Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[O:10])[S:6][CH:7]=1.[O:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36].[H-].[Na+].CCOC(C)=O>CN(C=O)C>[CH3:30][O:29][C:22]1[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=1[CH2:20][N:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:33]2[CH2:34][CH2:35][O:31][C:32]2=[O:36])[N:4]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:10]
Reactant: COc1ccc(CN(C(=O)NCc2cccc(F)c2)c2nc(CCl)cs2)c(OC)c1
Reactant: O=C1NCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(C(=O)NCc2cccc(F)c2)c2nc(CN3CCOC3=O)cs2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Chloromethyl-thiazol-2-yl)-1-(2,4-dimethoxy-benzyl)-3-(3-fluoro-benzyl)-urea (Intermediate 21, 0.3 mmol) was taken up in DMF (2 ml). A solution of the oxazolidin-2-one (or sultam) (1 eq.) with NaH (1 eq.) in DMF (2 ml) was added. The reaction was allowed to stir at room temperature for 2 hours. An aqueous workup with EtOAc was performed. Purified by column chromatography using a gradient of 0-100% EtOAc/hexanes to give 1-(2,4-dimethoxybenzyl)-3-(3-fluorobenzyl)-1-(4-((2-oxooxazolidin-3-yl)methyl)thiazol-2-yl)urea.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:13][CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>C(#N)C>[CH2:11]([O:10][C:1](=[O:9])[CH:2]([NH:13][CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:12]
Reactant: CCOC(=O)/C=C/C(=O)OCC
Reactant: NCc1cccc2ccccc12
Solvent: CC#N
Product: CCOC(=O)CC(NCc1cccc2ccccc12)C(=O)OCC
Yield: 73 %

Procedure:
3.12 ml(19.0 mmol) of diethyl fumarate and 3.0 g(19 mmol) of 1-aminomethyl naphthalene were added to acetonitrile, and then the solution was refluxed for 12 hours. Acetonitrile was removed under reduced pressure and column chromatography was performed using a mixed solution of hexane and ethyl acetate(3:1) as an eluent to obtain 4.57 g of the title compound(Yield 73%, MW 329).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].CN(C)C=O.Br[CH2:29][CH:30]1[CH2:32][CH2:31]1>O>[CH:30]1([CH2:29][N:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]4[N:6]([C:2]([CH3:1])=[N:3][N:4]=4)[N:7]=3)[CH:12]=2)[C:18](=[O:20])[CH3:19])[CH2:32][CH2:31]1
Reactant: BrCC1CC1
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(CC1CC1)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
A mixture of 3.0% of N-[3-(3-methyl-1,2,4-triazolo [4,3-b]pyridazin-6-yl)phenyl]acetamide, 0.6 g of sodium hydride (50% in oil) and 250 ml of dimethylformamide was stirred under argon for 1 hour, then 1.2 ml of (bromomethyl) cyclopropane was added. This mixture was stirred overnight, then poured into 200 ml of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and evaporated. The residue was chromatographed on a silica gel column, eluting with dichloromethane:methanol (95:5). The active fractions were combined, evaporated and the solid recrystallized from ethyl acetate-hexane, giving 1.5 g of the desired product as pink crystals, mp 118°-121° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]4)=[C:20]([O:30][CH3:31])[CH:19]=3)[S:16][C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:32]>C(Cl)Cl.C(OCC)C>[ClH:32].[ClH:32].[ClH:32].[CH3:31][O:30][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[S:16][C:10]3[CH2:9][NH:8][CH2:13][CH2:12][C:11]=3[N:14]=2)[CH:23]=[CH:22][C:21]=1[N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]1
Reactant: COc1cc(Nc2nc3c(s2)CN(C(=O)OC(C)(C)C)CC3)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(Nc2nc3c(s2)CNCC3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
1347 mg (3.05 mmol) 2-[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester was suspended in methylene chloride (30.5 ml) and 2M HCl in diethyl ether (15.3 ml) was added at room temperature. Initially a clear solution was obtained and then a solid precipitated. The reaction was stirred at room temperature over night. The reaction was diluted with diethyl ether, stirred for 15 minutes and the solid was filtered off, washed with diethyl ether and dried to yield 1370 mg (100%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine trihydrochloride as a light yellow solid. MS ISP (m/e): 342.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.91 (s, 1H), 9.68 (br, 2H), 9.31 (s, 1H), 7.66 (s, 2H), 7.48 (d, 1H), 7.45 (d, 1H), 4.22 (br s, 2H), 3.84 (s, 3H), 3.38 (m, 2H), 2.88 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[O-]CC.[Na+].[Na]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]#[N:10])[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=O)C(C#N)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A mixture of 45.3 g. (0.31 mol.) of p-chlorophenylacetonitrile and 107 g. (0.72 mol., 99 ml.) of diethyl oxalate in an alcoholic sodium ethoxide solution [prepared by dissolving 7.13 g. (0.31 g.-atom) of sodium in 120 ml. of absolute ethanol] was refluxed with stirring for 2 hours. The cooled reaction mixture was diluted with 700 ml. of water, acidified with acetic acid and cooled to ice bath temperature. The resulting solid was collected and recrystallized from aqueous methanol to give ethyl 3-(p-chlorophenyl)-3-cyanopyruvate, m.p. 134°-135°.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([O-:17])=O)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[K+].[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C>[CH:21]1([NH:27][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([CH2:10][N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[CH:2]3)=[CH:19][CH:18]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCCC1
Reactant: O=C([O-])c1ccc(Cn2cnc3ccccc32)cc1
Agent: [K+]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)c1ccc(Cn2cnc3ccccc32)cc1
Temperature: -5 °C
Reaction time: 8 h
Yield: 16.1 %

