Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH:7]12[CH2:14]C[CH:10]([CH2:11][CH2:12]1)[CH:9]=[C:8]2C(O)=O>C(Cl)Cl.CN(C=O)C>[CH:10]12[CH2:11][CH2:12][CH:7]([CH2:8][CH2:9]1)[CH:14]=[C:1]2[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1=CC2CCC1CC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1=CC2CCC1CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
Oxalyl chloride (2.0 M in CH2Cl2, 2.4 mL, 4.8 mmol, 1.2 eq) was added to a solution of compound 11B (600 mg, 3.95 mmol, 1 eq) in CH2Cl2 (8 mL) containing one drop of DMF. The reaction mixture was stirred at rt for 3 h and then concentrated under reduced pressure to give 680 mg of compound 11C which was used in the next step without purification. D. Bicyclo[2.2.2]oct-2-ene-2-carboxylic acid (4-nitro-3-trifluoromethylphenyl)-amide (11D)
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[NH2:9][CH:10]([C:12](O)=[O:13])[CH3:11].[ClH:15]>>[OH2:13].[ClH:15].[ClH:15].[NH2:9][CH:10]([C:12]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1)[CH3:11]
Reactant: Nc1ccccc1N
Reactant: CC(N)C(=O)O
Agent: Cl
Product: CC(N)c1nc2ccccc2[nH]1
Product: O
Temperature: -15 °C

Procedure:
Combine o-phenylenediamine (10.8 g, 100 mmol) and d,l-alanine (13.4 g, 150 mmol) in 6 N HCl (100 mL) Heat at reflux 75 hours, allow to cool, and chill at −15° C. Filter to remove 2.4 g solid. Decolorize the filtrate with charcoal, concentrate in vacuo to 30 g, and dilute with 95% EtOH (90 mL). Chill at −15° C., filter and wash with cold 90% EtOH to obtain the title compound as a white powder.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10]C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C[N:19](C)[CH:20]=[O:21]>CCOCC>[CH2:1]([O:8][CH2:9][CH2:10][N:19]=[C:20]=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCOCc1ccccc1
Reactant: CN(C)C=O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: O=C=NCCOCc1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To 3-benzyloxypropionic acid (129.6 g) in ether (310 ml) and N,N-dimethylformamide (4 ml) was added thionyl chloride (155 ml). The solution was refluxed for 2 hours, and solvents and excess thionyl chloride were removed by evaporation in vacuo. Yield 132 g of 3-Benzyloxypropionic acid chloride as an oil. To an ice cooled solution of the thus prepared acid chloride (132 g) in acetone (450 ml) was added a cold solution of sodium azide (48.5 g) in water (200 ml) at 5° C. After additional stirring at 5° C. for 30 minutes, the mixture was poured into water and toluene, and the aqueous phase was extracted twice with toluene. The combined organic phases were washed with brine. After drying (magnesium sulfate) the solution was heated slowly to 85° C. on a steam bath until evolution of nitrogen ceased. The solvent was removed in vacuo leaving 108.4 g of 2-benzyloxyethylisocyanate as an oil. A mixture of 2-benzyloxy-ethylisocyanate (10 g) and diethanolamine (5.72 g) in dichloromethane (60 ml) was refluxed for 2.5 hours. After cooling to room temperature, the solution was washed with brine. Drying (magnesium sulfate) and evaporation of the solvent yielded 11.4 g of N-(2-benzyloxyethyl)-N',N'-di-(2-hydroxyethyl)-urea as an oil. A solution of the urea derivative (11.4 g) in dichloromethane (55 ml) was cooled to 5° C., and thionyl chloride (8.3 ml) was added at a temperature below 10° C. After the addition the mixture was refluxed for 1 hour and then left over night at room temperature. The solution was washed with cold sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in 1,1,1-trichloroethane and refluxed for 3 hours. After cooling the solution was washed with sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacuo, yielding 6.6 g of the title compound 22a as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([NH:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]=O.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:16][CH2:17][C@H:18]([N:21]([CH3:31])[CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CCCN[C@H]2CC[C@H](c3ccc(OCc4ccccc4)cc3)CC2)cc1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-[4-(4-benzyloxy-phenyl)-cyclohexyl]-(3-phenyl-propyl)-amine (0.4 g, 1.0 mmol), 36.5% aq. formaldehyde (0.12 ml) and MeOH (7 ml) was stirred overnight at RT. Excess sodium borohydride was then added, and stirring was continued for 2 h. Evaporation of the solvent, addition of H2O, extraction with CH2Cl2, drying of the organic layer with Na2SO4, evaporation of the solvent and purification of the residue by chromatography over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2—MeOH—25% aq. NH3 140:10:1 trans-[4-(4-benzyloxy-phenyl)-cyclohexyl]-methyl-(3-phenyl-propyl)-amine (0.41 g, 99%) as a colorless oil. MS: m/e=413 (M+).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[OH2:6].[F:7][C:8]1[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:13]=[CH:12][C:9]=1[C:10]#N>C(O)(=O)C>[F:7][C:8]1[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:13]=[CH:12][C:9]=1[C:10]([OH:2])=[O:6]
Reactant: CCCCCc1ccc(C#N)c(F)c1
Reactant: O
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCCCCc1ccc(C(=O)O)c(F)c1

