Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:3]1.Cl.[NH2:23][OH:24]>N1C=CC=CC=1>[O:1]=[C:2]1[CH2:7][CH2:6][C:5](=[N:23][OH:24])[CH:4]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:3]1
Reactant: O=C1CCC(=O)C(C(c2ccccc2)c2ccccc2)N1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(=NO)C(C(c2ccccc2)c2ccccc2)N1
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
To a stirred solution of 2,5-dioxo-6-benzhydrylpiperidine (15.35 gm, 55 mmole) in pyridine (150 ml) was added hydroxylamine hydrochloride (10.63 gm, 165 mmole) and the reaction mixture was stirred for 15 min. The reaction mixture was concentrated under vacuum, and the contents were poured into 1N HCl (250 ml). The aqueous phase was extracted with methylene chloride (2×300 ml) and dried (anhyd. magnesium sulfate). The methylene chloride was removed under vacuum to afford 2-oxo-5-oximino-6-benzhydrylpiperidine (10.62 gms, 65%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([N+:16]([O-])=O)[CH:5]=1)[CH3:2].[Cl-].[NH4+].O>[Fe].CO>[NH2:16][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:13]([O:14][CH3:15])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOc1cc([N+](=O)[O-])c(C(=O)OC)cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCOc1cc(N)c(C(=O)OC)cc1OC
Yield: 82.7 %

Procedure:
A mixture of 24.110 g (94.5 mmol) methyl 4-ethoxy-5-methoxy-2-nitrobenzoate, 15.81 g (283 mmol) iron powder, 25.28 g (472 mmol) ammonium chloride, 135 ml water, and 350 ml methanol was heated to reflux under N2. At both 3 and 5.5 hours added the same amount of iron and ammonium chloride. Removed heat at 6.5 hours, added ethyl acetate and saturated sodium bicarbonate, filtered through celite and separated layers. Washed organic layer with saturated sodium bicarbonate, dried with magnesium sulfate, stripped solvent, and dried in vacuo, giving 17.594 g of pink solid: : mass spectrum (electrospray m/e): M+H=226.2.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[N:10]=[CH:9][N:8]=[C:7]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[NH:20][C:19]4=[O:27])[CH2:14][CH2:13]3)[C:6]=2[N:5]=[C:4]([O:28][CH3:29])[C:3]1=[O:30].Cl[C:32]1[C:41]2N=C(OC)C(=O)N(C3CC3)C=2N=CN=1.N1CCC(N2C3C=CC=CC=3NC2=O)CC1.C(N(CC)CC)C>C(O)CCC>[CH:1]1([N:2]2[C:11]3[N:10]=[CH:9][N:8]=[C:7]([N:12]4[CH2:13][CH2:14][CH:15]([N:18]5[C:22]6[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=6[NH:20][C:19]5=[O:27])[CH2:16][CH2:17]4)[C:6]=3[N:5]=[C:4]([O:28][CH3:29])[C:3]2=[O:30])[CH2:41][CH2:32]1
Reactant: COc1nc2c(Cl)ncnc2n(C2CC2)c1=O
Reactant: COc1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n(C)c1=O
Agent: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n(C2CC2)c1=O

Procedure:
8-Cyclopropyl-6-methoxy-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one was prepared in the same manner as 8-methyl-6-methoxy-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one. The reaction of 4-chloro-8-cyclopropyl-6-methoxypteridin-7(8H)-one (0.59 g, 2.33 mmol), 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (0.507 g, 2.33 mmol, triethylamine (0.708 g, 7.99 mmol, 0.98 mL). anhydrous n-butanol (8 mL) at 80° C. for 16 hours gave rise to 0.856 g of 8-cyclopropyl-6-methoxy-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one as a light brown solid, which was used without any further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]=O.[C:9](#[N:13])[CH2:10][C:11]#[N:12]>C(O)C.N1CCCCC1>[NH2:13][C:9]1[N:1]=[C:2]2[S:3][CH:4]=[CH:5][C:6]2=[CH:7][C:10]=1[C:11]#[N:12]
Reactant: Nc1sccc1C=O
Reactant: N#CCC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1cc2ccsc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
2-Amino-thiophene-3-carbaldehyde described in Preparation Example T-4 (38 mg, 0.30 mmol) and malononitrile (20 mg, 0.30 mmol) were dissolved in ethanol (1 mL) to which piperidine (several drops) had been added, and the solution was stirred for 1 hour under reflux. The reaction solution was cooled to room temperature, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=10:1), and the title compound (50 mg, 0.29 mmol, 96%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:23])[N:19]([CH2:21][CH3:22])[CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:25])[CH:3]=1.[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>>[CH3:36][O:35][C:33]([C:32]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[C:9]([C:15]3[CH:16]=[CH:17][C:18](=[O:23])[N:19]([CH2:21][CH3:22])[CH:20]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:25])[CH:3]=2)=[CH:28][C:27]=1[F:26])=[O:34]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CCn1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccc1=O
Product: CCn1cc(C(O)(C(C)c2ccc(-c3ccc(C(=O)OC)c(F)c3)cc2Cl)C(F)(F)F)ccc1=O

