Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([Br:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:14]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:12][C:9]1[CH:10]=[CH:11][C:2]2[NH:1][N:14]=[CH:13][C:3]=2[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(Br)ccc(N)c1C
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(Br)ccc2[nH]ncc12
Reaction time: 20 h
Yield: 85.4 %

Procedure:
To a solution of methyl 3-amino-6-bromo-2-methylbenzoate (5.44 g, 22.3 mmol) in acetic acid (110 mL) was added a solution of sodium nitrite (1.69 g, 24.5 mmol) in water (11 mL) at room temperature, and the mixture was stirred for 20 hr. The organic solvent was evaporated under reduced pressure. The residual aqueous solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=10/90→30/70) to give the title compound (4.86 g, yield 86%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Nc3ccc(F)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-fluoro-phenylamine to give N1-(4-fluoro-phenyl)-6-methoxy-N3-(5-methyl-1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 364(MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([NH2:29])[CH2:27][NH2:28]>C(O)C.CCOCC>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:28][CH2:27][CH2:26][NH2:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCCCCCCCCCCCCCc1ccccc1
Reactant: NCCN
Solvent: CCOCC
Solvent: CCO
Product: NCCNCCCCCCCCCCCCCCCCCCc1ccccc1

Procedure:
A solution of 15.8 grams (0.04 mole) of phenylstearyl bromide and 19.25 grams (0.32 mole) of ethylene diamine in 250 ml of ethanol was refluxed for 3 hours. The alcohol solvent was removed under reduced pressure and the resulting mixture separated into two layers. The lower layer was removed and 100 ml of water added to the top layer. The oily layer which then formed was dissolved in ether and washed free of residual ethylene diamine with water. The ether solution was dried over anhydrous sodium sulfate and the ether stripped off under reduced pressure to yield 13 grams (87% crude mass yield) of N-phenylstearyl ethylene diamine having the following analysis:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].CN(C)C=O.[NH2:17][C:18]1[C:33]([Cl:34])=[CH:32][C:21]([C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]2[OH:31])=[O:23])=[C:20]([O:35][CH3:36])[CH:19]=1>C(N(CC)CC)C>[NH2:17][C:18]1[C:33]([Cl:34])=[CH:32][C:21]([C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][C:5](=[O:6])[N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:27][C@H:26]2[OH:31])=[O:23])=[C:20]([O:35][CH3:36])[CH:19]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@@H]1CCNC[C@H]1O
Reactant: O=C(CCCCl)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@@H]1CCN(CCCC(=O)N2CCCC2)C[C@H]1O
Temperature: 70 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
To a stirred solution of 3.00 parts of 1-(4-chloro-1-oxobutyl)pyrrolidine in 67.5 parts of N,N-dimethylformamide were added 1.93 parts of trans-4-amino-5-chloro-N-(3-hydroxy-4-piperidinyl)-2-methoxybenzamide and 1.5 parts of N,N-diethylethanamine and the whole was stirred for 18 hours at 70° C. The reaction mixture was evaporated and the residue was taken up in a sodium carbonate solution in water. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.1 parts (47.8%) of trans-4-amino-5-chloro-N-[3-hydroxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]-2-methoxybenzamide; mp. 174.7° C. (compound 15).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:11][C:12]([NH2:14])=[O:13])(=[O:10])=[O:9].ClCC(N1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:11][C:12]([N:14]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:13])(=[O:10])=[O:9]
Reactant: NC(=O)CS(=O)(=O)c1ccccc1Br
Reactant: O=C(CCl)N1CCOCC1
Product: O=C(CS(=O)(=O)c1ccccc1Br)N1CCOCC1

