Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])=[O:14].C([O-])([O-])=O.[K+].[K+].CC#N>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.O>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1ccsc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)Cc1ccsc1-c1ccc(S(C)(=O)=O)cc1

Procedure:
Intermediate B (2.30 g, 9.78 mmol), 4-methylsulfonylphenylboronic acid (1.96 g, 9.78 mmol), K2CO3 (4.15 g, 30.0 mmol), tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.130 mmol), MeCN (30 ml) and water (10 ml) were heated at 70° C. for 1 hour. The organic phase was removed in vacuo and the crude material was dissolved in DCM. The mixture was purified by flash chromatography using 30% and 50% EtOAc in iso-hexane as eluent. Yield: 2.25 g (74%); white solid. 1H NMR (400 MHz, CDCl3): δ 3.11 (s, 3H), 3.67 (s, 2H), 3.74 (s, 3H), 7.13 (d, J 5.0 Hz, 1H), 7.39 (d, J 5.0 Hz, 1H), 7.67-7.72 (m, 2H), 7.98-8.04 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9]Br)=[C:4]([F:12])[CH:3]=1.[S-:13][C:14]#[N:15].[NH4+].C(=O)(O)[O-].[Na+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][S:13][C:14]#[N:15])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(CBr)c1ccc(Br)cc1F
Reactant: N#C[S-]
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Product: N#CSCC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the above-mentioned 1-(4-bromo-2-fluorophenyl)-2-bromo-1-ethanone, ammonium thiocyanate 2.15 g and acetonitrile 100 mL was stirred at 25° C. for one hour. To the reaction mixtures was added aqueous saturated sodium bicarbonate solution and the mixtures were extracted with ethyl acetate. The organic layers were washed with aqueous saturated sodium bicarbonate solution and were dried over anhydrous sodium sulfate. The resulting mixtures were concentrated under reduced pressure to give 1-(4-bromo-2-fluorophenyl)-2-thiocyanato-1-ethanone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH:30][S:31]([C:34]1[S:35][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[S:35][C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([C:22]([F:24])([F:23])[F:25])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[6-(3,4-dichloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.37) (0.40 g, 0.89 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.40 g, 1.16 mmol) according to the general procedure VI. Obtained as white foam (0.45 g), which was subsequently deprotected.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10]([CH2:12][C:13](O)=O)=[O:11])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].[CH3:19][O:20][C:21]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:22]=1C=O>N1C=CC=CC=1.N1CCCCC1>[CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[CH:5][C:6]([CH2:9][S:10](/[CH:12]=[CH:13]/[C:22]2[C:25]([O:31][CH3:32])=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:21]=2[O:20][CH3:19])=[O:11])=[CH:7][N:8]=1
Reactant: COc1ncc(CS(=O)CC(=O)O)cc1[N+](=O)[O-]
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1cc(OC)c(/C=C/S(=O)Cc2cnc(OC)c([N+](=O)[O-])c2)c(OC)c1
Yield: 10 %

