Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([O:17][CH2:18][CH2:19][O:20][CH3:21])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[CH3:34][N:35]([CH3:46])[C:36](=[O:45])[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([NH2:44])[CH:39]=1>CN(C=O)C.C(Cl)Cl>[CH3:34][N:35]([CH3:46])[C:36]([O:37][C:38]1[CH:39]=[C:40]([NH:44][C:14]([C:11]2([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH:41]=[CH:42][CH:43]=1)=[O:45]
Reactant: COCCOC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CN(C)C(=O)Oc1cccc(N)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COCCOC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of carboxylic acids from step B, pyridine (0.2 mL, 2.48 mmol), and DMF (catalytic, 2 drops) in CH2Cl2 (3.1 mL) was added dropwise oxalyl chloride (60 μL, 0.68 mmol, caution: exothermic). After gas evolution subsided, the reaction was stirred at ambient temperature for 30 minutes. 3-Aminophenyl dimethylcarbamate (112 mg, 0.62 mmol) was added in one portion to this solution, which was stirred for another 30 minutes. The reaction was quenched with saturated aq. NH4Cl, and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. Silica gel chromatography (80% ethyl acetate:hexanes) afforded the title compound as an off-white solid (150 mg). MS (ES+) [M+CH3CN]+=529.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][O:20][CH2:21][CH3:22].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[S:30][CH2:31][CH2:32][C:33](ON2C(=O)CCC2=O)=[O:34])C=CC=CC=1.CO>ClCCl>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][O:20][CH2:21][CH3:22])[N:5]([O:4][CH2:3][CH2:2][NH:1][C:33](=[O:34])[CH2:32][CH2:31][SH:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1OCCN
Reactant: O=C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)ON1C(=O)CCC1=O
Solvent: CO
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1OCCNC(=O)CCS
Temperature: 0 °C
Reaction time: 120 h
Yield: 46.7 %

Procedure:
A solution of 1-(2-aminoethoxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (30 mg, 0.10 mmol) and succinimido 3-(triphenylmethylthio)propanoate (54 mg, 0.12 mmol) in dichloromethane (1 mL) was stirred for 24 hours at room temperature. Methanol (1 mL) was added and stirring was continued for another 5 days. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane (2 mL) and triethylsilane (0.16 mL) and cooled to 0° C. Trifluoroacetic acid (0.4 mL) was added. The solution was stirred for 30 min; then it was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform) to provide 18.2 mg of N-(2-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]oxy}ethyl)-3-mercaptopropanamide as a solid. HRMS (ESI) calcd for C18H24N5O3S+H 390.1600, found 390.1579.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][O:8][C@@H:9]2[C@@H:17]([CH2:18][OH:19])[O:16][C@H:15]3[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]3)[C@H:10]2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:5][CH:4]=1.C1C(=O)N(Br)C(=O)C1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].ClCCl.O.CC1(C)N([O])C(C)(C)CCC1>[CH3:22][N:20]([CH3:21])[C:13]1[S:14][C@H:15]2[O:16][C@H:17]([CH:18]=[O:19])[C@@H:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:34][CH:33]=3)[C@H:10]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C@H:11]2[N:12]=1
Reactant: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C)S[C@H]3O[C@H](CO)[C@H]2OCc2ccc(OC)cc2)cc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C)S[C@H]3O[C@H](C=O)[C@H]2OCc2ccc(OC)cc2)cc1
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a mixture of ((3aR,5R,6S,7R,7aR)-6,7-bis(4-methoxybenzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methanol (500 mg, 1.0 mmol), TBAB (16.5 mg, 0.05 mmol), KHCO3 (461 mg, 4.6 mmol) and TEMPO (8 mg, 0.05 mmol) in dichloromethane (25 mL) and H2O (5 mL) was added NBS (201 mg, 1.13 mmol) at 15° C. After stirred for 30 min, the reaction mixture was quenched by saturated Na2SO3 (5 mL). The organic layer was dried over anhydrous magnesium sulfate and condensed to provide a residue, which was purified by silica gel column, eluted with 20-30% ethyl acetate in dichloromethane to give compound 11 as a yellow syrup (320 mg, 75% pure). (ES, m/z): [M+H]+ 487.0. 