Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.CN.[CH:26]([N:29](CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[CH3:26][NH:29][C:14](=[O:16])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1ccccc1Cc1ccccc1
Reaction time: 1.5 h
Yield: 44856.8 %

Procedure:
To a stirred solution of α-phenyl-o-toluic acid (2.0 g, 9.43 mmol) in methylene chloride (500 mL) at room temperature under argon was added by dropwise addition a solution of oxalyl chloride (0.988 mL, 11.3 mmol) in methylene chloride (50 mL). N,N-Dimethylformamide (10 drops) were added and the contents of the reaction flask were stirred 1.5 h. Solvent was removed in vacuo and methylene chloride (100 mL) and methylamine hydrochloride (950 mg, 14.1 mmol) was added. With ice-bath cooling a solution of N,N-diisopropylethylamine (4.10 mL, 23.6 mmol) in methylene chloride (10 mL) was added dropwise. Saturated sodium bicarbonate was added and the resulting mixture extracted with methylene chloride (3×). The combined organic extracts were dried with sodium sulfate (anh.). Filtration followed by removal of the solvent in vacuo gave a solid which after trituration with ether afforded N-Methyl-2-(phenylmethyl)benzamide (974 mg, 4.23 mol, 46%). MS [M+H]+ 226
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1[CH2:23][CH2:22]OCC1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:7]1[CH:2]=[C:3]([CH:8]=[CH:22][CH:23]=1)[C:4]#[N:5])=[O:9]
Reactant: C1COCCO1
Reactant: O=Cc1cnccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2ccncc2C=O)c1
Reaction time: 8 h

Procedure:
A flask was charged with 4-bromo-pyridine-3-carbaldehyde (186 mg, 1 mmol), 3-cyanophenelboronic acid (176 mg, 1.2 mmol), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), potassium phosphate (319 mg, 1.5 mmol) and 1,4-dioxane (10 mL). The reaction mixture was kept at 50° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with water, then brine. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield 3-(3-formyl-pyridin-4-yl)-benzonitrile as white crystals.
Reaction SMILES: S1C=CN=C1.[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[S:24][CH:25]=[C:26]([CH2:28][CH3:29])[N:27]=4)=[CH:18][CH:17]=3)[C:8]=12.Br[CH2:44][C:45]([C:47]1[CH:52]=CC(C)=C[CH:48]=1)=O>>[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:14]=[C:15]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23]4[S:24][CH:25]=[C:26]([C:28]5[CH:44]=[CH:45][C:47]([CH3:52])=[CH:48][CH:29]=5)[N:27]=4)=[CH:20][CH:21]=3)[C:8]=12
Reactant: CCc1csc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)n1
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: c1cscn1
Product: Cc1ccc(-c2csc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)n2)cc1

Procedure:
The procedure for thiazole synthesis, described in the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-ethyl-1,3-thiazol-2-amine, was employed with the exception that 2-bromo-4′-methylacetophenone (0.118 g, 0.554 mmol) was used as the alkylating agent. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 9.1-10.7 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-(4-methylphenyl)-1,3-thiazol-2-amine as an off-white powder (0.022 g, 0.038 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 8.88 min; MS (MH)+ 580.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:13]=[C:12]([CH2:14][CH3:15])[NH:11][N:10]=1.C(O[K])(C)(C)C.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.O.CO>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([N:11]2[C:12]([CH2:14][CH3:15])=[CH:13][C:9]([CH2:8][OH:7])=[N:10]2)=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCc1cc(COC2CCCCO2)n[nH]1
Agent: CC(C)(C)O[K]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(CO)nn1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.5 %

Procedure:
To a solution of 3-(tetrahydropyran-2-yloxy)methyl-5-ethylpyrazole (27.0 g, 0.13 mol) in dry THF (250 mL) was added tert-BuOK (14.4g, 0.13 mol) under nitrogen. After 10 min, 4-fluoronitrobenzene (18.1 g, 0.13 mol) was added. The mixture was heated to reflux for 10 hr, the solvent was then removed under vacuum The residue was taken up in ethyl acetate and washed with water, The organic layer was dried over MgSO4 and filtered. The filtrate was treated with active carbon (3.0 g, norit A alkaline) at reflux for 10 min and filtered through a pad of diatomaceous earth. The filtrate was concentrated to give a crude 7:1 mixture of regioisomers, which was dissolved in a 101: mixture of methanol and water (175 mL) and p-toluenesulfonic acid (1.2 g, 6.4 mmol) was added. The solution was stirred at room temperature for 12 hours and concentrated. The residue was taken up in ethyl acetate and washed with water. The organic layer was dried over MgSO4, filtered and concentrated to a crude solid. Recrystallization in a 1:1 mixture of hexane and ethyl acetate gave the title compound (15.6 g, 45%). mp: 151-152° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([N:32]1[C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:35][C:34](CO)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:35][C:34]([CH2:1][Br:5])=[N:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(-c2ccccc2)n(Cc2ccccc2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: BrCc1cc(-c2ccccc2)n(Cc2ccccc2)n1
Yield: 40.2 %

