Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([O:15]CC)=O)[CH2:9][CH2:8]2.[NH2:18][CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[C-]#N.[K+]>C1(C)C=CC=CC=1>[C:20]1([CH2:19][NH:18][C:13]([CH:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11]2)=[O:15])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1CCc2cccc(OC)c2O1
Reactant: NCc1cccc2ccccc12
Agent: [C-]#N
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(NCc1cccc2ccccc12)C1CCc2ccccc2O1
Reaction time: 2 h

Procedure:
33.0 g (0.14 mol) of ethyl 8-methoxy-chroman-2-carboxylate (content 87%) are heated together with 25.8 g (0.16 mol) of 1-aminomethylnaphthalene and 0.05 g of potassium cyanide at 120° C. for 8 hours and then at 130° C. for 2 hours. After cooling, the mixture is diluted with 100 ml of toluene and this solution is introduced onto silica gel K60. Elution with cyclohexane/ethyl acetate mixtures (100:0to 75:25) gives the amide in the form of a viscous syrup (32.9 g, 68%), which can be further reacted directly.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.CC1(C)C(C)(C)OB([C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][CH2:36][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38]3)=[CH:33][CH:32]=2)O1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:31]3[CH:40]=[C:39]4[C:34]([CH2:35][CH2:36][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38]4)=[CH:33][CH:32]=3)[C:16]2=[CH:15][N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN(C(=O)OC(C)(C)C)CC5)n[nH]c3n2)c1F
Temperature: 115 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (16.7 mg, 0.0400 mmol), tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (17.96 mg, 0.05000 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2.0 mg, 0.0024 mmol) and potassium phosphate (25.5 mg, 0.120 mmol) in 1,4-dioxane (0.50 mL) and water (0.15 mL) in a reaction vial was sealed, and degassed and recharged with nitrogen for three times. The mixture was stirred at 115° C. for 3 h. After cooling, the mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=524.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:10]O)[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C.O>COCCOC.[Fe](Cl)Cl>[Cl:1][C:2]1[N:7]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(Cc2cccc(Cl)n2)=NO)cc1
Agent: Cl[Fe]Cl
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: COCCOC
Product: COc1ccc(-c2cc3cccc(Cl)n3n2)cc1
Temperature: 15 °C
Reaction time: 1.5 h
Yield: 51.6 %

Procedure:
To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone oxime (38.7 g, 140 mmol) in 1,2-dimethoxyethane (150 mL) at 0° C. was added trifluoroacetic anhydride (20 mL, 140 mmol), keeping the temperature below 10° C. during the addition. After the addition was complete, the reaction was warmed to 15° C. The solution was then cooled to 4° C. and a solution of triethylamine (39 mL, 280 mmol) in 1,2-dimethoxyethane (15 mL) was added over a period of 0.5 hours. The mixture was allowed to warm to room temperature and was stirred at room temperature for 1.5 hours. To this mixture was added iron(II) chloride (0.18 g, 1.4 mmol) and the reaction was heated at 75° C. for 15 hours. The reaction mixture was poured into water (300 mL). The resulting suspension was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated to a solid. This solid was recrystallized from methanol to give 7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine (18.7 g, 52%) as pale yellow needles. 1H NMR (CDCl3): δ 7.91 (d, 2H), 7.43 (d, 1H), 7.01 (t,1H), 6.95 (d, 2H), 6.81 (d, 1H), 6.80 (s, 1H), 3.83 (s, 3H); MS m/z 259 (M+1).
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH3:20][N:21]=[C:22]=[O:23]>>[NH2:17][C:16]1[C:4]([C:2]#[N:3])=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:22]([NH:21][CH3:20])=[O:23]
Reactant: N#Cc1c(OC[C@@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CN=C=O
Agent: [Cl-]
Product: CNC(=O)N1CCC[C@H]1COc1cccc(N)c1C#N
Yield: 53 %