Procedure:
A stirred suspension of crude potassium 4-(1H-benzimidazylmethyl)benzoate (0.49 g, 1.7 mmol) in dry DMF (10 ml) under argon was treated with cyclohexylamine (0.2 g, 2.0 mmol) and triethylamine (0.34 g, 3.4 mmol). The solution was cooled to -5° C. and DPPA (0.53 g, 1.9 mmol) in DMF (10 ml) was added. The solution was allowed to warm to room temperature, stirred overnight and concentrated to give the crude product. Chromatography (silica gel, ethyl acetate) followed by crystallisation from toluene gave N-cyclohexyl 4-(1H-benzimidazylmethyl)benzamide (91 mg, 16%) as a white crystalline solid.
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[NH:26][C:25]4=[O:33])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[O:11])[CH:7]=[N:6][CH:5]=1)=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[N:9]=[C:8]([C:10]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:19][CH2:20][CH:21]([N:24]4[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[NH:26][C:25]4=[O:33])[CH2:22][CH2:23]3)[CH2:16][CH2:17]2)=[O:11])[CH:7]=[N:6][CH:5]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=Nc1cncc(C(=O)N2CCC(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)CC2)n1
Agent: [Pd]
Solvent: CCO
Product: Nc1cncc(C(=O)N2CCC(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)CC2)n1