Procedure:
In analogy to Example 150, step 2, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-ethyl-1H-pyridin-2-one (Example 183, step 2) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid to give the title compound as a colorless foam. MS (m/e)=512.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:12]>>[CH2:11]([O:13][C:14](=[O:19])[CH:15]([C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:16]([CH3:18])[CH3:17])[CH3:12]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(C)C
Product: CCOC(=O)C(C(=O)c1ccc(Cl)cc1)C(C)C
Yield: 82 %

Procedure:
4-Chlorobenzoyl chloride (2.5 ml) and isovaleric acid ethyl ester (1.5 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 8(a) to obtain the title compound (2.2 g, 82%) as a colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:29]([C:30](=[O:33])[NH:31][CH3:32])=[C:28]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[O:27][C:7]3=[N:8][C:9]=2[N:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19](S(C)(=O)=O)[C:20]([OH:22])=[O:21])[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][CH2:2]1.[O:41]=[C:42](C)[CH2:43]C(OCC)=O.BrCCCCN(C1N=C2OC(C3C=CC(C)=CC=3)=C(C(NC)=O)C2=CC=1C1CC1)S(C)(=O)=O>>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:29]([C:30](=[O:33])[NH:31][CH3:32])=[C:28]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)[O:27][C:7]3=[N:8][C:9]=2[N:10]([CH2:15][CH2:16][CH2:17][CH2:18]/[C:19](=[C:42](/[OH:41])\[CH3:43])/[C:20]([OH:22])=[O:21])[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCC(C(=O)O)S(C)(=O)=O)S(C)(=O)=O)c(C3CC3)cc12
Reactant: CCOC(=O)CC(C)=O
Agent: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCBr)S(C)(=O)=O)c(C3CC3)cc12
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCC/C(C(=O)O)=C(\C)O)S(C)(=O)=O)c(C3CC3)cc12

Procedure:
Prepared similarly to Example 46 6-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(p-tolyl)furo[2,3-b]pyridin-6-yl)methylsulfonamido)-2-(methylsulfonyl)hexanoic acid, by using ethyl 3-oxobutanoate in the alkylation with 6-(N-(4-bromobutyl)methylsulfonamido)-5-cyclopropyl-N-methyl-2-(p-tolyl)furo[2,3-b]pyridine-3-carboxamide, followed by hydrolysis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([CH:20]=[CH:21][N:22]=3)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:23]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([I:23])=[CH:21][N:22]=3)[N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3nccn3n2)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3ncc(I)n3n2)CC1