Procedure:
Prepared as in Example 209a from (S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 209b) and methyl isocyanate in 53% yield as a white solid. MS 275 (MH+).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:38][C:39]#[CH:40])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[CH:19]=[C:20]([CH:35]=[CH:36][CH:37]=1)[O:21][CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1)=[O:11])=O)(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>ClCCl>[NH2:8][C@@H:9]([CH2:38][C:39]#[CH:40])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[CH:37]=[CH:36][CH:35]=[C:20]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=1)=[O:11].[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC#Cc1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CC[C@H](N)C(=O)NCCCC#Cc1cccc(OC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of (S)-tert-butyl 4-(3-(5-(2-(tert-butoxycarbonylamino)pent-4-ynamido)pent-1-ynyl)phenoxy)piperidine-1-carboxylate (0.26 g, 0.47 mmol) in dichloromethane (4.0 ml), TFA (1.0 ml) was added. The resulting solution was stirred at room temperature for 1 hr, then concentrated. The resulting residue was purified over Gilson HPLC to yield the title compound as its corresponding TFA salt, as a white solid. MH+ 354.31
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][NH:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:27]([CH3:26])[C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CNc1cccnc1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN(c1cccnc1)c1cnc2c(n1)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Temperature: 150 °C
Yield: 28.6 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (125 mg, 292 μmol), N-methylpyridin-3-amine (47.4 mg, 439 μmol), xantphos (50.8 mg, 87.7 μmol), Pd2(dba)3 (26.8 mg, 29.2 μmol) and cesium carbonate (191 mg, 585 μmol) in dioxane (2 mL) was heated in a microwave at 150° C. for 20 min. The mixture was cooled and then filtered through a pad of celite. The filtrate was concentrated in vacuo then purified by chromatography (silica, ethyl acetate in hexanes) to give N-tert-butyl-2-(methyl(pyridin-3-yl)amino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (38 mg, 83.6 μmol, 29%) as a yellow gum. (EI/CI) m/z: 455.4 [M+H].
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:12](=[O:29])[C:13]2[C:18]([N+:19]([O-])=O)=[C:17]([F:22])[C:16]([F:23])=[C:15]([O:24][CH:25]([F:27])[F:26])[C:14]=2[F:28])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1>C(O)C>[CH:1]1([NH:4][CH:5]=[C:6]([C:12](=[O:29])[C:13]2[C:18]([NH2:19])=[C:17]([F:22])[C:16]([F:23])=[C:15]([O:24][CH:25]([F:26])[F:27])[C:14]=2[F:28])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(OC(F)F)c(F)c(F)c1[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(N)c(F)c(F)c(OC(F)F)c1F
Yield: 80.6 %

Procedure:
33.63 g (0.079 mole) of ethyl 3-cyclopropylamino-2-(3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoyl)acrylate [(XIXa): X=X'=F, R1 =OCHF2, R17 =C2H5 ] were dissolved in 1300 ml of ethanol with heating. A stream of hydrogen was then bubbled through the solution in the presence of 8.4 g of 5% w/w palladium-on-carbon at room temperature for 40 minutes, whilst stirring. At the end of this time, the reaction mixture was filtered, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was then purified by silica gel column chromatography using a 9:1 by volume mixture of toluene and ethyl acetate as the eluent, to give 25.1 g of ethyl 3-cyclopropylamino-2-(6-amino-3-difluoromethoxy-2,4,5-trifluorobenzoyl)acrylate [(XIXb): X=X'=F, R1 =OCHF2, R17 =C2H5 ] as a pale yellow powder, melting at 103°-104° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5](N)[CH:4]=1)#[N:2].Cl.N([O-])=[O:13].[Na+].C1(C)C=CC=CC=1>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([OH:13])[CH:4]=1)#[N:2]
Reactant: Cc1ccc(C#N)cc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C#N)cc1O
Reaction time: 20 h
Yield: 68.8 %