Procedure:
The crude 1,3-dihydro-1-{1-[1-(6-azido-2-pyrazinecarbonyl)piperidin-4-yl]piperidin-4-yl}-2H-benzimidazol-2-one was hydrogenated under 1 atm. of hydrogen in 20 mL of ethanol over 0.05 g of 5% palladium on carbon. The catalyst was removed by filtration and the filtrate concentrated to dryness under reduced pressure. Preparative thin layer chromatography using 20% methanol/10% conc. NH4OH/70% chloroform gave 35 mg of 1,3-dihydro-1-{1-[1-(6-amino-2-pyrazinecarbonyl)piperidin-4-yl]piperidin-4-yl}-2H-benzimidazol-2-one as a solid: 1H NMR (400 MHz, CDCl3) 8.12 (s, 1H), 8.02 (s, 1H), 7.85 (br s, 1H), 7.19-7.04 (m, 4H), 4.95 (br s, 1H), 4.62 (br s, 1H), 4.2 (br s, 1H), 3.65 (br s, 1H), 3.6-3.2 (m, 4H), 3.15 (m, 2H), 3.03 (m, 1H), 2.82 (m, 1H), 2.45-2.25 (m, 2H), 2.1-1.8 (m, 4H). The dihydrochloride salt was precipitated from chloroform/methanol: Analysis calculated for C21H27N7O2.0.45 CHCl3.0.65 NH4Cl: C: 46.25, H: 5.54, N: 18.38 found C: 46.28, H: 5.92, N: 18.48.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1>C(Cl)Cl>[CH2:21]([O:20][C:18]([CH:15]1[CH2:16][CH2:17][C:12](=[O:11])[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)C1CCC(=O)CC1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
To a solution of oxalyl chloride (6 mL, 68.8 mmol) in DCM (100 mL) at −78° C. was added dropwise a solution of DMSO (6.4 mL, 90 mmol) in DCM (20 mL). The mixture was stirred at this temperature for 15 min before the dropwise addition of a solution of ethyl 4-hydroxycyclohexane carboxylate (4.8 mL, 30 mmol) in DCM (20 mL). The mixture was stirred at −78° C. for 3 h before addition of TEA (29.3 mL, 210 mmol) in DCM (20 mL). The mixture was then gradually warmed to rt, washed with a sat. aq. NH4Cl solution and brine, dried over MgSO4 and concentrated. The residue was purified by chromatography over SiO2 (Hex/EA 1:1) to give the title ketone (4.6 g, 90% yield) as a colourless oil.
Reaction SMILES: [C:1](=[NH:23])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][CH:18]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:24]([CH:26]([CH2:31][C:32]1[CH:33]=[N:34][C:35]([O:38][CH3:39])=[N:36][CH:37]=1)[C:27](OC)=O)=[O:25].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:39][O:38][C:35]1[N:34]=[CH:33][C:32]([CH2:31][C:26]2[C:24](=[O:25])[N:23]=[C:1]([O:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]([O:12][C:13]4[CH:14]=[N:15][C:16]([C:19]([F:21])([F:22])[F:20])=[N:17][CH:18]=4)=[CH:10][CH:11]=3)[NH:2][CH:27]=2)=[CH:37][N:36]=1
Reactant: N=C(N)OCCc1ccc(Oc2cnc(C(F)(F)F)nc2)cc1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4cnc(C(F)(F)F)nc4)cc3)nc2=O)cn1
Reaction time: 1 h
Yield: 3 %

Procedure:
The same procedure as E121 from 2-(4-{[2-(trifluoromethyl)-5-pyrimidinyl]oxy}phenyl)ethyl imidocarbamate (60 mg, 0.184 mmol), methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (49.5 mg, 0.221 mmol) and K2CO3 (102 mg, 0.736 mmol) in NMP (1 mL), except that the temperature was 130° C. and the reaction time was 1 h, to afford the title compound (2.8 mg, 5.60 μmol, 3.04% yield). LCMS: rt=1.29 min, [M+H+]=501
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]2[CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(O)=O>ClCCl>[N:14]1([CH2:13][C:12]2[CH:28]=[CH:29][C:9]([C:3]([OH:8])([C:2]([F:1])([F:30])[F:31])[C:4]([F:6])([F:7])[F:5])=[CH:10][CH:11]=2)[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC(c1ccc(CN2CCCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reaction time: 24 h
Yield: 76.8 %

Procedure:
A mixture of tert-butyl 4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-1,4-diazepane-1-carboxylate (15.34 mmol, 7 g), dichloromethane (15 mL) and trifluoroacetic acid (15.00 mL) was stirred for 24 hours. The reaction was purified by SCX chromatography to give the title compound (4.2 g). MS (ESI) m/z 357.1 [M+H]+
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=O)=[CH:9][C:8]=1[CH:25]=[C:26]([Cl:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C=O>ClCCl>[Cl:3][C:14]1[N:13]([C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[C:8]([CH:25]=[C:26]([Cl:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:9]=2)[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[N:15]=1
Reactant: CCOC(=O)C(Cl)=Cc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cl)=Cc1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)ccc1Cl
Reaction time: 2 h

