Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6](/[CH:12]=[CH:13]/[CH:14]=[C:15](\[O:19][CH3:20])/[C:16]([OH:18])=O)=[CH:5]2.[NH2:21][CH:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[N:25]([CH3:30])[C:24]([CH3:32])([CH3:31])[CH2:23]1.O.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6](/[CH:12]=[CH:13]/[CH:14]=[C:15](\[O:19][CH3:20])/[C:16]([NH:21][CH:22]1[CH2:23][C:24]([CH3:31])([CH3:32])[N:25]([CH3:30])[C:26]([CH3:29])([CH3:28])[CH2:27]1)=[O:18])=[CH:5]2
Reactant: CO/C(=C\C=C\c1cc2cc(Cl)c(Cl)cc2[nH]1)C(=O)O
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: CO/C(=C\C=C\c1cc2cc(Cl)c(Cl)cc2[nH]1)C(=O)NC1CC(C)(C)N(C)C(C)(C)C1
Yield: 73 %

Procedure:
A solution of (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoic acid (736 mg, 3.65 mmol), 4-amino-1,2,2,6,6-pentamethylpiperidine (620 mg, 3.65 mmol), 1-hydroxy-7-azabenzotriazole hydrate (474.5 mg, 3.65 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (693.5 mg, 3.65 mmol) in DMF (2 ml) was stirred at RT overnight. The solution was poured into brine (20 ml) and repeatedly extracted with EtOAc. The organic phase was washed with 5% aq. CaCO3, dried (MgSO4) and evaporated under vacuum. The residue was chromatographed on silica gel using ethyl acetate:methanol:aq. ammonia (32%) 90:10:2 as eluent mixture. The collected fractions produced the pure title compound (0.8, yield 73%) as yellow crystals, m.p.=212° C.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[N:9]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1>C1COCC1>[CH3:1][C:11]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][N:9]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:10]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: -50 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a cold (−78° C.) solution of lithium diisopropylamide (LDA) (23.3 mmol) in THF (10 mL) under an argon atmosphere was added dropwise a solution of 1-tert-butyl 3-ethyl 1,3-piperidinedicarboxylate (3.0 g, 11.6 mmol) in THF (5 mL), then stirred at −50° C. for 2 hrs. To the resulting mixture was added a solution of Mel (1.98 g, 14 mmol) in THF at −50° C. The reaction mixture was allowed to warm to room temperature, and quenched with saturated aqueous NH4Cl solution. The mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (hexane:ethyl acetate, 9:1) to give 1-tert-butyl 3-ethyl 3-methyl-1,3-piperidinedicarboxylate as a pale yellow oil (2.27 g, yield; 72%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4]/[N:5]=[CH:6]/[C@H:7]1[CH2:12][CH2:11][C@:10]2([OH:27])[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([OH:26])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3.[N+]([O-])(O)=O.[C:32](N1C(C)=CC(C)=N1)(=[NH:34])[NH2:33]>C(O)C>[NH:1]([CH2:2][CH2:3][O:4]/[N:5]=[CH:6]/[C@H:7]1[CH2:12][CH2:11][C@:10]2([OH:27])[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([OH:26])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)[C:32]([NH2:34])=[NH:33]
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=N/OCCN)CC[C@]12O
Reactant: Cc1cc(C)n(C(=N)N)n1
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=N/OCCNC(=N)N)CC[C@]12O
Yield: 36 %

Procedure:
A solution of 0.95 g of (E)-17β-(2-aminoethoxyimino)methyl-5β-androstane-3β,14β-diol (I-ab) and 1.05 g of 1-amidino-3,5-dimethylpyrazole nitrate in 20 ml of ethanol was heated at reflux for 10 hrs. The solution was evaporated to dryness under reduced pressure and the crude product was purified by flash-chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 78/20/2 as eluant; the fractions containing the title compound were collected and evaporated to dryness under reduced pressure. The residue was ground with di-iso-propyl ether/ethanol to give 0.38 g of the title compound (I-ag), as a nitrate, white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Cl:10][CH2:11][C:12](O)=[O:13].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[Cl:10][CH2:11][C:12]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:13]
Reactant: O=C(O)CCl
Reactant: COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(NC(=O)CCl)cc1
Temperature: 30 °C
Reaction time: 3 h
Yield: 19.7 %