Procedure:
Into a reaction vessel was charged 4-cyano-2-aminotoluene (13) (132.0 g, 1.0 mol) and 6 N hydrochloric acid aqueous solution (800 ml), and an aqueous solution obtained by dissolving ice-cooled sodium nitrite (76.0 g, 1.1 mol) in water (320 ml) was dropped over 1.5 hours, further, the solution was stirred for approximately 20 hours under ref lux. To the reaction liquid was added toluene and extracted, then, a sodium hydroxide aqueous solution was added to the toluene layer to make the aqueous layer alkaline. The resulted aqueous layer was acidified with concentrated hydrochloric acid, then, extracted with ethyl acetate. The resulted ethyl acetate layer was washed with saturated saline, dried, and the solvent was distilled off under reduced pressure, to obtain 4-cyano-2-hydroxytoluene (14) (91.6 g, yield from (13) is 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19](=[O:21])[N:18]([CH3:22])[C:17]=2[CH:23]=1)=[O:12].[H-].[Na+].[CH3:26]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:26])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19](=[O:21])[N:18]([CH3:22])[C:17]=2[CH:23]=1)=[O:12]
Reactant: CI
Reactant: COc1ccc(CC(=O)c2ccc3oc(=O)n(C)c3c2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C(=O)c2ccc3oc(=O)n(C)c3c2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
5-[2-(2-Chloro-4-methoxy-phenyl)-acetyl]-3-methyl-3H-benzooxazol-2-one (2.45 g) was dissolved in DMF (60 mL). The mixture was cooled to 0° C. To this solution was added sodium hydride (55% in mineral oil, 403 mg) over a period of 10 minutes. The mixture was stirred for 10 minutes at 0° C. and then for 1 hour at r.t. The mixture was cooled to 0° C. and methyl iodide (0.49 mL) was added dropwise over a period of 10 minutes. Stirring was continued for 1.5 hours at r.t. The reaction mixture was poured into ice/water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a light brown foam (1.99 g, 76%). MS (m/e)=346.1 [M+H+].
Reaction SMILES: [S:1]1[CH:9]2[C:4]([CH2:5][NH:6][CH2:7][CH2:8]2)=[CH:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[Si:26]([O:10][C:2]1[S:1][C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C=C2CNCCC2S1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc2c(s1)CCNC2

Procedure:
A mixture of 5.00 g of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one.p-toluenesulfonate, 2.47 g of tert-butyldimethylchlorosilane, 1.66 g of triethylamine and 15 ml of methylene chloride was stirred at room temperature (20° C.) for 3 hours. The produced 2-(tert-butyldimethylsilyloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-p-toluenesulfonate was not isolated, 5.90 g of 2-chloro-α-methoxycarbonylbenzyl bromide and 3.02 g of triethylamine were added thereto, and the mixture was allowed to react.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:48])/[C:13](=[N:27]\[O:28][C:29]3([C:32]([O:34]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:33])[CH2:31][CH2:30]3)/[C:14]3[N:15]=[C:16]([NH:19]C(OC(C)(C)C)=O)[S:17][CH:18]=3)[C:9](=[O:49])[N:8]2[S:50]([OH:53])(=[O:52])=[O:51])[CH:5]=[N:4][CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:48])/[C:13](=[N:27]\[O:28][C:29]3([C:32]([OH:34])=[O:33])[CH2:30][CH2:31]3)/[C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)[C:9](=[O:49])[N:8]2[S:50]([OH:53])(=[O:51])=[O:52])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cncn2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/OC2(C(=O)O)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cncn2)cs1
Yield: 46.7 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (164 mg, 0.214 mmol), DCM (2.14 mL) and TFA (989 μl, 12.8 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (50 mg, 41%) as a white powder. LCMS: Rt=0.29 min, m/z=501.1 (M+1) Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 9.31 (d, J=9.0 Hz, 1H), 8.59 (s, 1H), 8.09 (s, 1H), 6.83 (s, 1H), 5.26 (dd, J=9.0, 5.5 Hz, 1H), 4.67 (dd, J=14.5, 4.3 Hz, 1H), 4.49-4.39 (m, 1H), 4.33 (ddd, J=7.4, 5.5, 4.3 Hz, 1H), 1.34-1.27 (m, 4H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][O:27][CH2:28][C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[CH2:28][O:27][CH3:26])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: COCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (13.9 mg, 43.2%), MS (ISP) m/z=403.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and 2-methoxyacetic acid
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]12[CH2:22][CH2:21][CH2:20][N:11]1[C@@H:12](C(Cl)(Cl)Cl)[O:13][C:14]2=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(Cl)(=O)C>CO>[CH3:12][O:13][C:14]([C@:10]1([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:22][CH2:21][CH2:20][NH:11]1)=[O:15]
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12COCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CO
Product: COC(=O)[C@]1(COCc2ccccc2)CCCN1
Temperature: 0 °C
Yield: 87.8 %