1H NMR (300 MHz, CDCl3) δ 9.61 (s, 1H), 7.22-7.34 (m, 4H), 6.83-6.92 (m, 4H), 6.11-6.13 (d, J=6.0 Hz, 1H), 4.17-4.67 (m, 8H), 3.83 (s, 6H), 3.00-3.04 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]([NH2:26])[CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:4]C1C=C2C(=CC=1)N(C1C=CC=CN=1)N=C2.[Cl:27][C:28]1[N:33]=[N:32][C:31]([N:34]2[C:42]3[C:37](=[CH:38][C:39](I)=[CH:40][CH:41]=3)[CH:36]=[N:35]2)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[N:33]=[N:32][C:31]([N:34]2[C:42]3[C:37](=[CH:38][C:39]([O:4][CH:3]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:2]([NH2:26])[CH3:1])=[CH:40][CH:41]=3)[CH:36]=[N:35]2)=[CH:30][CH:29]=1
Reactant: CC(N)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccccc1
Reactant: Clc1ccc(-n2ncc3cc(I)ccc32)nn1
Product: CC(N)C(Oc1ccc2c(cnn2-c2ccc(Cl)nn2)c1)c1ccccc1

Procedure:
Prepared as described for 118a using 1-(6-Chloro-pyridazin-3-yl)-5-iodo-1H-indazole (119b). Yield 35 mg (7%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[Br:19][C:20]1[C:21]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:22]([CH2:34]Br)[N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:24]=1[Br:25].CO>CN(C=O)C.ClCCl>[Br:19][C:20]1[C:21]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:22]([CH2:34][N:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[N:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C:24]=1[Br:25]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)c1c(Br)c(Br)n(Cc2ccc(F)cc2)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1c(Br)c(Br)n(Cc2ccc(F)cc2)c1CN(CC(=O)OC)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a stirring solution of methyl N-[(4-methylphenyl)sulfonyl]glycinate (51.75 g, 0.213 mol, prepared by the method of: Ginzel, K. D.; Brungs, P.; Steckhan, E. Tetrahedron 1989, 45, 1691-1701) in anhydrous DMF (0.5 L) was added NaH (60% in oil, 8.59 g, 0.215 mol) in one portion. The mixture was allowed to stir for 30 minutes (warms and returns to room temperature) at which time a solution ethyl 4,5-dibromo-2-(bromomethyl)-1-(4-fluorobenzyl)-1H-pyrrole-3-carboxylate (105.92 g, 0.213 mol) in anhydrous DMF (0.5 L) was added over 1 hour. The mixture was allowed to stir at room temperature for 16 hours, then the DMF was removed in vacuo (approx 2 Torr, 40° C. water bath) and the oily residue was dissolved in dichloromethane (0.75 L), the solution was washed with saturated aq. NH4Cl (0.5 L), brine (0.5 L), and dried (Na2SO4). Filtration and concentration in vacuo provided the crude alkylated material as a viscous reddish oil. The crude material was heated in the presence of MeOH (0.75 L) until the MeOH was boiling, then dichloromethane was added slowly until solution was achieved. The red solution was cooled to room temperature (see off-white crystals) and the crystallization was completed by cooling in a refrigerator (4° C.) for 16 hours. The ivory solid was isolated by filtration, the solid was rinsed with diethyl ether:hexanes (0.5 L, 10:90 v/v) and the solid was dried in a vacuum oven (approx. 20 Torr, 50° C.) overnight to furnish ethyl 4,5-dibromo-1-(4-fluorobenzyl)-2-({(2-methoxy-2-oxoethyl)[(4-methylphenyl) sulfonyl]amino}methyl)-1H-pyrrole-3-carboxylate (108.2 g, 77%) as a free flowing, fine, ivory solid. TLC (Merck, hexanes:EtOAc 75:25, UV-+, cerium molybdate-+−purple): Rf=0.38; LCMS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95 H2O (+0.1% HOAc):CH3CN—5 minutes, ESI, +mode): RT-4.436 min, m/e=680.8 (55), 681.8 (18), 682.9 (base), 683.9 (30), 684.8 (62), 686.8 (10)—M+Na; 1H-NMR (300 MHz, CDCl3): δ=1.24 (t, J=7.16 Hz, 3H), 2.14 (s, 3H), 3.49 (s, 3H), 3.89 (s, 2H), 4.19 (q, J=7.16 Hz, 2H), 4.55 (s, 2H), 7.02 (d, J=2.45 Hz, 2H), 7.04 (s, 2H), 7.28 (d, J=8.19 Hz, 2H), 7.59 (d, J=8.19 Hz, 2H)
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([Cl:19])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(Oc2ccccc2)c1

Procedure:
Added portionwise 25 g (0.12 mole) of 3-phenoxybenzoic acid, to 125 ml of thionyl chloride, then heated at reflux for 2 hrs. The solution was distilled to remove the excess thionyl chloride. Added 200 ml of AR toluene and evaporated in vacuo to give 23 g of red liquid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:9]([C:10]([N:31]2[CH2:30][CH:29]=[C:28]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:20])([F:34])[F:35])=[CH:23][CH:24]=3)[CH2:33][CH2:32]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Reactant: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Product: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)N2CC=C(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
According to the procedure described for the synthesis of example 4, step f, the title compound has been synthesized from 5-Methanesulfonyl-2-morpholin-4-yl-benzoic acid and 4-(4-Trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine. MS (m/e): 495.4 (MH+, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13]O)=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>>[Cl:18][CH2:13][C:12]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][O:10][C:11]=1[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1CO
Product: Cc1onc(-c2ccc(Cl)cc2)c1CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 3-(4-chlorophenyl)-5-methyl-4-isoxazolylmethanol (2.23 g) and thionyl chloride (5.0 ml) was stirred at 0° C. for 30 min. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were filtrated to give 4-chloromethyl-3-(4-chlorophenyl)-5-methylisoxazole (2.20 g, yield 91%). The crystals were recrystallized from diisopropyl ether. melting point: 91–92° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1)[CH2:2][CH2:3][CH3:4].C(OO)(=[O:18])C.O>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]2[CH:12]([O:18]2)[CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOCC1C=CCCC1
Reactant: CC(=O)OO
Solvent: ClCCl
Solvent: O
Product: CCCCOCCOCC1CCC2OC2C1

Procedure:
A 500 mL round bottom flask equipped with a stirrer bar was charged with 13.78 g (0.065 mol) 3-butoxyethoxymethylcyclohexene, and 100 niL of methylene chloride. Peracetic acid (15.5 g, 35 wt. % in acetic acid; 0.065 mol) in methylene chloride (80 mL) was added dropwise to above mixture over 30 min. in an ice bath. After the above mixture was reacted at room temperature overnight, 250 mL of water was added to above reaction mixture, the water layer was extracted with methylene chloride (2×150 mL), the organic layer was combined, and washed with saturated sodium carbonate solution (2×150 mL), then with water (2×150 mL) and dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][C:5](=[O:10])C(Cl)(Cl)Cl.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH:31]=1)[C:17]([NH:19][CH2:20][CH2:21][C:22]1[S:23][C:24]([S:27](=[O:30])(=[O:29])[NH2:28])=[CH:25][CH:26]=1)=[O:18]>CS(C)=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH:31]=1)[C:17]([NH:19][CH2:20][CH2:21][C:22]1[S:23][C:24]([S:27]([NH:28][C:5]([NH:4][CH3:3])=[O:10])(=[O:29])=[O:30])=[CH:25][CH:26]=1)=[O:18]
Reactant: CNC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(N)(=O)=O)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CNC(=O)NS(=O)(=O)c1ccc(CCNC(=O)c2cc(Cl)ccc2OC)s1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
120 mg of powdered NaOH and 141 mg of N-methyltrichloro-acetamide (0.8 mmol) were added to 299 mg (0.8 mmol) of 2-[2-(5-chloro-2-methoxybenzoylamino)ethyl]-5-sulfamoyl-thiophene in 9 ml of DMSO. The mixture was stir 65° C. for 1.5 hours. After cooling, it was stirred into ice water of pH 2. The precipitate was filtered off with suction and taken up in CH2Cl2, and the solution was washed with water and dried using MgSO4. After evaporating the solvent, a yellow-brown crude product remained which, after treatment with CH2Cl2 /5% methanol, crystallized at -4° C.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])[CH2:6][CH2:5]1)#[N:2].N>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])[CH2:6][CH2:5]1
Reactant: CCCCOC(=O)N1CCN(CC#N)CC1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCCCOC(=O)N1CCN(CCN)CC1
Yield: 98.2 %

Procedure:
A solution of 1-cyanomethyl-4-butoxycarbonylpiperazine (12 g) in ethanol (100 mL) saturated with ammonia, was hydrogenated over Raney Ni (5 g) at 1000 psi and 80° C. for 8 hours. The resulting mixture was filtered and evaporated to give 1-(2-aminoethyl)-4-butoxycarbonylpiperazine as a solid (12 g).