Procedure:
A mixture of concentrated sulphuric acid (150 ml) and water (150 ml) was added dropwise to a stirred solution of compound 21 (15.0 g, 0.078 mol) in glacial acetic acid (300 ml). The stirred mixture was heated under reflux for 48 h, cooled in a refrigerator overnight and the product was filtered off. The product was dissolved in ether, extracted into 10% sodium hydroxide, which was then acidified with 36% hydrochloric acid, washed with ether (twice), and the combined ethereal phases were washed with water and dried (MgSO4). The solvent was removed in vacuo to give a brown crystalline solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][Cl:14].Cl.[N:17]([O-])=O.[Na+]>O>[Cl:14][CH2:13][CH2:12][C:11]1[C:10](=[O:15])[C:4]2[C:3](=[C:8]([CH3:9])[CH:7]=[CH:6][CH:5]=2)[NH:2][N:17]=1
Reactant: Cc1cccc(C(=O)CCCCl)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cccc2c(=O)c(CCCl)n[nH]c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-(2-amino-3-methylphenyl)-4-chlorobutan-1-one hydrochloride (20 g, 0.081 Mol) and concentrated hydrochloric acid (1000 ml) at 0° was added dropwise a solution of sodium nitrite (6.07 g, 0.088 mol) in water (50 ml) maintaining the temperature below 5°. The reaction mixture was stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure to give a solid. The solid was washed with sodium acetate solution and collected by filtration and dried, 13.5 g. Recrystallization from methanol gave the title compound, m.p. 222-225°
Reaction SMILES: [CH:1]([CH:4]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[C:5]#N)([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:18].[OH2:22]>>[CH:1]([CH:4]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[C:5]([OH:18])=[O:22])([CH3:3])[CH3:2]
Reactant: O
Reactant: CC(C)C(C#N)c1ccc2ccccc2c1
Reactant: O=S(=O)(O)O
Product: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of α-isopropyl-2-naphthaleneacetonitrile (264.3 g, 1.263 mole), concentrated sulfuric acid (660 ml) and water (660 ml), is heated at 140° C. for 12 hours. The mixture is allowed to cool slowly during which the acid precipitates. The solid is collected by filtration, washed thoroughly with cold water (4 × 500 ml), and dried in a vacuum oven at 50° C. The yield is 281 g (97.6%). The solid is taken up in hexane (750 ml) and benzene (750 ml) and brought to boiling. The cloudy solution on cooling gives a white crystalline solid, which is collected and dried; (227 g, 2 crops, 78.8%); m.p. 129°-130° C. An analytical sample prepared in another run has a m.p. of 130°-131° C.
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=C(C#N)[CH:15]=3)[CH2:10][CH2:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:19].[CH3:20][CH2:21][OH:22]>[OH-].[Na+]>[CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:20]([C:21]([OH:19])=[O:22])[CH:15]=3)[CH2:10][CH2:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O
Reactant: N#Cc1ccc2c(c1)C(C1CCCCC1)=NCC2
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc2c(c1)C(C1CCCCC1)=NCC2