Procedure:
A solution of Intermediate 85b (6.39 g, 17.9 mmol) and sodium methoxide (580 mg, 10.8 mmol) in MeOH (100 mL) was stirred at RT for 18 h. The mixture was cooled to 0° C., then acetyl chloride (28.4 g, 359 mmol) added. This mixture was stirred at reflux for 1 h, then cooled and concentrated in vacuo. The residue was divided, applied to SCX-2 cartridges (3×70 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound as a pale yellow oil (3.92 g, 87%). 1H NMR (400 MHz, CDCl3): 1.62-1.86 (3H, m), 1.07-2.13 (1H, m), 2.48 (1H, br s), 2.93-3.11 (2H, m), 3.69-3.78 (4H, m), 4.53 (1H, d, J 12.9), 4.55 (1H, d, J 12.9), 7.21-7.37 (5H, m).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[SH:33].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:5]2[N:6]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=3)[CH:7]=[C:3]([CH2:2][S:33][C:27]3[C:26]([Cl:25])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:32])[N:4]=2)=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(-n2cc(CCl)nc2-c2ccc(Cl)cc2)cc1
Reactant: Sc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2cc(CSc3c(Cl)cccc3Cl)nc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (Example 159, Step 1) (250 mg, 0.656 mmole) and 2,6-dichlorothiophenol in 5 ml of dimethylformamide (235 mg, 1.31 mmol) was added 226 mg (1.64 mmol) of potassium carbonate. The resulting mixture was stirred rapidly at room temperature for two days. The mixture was partitioned between ethyl acetate and water and the aqueous layer was further extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using 50% ethyl acetate in hexane gave the title compound, 282 mg, as a pure white solid: mp (DSC) 202° C. Anal. Calc'd. for C23H17Cl3N2O2S2 (MW 523.89): C, 52.73; H, 3.27; N, 5.35. Found: C, 52.55; H, 2.98; N, 5.19.
Reaction SMILES: [CH3:1][C@@:2]12[C:11]3[C:12]([S:18]([C:21]4[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][C:24]([CH:30]([CH3:32])[CH3:31])=[CH:23][C:22]=4[CH:33]([CH3:35])[CH3:34])(=[O:20])=[O:19])=[CH:13][CH:14]=[C:15]4[NH:16][CH:17]=[C:9]([C:10]=34)[CH2:8][C@H:3]1[NH:4][CH2:5][CH2:6][O:7]2.C(=O)([O-])[O-].[Na+].[Na+].[Cl:42][CH2:43][C:44](Cl)=[O:45]>C(OCC)(=O)C>[Cl:42][CH2:43][C:44]([N:4]1[C@@H:3]2[CH2:8][C:9]3[C:10]4[C:15]([NH:16][CH:17]=3)=[CH:14][CH:13]=[C:12]([S:18]([C:21]3[C:22]([CH:33]([CH3:35])[CH3:34])=[CH:23][C:24]([CH:30]([CH3:32])[CH3:31])=[CH:25][C:26]=3[CH:27]([CH3:29])[CH3:28])(=[O:20])=[O:19])[C:11]=4[C@@:2]2([CH3:1])[O:7][CH2:6][CH2:5]1)=[O:45]
Reactant: O=C(Cl)CCl
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)c2ccc3[nH]cc4c3c2[C@@]2(C)OCCN[C@@H]2C4)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)c2ccc3[nH]cc4c3c2[C@@]2(C)OCCN(C(=O)CCl)[C@@H]2C4)c(C(C)C)c1
Yield: 89 %