Procedure:
A solution of 4-imidazo[1,2-b]pyridazin-6-yl-piperazine-1-carboxylic acid tert-butyl ester (3.6 g, 11.8 mmol) and N-iodosuccinimide [516-12-1] (3.1 g, 13.1 mmol) in DMF (120 mL) was stirred under N2 blanket at ambient temperature for 2 h then partitioned between 5% (w/v) aqueous sodium metabisulfite and ethyl acetate. The organic phase was washed with brine, dried (CaSO4), evaporated, and crystallized from ethyl acetate/heptane to provide a white crystalline powder, mp. 203-204° C. (dec.). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 9H) 3.45-3.51 (m, 4H) 3.51-3.58 (m, 4H) 7.19 (d, J=9.92 Hz, 1H) 7.61 (s, 1H) 7.85 (d, J=9.92 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 27.89, 45.06, 70.52, 78.95, 110.55, 125.66, 137.28, 137.71, 153.73, 154.88. LRMS (ESI) m/z 430.0 (M+H)]+, calc'd for C15H20IN5O2: 429.26.
Reaction SMILES: [CH2:1]([N:8]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:9][CH2:10][N:11]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](Cl)=[CH:21][NH:22]2)[C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)[OH:35].O>C(O)(=O)C>[CH2:1]([N:8]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:9][CH2:10][N:11]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][C:21](=[O:35])[NH:22]2)[C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N(CCN(C(=O)C(F)(F)F)c1cccc2[nH]cc(Cl)c12)Cc1ccccc1)C(F)(F)F
Reactant: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2c(cccc2N(CCN(Cc2ccccc2)C(=O)C(F)(F)F)C(=O)C(F)(F)F)N1
Temperature: 77.5 °C
Yield: 23 %

Procedure:
To a solution of N-[2-(benzyl-trifluoroacetyl-amino)-ethyl]-2,2,2-trifluoro-N-(3-chloro-1H-indol-4-yl)acetamide (1.4 g, 2.85 mmol) in acetic acid (18 mL) was added a mixture of 85% phosphoric acid (10 mL) and water (3 mL). The reaction was heated at 75-80° C. for 16 hours. The mixture was poured into water (100 mL) and the crude product crystallized as a solid. After filtration, the solids were dissolved in ethyl acetate (100 mL), washed with water (50 mL), saturated sodium bicarbonate solution (50 mL) and brine (20 mL), dried over anhydrous magnesium sulfate and filtered. Purification of the residue by chromatography (silica gel, 40% hexane-ethyl acetate) and crystallization from ether-petroleum ether afforded the title compound as a white solid, (0.31 g, 23.0%), mp 108-111° C.; MS EI m/e 473 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([CH:17]=[C:18]1[CH2:21][N:20]([C:22]2[C:36]([F:37])=[CH:35][C:25]([C:26]([NH:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[O:27])=[C:24]([F:38])[CH:23]=2)[CH2:19]1)#[N:16].N12CCCN=C1CCCCC2>C(#N)C>[C:15]([CH2:17][C:18]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][N:20]([C:22]2[C:36]([F:37])=[CH:35][C:25]([C:26]([NH:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:31])[F:32])=[O:27])=[C:24]([F:38])[CH:23]=2)[CH2:19]1)#[N:16]
Reactant: C[C@H](NC(=O)c1cc(F)c(N2CC(=CC#N)C2)cc1F)C(F)(F)F
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cc1F)C(F)(F)F
Temperature: 50 °C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 5.15 mmol), 4-[3-(cyanomethylene)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (1.78 g, 5.15 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL, 2.1 mmol) in acetonitrile (20.2 mL) was heated at 50° C. overnight. After cooling, the solvent was removed under reduced pressure. The residue was used in the next step without further purification. LCMS cacld. for C24H28BF5N5O3 (M+1)+: m/z=540.2. Found: 540.1.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH2:3][CH:4]=O.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:6][C:2]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:1])[CH2:3][CH2:4][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNC1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CC=O)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CCN2CCCC2)cn1