Procedure:
A solution of 2-((6-methoxy-5-nitropyridin-3-yl)methylsulfinyl)acetic acid (0.15 g, 0.5 mmol) in dry pyridine (20 mL) was treated with 2,4,6-trimethoxybenzaldehyde (0.20 g, 1 mmol) and piperidine (10 drops). The mixture was refluxed for 2-3 hrs. The mixture was evaporated and the residue was purified by flash chromatography; yield 10%; 1H-NMR (CDCl3): δ 3.83 (s, 6H, OCH3), 3.83 (s, 3H, OCH3), 3.89 (1H, CH), 4.07 (1H, CH), 4.09 (s, 3H, OCH3), 6.09 (s, 2H, Ph-H), 6.97 (d, 1H, J=15.2 Hz, CH), 7.28 (d, 1H, J=15.2 Hz, CH), 8.19 (d, 1H, J=2.3 Hz, Py-H), 8.29 (d, 1H, J=2.3 Hz, Py-H). HR-MS (ESI+) m/z 408.8426 C18H20N2O7S requires 408.0991.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CS(O[CH2:17][C@@H:18]1[C@:27]2([CH3:28])[C@H:22]([C:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][CH2:26]2)[CH2:21][CH2:20][C@:19]1([OH:32])[CH3:31])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([S:11][CH2:17][C@@H:18]2[C@:27]3([CH3:28])[C@H:22]([C:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][CH2:26]3)[CH2:21][CH2:20][C@@:19]2([CH3:31])[OH:32])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CC1(C)CCC[C@]2(C)[C@@H](COS(C)(=O)=O)[C@](C)(O)CC[C@@H]12
Reactant: COc1cc(S)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc(OC)cc(SC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
A mixture of 3,5-dimethoxybenzenethiol (20) (6.74 g, 39.60 mmol), ((1S,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)methyl methanesulfonate (12) (12.62 g, 39.60 mmol), and Cs2CO3 (38.70 g, 118.77 mmol) in CH3CN (560 mL) was stirred at room temperature for 1 h, then refluxed for 24 h. After cooling, the mixture was concentrated. Purification by chromatography on silica gel (Hexanes/EtOAc, 4:1) gave (1R,2R,4aS,8aS)-1-{[(3,5-dimethoxyphenyl)-sulfanyl]methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (21) (9.40 g, 60%) as a light yellow sticky mass.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)([CH3:3])[CH3:2].[Br:12]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl>[Br:12][C:9]1[CH:8]=[CH:7][C:6]([O:10][CH3:11])=[CH:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: COc1cccc(C(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.3 %

Procedure:
A mixture of 1-isopropyl-3-methoxy-benzene (Intermediate 142, 3.50 g, 23.3 mmols), molecular sieves, and silica gel in 150 mL CCl4 was treated with N-bromosuccinimide (4.98 g, 28.0 mmols) at 35° C. for 18 hours. An additional portion of N-bromosuccinimide (830.0 mg, 4.46 mmols) was added and stirring continued for 6 hours. The mixture was cooled to room temperature, H2O was added, and the mixture was filtered to remove the solids. The mixture was extracted with E2O and the combined organic layers were washed with 10% aqueous HCl, H2O, saturated aqueous NaHCO3, and saturated NaCl before being dried (MgSO4) and concentrated under reduced pressure. Column chromatography (2.5% EtOAc-hexanes) afforded 4.34 g (81%) of the title compound as a pale-yellow oil.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@H:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][N:5]1[CH3:19])([OH:3])=O.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:1]([C@@H:4]2[CH2:8][C@H:7]([S:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH2:6][N:5]2[CH3:19])=[O:3])[CH2:25][CH2:24]1
Reactant: OCCN1CCNCC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCO)CC3)N(C)C2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
800 mg of N,N'-carbonyldiimidazole were added to a suspension of 1.13 g of (2S,4S)-2-carboxy-4-(4-methoxybenzylthio)-1-methylpyrrolidine in 20 ml of dry acetonitrile, and the resulting mixture was stirred at 40° C. for 30 minutes. At the end of this time, the reaction mixture was ice-cooled, and 600 mg of N-hydroxyethylpiperazine were added to the mixture. The temperature was allowed to rise to room temperature over a period of 30 minutes. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was purified by reverse phase column chromatography using LiChroprep RP-8 (trade mark) as the stationary phase and 70% v/v aqueous methanol as the eluent, to give 1160 mg of the title compound as a colorless oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]1[O:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:16][C:15](=[O:17])[O:14][C:11]3=2)[O:6][CH2:5]1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH2:18]([NH:2][CH2:3][CH:4]1[O:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:16][C:15](=[O:17])[O:14][C:11]3=2)[O:6][CH2:5]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC[C@H]1COc2ccc3[nH]c(=O)oc3c2O1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=c1[nH]c2ccc3c(c2o1)OC(CNCc1ccccc1)CO3
Temperature: 50 °C