Procedure:
13.8 ml of phosphoryl chloride were added dropwise to 12.6 g of 3-[4-chloro-3-(2-chloro-2-ethoxycarbonylethenyl)-phenyl]-2,4-dioxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine, and stirring was carried out for 2 hours at room temperature. Thereafter, 2.1 ml of dimethylformamide were added and stirring was continued for 15 hours at 110-115° C. The reaction mixture was evaporated down under reduced pressure, the residue was added to 150 ml of ice water and the mixture was extracted with twice 100 ml of dichloromethane. The combined organic phases were washed with water, 10% strength sodium bicarbonate and again with water, dried over sodium sulfate and evaporated down. The oil obtained was subjected to flash chromatography (dichloromethane), and the crystalline solid obtained therefrom was stirred with petroleum ether, removed, washed with a little petroleum ether and dried.
Reaction SMILES: [NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:11]=[C:9]([I:10])[C:8]([O:12][C:13]2[CH:20]=[C:18]([I:19])[C:17]([OH:21])=[C:15]([I:16])[CH:14]=2)=[C:6]([I:7])[CH:5]=1.Cl.[CH3:26]O>>[CH3:26][O:23][C:22](=[O:24])[C@H:2]([CH2:3][C:4]1[CH:5]=[C:6]([I:7])[C:8]([O:12][C:13]2[CH:14]=[C:15]([I:16])[C:17]([OH:21])=[C:18]([I:19])[CH:20]=2)=[C:9]([I:10])[CH:11]=1)[NH2:1]
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1

Procedure:
Thyroxine (20 g) was suspended in dry methanol (500 ml). The suspension was saturated with hydrogen chloride gas, cooled and saturated again. The crystals were collected, washed with methanol and ether, and then dried. The resulting thyroxine methyl ester hydrochloride crystals were added to 500 ml of methanol and an equimolar concentration of concentrated sodium hydroxide was added with stirring. Deionized distilled water (500 ml) was added to this solution. The solution was chilled to recrystallize the thyroxine methyl ester from the solution. The crystals were then collected and air dried.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C@@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:33][CH3:34])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([C@@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:33][CH3:34])=[CH:30][CH:31]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: CC[C@H](NC(=O)OC(C)(C)C)c1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 69.7 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (640 mg, 2.1 mmol) was reacted with (S)-tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (1.13 g, 3.12 mmol) to afford the desired product (680 mg, 71%) as a light brown solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: B(F)(F)F.CCOCC.[BH4-].[Na+].[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]([CH3:32])=[C:25]([CH2:27][CH2:28][C:29](O)=[O:30])[N:26]=2)=[CH:18][CH:17]=1)=[O:15]>O1CCCC1>[OH:30][CH2:29][CH2:28][CH2:27][C:25]1[N:26]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:21][CH:20]=2)[O:23][C:24]=1[CH3:32]
Reactant: COC(=O)c1ccc(-c2nc(CCC(=O)O)c(C)o2)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2nc(CCCO)c(C)o2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Boron trifluoride etherate (4 g) was added dropwise with stiffing to a mixture of sodium borohydride (720 mg, 19.03 mmol, 2.02 equiv) in tetrahydrofuran (35 mL) maintained under nitrogen at 0° C. The resulting solution was warmed to room temperature and stirred for 2 h. The above mixture was cooled to 0° C. then 3-[2-[4-(methoxycarbonyl)-phenyl]-5-methyl-1,3-oxazol-4-yl]propanoic acid (2.72 g, 9.40 mmol, 1.00 equiv) was added in several batches. The reaction mixture was stirring at room temperature overnight and then quenched with 5 mL of methanol and 60 mL of water. The resulting solution was extracted with 50 mL of ethyl acetate. The organic layer was dried over anhydrous calcium chloride and concentrated under vacuum to give 2.2 g (85%) of methyl 4-[4-(3-hydroxypropyl)-5-methyl-1,3-oxazol-2-yl]benzoate as a white solid. LC-MS: (ES, m/z): 276 [M+H]+, 146, 115.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](Cl)=[O:8].[C:10]([O:13][C:14]1[C:23]2[C:18](=[C:19]([NH2:24])[CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:15]=1)(=[O:12])[CH3:11].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[C:10]([O:13][C:14]1[C:23]2[C:18](=[C:19]([NH:24][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:8])[CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=2)[CH:15]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Oc1cc(-c2cccc(C(F)(F)F)c2)nc2c(N)cccc12
Reactant: O=C(Cl)c1cnccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(-c2cccc(C(F)(F)F)c2)nc2c(NC(=O)c3cnccn3)cccc12
Temperature: 40 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
Pyrazine-2-carbonyl chloride 40 (100 mg) was added to a solution of 8-amino-2-(3-(trifluoromethyl)phenyl)quinolin-4-yl acetate 39 (50 mg, 0.145 mmol) and triethylamine (0.20 mL) in dichloromethane (3 mL). The reaction mixture was stirred at 40° C. for 16 h. The reaction mixture was poured into dilute NaHCO3 (10 mL), and extracted with 3×30 mL dichloromethane. The combined organic layers were dried (MgSO4) and the solvent removed in vacuo. The crude residue was purified by MPLC (97:3 dichloromethane:methanol) to give 41 (33 mg, 50% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([O:12][CH3:13])[N:6]=[C:5]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)[N:4]=1.[H][H]>[Ni]>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH2:23][N:14]1[C:5]1[N:6]=[C:7]([O:12][CH3:13])[C:8]([NH2:9])=[C:3]([O:2][CH3:1])[N:4]=1
Reactant: [H][H]
Reactant: COc1nc(N2CCc3ccccc3C2)nc(OC)c1[N+](=O)[O-]
Agent: [Ni]
Product: COc1nc(N2CCc3ccccc3C2)nc(OC)c1N

