClC(Cl)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:8][N:9]=1)[CH:5]=[N:25][OH:26]
Reactant: O=Cc1cc(Cl)ncc1C#Cc1ccccc1Cl
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: ON=Cc1cc(Cl)ncc1C#Cc1ccccc1Cl
Temperature: 50 °C

Procedure:
A mixture of 2-chloro-5-((2-chlorophenyl)ethynyl)isonicotinaldehyde (1.1 g, 4.0 mmol), sodium acetate (490 mg, 6 mmol), and hyroxylamine hydrochloride (415 mg, 6 mmol) in ethanol (23 mL) and dichloroethane (13 mL) was heated at 50° C. for 15 minutes. The cooled reaction mixture was evaporated in vacuo to afford a residue that was redissolved in ethyl acetate (150 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a white solid that was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:18].O1CCOCC1>CO>[ClH:18].[NH:8]1[CH2:13][CH2:12][C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(CO)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: OCC1(CO)CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (1-tert-butoxycarbonylpiperidine-4,4-diyl)dimethanol, 4M HCl-dioxane solution and MeOH was stirred for two hours at room temperature to give piperidine-4,4-diyldimethanol hydrochloride.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)(=[O:3])[CH3:2].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>N1C=CC=CC=1>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCc1cccc(N)c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1cccc(CCNC(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
N-Acetyl-N-(3-aminophenethyl)amine (1.7 g, Production Example 29b) was dissolved in pyridine (5 ml). Under ice-cooling, ethyl chloroformate (1.4 ml) was added dropwise thereinto, followed by stirring at room temperature for one hour. Then, the mixture was ice-cooled again and water was added thereto. The mixture was extracted with ethyl acetate, and the extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (2.358 g, 97%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31][C:32]1[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:34][CH:33]=1.C(CN)O>>[C:39]([O:38][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:19]2[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)/[S:21][C:20]2=[O:22])=[CH:44][CH:43]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Solvent: NCCO
Product: CC(C)(C)OC(=O)c1ccc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)cc1

Procedure:
4-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}benzoic acid tert-butyl ester was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and tert-butyl 4-bromomethyl-benzoate (in place of tert-butyl bromoacetate) following General Procedure I, and converted to the corresponding ethanolamine salt following General Procedure T.
Reaction SMILES: C(O)CCCCC.[CH2:8]1[O:12][C:11]2[CH:13]=[C:14]([CH:17](O)[C:18]([C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)=O)[CH:15]=[CH:16][C:10]=2[O:9]1.[NH2:30][C:31]([NH2:33])=[S:32]>O>[CH2:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[N:30]=[C:31]([SH:32])[NH:33][C:18]=3[C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)=[CH:13][C:11]=2[O:12]1
Reactant: NC(N)=S
Reactant: O=C(c1ccc2c(c1)OCO2)C(O)c1ccc2c(c1)OCO2
Solvent: O
Solvent: CCCCCCO
Product: Sc1nc(-c2ccc3c(c2)OCO3)c(-c2ccc3c(c2)OCO3)[nH]1
Temperature: 0 °C

Procedure:
A hexanol solution (170 ml.) of 10.9 g. (0.036 mole) of piperoin and 5.5 g. (0.072 mole) of thiourea was refluxed for 4 hours, with continuous azeotropic water removal. The mixture was cooled to 0° C. and the solid collected, washed with ether and dried. Recrystallization from dimethylformamide gave 4,5-bis(3,4-methylenedioxyphenyl)-2-mercaptoimidazole, m.p. 282°-283° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[NH:6][CH:5]=1.N1C=CN=C1.[CH:19]([Si:22](Cl)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[CH:19]([Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][NH2:1])([CH3:21])[CH3:20]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc2[nH]cc(CCN)c2c1)(C(C)C)C(C)C

Procedure:
A solution of 3-(2-amino-ethyl)-1H-indol-5-ol (3.0 g), imidazole (9.6 g), and triisopropylsilyl chloride (4.5 mL) was stirred in 20 mL N,N-dimethylformamide for 6 h. The solution was diluted with 100 mL of ethyl acetate and washed with 100 mL of sodium carbonate and 100 mL of saturated sodium chloride (3 times). The organic phase was dried over sodium sulfate and the solvent was evaporated. Silica gel chromatography (2% methyl alcohol in dichloromethane) gave 2-(5-triisopropylsilanyloxy-1H-indol-3-yl)-ethylamine (2.6 g). This compound was cyclized with formaldehyde by Procedure OO to afford 6-triisopropylsilanyloxy-2,3,4,9-tetrahydro-1H-β-carboline, which was protected with tert-butoxycarbonyl group by Procedure CC to give 6-triisopropylsilanyloxy-1,3,4,9-tetrahydro-β-carboline-2-carboxylic acid tert-butyl ester.