Procedure:
The title compound was prepared in a manner similar to that described for 2-((2-bromophenyl)sulfonyl)acetamide using 2-chloro-1-morpholinoethanone in Step A. 1H NMR (600 MHz, DMSO-d6) δ 8.06-8.01 (m, 1H), 7.93-7.88 (m, 1H), 7.68-7.60 (m, 2H), 4.84 (s, 2H), 3.63-3.55 (m, 4H), 3.53-3.48 (dd, J=5.6, 4.0, 2H), 3.42-3.37 (d, J=5.2, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH:9]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][C:3]=1[CH3:30].[Cl:31][C:32]1[CH:33]=[C:34]([C:39](=O)[C:40]([F:43])([F:42])[F:41])[CH:35]=[C:36]([Cl:38])[CH:37]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH:9]=[C:39]([C:34]2[CH:35]=[C:36]([Cl:38])[CH:37]=[C:32]([Cl:31])[CH:33]=2)[C:40]([F:43])([F:42])[F:41])=[CH:4][C:3]=1[CH3:30]
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: Cc1cc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1Br
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Yield: 86.8 %

Procedure:
473 mg of 1-(4-Bromo-3-methyl-phenyl)-2-(triphenylphosphanylidene)-ethanone (Va) was refluxed with 243 mg of 1-(3,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone (VIa) (Journal of Physical Organic Chemistry (1989), 2(4), 363-6) in 3 ml of toluene for 3 hours. The solvent was then evaporated, and the residue was triturated with the mixture hexane:ethyl acetate 20:1. The solid that separated was filtered off and the filtrate after evaporation was purified on silica gel (40 g, hexane:acetate 10:1) giving 380 mg (86%) of 1-(4-Bromo-3-methyl-phenyl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-en-1-one (IVa) as a yellow oil which solidified on standing (mixture of E and Z isomers). 1H-NMR (CDCl3, δ in ppm): 2.41 (s) and 2.46 (s) (total of 3H), 6.80-7.80 (m, total of 7H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([CH2:21]CC(O)=O)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:41]CC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([CH2:21][OH:41])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cncc(CCC(=O)O)c2)CC1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cncc(CO)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of 4-(1-phenyl-1-(5-carboxyethylpyridin-3-yl)-methylene)-piperidine-1-carboxylic acid tert-butyl ester (0.058 g, 0.137 mmol) in dry THF (2 mL) was added LAH (0.334 mL, 0.949 mmol) portionwise over 10 min. The mixture was stirred at room temperature for an additional 30 min and then it was quenched with a saturated aqueous solution of Rochelle's salt (5 mL). The resulting mixture was filtered and the filtrate concentrated to dryness to give the title compound (0.046 g, 87%) as a clear brown oil:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[O:13][CH2:14][C:15]1[S:19][C:18](/[C:20](/[CH2:27][CH3:28])=[CH:21]/[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:41](=O)([O-])[O-].[K+].[K+].IC>CC(=O)CC>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[CH2:32][O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:35])[CH3:36])[O:13][CH2:14][C:15]1[S:19][C:18](/[C:20](/[CH2:27][CH3:28])=[CH:21]/[CH2:22][CH2:23][C:24]([O:26][CH3:41])=[O:25])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC/C(=C\CCC(=O)O)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: CC/C(=C\CCC(=O)OC)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1