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [1-(1,1-dimethyl-3-oxo-propyl)-1H-imidazol-4-yl]-amide was reacted with pyrrolidine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.9, 23.6, 28.4, 28.7, 36.0, 42.1, 43.2, 51.3, 53.1, 54.4, 57.5, 103.0, 105.3, 112.4, 112.6, 131.2, 137.8, 169.0, 169.2. MS m/z 476.2 (M+1).
Reaction SMILES: Br[C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[CH2:7]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH3:8].Cl.[OH-].[K+]>C(Cl)Cl>[CH2:7]([N:9]1[CH2:14][CH2:13][N:12]([C:2]([CH3:6])([CH3:5])[CH:3]=[O:4])[CH2:11][CH2:10]1)[CH3:8]
Reactant: CC(C)(Br)C=O
Reactant: CCN1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN1CCN(C(C)(C)C=O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
To a cooled (0° C.) solution of 2-bromo-2-methyl-propanal (2504 mg, 16.58 mmol), prepared as in Example 5, in 15 mL of DCM was added 1-ethylpiperazine (2.53 mL, 19.9 mmol) and TEA (2.31 mL, 16.58 mmol) and the solution stirred at rt for 24 hours. The mixture was worked up with 1N HCl (50 mL) and DCM (50 mL×2). The aqueous was basified with KOH to pH ˜11 and washed with DCM (50 mL×3). The organic layers were washed with saturated sodium chloride, dried (MgSO4), and then concentrated to obtain 2-(4-ethylpiperazin-1-yl)-2-methyl-propanal (90% yield) as an oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14](OC)=[S:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C(O)(=[O:22])C>O1CCCC1.CN(C)C=O>[OH:22][C:8]1[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:14]=2[S:15][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=S)c1ccncc1Cc1ccccc1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Oc1c(-c2ccccc2)sc2cnccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
A solution of 4.8 g (19 mmol) of methyl 3-phenylmethylthiopyridine-4-carboxylate in 10 mL of tetrahydrofuran was added to a slurry of 2.40 g (60 mmol) of 60% sodium hydride in 10 mL of N,N-dimethylformamide and the resulting mixture was stirred at 60° C. for 3 hours. The solution was poured onto ice water and acidified with glacial acetic acid. The filtrate was collected to afford 1.6 g (38%) of white solid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([C:19]([O:21]CC)=[O:20])[C:3]1=[O:24].[OH-].[Na+].Cl>C(O)C.O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([C:19]([OH:21])=[O:20])[C:3]1=[O:24]
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cccnc2n(C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(=O)c(C(=O)O)c(-c2ccccc2Cl)c2cccnc21
Yield: 83.6 %

Procedure:
To a solution of ethyl 1-methyl-4-(2-chlorophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylate (4.6 g, 13.4 mmol) in ethanol (20 ml) was added sodium hydroxide (2.1 g, 52.5 mmol), and the mixture was refluxed for 0.5 hour. The mixture was diluted with water, and the pH value thereof was adjusted to pH 4 with 2N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from ethyl acetate to give the title compound (3.52 g, 11.2 mmol) as a colorless crystal.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:11]2)=[CH:6][CH:5]=1.[N+]([NH:28][C:29](N)=[O:30])([O-])=O.CN(C)C=O>O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N:19]3[CH2:24][CH2:23][N:22]([C:29]([NH2:28])=[O:30])[CH2:21][CH2:20]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: COc1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-n2nc(N3CCN(C(N)=O)CC3)c3ccccc32)cc1
Yield: 85.4 %

Procedure:
A solution of 1-(4-methoxyphenyl)-3-(1-piperazinyl)-1H-indazole hydrochloride (5.0 g, 0.01 mol), nitrourea (4.0 g, 0.04 mol) and dimethylformamide (200 ml) was warmed on a steam bath for 2 hours. The reaction mixture was poured into H2O and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was dried with MgSO4 and concentrated to 5.3 g of an oil. Crystallization was achieved with toluene affording 3.3 g (65%) of a powder. The powder was recrystallized again from toluene to afford 3.0 g of 4-[1-(4-methoxyphenyl)-1H-indazol-3-yl]-1-piperazine carboxamide, m.p. 155°-157° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>CN(C)C=O>[CH:21]([S:22]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH2:9])=[O:8])=[CH:10][CH:11]=1)(=[O:24])=[O:23])=[CH2:20]
Reactant: NCc1ccc(C(N)=O)cc1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CS(=O)(=O)NCc1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 299.6 %

Procedure:
A solution of 4-aminomethylbenzamide (0.58 g) and triethylamine (1.1 ml) in dimethylformamide (DMF; 6 ml) was added to a solution of 2-chloroethanesulphonyl chloride (0.63 g) in DMF (4 ml) at -60° under nitrogen over 30 mins. The mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was evaporated to give a semi-solid (2.78 g) which was purified by column chromatography (D) to give the title compound as a solid (0.54 g) m.p. 142°-4°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[C@@H:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][NH:23][C@@H:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: COc1cc(C=O)cc(OC)c1
Product: COc1cc(CN[C@H]2CCCc3ccccc32)cc(OC)c1