Procedure:
A mixture of 4-methoxyaniline (5.00 g, 40.6 mmol), chloroacetic acid (8.6 g, 91.5 mmol), EDCI (12.0 g, 61.2 mmol), HOBT (8.4 g, 61.3 mmol) and NMM (13 mL, 122 mmol) in anhydrous CH2Cl2 (50 mL) was stirred at 30° C. for 3 hours. The mixture was quenched with ice water, and then extracted with CH2Cl2 (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column (PE/EtOAc=5/1) to give the product (1.60 g, yield 20%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:15])[F:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[CH:9]=[C:10]([CH:13]([F:14])[F:15])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:34][CH2:33]1)(=[O:37])[CH3:36]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f60) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH:12]([CH3:14])[CH3:13])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH:12]([O:11][C:5]1[CH:4]=[C:3]([NH:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:2]=[CH:7][C:6]=1[N+:8]([O-:10])=[O:9])([CH3:14])[CH3:13]
Reactant: NC1CCOCC1
Reactant: CC(C)Oc1ccc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1cc(NC2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
A mixture of 0.75 g of 5-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 0.42 g of 4-aminotetrahydropyran and 0.8 g of potassium carbonate in 6 ml of DMSO is stirred at 50° C. overnight. The mixture is diluted with 100 ml of water and extracted three times with 50 ml of ethyl acetate. The organic phases are combined and then dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 50 g silica column, elution being carried out with a dichloromethane/methanol (95/5 v/v) mixture, so as to obtain 0.69 g of (3-isopropoxy-4-nitrophenyl)(tetrahydropyran-4-yl)amine in the form of a yellow foam.
Reaction SMILES: COCN[C:5]([C:7]1[O:8][C:9]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:12][C:10]=2[CH:11]=1)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:19]1([CH2:18][CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:9]3[O:8][C:7]([CH:5]=[O:6])=[CH:11][C:10]=3[CH:12]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: COCNC(=O)c1cc2cc(OCCN3CCOCC3)ccc2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cc2cc(OCCN3CCOCC3)ccc2o1
Yield: 97.2 %

Procedure:
To a solution of 5-(2-morpholin-4-yl-ethyloxy)benzofuran-2-carboxylic acid methoxy methyl amide (0.2 g) of Example 20a in THF was added LAH (2.0 mL of a 1 M solution in THF). The reaction was stirred until complete consumption of the starting material. Workup gave 160 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([OH:27])=O)=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[C:7]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:27])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3F)nc2c1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccnc3F)nc2c1
Yield: 50.7 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(2-fluoropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (80 mg, 210 μmol, 1 eq.) and morpholine (54.8 μl, 629 μmol) as starting materials. The reaction affords 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(2-fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (48 mg, 50.8%) as white solid. mp: 267-269° C., MS: m/z=451.0 (M+H+).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1)[CH2:2][CH3:3].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[O:12]>CC(C)=O>[CH2:15]([O:14][C:10](=[O:13])[CH:11]([OH:12])[N:7]1[CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]1=[O:9])[CH3:16]
Reactant: CCOC(=O)C=O
Reactant: CCCC1CNC(=O)C1
Solvent: CC(C)=O
Product: CCCC1CC(=O)N(C(O)C(=O)OCC)C1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
In a 250 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, a mixture of 4-propyl-pyrrolidin-2-one (0.5 g, 3.9 mmol) and ethyl glyoxylate (50% in toluene, 2.4 ml, 11 mmol) in acetone is heated up at 60° C. for 6 h and another portion of ethyl glyoxylate (0.4 ml) is added. After 17 h at 50° C., the reaction mixture is concentrated in vacuo to give the crude hydroxy-(2-oxo-4-propyl-pyrrolidin-1-yl)-acetic acid ethyl ester a19 (2.02 g). It is used in the next step without any further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2)=[CH2:2].[OH:15][C@@H:16]1[CH2:20][NH:19][CH2:18][C@@H:17]1[CH2:21][NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCO>[C:26]1([CH2:25][O:24][C:23](=[O:32])[NH:22][CH2:21][C@@H:17]2[C@H:16]([OH:15])[CH2:20][N:19]([CH2:2][CH2:1][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[N:11]=4)[N:6]=[CH:5][CH:4]=3)[CH2:18]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(NC[C@H]1CNC[C@H]1O)OCc1ccccc1
Reactant: C=Cc1ccnc2ccc(OC)nc12
Solvent: CCO
Product: COc1ccc2nccc(CCN3C[C@H](CNC(=O)OCc4ccccc4)[C@H](O)C3)c2n1
Yield: 79.6 %

Procedure:
To a stirred solution of 8-ethenyl-2-(methyloxy)-1,5-naphthyridine (4.2 mmole) in EtOH (5 mL) was added phenylmethyl {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (1.05 g, 4.2 mmole). After 24 h at 80° C. the reaction contents were purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) affording the title compound (1.46 g, 80%) as a light yellow foam: LC-MS (ES) m/e 437 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[F:20][C:17]([F:18])([F:19])[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:16]
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(NC1CCNCC1)C(F)(F)F

Procedure:
A suspension of 92 g of 1-benzyl 4-trifluoromethylcarbonylamino piperidine (X) and 9 g of wet 10% palladium on charcoal in 1000 ml of methanol is left under agitation for 8 days in a hydrogen atmosphere at room temperature. Then it is filtered, the filtrate is evaporated and the residue chromatographed on a silica column (M.P.L.C.). By eluting with pure methanol, 44 g of the expected product are obtained.
Reaction SMILES: C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@@H:12]12[C:20](=O)[NH:19][C:18](=O)[C@@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17]2.[OH-].[Na+]>O>[CH2:18]1[C@@H:13]2[C@@H:12]([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:20][NH:19]1
Reactant: O=C1NC(=O)[C@@H]2CCCC[C@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: C1CC[C@H]2CNC[C@H]2C1
Temperature: 0 °C

Procedure:
Cis-4-cyclohexene-1,2-dicarboximide (10.9 g) was hydrogenated over 10% palladium on carbon (1 g) in absolute ethanol (420 ml) at 50 psi for 10 minutes. The mixture was filtered then evaporated to give cis-cyclohexane-1,2-dicarboximide (10.6 g). To anhydrous diethyl ether (200 ml) was cannulated under nitrogen a 1M diethyl ether solution (200 ml) of lithium aluminium hydride. To the foregoing solution, under reflux, was added cis-cyclohexane-1,2-dicarboximide (10.6 g) portionwise over 10 minutes. The reaction mixture was heated to reflux for 3 hours. After cooling to 0° C., water (7 ml) was added followed by 4N sodium hydroxide (7.6 ml) and water (23 ml). The white suspension was stirred whilst warming to room temperature. The solid was removed by filtration then the filtrate dried (sodium sulphate) and evaporated to give a cream oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH:12]1[CH2:14][CH2:13]1)[C:6](=[O:15])[CH2:5]2.[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]1[CH2:26][O:25]1)([CH3:19])([CH3:18])[CH3:17].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]([OH:25])[CH2:26][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH:12]1[CH2:13][CH2:14]1)[C:6](=[O:15])[CH2:5]2)([CH3:18])([CH3:17])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CO1
Reactant: Nc1cc(F)c2c(c1)CC(=O)N2C1CC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H](O)CNc1cc(F)c2c(c1)CC(=O)N2C1CC1

Procedure:
5-Amino-1-cyclopropyl-7-fluoro-1,3-dihydro-indol-2-one (0.560 g, 2.72 mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (0.472 g, 2.72 mmol) and lithium trifluoromethanesulfonate (0.415 g, 2.72 mmol) in acetonitrile (5 ml) are heated at 85° C. for 4.5 hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Final purification by flash chromatography (70% Ethyl acetate/hexane) gives the title compound as a yellow solid. HPLC r.t. 3.98 min; MS for C19H26FN3O4 m/z 380.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=1[CH:18]=[N:19][N:20]3C(OC)=O)=[O:14])[CH2:7][CH2:6]2.Cl>>[NH:20]1[C:21]2[C:17](=[C:16]([NH:15][C:13]([NH:12][CH:8]3[C:9]4[C:5](=[CH:4][C:3]([C:2]([F:1])([F:29])[F:30])=[CH:11][CH:10]=4)[CH2:6][CH2:7]3)=[O:14])[CH:24]=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCc4cc(C(F)(F)F)ccc43)cccc21
Agent: Cl
Product: O=C(Nc1cccc2[nH]ncc12)NC1CCc2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared using the procedure in Example 9, except using methyl 4-[({[5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate instead of methyl 4-[({[5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate. 1H NMR (DMSO-d6) δ 1.06 (t, 2.4H, EtOH), 1.82-1.94 (m, 1H), 2.52-2.60 (m, 1H), 2.85-2.97 (m, 1H), 2.98-3.10 (m, 1H), 3.44 (q, 1.6H, EtOH), 5.28 (m, 1H), 7.08 (m, 2H), 7.21 (m, 1H), 7.56 (m, 2H), 7.63 (s, 1H), 7.69 (d, 1H), 8.17 (s, 1H), 8.91 (s, 1H); MS (ESI+) 361 (M+H)+; Elemental: Calculated for C18H15N4OF3.HCl.0.8EtOH.0.1H2O: C54.06, H4.86, N12.87; Found: C54.02, H4.58 N12.62.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][C:7]=1[N:14]1[C:19](=[O:20])[NH:18][C:17](=[O:21])[N:16]([CH3:22])[C:15]1=[O:23]>C(Cl)Cl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[N:14]1[C:19](=[O:20])[NH:18][C:17](=[O:21])[N:16]([CH3:22])[C:15]1=[O:23]
Reactant: COc1ccc(Br)c(-n2c(=O)[nH]c(=O)n(C)c2=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(=O)[nH]c(=O)n(-c2cc(O)ccc2Br)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of boron tribromide in methylene chloride (98.75 mL of a 1M solution in methylene chloride) is added to a mixture of 1-(2-bromo-5-methoxyphenyl)-3-methyl-s-triazine-2,4,6-(1H, 3H, 5H)-trione (14.4 g, 0.438 mol) in methylene chloride at 0° C. The reaction mixture is stirred at room temperature for 1 hour and filtered to obtain a solid. The solid is washed with water and air-dried to give the title product as a white solid, mp 265°-270° C.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH:13]=O.[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[OH-].[Na+]>ClCCl.C(Cl)(Cl)Cl.C(O)(=O)C>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][N:15]1[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CCn1c(=O)ccc2ccncc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccncc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.9 %

Procedure:
To a solution of 2.5 g of (2-oxo-1,7-naphthyridin-1(2H)-yl)acetaldehyde in 25 mL of dichloromethane, 2.6 g of tert-butyl (piperidin-4-yl)carbamate and 0.76 mL of acetic acid, and 4.2 g of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 4 hours and then left overnight. Thereto was added chloroform and the reaction mixture was adjusted to pH 9.1 with a saturated aqueous sodium hydrogen carbonate solution and a 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, and the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resultant residue, diethyl ether was added, and the solid was filtered off to obtain 2.8 g of tert-butyl (1-(2-(2-oxo-1,7-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a slightly yellow solid.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)([CH3:5])[CH3:4].[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18]Cl)[CH:17]=1>CN(C=O)C>[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:3]([CH3:5])[CH3:4])[CH:17]=1
Reactant: ClCc1cncc(Br)c1
Reactant: CC(C)c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1nccn1Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.1 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 0.073 g, 1.82 mmol) in DMF (3 mL) was added 2-isopropyl-1H-imidazole (0.173 g, 1.57 mmol) and the reaction mixture was stirred at room temperature for 20 min. Then, 3-bromo-5-chloromethyl-pyridine (0.25 g, 1.21 mmol) was added and the resulting suspension was heated at 60° C. overnight. The mixture was quenched with water (2 mL) and extracted with EtOAc (2×10 mL). Combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.275 g, 81%) as a light yellow oil. MS: 280.0, 282.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[O:33][C:34]([CH:37]=[O:38])=[CH:35][CH:36]=2)=[CH:4][N:3]=1.[BH4-].[Na+]>CN(C)C=O.CO>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[O:33][C:34]([CH2:37][OH:38])=[CH:35][CH:36]=2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(-c4ccc(C=O)o4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(-c2csc3c(-c4ccc(CO)o4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.3 %

Procedure:
A mixture of N-{4-[4-amino-7-(5-formyl-2-furyl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide (0.060 g, 0.12 mmol) and sodium borohydride (0.013 g, 0.344 mmol) in N,N-dimethylformamide (4 mL) and methanol (4 mL) was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (10 mL) and 0.1 N hydrochloric acid (10 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was purified by preparative RP-HPLC (Rainin C18, 8 mm, 300 Å, 25 cm; 40% acetonitrile—0.1M ammonium acetate isocratic for 5 minutes, then 40–100% acetonitrile—0.1M ammonium acetate over 30 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyophilized to give the title compound (2.1 mg, 0.004 mmol) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
20 g (126 mmol) 5-fluoro-2-nitro-phenol are dissolved in 300 ml acetone. 22.6 g (163 mmol) potassium carbonate are added and the mixture is stirred for 30 min at 20° C. Over a period of 10 min, 9.4 ml (150 mmol) methyl iodide, diluted in 50 ml acetone, is added and the mixture is stirred for a further 18 h at 20° C. Then it is left for another 12 h at 65° C. with stirring. The solvent is eliminated in vacuo, the residue is taken up in water and extracted three times with ethyl acetate. Then the combined organic phases are extracted three times with 10% aqueous sodium carbonate solution. The organic phase is dried over magnesium sulphate. The solvent is eliminated in vacuo.