Procedure:
4.3 g (7.1 mmol) of (E)-5-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-4-heptenoic acid are dissolved in 70 mL of 2-butanone, and 1.1 g of potassium carbonate (7.8 mmol) and 2.2 mL of iodomethane (35 mmol) are added. The medium is refluxed for 12 hours, cooled and filtered. The filtrate is concentrated under reduced pressure and then purified by chromatography on a column of silica. A yellow oil is obtained (m=4.34 g; Y=98%).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.C(O)(=O)C.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:8]([NH:7][C:6]1[CH:11]=[C:2]([F:1])[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]=1[OH:9])[CH3:10]
Reactant: Cc1nc2cc(F)c([N+](=O)[O-])cc2o1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCNc1cc(F)c([N+](=O)[O-])cc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
5-Fluoro-2-methyl-6-nitro-benzoxazole (2.556 g, 13.03 mmol) was dissolved in Tetrahydrofuran (90 mL) and Acetic acid (4.5 mL, 79 mmol). Sodium borohydride (1.48 g, 39.1 mmol) was added and the reaction was stirred at room temperature for 90 min, then poured into 100 mL satd. sodium bicarbonate. The solution was extracted 3×50 mL DCM and the combined organics were washed with 1:1 brine:satd. sodium bicarbonate (50 mL) and dried over sodium sulfate, then conc. onto 10 g Celite. The crude product was chromatographed (120 g silica gel, ISCO, 0-20-40% EtOAc:Hex) to afford 2-Ethylamino-4-fluoro-5-nitro-phenol as a yellow solid (2.20 g, 84%). 1H-NMR (CDCl3): 7.55 (d, 1H, J=6.8 Hz), 6.26 (d, 1H, J=13.2 Hz), 5.51 (s, 1H), 5.05 (s, 1H), 3.26 (m, 2H), 1.34 (t, 3H, J=6.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([NH:31][CH2:30][CH2:29][C:23]2[C:22]3[C:26](=[CH:27][CH:28]=[C:20]([C:19]([F:33])([F:18])[F:32])[CH:21]=3)[NH:25][CH:24]=2)=[O:12])[CH:6]=1
Reactant: NCCc1c[nH]c2ccc(C(F)(F)F)cc12
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(C(F)(F)F)cc12)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
A mixture of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.08 g, 0.334 mmol), 2-(5-(trifluoromethyl)-1H-indol-3-yl)ethanamine (0.080 g; 0.334 mmol), HATU (0.127 g; 0.334 mmol) and N,N diisopropylethylamine (0.144 mL; 0.836 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane) and by preparative HPLC method 2 to yield 0.013 g (9%) of 5-(2,5-difluorobenzyl)-N-(2-(5-(trifluoromethyl)-1H-indol-3-yl)ethyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:24])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1

Procedure:
A mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin4-one (2.82 g, 0.01 mol), thionyl chloride (40 ml) and DMF (0.28 ml) was stirred and heated to reflux for 1 hour. The mixture was evaporated, the residue was taken up in toluene and evaporated to dryness to give 7-benzyloxy-4-chloro-6-methoxyquinazoline (3.45 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][Si:8]([CH3:13])(OC)[O:9]C.[SiH4].[OH-].[K+:16]>O>[NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][SiH:8]([CH3:13])[O-:9].[K+:16]
Reactant: CO[Si](C)(CCCNCCN)OC
Agent: [K+]
Agent: [OH-]
Agent: [SiH4]
Solvent: O
Product: C[SiH]([O-])CCCNCCN
Yield: 40 %

Procedure:
About 103 g of N-(2-aminoethyl)-3-aminopropylmethyldimethoxysilane (commercially available under the name "Silan GF 95" from Wacker-Chemie GmbH, Munich) are metered into a solution containing 63.7 g of potassium hydroxide (88% strength in water) in 200 g of water, while stirring vigorously. First methanol and then about 70 g of water are distilled off from the mixture by heating. The mixture is then made up to a total weight of 317 g by addition of water. A 40% potassium N-(2-aminoethyl)-3-aminopropylmethylsilanolate solution is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:26]=3[N:27]=2)[CH:19]=[C:18]([Cl:34])[CH:17]=1)(=[O:14])=[O:13].[N:35]([Si](C)(C)C)=[N+:36]=[N-:37].C([Sn](=O)CCCC)CCC.Cl>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][C:29]([C:32]4[NH:37][N:36]=[N:35][N:33]=4)=[CH:28][C:26]=3[N:27]=2)[CH:19]=[C:18]([Cl:34])[CH:17]=1)(=[O:13])=[O:14]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc2sc(Oc3cc(Cl)cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)c3)nc2c1
Agent: CCCC[Sn](=O)CCCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1cc(Cl)cc(Oc2nc3cc(-c4nnn[nH]4)ccc3s2)c1)c1ccc(C(F)(F)F)cc1Cl
Temperature: 90 °C
Yield: 85.1 %