Procedure:
1-cyclohexyl-3,4-dihydroisoquinoline-7-carbonitrile (1.01 g) was dissolved in EtOH (15 mL), to which a 6 M aqueous NaOH solution (7.0 mL) was then added, followed by stirring under heating at reflux for 6 hours. Water was added to the mixture which was then washed with EtOAc. A 1 M aqueous HCl solution was added to the mixture to have a pH of about 3 and then a saturated aqueous sodium sulfate solution was added thereto. The mixture was extracted with a 4:1 mixed solution of chloroform-iPrOH, washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated to obtain 1-cyclohexyl-3,4-dihydroisoquinoline-7-carboxylic acid (1.09 g).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClCCCl.O>[O:15]=[C:9]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: COc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: COc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Anisole (70.0 g) and succinic anhydride (65.0 g) were dissolved in 1,2-dichloroethane (1 liter) and the mixture was cooled to 0° C. To the resulting suspension there was added, in portions, AlCl3 (172 g) and the resulting mixture was stirred with a mechanical stirrer for 1 hour. The mixture was then poured into a mixture of ice and water (about 1 liter) containing 50 ml of concentrated HCl. The resulting white solid was collected by filtration, washed with water and air dried to yield the title compound, m.p. 145°-147° C.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][N:5]=[C:4]([S:17]([CH3:20])(=[O:19])=[O:18])[N:3]=1.FC1C=C(F)C=CC=1OC1C([C:36]2[CH:37]=[C:38]([O:44][CH3:45])[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=2)=NC(CS(C)(=O)=O)=NC=1>>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[C:2]([C:36]2[CH:37]=[C:38]([O:44][CH3:45])[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=2)=[N:3][C:4]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:5][CH:6]=1
Reactant: CS(=O)(=O)c1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Reactant: COc1cc(-c2nc(CS(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O
Product: COc1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O

Procedure:
The title compound of Example 149, step 3 was reacted with 3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (see Example 146, step 3) in a manner similar to Example 149, step 4 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.35 (d, J=2.0 Hz, 1H), 8.18 (s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.12-7.08 (m, 1H), 7.08-7.04 (m, 1H), 3.93 (s, 3H), 3.70 (s, 3H), 3.38 (s, 3H). LCMS: 423.9 (M+1)+
Reaction SMILES: [CH:1]([NH:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)=[O:2].[N+:13]([O-])([OH:15])=[O:14]>>[CH:1]([NH:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH2:5]1)=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=CNC1Cc2ccccc2C1
Product: O=CNC1Cc2ccc([N+](=O)[O-])cc2C1
Reaction time: 1 h

Procedure:
2-Formylaminoindane (15 g) was added portionwise to fuming nitric acid (30 ml, density=1.5 g/ml) whilst keeping the temperature at between 0° and -5°. Stirring was continued for 1 hour at 0° before pouring the reaction mixture onto ice/water and extracting with methylene chloride. The organic layer was washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated in vacuo to give an oil which was purified by column chromatography on silica eluting with methylene chloride containing hexane (20% down to 0%) and then methylene chloride containing methanol (0% up to 2%). The product-containing fractions were combined and evaporated to give the title compound, yield 7.7 g, m.p. 91°-92°.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[F:20][C:21]1[C:29]([F:30])=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([I:31])[CH:22]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:20][C:21]1[C:29]([F:30])=[CH:28][C:24]([C:25]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]2[CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[O:26])=[C:23]([I:31])[CH:22]=1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: O=C(O)c1cc(F)c(F)cc1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (1.89 g, 3.38 mmol), 4,5-difluoro-2-iodobenzoic acid (0.8 g, 2.817 mmol), DIPEA (1.5 mL, 8.45 mmol) and HATU (1.07, 2.817 mmol) in DMF (15 ml) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHCO3 and brine successively. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound. MS (ESI) 525 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([C:26]([OH:28])=O)[CH:20]=2)=[O:18])[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].Cl.[CH2:30]([NH2:32])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([C:26]([NH:32][CH2:30][CH3:31])=[O:28])[CH:20]=2)=[O:18])[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)cc(C(=O)O)n1
Reactant: CCN
Agent: Cl
Product: CCNC(=O)c1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)cc(C)n1