Procedure:
Carbon tetrabromide (2.5 g, 7.6 mmol) and then triphenylphosphine (2.0 g, 7.6 mmol) was added to (1-benzyl-5-phenyl-1H-pyrazol-3-yl)methanol (1.0 g, 3.8 mmol) in dicholomethane (38 mL) at 0° C. Upon completion of the reaction as monitored by LCMS, the reaction was filtered through silica washing with methylene chloride and then purified on an ISCO using 0-30% ethyl acetate/hexanes to give 1-benzyl-3-(bromomethyl)-5-phenyl-1H-pyrazole (0.5 g, yield 43%). MS (ESI) m/z: Calculated for C17H15BrN2: 326.04. found: 327.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][N:11]1C(=O)C2=CC=CC=C2C1=O.[BrH:22]>>[BrH:22].[BrH:22].[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11]
Reactant: Cc1ncoc1CSCCN1C(=O)c2ccccc2C1=O
Agent: Br
Product: Cc1ncoc1CSCCN

Procedure:
Phthalimidoethanethiol (2 g) was added portionwise with stirring to a solution of sodium ethoxide (prepared from 0.23 g of sodium) in ethanol (20 ml) at 0° under a nitrogen atmosphere. After stirring at 0° for a further 21/2 hours, the resulting yellow solution was cooled with an ice-salt bath and a solution of 4-methyl-5-chloromethyloxazole (0.86 g) in ethanol (5 ml) was added dropwise over 10 minutes. After addition the mixture was stirred at room temperature overnight, then acidified with ethanolic hydrogen chloride andevaporated to dryness. Addition of water precipitated unreacted phthalimidoethanethiol (0.6 g) which was removed by filtration. The filtrate was concentrated and basified with aqueous sodium bicarbonate solution to furnish a white precipitate which, on recrystallisation from aqueous ethanol, gave 4-methyl-5-[(2-phthalimidoethyl)thiomethyl]oxazole (0.75 g). A stirred mixture of this phthalimide derivative (0.62 g) in aqueous hydrobromic acid (40 ml. 18%) was heated under reflux overnight. After cooling to 0°, the resulting clear solution was filtered and the filtrate evaporated to dryness. Recrystallisation of the residue from ethanol gave 4-methyl-5-[(2-aminoethyl)thiomethyl]oxazole dihydrobromide (0.52 g).
Reaction SMILES: C(O)C.[NH2:4][CH:5]1[C:26](=[O:27])[N:7]2[C:8]([C:13]([O:15]CC3C=CC([N+]([O-])=O)=CC=3)=[O:14])=[C:9]([Cl:12])[CH2:10][S:11][C@H:6]12.Cl>[Fe].O>[NH2:4][CH:5]1[C:26](=[O:27])[N:7]2[C:8]([C:13]([OH:15])=[O:14])=[C:9]([Cl:12])[CH2:10][S:11][C@H:6]12
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To a mixture of ethanol (240 ml) and water (50 ml), p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (20 gm) was added. Iron powder (20 gm) was charged at 30° C., followed by the addition of concentrated HCl (25 ml) in an ethanol (930 ml) and water (5.0 ml) mixture over a period of 15 minutes. The reaction mixture was stirred for 1 hour. After completion of the reaction, aq. KHCO3 was added to bring the pH to 8.0, followed by the addition of activated carbon. After stirring for 10 minutes, the mixture was filtered. To the filtrate was added aq. HCl to bring the pH to 4.0. The product thus separated was filtered and dried to yield 8.42 gm (73%) of white crystalline product.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].C(N(CC)CC)C.C[O:21][C:22](=O)[N:23]=[C:24](SC)[C:25]([C:39]1[CH:44]=[C:43]([O:45][CH2:46][CH3:47])[C:42]([O:48][CH3:49])=[CH:41][C:40]=1[F:50])=[N:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[C:36]([CH3:38])[O:35][N:34]=2)=[CH:29][CH:28]=1>CN(C=O)C>[CH2:46]([O:45][C:43]1[C:42]([O:48][CH3:49])=[CH:41][C:40]([F:50])=[C:39]([CH:25]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[N:37]=[C:36]([CH3:38])[O:35][N:34]=3)=[CH:31][CH:32]=2)[C:24]2[NH:23][C:22](=[O:21])[N:2]([C:4]3[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=3[C:6]([OH:8])=[O:7])[N:3]=2)[CH:44]=1)[CH3:47]
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c(F)cc1OC
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)c(F)cc1OC
Temperature: 90 °C
Reaction time: 14 h
Yield: 63.1 %