Procedure:
3,5-Dimethoxybenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:21]([O:23]CC)=[O:22])[N:15]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:16]=2)=[O:10])=[C:4]([CH3:26])[CH:3]=1.O.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:21]([OH:23])=[O:22])[N:15]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:16]=2)=[O:10])=[C:4]([CH3:26])[CH:3]=1
Reactant: CCOC(=O)c1nc(NC(=O)Nc2ccc(Cl)cc2C)cn1CC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(CC2CC2)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.6 g (28.1 mmol) of ethyl 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-(cyclopropylmethyl)-1H-imidazole-2-carboxylate are suspended in 158 ml of ethanol. With ice cooling, 16.4 ml of water and 6 ml (112 mmol) of a 50% aqueous sodium hydroxide solution are added. The reaction mixture is stirred at room temperature for 1 h and then concentrated in vacuo. The residue is taken up in 100 ml of isopropanol, and 100 ml of 1N hydrochloric acid are added with ice cooling. The crystals are collected by suction filtration and dried at 40° C. in vacuo.
Reaction SMILES: [OH-:1].[Na+].ClCl.C[C:6]([C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:7]>O>[F:23][C:22]([F:25])([F:24])[CH2:21][O:20][C:9]1[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]=1[C:6]([OH:7])=[O:1]
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: [OH-]
Agent: ClCl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Temperature: 50 °C
Yield: 94.5 %

Procedure:
To a solution of 7.3 moles (292 g.) of sodium hydroxide in 600 ml. of water is added ice to make the total volume of 1.75 liters. Chlorine gas is passed into the solution while maintaining the temperature below 10° C. until it is neutral to litmus, and 2.19 moles (87.6 g.) of sodium hydroxide dissolved in 200 ml. of water is added. The combined solution is warmed to 50° C., and 0.73 mole (230 g.) of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is added slowly. The reaction mixture is stirred while heating until an exotherm begins about 75° C. and is thereafter maintained at about 80° C. by cooling. The mixture is stirred for about 16 hours at about 80° to 90° C. while monitoring the extent of the reaction by thin-layer chromatography. The excess hypochlorite is then destroyed by adding 75 g. of sodium bisulfite in 250 ml. of water, and the mixture is cooled to about 25° C. and carefully acidified with 10 percent hydrochloric acid. The light yellow solid product is collected by filtration, washed with water, and dried. A 94.5 percent yield of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid, m.p 120° to 122° C., is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH3:34])[CH:26]=3)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:35][CH3:36])[CH:10]=1.ClC1C(C2C3C(=CC=CC=3)N(C)C=2)=NC(NC2C=C([N+]([O-])=O)C(F)=CC=2OC)=NC=1.CCN(C(C)C)C(C)C>FC(F)(F)CO>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH3:34])[CH:26]=3)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:35][CH3:36])[CH:10]=1
Reactant: CNCCN(C)C
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: OCC(F)(F)F
Product: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 62 %

Procedure:
N1,N1,N2-trimethylethane-1,2-diamine (80 mg, 0.79 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129, (which may be prepared by the method described for Intermediate 87); 350 mg, 0.79 mmol) and DIPEA (0.342 mL, 1.97 mmol) in 2,2,2-trifluoroethanol (5 mL). The mixture was heated in a microwave at 140° C. for 1 h. The cooled reaction mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and appropriate fractions were combined and concentrated in vacuo onto silica. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (230 mg, 62%) as an orange solid; 1H NMR: 2.16 (6H, s), 2.45-2.49 (2H, t, obscured by DMSO peak), 2.86 (3H, s), 3.26 (2H, t), 3.87 (3H, s), 3.95 (3H, s), 6.85 (1H, s), 7.11 (1H, t), 7.21 (1H, d), 7.25 (1H, t), 7.52 (1H, d), 8.10 (1H, s), 8.31 (1H, d), 8.33 (1H, s), 8.36 (1H, d), 8.62 (1H, s); m/z: ES+ MH+ 476.40.