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[C:10](OC(=O)C)(=[O:12])[CH3:11].C([O-])(O)=O.[Na+].CCOCC>C(#N)C.C1COCC1.[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[C:10]([O:9][C:3]1([C:1]#[CH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)(=[O:12])[CH3:11]
Reactant: C#CC1(O)CCCCC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOCC
Product: C#CC1(OC(C)=O)CCCCC1
Reaction time: 2 h
Yield: 110.7 %

Procedure:
To 3.1 g (25 mmol) 1-ethynyl-1-cyclohexanol in 25 ml acetonitrile were added 7.1 ml (75 mmol, 3 eq) acetic anhydride at −20° C. 12.3 mg (0.03 mmol) scandiumtriflate in 300 μl THF were added and the solution was stirred for 2 h. Additional 12.3 mg (0.03 mmol) scandiumtriflate in 300 μl THF were added and stirring was continued for 30 min. A saturated aqueous solution of NaHCO3 and ether were added. The layers were separated and the inorganic one was extracted with ether. The combined organic phases were washed with brine and dried over Na2SO4. Evaporation yielded 4.6 g crude 1-ethynylcyclohexyl acetate as colorless oil, MS: 166 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:16])[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][C:4]=1[NH:17][C:18]([NH2:20])=[S:19].BrBr>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]2[N:17]=[C:18]([NH2:20])[S:19][C:5]=2[C:6]([N:9]([CH3:16])[CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N(C)C2CCOCC2)cc1NC(N)=S
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(N(C)C2CCOCC2)c2sc(N)nc12

Procedure:
0.28 g (0.95 mmol) {2-methoxy-5-[methyl-(tetrahydro-pyran-4-yl)-amino]-phenyl}-thiourea were dissolved in 15 ml chloroform and 0.05 ml (1.0 mmol) Br2 were added slowly at room temperature. After 24 hrs of reflux the mixture was concentrated in vacuo and the residue suspended in water. Sodium bicarbonate solution was added until the pH was 10, and the crystals were collected by filtration. These were subjected to column chromatography (ethyl acetate) to afford 0.41 g (41 (%o) of 4-methoxy-N7-methyl-N7-(tetrahydro-pyran-4-yl)-benzothiazole-2,7-diamine as an off-white solid. ES-MS m/e (%): 294 (M+H+, 100).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:14][S:15]SC.N(OC(C)(C)C)=O.O>C(Cl)(Cl)Cl>[CH3:14][S:15][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Nc1cc(CO)cc(C(F)(F)F)c1
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CSc1cc(CO)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3-amino-5-(trifluoromethyl)phenyl]methanol (319 mg, 1.67 mmol) (Step A, Example 24) in CHCl3 (5 mL) was added dimethyl disulfide (296 μL, 3.34 mmol). Next, t-butyl nitrite (285 μL, 2.4 mmol) was added dropwise by syringe. The reaction was stirred at room temperature for two hours and then poured into H2O (15 mL). The mixture was extracted with EtOAc (50 mL), washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 0% to 50% EtOAc/hexanes afforded [3-(methylthio)-5-(trifluoromethyl)phenyl]-methanol. The [3-(methylthio)-5-(trifluoromethyl)phenyl]methanol was contaminated with minor impurities that were removed after the next step. Rf=0.53 (50% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 7.63 (s, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 4.71 (s, 2H), 2.51 (s, 3H).
Reaction SMILES: [C:1]([O:9][CH:10]([CH2:52][OH:53])[CH2:11][O:12][C@H:13]1[O:42][C@H:41]([CH2:43][O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:14]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54]([O-:57])(O)=O.[Na+]>CCOCC>[C:1]([O:9][CH:10]([CH2:52][O:53][C@H:13]1[O:42][C@H:41]([CH2:43][O:57][CH2:54][C:7]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:14]1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:11][O:12][C@H:13]1[O:42][C@H:41]([CH2:43][O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@H:32]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@H:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:14]1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC(CO)CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)c1ccccc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(OC(CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