Procedure:
(8S)-8-Aminomethyl-7,8-dihydro-3H-1,6,9-trioxa-3-aza-cyclopenta[a]-naphthalen-2-one hydrochloride (0.49 g, 1.8 mmole), benzyl bromide (0.20 mL, 1.8 mmole) and 0.31 mL (1.8 mmole) of N,N-diisopropylethylamine were combined in 20 ml DMSO and heated at 50° C. under nitrogen for 6 hours. After completion, the reaction was cooled to room temperature and partitioned between 400 mL each of ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was removed and washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude residue was column chromatographed on silica gel using first methylene chloride, then 1% methanol in methylene chloride to elute the dialkylated product and finally 3% methanol in methylene chloride to elute the monoalkylated product (0.16 g, 28%). The latter was recrystallized from ethanol with the addition of a solution of fumaric acid (0.065 g) in hot ethanol to give 0.06 g of the (S)-enantiomer of the title compound as an off-white solid hemifumarate, one-quarter hydrate, m.p. 220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1.Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][N:6]([CH2:21][CH2:22][CH2:23][C:24]#[N:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1
Reactant: N#CCCCBr
Reactant: Clc1ccc(CNCc2ccc(Cl)c(Cl)c2)cc1Cl
Product: N#CCCCN(Cc1ccc(Cl)c(Cl)c1)Cc1ccc(Cl)c(Cl)c1

Procedure:
Using a procedure analogous to Example 6, Bis-(3,4-dichlorobenzyl)amine (2.71 g, 8.09 mM) was reacted with 4-bromobutyronitrile (0.81 ml) to give the title compound as an oil 1.97 g.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.ClC1C=CC=C(C(OO)=[O:29])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6]([C:7]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1)=[O:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)c1ccccc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccccc1CS(=O)c1nc2ccccc2[nH]1
Temperature: 0 °C
Yield: 58.6 %

Procedure:
2-(2-Dimethylaminobenzylthio)benzimidazole (4.8 g) was dissolved in a mixture of 40 ml of chloroform and 5 ml of methanol. After the solution was chilled to 0° C., 3.86 g of m-chloroperbenzoic acid (purity: 70%) was added portionwise. Ten minutes later, a saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The chloroform solution was washed with saturated brine and then dried over anhydrous sodium sulfate. The chloroform was distilled off under reduced pressure and the residue was recrystallized from a mixture of chloroform and ether to obtain 2.97 g of 2-(2-dimethylaminobenzylsulfinyl)benzimidazole as a colorless crystalline product (m.p. 116° C., decomposed).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:12][C:11]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[N:10]1.ClC1C=CC=C(C(OO)=[O:43])C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:27])=[O:43])=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:12][C:11]([C:28]([F:33])([F:34])[C:29]([F:32])([F:30])[F:31])=[N:10]1
Reactant: CSc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(Cl)cc3Cl)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CS(=O)c1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(Cl)cc3Cl)c2)cc1

