Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]2[N:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]=[C:10]([NH:17][CH:18]3[CH2:20][CH2:19]3)[C:9]=2[N+:21]([O-])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].N>O1CCOCC1.O.C(OCC)(=O)C>[N:1]1([C:8]2[N:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]=[C:10]([NH:17][CH:18]3[CH2:19][CH2:20]3)[C:9]=2[NH2:21])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1c(NC2CC2)nc(C2CC2)nc1N1CCCCCC1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1c(NC2CC2)nc(C2CC2)nc1N1CCCCCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 3 %

Procedure:
To a suspension of 6-(1-azepanyl)-N,2-dicyclopropyl-5-nitro-4-pyrimidinamine 197 (0.5 g, 16 mmol) in 1,4-dioxane (35 ml) and water (35 ml) is added sodium hydrosulfite (2.19 g, 13 mmol) and ammonia (25% solution, 1.2 ml). The mixture is stirred at room temperature for 10 h then diluted with ethyl acetate and washed three times with water. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo to afford a yellow oil. The crude oil is purified by column chromatography (dichloromethane/ethanol/ammonia: 95/5/0.5) to give pure 6-(1-azepanyl)-N4,2-dicyclopropyl-4,5-pyrimidinediamine 63 (137 mg, 30%) as a reddish solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CS([C:12]1[N:17]=[C:16]([Sn:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:15]=[CH:14][N:13]=1)(=O)=O.O1CCOCC1>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:12]2[N:17]=[C:16]([Sn:18]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:15]=[CH:14][N:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(S(C)(=O)=O)n1
Solvent: O
Solvent: C1COCCO1
Product: CCCC[Sn](CCCC)(CCCC)c1ccnc(N2CCN(C)CC2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
1-Methylpiperazine (0.160 mL, 1.44 mmol) was added to a solution of 2-(methylsulfonyl)-4-(tributylstannyl)pyrimidine (0.250 g, 0.481 mmol, synthesized as described in Majeed, A. J., et al. Tetrahedron 1989, 45, 993-1006) and 1,4-dioxane (1.0 mL) under nitrogen. After about 2 h, the solution was warmed to about 50° C. After about 30 min, the solution was warmed to about 80° C. After about 30 min, a reflux condenser was attached and the solution was warmed to about 100° C. After about 16 h, the brown solution was allowed to cool to ambient temperature. Water (5 mL) was added. The mixture was extracted with EtOAc (2×5 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 2-10% MeOH/DCM to afford 2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)pyrimidine (0.127 g, 56%): 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=4.6 Hz, 1H), 6.63 (d, J=4.6 Hz, 1H), 3.98-3.82 (m, 4H), 2.63-2.48 (m, 4H), 2.40 (s, 3H), 1.70-1.43 (m, 6H), 1.42-1.20 (m, 6H), 1.18-0.97 (m, 6H), 0.88 (t, J=7.3 Hz, 9H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[CH2:30]1[NH:33][CH2:32][CH:31]1[OH:34].Cl>C(Cl)Cl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:33]1[CH2:30][CH:31]([OH:34])[CH2:32]1)=[N:6]2
Reactant: OC1CNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(O)C3)nc2c1C#N

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (100 mg, 0.35 mmol) was dissolved in methylene chloride (2 ml), then diisopropylethylamine (237 μl, 1.39 mmol) and 3-hydroxy-1-azetidine hydrochloride (76 mg, 0.70 mmol) were added, followed by heating under reflux in a sealed tube under nitrogen atmosphere for 6 hours. After cooling, dilution with methylene chloride and washing with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resisting residue was recrystallized and purified with n-hexane/ethyl acetate to obtain the entitled compound (123 mg, quant) as a yellow white solid.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12](O)=[O:13])[N:9]=[CH:8]2)[CH:2]=1.C(Cl)(=O)C([Cl:24])=O>>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]([Cl:24])=[O:13])[N:9]=[CH:8]2)[CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Product: O=C(Cl)c1cn(-c2cccc(-c3ccccc3)c2)cn1