Procedure:
To a solution of 2-Chloro-N-[3-chloro-5-(5-cyano-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide (Example 286, 55 mg, 0.1 mmol) in 5 mL of toluene was added azidotrimethylsilane (Aldrich, 26 uL, 0.2 mmol) and dibutyltin oxide (Aldrich, 3 mg, 0.01 mmol). The mixture was heated at 90° C. overnight till there was no starting material remained by TLC. Cooled to room temperature, 1N HCl and EtOAc was added. The mixture was extracted 3× with EtOAc (30 mL). The organic layers were washed twice with a brine solution (300 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography, eluted with 10% EtOAc/CH2Cl2 then 10% MeOH/CH2Cl2 to give 50 mg (85%) of product. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J=8.2 Hz, 1H), 8.30 (d, J=1.6 Hz, 1H), 8.21 (d, J=8.5 Hz, 1H), 8.19 (s, 1H), 8.03 (dd, J=8.4, 1.6 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.44 (t, J=2.0 Hz, 1H), 7.18 (t, J=2.0 Hz, 1H), 7.12 (t, J=1.9 Hz, 1H). MS (EI): m/z 585 (M−H).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[C:6]([CH2:9][S:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=O)(O)=O.[CH3:20][N+:21]([CH3:24])=[CH:22][Cl:23].[Cl-:25]>CN(C=O)C>[CH3:20][N+:21]([CH3:24])=[CH:22][Cl:23].[Cl-:3].[Cl:25][C:13]1[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][C:9]=1[CH2:6][NH:21][CH3:20]
Reactant: O=C(O)CSc1ccccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CNCc1sc2ccccc2c1Cl
Temperature: 25 °C
Yield: 68 %

Procedure:
Vilsmeier reagent was prepared via the dropwise addition of POCl3 (7.9 mL, 84 mmol) into ice-cold DMF (14 mL). A solution of 2-carboxymethylsulfanyl-benzoic acid (3.0 g, 14 mmol) in DMF (15 mL) was added dropwise to the Vilsmeier reagent. The resulting mixture was warmed to room temperature and then heated to 80° C. for 3.5 h. The reaction mixture was cooled to ambient temperature. Crushed ice was added until a bright yellow precipitate appeared. The solid was isolated by filtration. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate 3:2) gave the title compound (1.87 g, 68%) as a yellow powder: 1H NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 8.03 (m, 1H), 7.86 (m, 1H), 7.59-7.53 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.Br[CH2:30][CH2:31][CH2:32][CH:33]=[CH2:34].N>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][N:23]([CH2:34][CH2:33][CH2:32][CH:31]=[CH2:30])[CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:26])[F:27])[CH:4]=1
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Reactant: C=CCCCBr
Agent: N
Product: C=CCCCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(OC)cc3C(F)(F)F)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (22 mg, 63%) from (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) and 5-bromo-1-pentene (23 mg, 0.15 mmol). 1H NMR (CDCl3, 300 MHz) δ 1.68-1.79 (m, 2H), 2.01-2.26 (m, 7H), 2.43-2.62 (m, 4H), 2.71 (t, J=6.3 Hz, 2H), 2.83-2.92 (br, 1H), 2.95-3.07 (br, 1H), 3.27-3.44 (m, 3H), 3.86 (s, 3H), 4.93-5.05 (m, 2H), 5.70-5.85 (m, 1H), 6.80 (s, 1H), 6.84 (s, 1H), 7.02 (dd, J=8.1, 2.6 Hz, 1H), 7.18-7.24 (m, 2H) ppm. MS (CI, NH3): 457.2 (base, M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].C[O:12]B(OC)OC.Cl.OO>CCCCCC>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[OH:12]
Reactant: COB(OC)OC
Reactant: COc1ccc(F)c(F)c1
Agent: Cl
Agent: OO
Solvent: CCCCCC
Product: COc1ccc(F)c(F)c1O