Procedure:
The title compound is prepared from 4-((1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)carbamoyl)-6-methylpicolinic acid (15 mg, 0.04 mmol, Step-2, single enantiomer) and ethanamine hydrochloride by the similar manner in Example-2.
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][N:23](C(OC(C)(C)C)=O)[CH:24]2[CH2:26][CH2:25]2)=[C:14]([CH:34]=O)[CH:13]=3)[CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH3:8].[CH:24]1([N:23]2[CH:34]=[C:14]3[CH:13]=[C:12]4[C:17](=[N:16][C:15]3=[CH:22]2)[N:18]2[C@@H:10]([CH2:9][NH:8][CH2:20][C@H:19]2[CH3:21])[CH2:11]4)[CH2:26][CH2:25]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(C=O)c(CN(C(=O)OC(C)(C)C)C4CC4)nc3N21
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNC[C@H]2Cc3cc4cn(C5CC5)cc4nc3N21
Product: N
Yield: 22.7 %

Procedure:
A solution of 0.040 g (4R,9aR)-6-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-7-formyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 0.50 ml trifluoroacetic acid was kept at room temperature for 18 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with dichloromethane:methanol:ammonia=90:10:1 to yield 0.0025 g of the title compound as colorless foam (MS: 269.4 (M+H+)).
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:6][N:7]=1)=O.[CH3:15][C:16]([S@@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(Cl)Cl>[C:16]([S@@:19](/[N:21]=[CH:1]/[C:3]1[S:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:6][N:7]=1)=[O:20])([CH3:18])([CH3:17])[CH3:15]
Reactant: CC(C)(C)OC(=O)c1cnc(C=O)s1
Reactant: CC(C)(C)[S@@](N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cnc(/C=N/[S@@](=O)C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of tert-butyl 2-formylthiazole-5-carboxylate (15.7 g, 74 mmol) and (S)-2-methylpropane-2-sulfinamide (10.7 g, 88 mmol) in DCM (750 mL) at 0° C. was added cesium carbonate (48.2 g, 148 mmol). The mixture was warmed to rt and stirred for 8 h. To the solution was added water (200 mL). After separation, the aqueous phase was extracted with DCM (3×200 mL). The combined organic phases were dried (Na2SO4), and concentrated. Flash column chromatography (petroleum ether: EtOAc, 100:1 to 10:1) afforded (S,E)-tert-butyl 2-((tert-butylsulfinylimino)methyl)thiazole-5-carboxylate (18.9 g, 81%). 1H NMR (CDCl3, 400 MHz) δ 8.67 (s, 1H), 8.39 (s, 1H), 1.52 (s, 9H), 1.22 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH2:6]O.P(Br)(Br)[Br:13]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH2:6][Br:13]
Reactant: OCC=Cc1ccccc1Br
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCC=Cc1ccccc1Br
Temperature: 0 °C
Yield: 85 %

Procedure:
All of the o-bromocinnamylalcohol (159 mM) from Step A was dissolved in 300 ml of carbon tetrachloride under nitrogen and chilled to 0°. Then 100 ml of carbon tetrachloride containing phosphorous tribromide (5.62 ml; 59.8 mM) was added dropwise. After stirring at 0° for an additional hour the reaction was poured into ice water and partitioned. The aqueous layer was extracted once with methylene chloride and the combined organic layers were washed with cold 1.5N aqueous sodium hydroxide. Drying over magnesium sulfate followed by solvent removal gave a pale yellow oil, which was purified by short path distillation at 0.2 torr. The o-bromocinnamyl bromide was distilled at 105° and 37.3 g (85% yield) was isolated.
Reaction SMILES: [NH4+:1].[OH-].[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.[NH4+:12].[Cl-].[C-:14]#N.[Na+]>CO>[NH2:1][C:8]1([C:14]#[N:12])[CH2:9][CH2:10][CH:5]([CH2:4][OH:3])[CH2:6][CH2:7]1
Reactant: [C-]#N
Reactant: O=C1CCC(CO)CC1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC1(N)CCC(CO)CC1
Reaction time: 16 h
Yield: 67 %

Procedure:
To a stirred solution of NH4OH (125 mL) and methanol (50 mL) was added 4-(hydroxymethyl)cyclohexanone (10 g, 78 mmol), NH4Cl (8.35 g, 156 mmol) and NaCN (7.65 g, 156 mmol). After 16 h at room temperature, the reaction mixture was extracted with CH2Cl2 (250 mL×2), and 4:1 chloroform:2-propanol, and the combined organic fractions washed with water (500 mL), dried (Na2SO4), filtered and concentrated to afforded the title compound as a colorless liquid (8 g, 67% yield). 1H NMR (500 MHz, CDCl3) δ: 3.51 (d, 2H, J=4.58 Hz), 2.07-2.09 (m, 2H), 1.86-1.91 (m, 4H), 1.68 (s, 2H), 1.47-1.53 (m, 3H), 1.41 9 brs, 1H), 1.30-1.36 9 m, 2H). LCMS (M+H)=155.18.
Reaction SMILES: Br[C:2]1([O:8][CH:9]2[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1.[Li]CCCC.[B:17](OCC)([O:21]CC)[O:18]CC.Cl>C1COCC1>[CH:9]1([O:8][C:2]2[CH:7]=[CH:6][C:5]([B:17]([OH:21])[OH:18])=[CH:4][CH:3]=2)[CH2:11][CH2:10]1
Reactant: BrC1(OC2CC2)C=CC=CC1
Reactant: CCOB(OCC)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 36 %

Procedure:
To a solution of 4-bromo-4-cyclopropoxybenzene (5.0 g, 23.4 mmol, see Example 39(c)) in THF (80 mL) at −78° C. was added n-BuLi (2.5 M solution in hexane; 9.76 mL, 24.4 mmol) over 17 min. After 40 min, B(OEt)3 (5.9 mL, 34.3 mmol) was added and the reaction was warmed to room temperature and stirred at ambient temperature for 18 h. After re-cooling to 0° C., HCl (1M solution; 70 mL, aq.) was added. After 30 min the mixture was extracted with t-BuOMe (3×50 mL), the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was washed with light petrol and filtered yielding the sub-title compound (1.5 g, 34%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:18])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:24][CH:23]=[CH2:22])[C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:18])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2cc(Br)ccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(Br)ccc2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
((S)-6-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (4.85 g, 14.87 mmol) was dissolved in dimethylformamide (40 ml). Sodium hydride (50% in oil) (785 mg, 16.35 mmol) was added and stirred for 15 minutes at room temperature. Allyl bromide (1.41 ml, 16.35 mmol) was added and the reaction mixture was stirred at room temperature overnight. To the reaction mixture was added H20 (500 ml) and extracted three times with 100 ml diethylether. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield 5.5 g of crude product. The crude product was purified with silica gel chromatography with cyclohexane/ethyl acetate (95:5) as eluent, yielding the purified product (3.9 g, 68%).
Reaction SMILES: Cl.[C:2]([S:21][CH2:22][CH2:23][NH2:24])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:25][C:26]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)(=[O:38])=[O:37])=[C:31]2[C:27]=1[CH:28]=[C:29]([C:44](O)=[O:45])[NH:30]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[CH3:25][C:26]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)(=[O:38])=[O:37])=[C:31]2[C:27]=1[CH:28]=[C:29]([C:44]([NH:24][CH2:23][CH2:22][S:21][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:45])[NH:30]2
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.6 %

Procedure:
To a mixture of 2-(tritylthio)ethylamine hydrochloride (0.93 g), triethylamine (0.37 mL) and N,N-dimethylformamide (15 mL) were added 4-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.73 g), 1H-1,2,3-benzotriazol-1-ol (0.47 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.59 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (1.31 g, yield 95%) as pale-yellow crystals. melting point 241-242° C.