Procedure:
A solution of 10a (2.0 g, 7.6 mmol) in oxalyl chloride (30 ml) was stirred at 60° C. overnight. Excess oxalyl chloride was removed under reduced pressure to leave 11a.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]=[C:6]([C:21]([NH:23][NH2:24])=[O:22])[CH:5]=1)[CH3:2].O.[F:26][C:27]([F:34])([C:30]([F:33])([F:32])[F:31])[CH:28]=O.C1C=CC=CC=1.Cl>C(OCC)(=O)C.O>[F:26][C:27]([F:34])([C:30]([F:33])([F:32])[F:31])[CH:28]=[N:24][NH:23][C:21](=[O:22])[C:6]1[CH:5]=[C:4]([NH:3][CH2:1][CH3:2])[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[N:7]=1
Reactant: CCNc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Reactant: O=CC(F)(F)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCNc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN=CC(F)(F)C(F)(F)F)c1
Reaction time: 8 h

Procedure:
4-ethylamino-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.30 g, 0.00088 mol) was mixed with 2,2,3,3,3-pentafluoropropionaldehyde monohydrate (0.29 g, 0.00088×2.0 mol) and benzene, and further with a small amount of concentrated hydrochloric acid. The obtained mixture was refluxed and dehydrated for about 8 hours using a water separator. The obtained reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, and the organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated. The obtained concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[N:15][C:13]1[C:12]2[C:7]([N:6]=[C:5]3[C:14]=1[CH2:1][CH2:2][CH2:3][CH2:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: O=Cc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: Clc1ccccc1C=Nc1c2c(nc3ccccc13)CCCC2

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.0 g) was suspended in 400 ml of toluene to which morpholine (3.5 g) and 2-chlorobenzaldehyde (3.5 g) were successively added. The reaction mixture was refluxed overnight and then an additional 1.7 g of aldehyde was added. Reflux was continued for an additional sixteen (16) hours and then the reaction mixture was concentrated and purified by flash chromatography (CH2Cl2, then 20% EtOAc/CH2Cl2). Fractions containing the product were concentrated and recrystallized from Et2O/pentane to give 2.10 g of analytically pure product, m.p. 165°-166° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[C:9]([NH:16][C@H:17]([C:19](O)=[O:20])[CH3:18])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1(N=C=NC2CCCCC2)CCCCC1.CO>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:19](=[O:20])[C@H:17]([CH3:18])[NH:16][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10]
Reactant: COCCOCCO
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Solvent: ClCCl
Product: COCCOCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(2-Methoxyethoxy)ethanol (1.28 g, 10.5 mmol), 4-N,N′-(dimethyl)aminopyridine (128 mg, 1 mmol) and N-Boc-(L)-alanine (2 g, 10.5 mmol) were dissolved in freshly distilled CH2Cl2 (25 mL). The reaction mixture was cooled to 0° C. (ice bath) and dicyclohexylcarbodiimide (DCC, 2.39 g, 1.1 mmol) was added portionwise. The reaction mixture was stirred for 1 h at 0° C. and then warmed up to room temperature over 2 h. The dicyclohexyl urea was filtered off, washed with ethyl acetate (2×20 mL) and the solvents evaporated. Column chromatography (SiO2, 0.060-0.200 mm/1% MeOH in CH2Cl2) yielded compound 2a as a colorless to pale yellow oil (2.40 g, 8.3 mmol, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH3:14])[C:7]([CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1)=[C:6]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:38])[CH3:37].C(=O)(O)[O-].[Na+]>ClCCl>[C:36]([N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([C:7]2[N:8]([CH3:14])[C:9](=[O:13])[C:10]3[C:5]([C:6]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:16]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(=O)n(C)c(C3CCCNC3)c(-c3ccccc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(=O)n(C)c(C3CCCN(C(C)=O)C3)c(-c3ccccc3)c2c1

Procedure:
To a dichloromethane (0.100 mL) solution of (±)-6-methoxy-2-methyl-4-phenyl-3-piperidin-3-ylisoquinolin-1(2H)-one (30 mg, 0.086 mmol) and N,N-diisopropylethylamine (0.017 mL, 0.095 mmol) was added acetyl chloride (0.007 mL, 0.095 mmol). After 24 hours saturated sodium bicarbonate and additional dichloromethane were added. The layers were separated and the organic phase dried with anhydrous magnesium sulfate. Evaporation of the solvent in vacuo followed by trituration with ether-EtOAc gave a white solid which was isolated by vacuum filtration to give the titled product. ESI+MS: 391.3 [M+H]+.
Reaction SMILES: [CH3:1][C@:2]1(CN2CCN(C(OC(C)(C)C)=O)CC2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.C1(C2C=CC(C=O)=CC=2)C=CC=CC=1.[B-]C#N.[Na+].C(O)(=O)C>>[CH3:1][CH:2]1[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: O=Cc1ccc(-c2ccccc2)cc1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC1Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 146.7 %

Procedure:
A mixture of tert-butyl (R)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylate prepared in Example 396 (100 mg, 0.27 mmol) and trifluoroacetic acid (2 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 ml) and neutralized with triethylamine (1 ml, 7.17 mmol), and then the solution was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml). To the solution, 4-phenylbenzaldehyde (149 mg, 0.82 mmol), sodium cyanotrihydroborate (51 mg, 0.82 mmol) and acetic acid (48 μl, 0.82 mmol) were added in this order followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added a saturated sodium hydrogencarbonate solution. The precipitates were filtered off and purified by silica gel column chromatography (ethyl acetate) to afford (R)-2-(biphenyl-4-ylmethyl)piperazin-1-ylmethyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (67 mg, yield 57%) as a light yellow powder.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:29])[O:4][C:5]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=[C:7]([NH:21][S:22]([N:25]2[CH2:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH:6]=1.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>ClCCl>[N:25]1([S:22]([NH:21][C:7]2[N:8]=[C:9]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])[N:10]=[C:5]([O:4][C@H:3]([CH3:29])[CH2:2][NH:1][C:36](=[O:38])[CH3:37])[CH:6]=2)(=[O:23])=[O:24])[CH2:26][CH2:27][CH2:28]1
Reactant: C[C@H](CN)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of N-[6-((R)-2-amino-1-methylethoxy)-2-[[(2,3-Difluorophenyl)methyl]thio]pyrimidin-4-yl]azetidine-1-sulfonamide (the title product of Example 42) (0.05 g) in dichloromethane (10 mL) was added pyridine (0.02 mL), followed by acetic anhydride (0.02 mL). The mixture was stirred overnight at room temperature. Pyridine (0.02 mL) and acetic anhydride (0.02 mL) were added and the reaction mixture was stirred for a further 2 h Pyridine (1.0 mL) and acetic anhydride (0.50 mL) were added and the reaction mixture was stirred for a further 2 h. The reaction mixture was diluted with dichloromethane, washed with aqueous citric acid, H2O, dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using 40% EtOAc in isohexane as eluent. The isolated product was further purified by reverse phase HPLC eluting with acetonitrile/aq. 0.1% ammonium acetate mixtures to give the title compound as a white solid. Yield: 55 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5](O)=[O:6].[NH2:17][C:18]([NH2:20])=[NH:19]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5]([NH:19][C:18]([NH2:20])=[NH:17])=[O:6]
Reactant: O=C(O)c1ccc(N2CCCCC2)c(Cl)c1
Reactant: N=C(N)N
Product: Cl
Product: N=C(N)NC(=O)c1ccc(N2CCCCC2)c(Cl)c1

Procedure:
From 3-chloro-4-piperidinobenzoic acid and guanidine (procedure B), colorless crystals, m.p. 155° C.,
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]([Cu])#[N:12].CCOC(C)=O>CN(C=O)C.O>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([C:11]#[N:12])=[N:7][CH:6]=1)(=[O:10])[CH3:9]
Reactant: N#C[Cu]
Reactant: CC(=O)c1ccc(Br)nc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1ccc(C#N)nc1
Temperature: 110 °C
Yield: 82.1 %