Procedure:
Using the procedure of Example 39, 125 g of 3,4-difluoroanisole (commercial) and 500 ml of a 1.6 M solution of N-butyl-lithium in hexane were reacted at −72° C., and then 92.4 ml of trimethylborate, 500 ml of hydrochloric acid and 120 g of intermediate compound were reacted and the product was reacted with 440 ml of 30% hydrogen peroxide to obtain 82.4 g of the expected product melting at 46.6° C.
Reaction SMILES: ClS(N=C=O)(=O)=O.COC1C=CC(CO)=CC=1.[CH3:18][O:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][O:25][C:26]([NH:28][S:29](Cl)(=[O:31])=[O:30])=[O:27])=[CH:22][CH:21]=1.[CH3:35][O:36][C:37]1[CH:73]=[CH:72][C:40]([CH2:41][O:42][C:43]([N:45]2[CH2:49][C@@H:48]([S:50][C:51]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:47][C@H:46]2[CH2:70][NH2:71])=[O:44])=[CH:39][CH:38]=1.C(N(CC)CC)C>ClCCl>[CH3:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:41][O:42][C:43]([N:45]2[CH2:49][C@@H:48]([S:50][C:51]([C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:47][C@H:46]2[CH2:70][NH:71][S:29](=[O:31])(=[O:30])[NH:28][C:26]([O:25][CH2:24][C:23]2[CH:33]=[CH:34][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[O:27])=[O:44])=[CH:72][CH:73]=1
Reactant: COc1ccc(COC(=O)NS(=O)(=O)Cl)cc1
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN)cc1
Agent: COc1ccc(CO)cc1
Agent: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(=O)NS(=O)(=O)NC[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc(OC)cc2)cc1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
To a solution of chlorosulfonyl isocyanate (3.95 ml: 45.4 mmole) in dichloromethane (70 ml), p-methoxybenzyl alcohol (5.66 ml: 45.4 mmole) is added at -50° C. The mixture is stirred at -50° C. for 15 minutes. The resulting solution of p-methoxybenzyloxycarbonylsulfamoyl chloride is added to a solution of (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-aminomethyl-4-tritylthiopyrrolidine (obtained in the above Steps 6 or 8) (12.21 g: 22.7 mmole) and triethylamine (6.38 ml: 45.6 mmole) in dichloromethane (300 ml) at -78° C., and the mixture is stirred for 10 minutes, successively washed with dilute hydrochloric acid and brine, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-p-methoxybenzyloxycarbonylsulfamoylaminomethyl-4-tritylthiopyrrolidine (16.31 g). Yield: 91.6%.
Reaction SMILES: C(O)(=O)C.Br.C(OC([NH:16][C@H:17]([C:24]([N:26]1[CH2:39][CH2:38][CH2:37][C@H:27]1[C:28]([NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:29])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1)=O)C1C=CC=CC=1>CCOCC>[NH2:16][C@H:17]([C:24]([N:26]1[CH2:39][CH2:38][CH2:37][C@H:27]1[C:28]([NH:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)=[O:29])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCC1)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCC1
Temperature: 25 °C
Yield: 188.2 %

Procedure:
To 15 ml of ice-cooled acetic acid solution of 25% hydrobromic acid was added 1.14 g of compound (37) and the reaction was maintained for 3 hours at room temperature. The reaction mixture thus obtained was added to 150 ml of desiccated ether, the precipitates thus formed were quickly collected by filtration and dried overnight in a desiccator at reduced pressure to provide 1.53 g of L-histidyl-N-cyclohexyl-L-prolinamide.2-hydrobromide.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]1N2CCN(CC2)C1>CCOC(C)=O.O>[CH3:14][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c2ccccc2c2ccccc21
Temperature: 92.5 °C
Yield: 961.2 %

Procedure:
To a solution of carbazole (1.03 g, 6.16 mmol) in DMC (10 mL), DABCO (0.069 g, 0.62 mmol) is added and the resulting solution is heated to 90-95° C. for 24 h. The reaction is cooled to RT, and diluted with EtOAc (40 mL) and H2O (40 mL). The organic layer is separated and washed in sequence with H2O (50 mL), 10% aqueous citric acid (2×40 mL) and H2O (3×40 mL). The organic layer is dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 9-methylcarbazole (about 1.08 g, 97%) as a beige solid: 1H NMR (CDCl3) δ8.06 (d, 2H), 7.43 (t, 2H), 7.31 (d, 2H), 7.20 (t, 2H), 3.71 (s, 3H); 13C NMR (CDCl3) δ141.0, 125.7, 122.8, 120.3, 118.9, 108.5, 29.0; MS m/z 181 [M+1]+.