Procedure:
The compound of Example 42 was prepared in accordance with the same procedures as in Example 37, using the compound prepared in Example 25 and meta-chloroperbenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][C:6]=2[CH:14]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[NH:26][N:25]=[N:24][N:23]=4)[CH:17]=3)(=[O:12])=[O:11])=[CH:7][C:6]=2[CH:14]=1
Reactant: Cc1ccc2sc(S(=O)(=O)Cl)cc2c1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: Cc1ccc2sc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)cc2c1
Yield: 24.7 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-methyl-benzothiophene-2-sulfonyl chloride (30 mg, 0.12 mmol) and 5-(3-aminophenyl)tetrazole (20 mg, 0.12 mmol) giving the title compound as a white solid (11 mg, 25%). 1H NMR (400 MHz, MeOH-d4) δ ppm 2.40 (s, 3 H) 7.25-7.30 (m, 1 H) 7.34-7.40 (m, 1 H) 7.45 (t, J=7.91 Hz, 1 H) 7.62-7.65 (m, 1 H) 7.68-7.74 (m, 2 H) 7.78 (s, 1 H) 7.94 (t, J=1.88 Hz, 1 H). MS (ESI+) calcd for C16 H13N5O2S2 371.051066, found 371.050166.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].[H-].[Na+].Br[CH2:17][C:18]([CH3:27])=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.O>CN(C)C=O>[CH3:12][C:4]1[C:3]([CH3:13])=[C:2]([O:1][CH2:17][C:18]([CH3:27])=[CH:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][CH:10]=[O:11]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: CC(=Cc1ccc(C)cc1)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=Cc1ccc(C)cc1)COc1cc(C)c(NC=O)c(C)c1C
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
To a solution of N-(4-hydroxy-2,3,6-trimethylphenyl)formamide (9.31 g, 52.0 mmol) in N,N-dimethylformamide (120 ml) was added at 0° C. under nitrogen atmosphere sodium hydride (a 60% dispersion in liquid paraffin, 2.11 g, 52.8 mmol) and the resulting mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added a solution of 1-(3-bromo-2-methyl-1-propenyl)-4-methylbenzene (12.48 g, 55.44 mmol) in N,N-dimethylformamide (20 ml) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate-isopropyl ether to obtain 7.34 g (44% yield) of the title compound. Melting point: 167-169° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:21]([CH2:22]Br)=[CH:20][C:19]3[C:18]([CH3:25])([CH3:24])[CH2:17][CH2:16][C:15]([CH3:27])([CH3:26])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35]([SH:39])[CH2:36][CH2:37][CH3:38]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:21]([CH2:22][S:39][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:20][C:19]3[C:18]([CH3:25])([CH3:24])[CH2:17][CH2:16][C:15]([CH3:27])([CH3:26])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(/C=C/c2cc3c(cc2CBr)C(C)(C)CCC3(C)C)cc1
Reactant: CCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCSCc1cc2c(cc1/C=C/c1ccc(C(=O)OC)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 58.4 %

Procedure:
A solution of 445 mg (1 mmol) of Methyl-4-[(E)-2-(3-Bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate, 418 mg (3 mmol) of potassium carbonate and 180 mg (2 mmol) of 1-butanethiol in 10 mL dimethylformamide was heated to reflux. After 40 minutes, the reaction mixture was cooled to room temperature, then diluted with water. The mixture was extracted with ethyl acetate, the organic extracts washed with brine, dried over sodium sulfate, then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5% ethyl acetate/hexane) to give 263 mg (58%) of Methyl-4-[(E)-2-(3-Butylthiomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].[CH2:18]([O:20][P:21](Cl)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:19]>C1COCC1>[CH2:18]([O:20][P:21](=[O:25])([O:22][CH2:23][CH3:24])[O:17][C:8]1[CH:9]=[CH:10][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:12][C:7]=1[C:3]([CH3:6])([CH3:5])[CH3:4])[CH3:19]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (60% in mineral oil, 6.99 g, 174.7 mmol) in THF (350 mL) was added dropwise a solution of 2,4-di-tert-butylphenol (35 g, 169.6 mmol) in THF (150 mL) at 0° C. The mixture was stirred at 0° C. for 15 min and then phosphorochloridic acid diethyl ester (30.15 g, 174.7 mmol) was added dropwise at 0° C. After addition, the mixture was stirred at this temperature for 15 min. The reaction was quenched with sat. NH4Cl (300 mL). The organic layer was separated and the aqueous phase was extracted with Et2O (350 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give crude phosphoric acid 2,4-di-tert-butyl-phenyl ester diethyl ester as a yellow oil (51 g, contaminated with some mineral oil), which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:10]([S:11]([NH:14][CH3:15])(=[O:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:16])[NH:6]2.[CH2:17]([O:19][C:20](=[O:33])[CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][CH:26]=1)=[O:24])[CH3:18].N1CCCCC1>C(O)C>[CH2:17]([O:19][C:20](=[O:33])[CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[C:10]([S:11](=[O:12])(=[O:13])[NH:14][CH3:15])[C:2]=3[CH3:1])[NH:6][C:5]2=[O:16])[NH:27][CH:26]=1)=[O:24])[CH3:18]
Reactant: CCOC(=O)CNC(=O)c1c[nH]c(C=O)c1C
Reactant: CNS(=O)(=O)c1ccc2c(c1C)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)CNC(=O)c1c[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)NC)c(C)c32)c1C
Yield: 51.7 %