Procedure:
A suspension of Raney®-Nickel in a methanolic solution of 4b (0.57 g in 50 ml, 1.8 mmol) was shaken under 50 psi of hydrogen atmosphere for 12 hours. The mixture was filtered and the filtrate was concentrated and used for the next step without further purification (0.51 g, 1.78 mmol, 99%).
Reaction SMILES: [I:1]I.[S:3]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[O:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)=[N:4]1>C(#N)C.C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[S:3]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[O:14][C:13](=[O:15])[N:12]([C:16]3[CH:17]=[CH:18][C:19]([I:1])=[CH:20][CH:21]=3)[CH2:11]2)=[N:4]1
Reactant: O=C1O[C@@H](COc2cnsn2)CN1c1ccccc1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C1O[C@@H](COc2cnsn2)CN1c1ccc(I)cc1
Reaction time: 24 h
Yield: 73.4 %

Procedure:
Iodine (0.67 g, 2.64 mmol) was added portionwise to a stirred solution of 5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-phenyloxazolidin-2-one (0.7 g, 2.53 mmol) and silver trifluoroacetate (0.727 g, 3.29 mmol) in acetonitrile (4 ml) and chloroforrn (6 ml). The mixture was stirred for 24 hours in the dark. The mixture was filtered and the filtrate evaporated. The residue was extracted with EtOAc and the extract washed with water, dilute ammonia (0.1 ml of 0.88SG ammonia in 25 ml water), water and brine, dried (Na2SO4) and evaporated to give the title product as a solid (0.749 g, 73%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].Cl.[CH:13](O)=O>>[NH:1]1[C:2]2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][C:10]=2[N:11]=[CH:13]1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: O=CO
Agent: Cl
Product: O=C(O)c1ccc2nc[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3,4-Diaminobenzoic acid (20 g, 0.13 mol) was suspended in formic acid (120 ml) while cooling. After that hydrochloric acid (12 ml) was added. An obtained reaction mass was agitated for 24 hours at a room temperature. Reaction mixture was filtered through fiber glass filter. Then filter cake was dissolved in water (400 ml), pH was adjusted to 2.0 with ammonia solution and reaction mass was agitated overnight. Resulting suspension was filtered, pH of filtrate was adjusted to 3.0 with ammonia solution and reaction mass was agitated for two hours. Precipitate was filtered and dried at ˜100° C. H1NMR (Brucker Avance-300, DMSO-d6, δ, ppm): 7.695 (d, H, CHAr(7)); 7.877 (dd, H, CHAr(6)); 8.25 (d, H, CHAr(4)); 8.44 (s, H, (s, H, CHAr(2)); 12.82 (s, 2H, NH, COOH). Yield was 11.3 g (54%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][C:32](=[O:33])[N:34]([CH3:36])[CH3:35])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)CCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(OC(F)F)ccc21
Reaction time: 15 h

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(dimethylamino)-3-oxopropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (70 mg, 111 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-5% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-[5-difluoromethoxy-1-(2-dimethylcarbamoyl-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide