Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)CCC.Br[C:35]1[N:36]=[C:37]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH3:52])[CH2:47][CH2:46]2)[C:38]2[C:43]([CH:44]=1)=[CH:42][CH:41]=[CH:40][CH:39]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:51]([N:48]1[CH2:47][CH2:46][N:45]([C:37]2[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:44]=[C:35]([C:6]3[CH:7]=[CH:8][C:9]([S:12]([CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:13])=[O:14])=[CH:10][CH:11]=3)[N:36]=2)[CH2:50][CH2:49]1)[CH3:52]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(S(=O)(=O)CCCOCc2ccccc2)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)CCCOCc4ccccc4)cc3)cc3ccccc23)CC1
Yield: 72.7 %

Procedure:
(4-Tributylstannylphenyl)(3-benzyloxypropyl)sulfone (5.78 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (2.13 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.58 g) in xylene in nitrogen atmosphere for 7 hr. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate and adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, which was then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1-(4-ethylpiperazin-1-yl)-3-[4-(3-benzyloxypropyl)sulfonylphenyl]isoquinoline (2.56 g) as a pale brown amorphous.
Reaction SMILES: C(O)(=O)C.[O:5]1[CH2:8][C:7](=O)[CH2:6]1.C([BH3-])#N.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:23]=[C:22]([NH:24][C:25]3[N:26]=[CH:27][C:28]4[S:33][C:32]([C:34]([NH2:36])=[O:35])=[C:31]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[O:43][C:44]([F:47])([F:46])[F:45])[C:29]=4[N:30]=3)[N:21]([CH:48]([CH3:50])[CH3:49])[N:20]=2)[CH2:15][CH2:14]1>C1COCC1>[O:5]1[CH2:6][CH:7]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[CH:23]=[C:22]([NH:24][C:25]4[N:26]=[CH:27][C:28]5[S:33][C:32]([C:34]([NH2:36])=[O:35])=[C:31]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=6[O:43][C:44]([F:45])([F:46])[F:47])[C:29]=5[N:30]=4)[N:21]([CH:48]([CH3:50])[CH3:49])[N:20]=3)[CH2:17][CH2:18]2)[CH2:8]1
Reactant: O=C1COC1
Reactant: CC(C)n1nc(C2CCNCC2)cc1Nc1ncc2sc(C(N)=O)c(-c3ccccc3OC(F)(F)F)c2n1
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)n1nc(C2CCN(C3COC3)CC2)cc1Nc1ncc2sc(C(N)=O)c(-c3ccccc3OC(F)(F)F)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1 ml of acetic acid, 6 microliters of 3-oxetanone and 190 mg of amberlite resin IRA400 cyanoborohydride (Aldrich, loading 2×10−3 mol/g) are added, at ambient temperature, to a solution of 50 mg of 2-{[3-(piperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide in 3 ml of anhydrous THF, under an argon atmosphere. After stirring for 4 h at ambient temperature, 10 microliters of 3-oxetanone and 186 mg of the same amberlite resin IRA400 cyanoborohydride are added and the mixture is left to stir for a further 15 h. A further 6 microliters of 3-oxetanone and 100 mg of amberlite resin IRA400 cyanoborohydride are added and the mixture is then left to stir for 2 h. The mixture is filtered and the resin is washed with 50 ml of ethyl acetate then 20 ml of ethanol. The filtrate is concentrated under vacuum and the crude product is purified by flash chromatography on silica gel, elution being carried out with a dichloromethane/methanol/NH4OH (96/4/0.1%) mixture, so as to obtain 30 mg of 2-({3-[1-(oxetan-3-yl)piperidin-4-yl]-1-(propan-2-yl)-1H-pyrazol-5-yl}amino)-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide in the form of a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=O)[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=O.[OH-].[Na+]>Cl>[CH3:1][N:2]([CH2:3][CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH2:6]1)[CH3:17]
Reactant: CN(C)C(=O)CC1Cc2ccccc2NC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCC1CNc2ccccc2C1
Yield: 75.1 %

Procedure:
Borane-THF complex (1M; 15 ml) was added to N,N-dimethyl-2-oxo-1,2,3,4-tetrahydro-3-quinolineacetoamide (590 mg), which was heated under reflux for 3.5 hours. 6N hydrochloric acid (10 ml) was added to the reaction mixture, which was heated under reflux overnight. 6N sodium hydroxide was added to the reaction mixture to adjust pH to 7 and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: hexane/ethyl acetate=1/1) to obtain the entitled compound (390 mg) as an oily substance.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[N:22]=[CH:21]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:25]([C:23]3[N:22]=[CH:21][S:20][CH:24]=3)=[O:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cscn1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1cscn1
Yield: 68 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 4-thiazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 68% yield.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH2:20][N:19]2[C:21]3[CH:22]=[C:23]([C:34]([NH:36][S:37]([N:40]([CH2:42][CH:43]([O:46][CH3:47])[O:44][CH3:45])[CH3:41])(=[O:39])=[O:38])=[O:35])[CH:24]=[CH:25][C:26]=3[C:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:18]2[C:17]2[CH:48]=[CH:49][CH:50]=[CH:51][C:16]=2[O:15][CH2:14]1)C1C=CC=CC=1.CC(O)=O>CO.[Pd]>[CH:28]1([C:27]2[C:26]3[CH:25]=[CH:24][C:23]([C:34]([NH:36][S:37]([N:40]([CH2:42][CH:43]([O:46][CH3:47])[O:44][CH3:45])[CH3:41])(=[O:39])=[O:38])=[O:35])=[CH:22][C:21]=3[N:19]3[C:18]=2[C:17]2[CH:48]=[CH:49][CH:50]=[CH:51][C:16]=2[O:15][CH2:14][CH:13]([CH2:12][O:11][CH2:10][CH2:9][NH:8][CH3:1])[CH2:20]3)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(COCCN(C)Cc1ccccc1)COc1ccccc1-3)OC
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CNCCOCC1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)CC(OC)OC)cc3n2C1
Reaction time: 12 h

Procedure:
A solution of (7R or 7S)-7-({2-[benzyl(methyl)amino]ethoxy}methyl)-14-cyclohexyl-N-{[(2,2-dimethoxyethyl)(methyl)amino]sulfonyl}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxamide in MeOH (0.06 M) was treated with AcOH (1 eq) and Pd/C (2 eq). The resulting mixture was stirred for 12 h under an H2 atmosphere. The mixture was filtered and then concentrated in vacuo to afford the title compound. The crude material was used in the next step without further purification. (ES+) m/z 643 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][C:19]([OH:21])=O)[S:17][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH:10]([CH3:26])[N:9]=1.ON1C2C=CC=CC=2N=N1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][C:19]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:21])[S:17][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH:10]([CH3:26])[N:9]=1
Reactant: C1COCCN1
Reactant: Cc1nnc2n1-c1sc(CC(=O)O)cc1C(c1ccccc1Cl)=NC2C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc2n1-c1sc(CC(=O)N3CCOCC3)cc1C(c1ccccc1Cl)=NC2C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.1 g of 2-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]acetic acid in 15 ml of dimethylformamide are added 0.4 g of N-hydroxybenzotriazole and 0.27 ml of morpholine and stirred at room temperature for 10 minutes. To the mixture is added 0.65 g of dicyclohexyl carbodiimide under ice-cooling and stirred for 1 hour and furthermore stirred at room temperature for 18 hours. The resulting dicyclohexylurea is filtered off and to the filtrate is added 50 ml of chloroform. The solution is washed with 5% aqueous sodium hydrogen-carbonate carbonate solution and water and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure and the residue is crystallized from isopropyl ether. The precipitated crystals are collected by filtration and recrystallized from ethyl acetate to give 0.9 g of 2-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]acetic acid morpholide as colorless crystals, melting at 126°-129° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(O)c(Cl)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (100 g) in chloroform (1 L) was added N-chlorosuccinimide (120 g) at ambient temperature and the mixture was stirred at 50° C. for 18 hours. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The crude crystals was washed with diisopropyl ether and recrystallized from a mixture of ethyl acetate and n-hexane to obtain 3-chloro-4-hydroxybenzaldehyde (85.8 g) as colorless crystals.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC#N)C(=O)COC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[CH:52][C:53]4[N:58]([CH2:59][C:60]#[N:61])[C:57](=[O:62])[CH:56]([CH2:63][O:64][CH3:65])[O:55][C:54]=4[N:66]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1)(C)(C)C>>[NH2:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)=[CH:52][C:53]4[N:58]([CH2:59][C:60]#[N:61])[C:57](=[O:62])[CH:56]([CH2:63][O:64][CH3:65])[O:55][C:54]=4[N:66]=3)=[CH:46][CH:45]=2)[CH2:41][CH2:42][CH2:43]1
Reactant: COCC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(CC#N)C1=O
Agent: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Product: COCC1Oc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc2N(CC#N)C1=O
Yield: 64.6 %

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, tert-butyl(1-(4-(1-(cyanomethyl)-3-(methoxymethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (35 mg, 0.063 mmol) was reacted to afford the title compound (18.5 mg). 1H NMR (500 MHz, CH3OD) 7.63 (s, 1H), 7.45 (d, 2H), 7.39 (d,2H), 7.32 (m, 3H), 7.26 (m, 2H), 5.28 (t, 1H), 5.16 (dd, 2H), 4.01 (dd, 2H), 2.74-2.79 (m, 2H), 2.55-2.61 (m, 2H), 2.22-2.26 (m, 1H), 1.96-1.99 (m, 1H). LCMS (Method D): RT=0.78 min, M+H+=456.2.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][C:7]([Cl:12])=[N:6][C:5]=2[S:4][C:3]=1[CH3:13].C(O)C.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(N(CC)CC)C>O>[Br:1][C:2]1[C:10]2[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:8][C:7]([Cl:12])=[N:6][C:5]=2[S:4][C:3]=1[CH3:13]
Reactant: NCc1ccccn1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1Br
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: Cc1sc2nc(Cl)nc(NCc3ccccn3)c2c1Br
Temperature: 60 °C
Yield: 79.9 %

Procedure:
A stirred mixture of 5-bromo-2,4-dichloro-6-methylthieno[2,3-d]pyrimidine (1.0 g, 3.35 mmol), ethanol (40 ml), 2-aminomethylpyridine (0.40 ml, 3.69 mmol) and triethylamine (0.50 ml, 3.69 mmol) was heated at a temperature of 60° C. for 1 hour. The reaction mixture was then cooled to ambient temperature, diluted with water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give a residue. Purification by flash chromatography (silica) eluting with dichloromethane followed by 5% ethyl acetate in dichloromethane gave (5-bromo-2-chloro-6-methylthieno[2,3-d]pyrimidin-4-yl)pyridin-2-ylmethylamine as a white solid (0.99 g).
Reaction SMILES: [H][H].[ClH:3].[N+:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[OH:16])([O-])=O>[Pd].[Rh]>[ClH:3].[NH2:4][C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[OH:16]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: [Rh]
Agent: Cl
Product: Nc1ccc(O)c(N)c1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
Onto the bottom of a cylindrical reactor there is placed a chamber made of a foil with the thickness of 100 mcm and the working surface area of 50 cm2. The foil is made of an alloy consisting of 98% by mass of palladium and 2% by mass of rhodium. Commercial hydrogen comprising a mixture of hydrogen with nitrogen (at the volume ratio therebetween of 1:1). Under the pressure of 10 atm is continuously supplied at the rate of 60 ml/min into the chamber. Outside the chamber into the reactor there are charged 300 ml of a 30% aqueous solution of hydrochloric acid and 120 g of 2,4-dinitrophenol. The reactor is heated to the temperature of 110° C. and the pressure therein is increased to 10 atm. Under these conditions the process of hydrogenation is conducted under stirring for 5 hours. After cooling and precipitation with a 37% hydrochloric acid there are obtained 116.9 g of 2,4-diaminophenol hydrochloride which corresponds to 91% based on the starting 2,4-dinitrophenol.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[F:9])=[O:7].[CH3:18][Si:19]([CH3:50])([CH3:49])[CH2:20][CH2:21][O:22][CH2:23][N:24]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:25]1[N:30]2[N:31]=[CH:32][CH:33]=[C:29]2[N:28]=[C:27]([CH:34]2[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]2)[CH:26]=1>C1COCC1.C(Cl)Cl>[CH3:46][Si:45]([CH3:48])([CH3:47])[CH2:44][CH2:43][O:42][CH2:41][N:24]([CH2:23][O:22][CH2:21][CH2:20][Si:19]([CH3:50])([CH3:49])[CH3:18])[C:25]1[N:30]2[N:31]=[CH:32][CH:33]=[C:29]2[N:28]=[C:27]([CH:34]2[CH2:39][CH2:38][C:37](=[C:8]([F:9])[C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH2:36][CH2:35]2)[CH:26]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2ccnn12
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(F)=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
To a 250 mL roundbottom flask containing 80 mL THF was charged sodium hydride (60% w/w in mineral oil, 12.86 mmol, 515 mg). This suspension was broken up in the sonicaid and then cooled to 0° C. in icebath. Triethyl 2-fluoro-2-phosphonoacetate (12.86 mmol, 3.12 g) was taken up in THF (10 mL) and added dropwise to stirring NaH suspension. The resulting solution was allowed to stir at 0° C. for 10 minutes. 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone (6.43 mmol, 3.16 g) was taken up in THF (10 mL) and added dropwise to the stirring solution. The reaction was allowed to warm to room temperature and stir 18 hours. At 18 hours, the reaction was diluted with DCM (400 mL) and washed with H2O. The organic layer was collected and dried over Na2SO4. This solution was reduced in vacuo and purified via flash chromatography to yield the title compound (3.43 g, 5.92 mmol).
Reaction SMILES: [C:1]([C:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH2:5][CH2:6][CH3:7])[CH3:4])#[N:2].CC(O)(C)C>CO.[Ni]>[NH2:2][CH2:1][C:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])[CH2:5][CH2:6][CH3:7]
Reactant: CCCC(C)(C#N)NC(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CC(C)(C)O
Solvent: CO
Product: CCCC(C)(CN)NC(=O)OC(C)(C)C

Procedure:
61.0 g (212.98 mmol) of rac-tert-butyl (2-cyanopentan-2-yl)carbamate-2-methylpropan-2-ol from Example 151A were dissolved in 618 ml of 7 N ammoniacal methanol and admixed under argon with 66 g of Raney nickel (50% aqueous slurry). Subsequently, the reaction mixture was hydrogenated in an autoclave at 20-30 bar overnight. The reaction mixture was filtered through Celite, rinsed well with methanol and concentrated. 43.70 g (95% of theory) of the target compound were obtained.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.Cl.[CH:23]1([CH2:26][O:27][NH2:28])[CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH:23]1([CH2:26][O:27][NH:28][C:13](=[O:15])[C@H:12]([N:9]2[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]4[C:6]3=[C:11]([C:2]([F:1])=[CH:3][N:4]=4)[CH2:10]2)[CH:16]([CH3:18])[CH3:17])[CH2:25][CH2:24]1
Reactant: NOCC1CC1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](C(=O)NOCC1CC1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 27.2 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol). DMF (0.5 mL), O-(cyclopropylmethyl)hydroxylamine hydrochloride (6.4 mg, 0.051 mmol), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (5 mg, 23%). 1H NMR (400 MHz, CD3OD) δ 0.16-0.24 (m, 2 H) 0.39-0.55 (m, 2 H) 0.93 (d, J=6.57 Hz, 3 H) 1.05 (d, J=6.32 Hz, 3 H) 1.06-1.15 (m, 1 H) 2.53 (dt, J=11.24, 6.51 Hz, 1 H) 3.55-3.73 (m, 2 H) 4.94 (d, J=11.37 Hz, 1 H) 5.07 (d, J=19.20 Hz, 1 H) 5.46 (d, J=18.44 Hz, 1 H) 7.86 (s, 1 H) 8.17 (d, J=3.28 Hz, 1 H). [M+H] calc'd for C18H21FN4O3, 361; found, 361.4.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[CH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[OH2:18].[OH-].[Na+].OO>C1COCC1.C(OCC)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][OH:18])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: O
Reactant: C=C1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (4.48 g, 19.71 mmol) was dissolved in THF (100 mL) and the stirred solution was cooled to 0° C. Borane-dimethylsulfide complex (1.9 mL, 19.7 mmol) was added and the reaction mixture was allowed to warm to RT o/n. After 16 h, water was added dropwise until no bubbling was observed. The stirred mixture was then cooled to 0° C. Aqueous NaOH (5M in H2O, 5.3 mL, 26.6 mmol), then H2O2 (30 wt % in H2O, 6.0 mL, 58.5 mmol) were added dropwise. The reaction was then warmed to 50° C. After 30 min, the mixture was diluted with ethyl ether and washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (25% to 75% EtOAc/Hex) to afford the title compound (2.08 g, 41%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1.[OH:27]O>O1CCCC1.O.CCOC(C)=O.C[Re](=O)(=O)=O>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N+:18]=4[O-:27])[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: OO
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1ccccn1
Agent: C[Re](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1cccc[n+]1[O-]
Temperature: 80 °C

Procedure:
Methyltrioxorhenium(VII) (2 mg, 0.008 mmol) was added to a solution of 7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (20 mg, 0.06 mmol) from Example 15, in tetrahydrofuran (2 mL) at room temperature and then 3.0 M hydrogen peroxide in water (0.04 mL) was added. The reaction mixture was heated to 80° C. for 20 min. allowed to cool and was diluted with water and EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the crude product. The product was purified by preparative HPLC on a C-18 column eluting with a water:MeCN gradient buffered pH 10 to give the title compound as a white amorphous solid (0.007 g, 30%). LCMS calc. for C19H17N4O4 (M+H)+: m/z=365.1. found: 365.1. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.37 (d, J=5.8 Hz, 1H), 7.39 (td, J=7.2, 6.5, 2.0 Hz, 1H), 7.25 (td, J=7.7, 0.9 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.63 (dd, J=7.9, 2.0 Hz, 1H), 5.84 (d, J=2.2 Hz, 1H), 4.78 (dd, J=11.6, 1.3 Hz, 1H), 4.36 (dd, J=11.6, 3.4 Hz, 1H), 2.17 (s, 3H), 2.00 (s, 3H).
Reaction SMILES: [H-].[Na+].C(O)(C)(C)C.[CH3:8][O:9][C:10]([CH2:12][O:13][C:14]1[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=1[O:16][CH2:17][C:18](OC)=[O:19])=[O:11].C(O)(=O)C>C1(C)C(C)=CC=CC=1>[O:19]=[C:18]1[CH:12]([C:10]([O:9][CH3:8])=[O:11])[O:13][C:14]2[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=2[O:16][CH2:17]1
Reactant: COC(=O)COc1ccccc1OCC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: COC(=O)C1Oc2ccccc2OCC1=O
Yield: 74.4 %

Procedure:
To a mixture of 4.1 g of 60% sodium hydride in 150 ml of xylene is added 0.3 ml of tert-butanol, and a solution of 10 g of methyl 2-methoxycarbonylmethyloxyphenoxyacetate in 100 ml of xylene is added dropwise to the mixture at 140°-150° C. (for 8 hours). To the reaction mixture 7 g of acetic acid is added and the precipitates are filtered off. The filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=3:1 2:1), to give 6.5 g of methyl 3-oxo-3,4-dihydro-2H-1,5-benzodioxepin-2-carboxylate as a colorless oil. Mass spectrum m/e: 222 (M+). IR νmaxneat cm-1 : 1750. NMR (CDCl3) δ: 3.75(3H, singlet, OCH3), 4.68 (2H, double doublet, C4 --H), 5.32 (1H, singlet, C2 --H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[N:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)=[N:26][CH:27]=1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc(-n2cccn2)nc1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(-n2cccn2)nc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 6-pyrazol-1-yl-nicotinic acid. MS: 431.4 (M+H).