Procedure:
After adding 16 mg of 2-hydrazinobenzoic acid hydrochloride and 25 μl of triethylamine to a solution of 85 mg of {2-(5-ethoxy-2-fluoro-4-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanyl-ethylidene}carbamic acid methyl ester (see Example (115b)) in 3 ml of DMF, the mixture was stirred at 90° C. for 14 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of a methanol:THF=2:1 mixed solvent. After adding 35 μl of acetic acid and 55 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 6 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give 2-(3-{(5-ethoxy-2-fluoro-4-methoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-1-yl)benzoic acid (30 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH:16]([OH:27])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](Cl)[N:30]=1>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][CH:13]([CH:16]([O:27][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[N:30]=2)[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(Oc2cccc(Cl)n2)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 90 °C
Yield: 95.5 %

Procedure:
To a suspension of NaH (60% in mineral oil, 56 mg, 1.4 mmol) in DMF (2.3 mL) was added 4-[hydroxy-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.696 mmol) followed by 2,6-dichloropyridine (309 mg, 2.09 mmol). The mixture was heated to 90° C. for 2 h then concentrated in vacuo. Aqueous work-up and purification gave 4-[(6-chloro-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as a colourless foam (313 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]([C:11]1[C:26]2[O:25][CH2:24][C:18]3([CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:17][O:16][C:15]=2[C:14]([O:27][CH3:28])=[CH:13][CH:12]=1)=[O:10].[OH:30]O>C(Cl)Cl.C[Re](=O)(=O)=O.O=[Mn]=O>[Cl:29][C:6]1[CH:5]=[N+:4]([O-:30])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([C:11]1[C:26]2[O:25][CH2:24][C:18]3([CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH2:17][O:16][C:15]=2[C:14]([O:27][CH3:28])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(CCOCC1)CO2
Reactant: OO
Agent: C[Re](=O)(=O)=O
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Cc2c(Cl)c[n+]([O-])cc2Cl)c2c1OCC1(CCOCC1)CO2
Reaction time: 18 h

Procedure:
To a solution 2-(3,5-Dichloropyridin-4-yl)-1-{9-methoxy-spiro[2H-1,5-benzodioxepin-3(4H),4′-tetrahydropyran]-6-yl}ethanone [127] (66 mg, 150 μmmol) in CH2Cl2 (2 mL) was added 30% H2O2 (45 μL) and methyltrioxorhenium(VII) (10 mg). The mixture was stirred for 18 h, added MnO2 (10 mg) and was stirred for another hour. CH2Cl2 (10 mL) was added and the organic phase was washed with water. The combined organic phase was dried over MgSO4 and evaporated to dryness under reduced pressure. Standard HPLC purification afforded 5.6 mg of the product.
Reaction SMILES: [CH:1]([N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([N+:17]([O-])=O)[CH:9]=2)([CH3:3])[CH3:2]>C(O)(=O)C.[Fe]>[CH:1]([N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([NH2:17])[CH:9]=2)([CH3:3])[CH3:2]
Reactant: CC(C)n1c2c(c3cc([N+](=O)[O-])ccc31)CCCC2
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)n1c2c(c3cc(N)ccc31)CCCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 58.7 %

Procedure:
6-Nitro-1,2,3,4-tetrahydrocarbazole (5.04 g) prepared by the method described in Journal of Chemical Society, p.833 (1924) was dissolved in 50 mL of acetone, and the solution was added with 2.25 g of potassium hydroxide and 8.45 g of isopropyl iodide, warmed to 50° C. and stirred for 3 hours. The reaction mixture was added with water and the deposited precipitates were collected to obtain 2.60 g of N-isopropyl-6-nitro-1,2,3,4-tetrahydrocarbazole. The resulting N-isopropyl-6-nitro-1,2,3,4-tetrahydrocarbazole (2.60 g) was dissolved in 100 mL of acetic acid, and the solution was added with 2.75 g of iron powder, warmed to 50° C., and stirred for 3 hours. The reaction mixture was filtered and the filtrate was diluted by adding water. The reaction mixture was made basic with 1 N sodium hydroxide and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane/ethyl acetate=7/3) to obtain 1.35 g of N-isopropyl-6-amino-1,2,3,4-tetrahydrocarbazole.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]#[N:11])[CH:5]=1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][NH2:11])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccnc(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1ccnc(CN)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
To a stirring solution of 149 mg (1.01 mmol) of 4-isopropylpicolinonitrile in 7 mL of THF at 0° C. was added 150 mg (3.95 mmol) of LiAlH4. After about 15 min., 250 mg of LiAlH4 was added, and after about 15 min. the ice bath was removed and stirring was continued with warming to r.t. After 40 min., 400 μL of H2O, 400 μL of 15% NaOH (aq), and 1.2 mL of brine were added in succession. The mixture was stirred for 85 min., filtered through Celite, and conc. to give 143 mg of (4-isopropylpyridin-2-yl)methanamine which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[CH3:15][S:16]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCCO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
A solution of 28.6 g of 5-(tert-butoxycarbonylamino)pentan-1-ol in 100 ml of pyridine is cooled to 0° C. and 16.2 g of methanesulfonyl chloride are added dropwise in 3 hours at 0° C. The reaction mixture is stirred overnight at RT and concentrated under vacuum. The residue is taken up with water and extracted with AcOEt, the organic phase is washed three times with water, three times with a 5% solution of potassium hydrogensulfate, three times with water and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum to give 39 g of the expected product, which is used as such in the next step.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[C:16]4[C:21]([CH:22]=[C:23]5[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]5)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:29][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:13]2[C:14]3[C:5]([CH:6]=[C:7]4[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]4)=[CH:4][CH:3]=[CH:2][CH:1]=3)=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[CH:27]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(-c3c4ccccc4cc4ccccc34)c3ccccc3cc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c(-c2c3ccccc3cc3ccccc23)c2ccccc12
Yield: 81.8 %