Procedure:
4-Methyl-5-methylaminosulfonyl-2-oxindole (50 mg, 0.21 mmol) was condensed with [(5-formyl-4-methyl-1H-pyrrole-3-carbonyl)-amino]-acetic acid ethyl ester (100 mg, 0.42 mmol) and piperidine (0.1 mL) in ethanol (2 mL) to give 50 mg (52%) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:25]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl>[CH:25]1([CH2:30][NH:31][C:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:12])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NCC1CCCC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NCC1CCCC1)c1ccc2cc[nH]c2c1
Yield: 101.8 %

Procedure:
A solution of indole-6-carboxylic acid (9.41 g) and 1,1'carbonyldiimidazole (10.6 g) in methylene chloride (290 ml) was heated at reflux, under nitrogen, for 30 minutes. The solution was cooled and treated with cyclopentylmethylamine (7.0 g). This mixture was heated to reflux for 30 minutes. The resultant solution was then diluted with methylene chloride, washed successively with 10% (v/v) hydrochloric acid, 20% (w/v) aqueous sodium hydroxide, and brine, dried (MgSO4), and evaporated to give 6-(N-cyclopentylmethylcarbamoyl)indole (14.4 g, 91%) as an ivory powder, mp 148°-150°; NMR (80 MHz, DMSO-d6): 3.19(dd, 2H, CH2NH), 6.46(br d, 1H, H3 -indole), 7.91(d, 1H, H7 -indole), 8.29(t, 1H, CH2NH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:6][C:5]=1[NH2:20].[C:22](Cl)(Cl)=[O:23]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[C:7]([C:16]([F:17])([F:18])[F:19])=[CH:6][C:5]=1[N:20]=[C:22]=[O:23]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1cc(N2CCSCC2)c(C(F)(F)F)cc1N
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N2CCSCC2)c(C(F)(F)F)cc1N=C=O
Temperature: 25 °C
Yield: 100 %

Procedure:
To a suspension of 100 mg (0.312 mmol) of 2-amino-5-thiomorpholin-4-yl-4-trifluoromethyl-benzoic acid methyl ester in 2 ml of dry toluene 1.5 ml of a 20% solution of phosgene in toluene are added at 0° C. After warming to room temperature, a stream of phosgene is introduced into the suspension and simultaneously heating is started. At reflux, the stream of phosgene is maintained for two hours, then replaced by a stream of argon for an additional hour. The toluene is distilled off leaving 126 mg (>100%) of 2-isocyanato-5-thiomorpholin-4-yl-4-trifluoromethyl-benzoic acid methyl ester as a brown solid, sufficiently pure for the next step. 1H-NMR (CDCl3, 360 MHz): 2.75-2.80 (m, 2H); 3.15-3.20 (m, 2H); 4.00 (s, 3H); 7.40 (s, 1H); 7.95 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:13][C:14]1[CH:15]=[C:16]([OH:22])[CH:17]=[C:18]([Cl:21])[C:19]=1[Cl:20].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:18]([Cl:21])[C:19]=1[Cl:20])[O:22][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Oc1cc(Cl)c(Cl)c(Cl)c1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1cc(Cl)c(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 8.68 g (0.0475 moles) of 2-chloro-5-nitrobenzonitrile 9.67 g (0.0489 moles) of 3,4,5-trichlorophenol, 6.75 g (0.0489 moles) of anhydrous K2CO3, and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was cooled to room temperature and diluted with 150 ml of water. The product separated as a solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized from a mixture of 200 ml of absolute ethanol and 100 ml of acetone to give 11.62 g (71% yield) of purified 2-(3,4,5-trichlorophenoxy)-5-nitrobenzonitrile as small white crystals, mp 162°-164° C.