Procedure:
To a solution of trans-4,6,6a,8,9,10a-hexahydro-10a-methyl-1-(2,4,6-triisopropylphenylsulfonyl)-7H-indolo[3,4-gh][1.4]benzoxazine (106 mg, 0.21 mmol) in ethyl acetate (10 ml) was added a saturated aqueous solution of sodium carbonate (2 ml). To the mixture was added, while stirring vigorously, chloroacetyl chloride (1.2 equivalent). After completion of the reaction, the organic layer was separated, washed with an aqueous saline solution and dried (anhydrous Na2SO4). The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatography, eluting with n-hexane-ethyl acetate (4:1) to afford 109 mg (89%) of the title compound as an amorphous crystalline product.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2([C:24]([F:27])([F:26])[F:25])[O:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][C:15]([O:17]COCCOC)=[CH:16][C:7]2=3)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[CH:1]1([C:4]#[C:5][C:6]2([C:24]([F:26])([F:27])[F:25])[O:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:7]2=3)[CH2:3][CH2:2]1
Reactant: COCCOCOc1ccc2c(c1)C(C#CC1CC1)(C(F)(F)F)OC(=O)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2ccc(O)cc2C(C#CC2CC2)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To 150 mg (0.39 mmol) of 8 was added 2 mL of trifluoroacetic acid. The mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (2 mm silica gel plate, E. Merck) using 5% methanol in dichloromethane to give 110 mg (0.37 mmol, 96%) of 9 as a colorless oil [LC-MS; M+H 298.1].
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:28][CH:29]([F:31])[F:30])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])[C:10]([CH2:17][CH3:18])=[N:11]2.CO.O.[OH-].[Na+]>C(O)(=O)C>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[CH2:19][C:9]1[C:10]([CH2:17][CH3:18])=[N:11][C:12]2[C:7]([C:8]=1[O:28][CH:29]([F:30])[F:31])=[C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])[CH:15]=[CH:14][C:13]=2[F:16]
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(Cl)cc1Cl

Procedure:
A solution of [3-(2,4-dichlorobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.17 g), methanol (6 mL), water (0.3 mL) and 5.0 M aqueous sodium hydroxide solution (0.15 mL) was stirred at room temperature for 1 hour. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the solvent removed under reduced pressure. The residue was diluted with water and the solid collected by filtration. Purification by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (1:0 to 3:1 by volume) gave title compound as a white solid, 0.030 g.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]1[S:26][CH:25]=[C:24]([C:27]#[N:28])[C:23]=1[CH3:29].[Br:30]C(Br)(Br)Br>O1CCCC1>[Br:30][CH2:21][C:22]1[S:26][CH:25]=[C:24]([C:27]#[N:28])[C:23]=1[CH3:29]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1c(C#N)csc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(C#N)csc1CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 g (115 mmol) of triphenylphosphine were added at 5° C. to a solution of 16 g (104 mmol) of 5-hydroxymethyl-4-methylthiophene-3-carbonitrile in 300 ml of tetrahydrofuran. Then, a solution of 38 g (115 mmol) of tetrabromomethane in 100 ml of tetrahydrofuran was added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated on a rotary evaporator under a water pump vacuum and the residue was purified by column chromatography (eluant petroleum ether:dichloromethane 1:1). This gave 17 g (76%) of the title compound as yellow oil. 1H NMR (270 MHz, DMSO-d6): δ=2.25 (s, 3H), 5.0 (s, 2H), 8.5 (s, 1H).