Procedure:
In a flask were placed 35 g of 9,9′-bianthryl, 18.0 g of N-bromosuccinimide and 500 mL of carbon tetrachloride, and the mixture was stirred overnight. The reaction mixture was filtered, the filtrate was passed through a column filled with alumina. Carbon tetrachloride was evaporated from the solution under a reduced pressure, and then the residue was recrystallized from petroleum ether, to give 35 g(yield: 80%) of 10-bromo-9,9′-bianthryl. Then, in a 100 mL three-necked flask were placed 18.3 g of 10-bromo-9,9′-bianthryl, 10 g of diphenylamine, 8.5 g of potassium carbonate, 0.2 g of copper powder and 50 mL of nitrobenzene, and the mixture was stirred at 200° C. for 30 hours. After completion of the reaction, toluene was added to the mixture. The mixture was filtered to remove inorganics. Toluene and nitrobenzene were evaporated under a reduced pressure. The residue was purified by column chromatography on silica gel eluting with a 1:2 mixture of toluene and ligroin, to give 15 g(yield: 60%) of 10-diphenylamino-9,9′-bianthryl.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=[O:39])=[CH:33][CH:32]=1)=O>>[C:38]([CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:29][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:32][CH:33]=1)([OH:40])=[O:39]
Reactant: O=Cc1ccc(CC(=O)O)cc1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Yield: 92.2 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (296 mg) and (4-formylphenyl)acetic acid (630 mg) according to an analogous synthetic method to Example 212,the title compound (379 mg) was obtained.
Reaction SMILES: [OH:1][CH:2]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[S:9]([N:12]([CH3:27])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10])[CH3:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>C(#N)C>[C:2]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[S:9]([N:12]([CH3:27])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10])(=[O:1])[CH3:3]
Reactant: CC(O)c1sccc1S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)c1sccc1S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
To a solution of 2-(1-hydroxyethyl)-N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-3-sulfonamide (180 mg) in acetonitrile (10 mL) was added Dess-Martin reagent (212 mg), and the mixture was stirred at room temperature for 16 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (153 mg, yield 87%) as white crystals. melting point 156° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][CH:15]=[CH:14][C:13]=3[CH:12]=[C:11]([CH:18]=[O:19])[CH:10]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][CH:15]=[CH:14][C:13]=3[CH:12]=[C:11]([CH:18]=[O:19])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(C=O)cc3ccoc23)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=Cc1cc(-c2ccc(O)cc2)c2occc2c1
Temperature: 190 °C
Yield: 161.1 %

Procedure:
To a 10 ml round bottom flask was added 7-(4-methoxyphenyl)-benzofuran-5-carbaldehyde (0.50 g, 1.98 mmol), and pyridine hydrochloride (1.2 g, 5.2 mmol). The mixture was heated to 190° C. for 2 h, cooled slightly, then water (10 ml) was added to dissolve the remaining pyridine hydrochloride. The aqueous was extracted with EtOAc (3×), passed through a silica plug, and concentrated to 450 mg (96%) of crude product as a light yellow foam. The crude from this reaction was combined with a second batch (1 g scale reaction) and purified by column chromatography (1:1 EtOAc/Hexanes) to afford 760 mg of product as a yellow solid: mp 154–155° C.; 1H NMR (300 MHz, DMSO-d6): δ 6.95 (2H, d, J=8.6 Hz), 7.21 (1H, d, J=2.2 Hz), 7.76 (2H, d, J=8.6 Hz), 7.98 (1H, d, J=1.5 Hz), 8.19 (1H, d, J=1.5 Hz), 8.22 (1H, d, J=2.2 Hz), 9.81 (1H, s), 10.12 (1H, s); MS (ESI) m/z 237 ([M−H]−).