Trimethylsilyl trifluomethanesulfonate (35 μL, 0.19 mmol) was added dropwise to a stirred solution of the glycerol 39 (376 mg, 0.523 mmol) and O-(2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl)trichloroacetimidate (385 mg, 0.562 mmol) in dry ether (20 mL) under argon. After 90 min. solid NaHCO3 (100 mg) was added and the mixture stirred for a further 10 min. The reaction mixture was partitioned between ether (50 mL) and sat. NaHCO3 (40 mL). The aqueous phase was re-extracted with ether (50 mL) and the combined ethereal extract washed with 2M HCl (50 mL), sat. NaHCO3 (40 mL) and H2O (60 mL). After drying (MgSO4) and filtration the solvent was removed at reduced pressure to give the crude product that was purified by column chromatography on silica gel. Gradient elution with ethyl acetate/petroleum ether (10:90→20:80) afforded the title compound 41 (278 mg, 0.224 mmol, 61%) as a thin film; [α]D20 +64.2 (c 1.30, ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.05-7.99 (m, 2H), 7.50-7.42 (m, 1H), 7.35-7.10 (m, 42H), 5.57-5.45 (m, 1H), 4.95-4.82 (m, 4H), 4.79-4.30 (m, 15H), 4.00-3.72 (m, 11H), 3.55-3.38 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 166.3, 139.2, 139.1, 139.0, 138.5, 133.4, 130.6, 130.2, 128.7, 128.65, 128.6, 128.1, 127.8, 98.7 (1JCH 168 Hz), 98.3 (1JCH 168 Hz), 79.3, 79.2, 76.9, 75.6, 75.2, 73.8, 73.8, 73.5, 73.4, 72.9, 70.0, 69.3, 69.2, 67.3, 66.7; HRMS-ESI (+ve) (Found: m/z 1258.5888 (MNH4+). C70H84NO14 requires m/z 1258.886).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:11][CH2:12][CH2:13][S:14]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])(=[O:10])=[O:9].[F:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[C:39]1[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=1>>[CH:17]1([S:14]([CH2:13][CH2:12][CH2:11][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:28]2[CH:27]=[CH:26][C:25]([C:39]3[CH:44]=[N:43][C:42]([NH2:45])=[N:41][CH:40]=3)=[C:24]([F:23])[CH:29]=2)(=[O:10])=[O:9])(=[O:16])=[O:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=S(=O)(CCCS(=O)(=O)C1CCCCC1)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)CCCS(=O)(=O)C3CCCCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 1-bromo-2-((3-(cyclohexylsulfonyl)propyl)sulfonyl)benzene and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C25H28FN3O4S2, 517.15; m/z found, 518.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.59-8.51 (d, J=1.4, 2H), 8.20-8.14 (dd, J=8.0, 1.3, 1H), 7.82-7.76 (m, 1H), 7.72-7.67 (m, 1H), 7.59-7.52 (m, 1H), 7.51-7.46 (dd, J=7.7, 1.3, 1H), 7.38-7.31 (m, 2H), 3.16-3.08 (t, J=7.5, 2H), 3.08-3.01 (t, J=7.3, 2H), 2.94-2.82 (m, 1H), 2.07-1.97 (m, 4H), 1.91-1.80 (m, 2H), 1.79-1.62 (d, J=13.0, 1H), 1.48-1.35 (m, 2H), 1.35-1.25 (m, 2H), 1.24-1.12 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:20]([NH2:22])=[O:21])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.[CH3:25][C:26]1[C:31]([C:32](O)=[O:33])=[CH:30][N:29]=[C:28]([Cl:35])[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[Cl:35][C:28]1[N:29]=[CH:30][C:31]([C:32]([NH:1][C:2]2[CH:24]=[CH:23][C:5]3[CH2:6][CH2:7][C:8]4[C:9]([C:20]([NH2:22])=[O:21])=[N:10][N:11]([C:13]5[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=5)[C:12]=4[C:4]=3[CH:3]=2)=[O:33])=[C:26]([CH3:25])[CH:27]=1
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(N)cc1-2
Reactant: Cc1cc(Cl)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ncc1C(=O)Nc1ccc2c(c1)-c1c(c(C(N)=O)nn1-c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of example 244 (3.872 mmoles), 4-methyl-6-chloronicotinic acid from step 2 (5.828 mmoles), and HATU (5.844 mmoles) were dissolved in 20 mL DMF followed by the addition of 1.9 mL triethylamine. The mixture was stirred at room temperature overnight. The solvent was then stripped and the residue suspended in water, filtered, and washed with water. The solid was recrystallized from acetonitrile, then redissolved in acetonitrile, decolorized with decolorizing carbon, and dried over anhydrous MgSO4. The solvent was then stripped down to a solid. Mp: 280-284° C. 1H NMR (d6-DMSO, 400 MHz): δ 2.28 (s, 3H); 2.84-2.98 (m, 4H); 7.25-7.44 (m, 6H); 7.49 (s, 1H); 7.51-7.62 (m, 3H); 8.35 (s, 1H); 10.31 (s, 1H). 13C NMR (DMSO, 100 MHz): δ 19.13, 20.35, 29.67, 115.01, 117.07, 117.30, 120.08, 121.34, 126.19, 126.60, 128.72, 128.81, 129.58, 132.80, 133.42, 136.81, 136.84, 137.64, 139.71, 143.19, 148.42, 149.96, 151.59, 161.44, 163.88, 164.47, 164.78. M+1=476.