Procedure:
A mixture of 1-(6-bromopyridin-3-yl)ethanone (200 mg, 1.0 mmol) and CuCN (179 mg, 2.0 mmol) in anhydrous DMF (5 mL) was heated at 110° C. for 18 h under N2. The mixture was cooled to room temperature and diluted with water. After addition of EtOAc and filtration, the aqueous layer was extracted with EtOAc. The organic layer was washed with sat. NaHCO3 (aq), brine, and then dried (MgSO4) and concentrated. The product 5-acetylpicolinonitrile (120 mg) was obtained by silica gel chromatography (elution with 0-20% EtOAc/Hex).
Reaction SMILES: C1C2[C:10]3=CC4C=CC(C(O)=O)=CC=4[N:9]3[CH2:8]C=CC=2C=CC=1.CN(C)S(N)(=O)=[O:25].Cl.CN(C)CCCN=C=NCC.C[C:42]([N:44]([CH3:46])[CH3:45])=[O:43]>CN(C1C=CN=CC=1)C>[N:44]1([C:42]([OH:25])=[O:43])[CH2:46][CH2:10][NH:9][CH2:8][CH2:45]1
Reactant: CN(C)S(N)(=O)=O
Reactant: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Reactant: CC(=O)N(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: O=C(O)N1CCNCC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[4-[(1,1-dimethylethoxy)carbonyl]-1-piperazinyl]carbonyl] (100 mg, 0.18 mmol), N,N-dimethylsulfamide (110 mg, 0.89 mmol) and DMAP (110 mg, 0.90 mmol) in dimethylacetamide (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (135 mg, 0.71 mmol). The reaction solution was stirred at 50° C. overnight, concentrated, purified by preparative HPLC (MeOH/2O with NH4OAc buffer) to yield 1-piperazinecarboxylic acid, 4-[[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]carbonyl]-, 1,1-dimethylethyl ester (49 mg, 0.073 mol, 40%) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.58 (br d, J=7.6 Hz, 1H), 7.63-7.46 (m, 3H), 7.40 (br d, J=7.3 Hz, 1H), 6.87 (s, 1H), 5.15 (br s, 1H), 4.37 (br s, 1H), 3.56-3.22 (m, 8H), 3.06 (s, 6H), 2.89-2.81 (m, 1H), 2.15-1.15 (m, 10H), 1.44 (s, 9H). LCMS: m/e 676 (M+H)+, ret time 2.05 min, column B, 2 minute gradient.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[N:16]=[C:15](Cl)[N:14]=[C:13]4[N:18]([CH3:21])[N:19]=[CH:20][C:12]=34)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](B2OC(C)(C)C(C)(C)O2)=[N:23]1>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[N:16]=[C:15]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]5[C:25]=4[CH:24]=[N:23][NH:22]5)[N:14]=[C:13]4[N:18]([CH3:21])[N:19]=[CH:20][C:12]=34)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cn1ncc2c(Nc3ccc4c(c3)OCO4)nc(Cl)nc21
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Solvent: O
Product: Cn1ncc2c(Nc3ccc4c(c3)OCO4)nc(-c3cccc4[nH]ncc34)nc21

Procedure:
Benzo[1,3]dioxol-5-yl-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-amine was reacted with indazole boronic acid pinacol ester in General Procedure A. Addition of water gave a solid which was purified by preparative HPLC and trituration to give 156. NMR: (CDCl3): 3.52 (s, 3H, CH3), 4.17 (s, 3H, CH3), 6.10 (s, 2H, CH2), 6.92 (d, H, ArH, J=8.16 Hz), 7.00 (d, H, ArH, J=8.16 Hz), 7.10 (s, H, ArH), 7.16 (sbr, H, NH), 7.23 (s, H, ArH), 7.55 (t, H, ArH, J=8.17 Hz), 7.64 (d, H, ArH, J=8.31 Hz0, 8.41 (d, H, ArH, J=7.26 Hz), 9.16 (s, H, ArH), 10.20 (sbr, H, NH). MS: (ESI+) MH+=386.04
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[N:29]=[C:28]([NH:30][CH:31]([CH3:33])[CH3:32])[C:27]([F:34])=[C:26]([NH:35][NH2:36])[N:25]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[Cl:23][C:24]1[N:25]=[C:26]([NH:35][NH:36][C:8](=[O:10])[C@H:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[C:27]([F:34])=[C:28]([NH:30][CH:31]([CH3:33])[CH3:32])[N:29]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: CC(C)Nc1nc(Cl)nc(NN)c1F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)Nc1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
A mixture of (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (268 mg, 0.88 mmol), 2-chloro-5-fluoro-6-hydrazino-N-(1-methylethyl)-4-pyrimidinamine (assumed 253 mg of free base, 0.97 mmol), EDC (186 mg, 0.97 mmol), HOAt (132 mg, 0.97 mmol), and NMM (0.64 mL, 5.82 mmol) in DMF was stirred at room temperature overnight. The reaction mixture was then purified via reverse phase HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(1-methylethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (74 mg, 17%). LCMS: (M+H)+: 507.1.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:7][C:6]=12.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)#[CH:22]>>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][N:5]3[N:4]=[CH:3][C:2]([C:22]#[C:21][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[C:6]3[N:7]=2)=[CH:12][CH:13]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: FC(F)(F)c1ccc(-c2ccn3ncc(I)c3n2)cc1
Product: Nc1ccc(C#Cc2cnn3ccc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-iodo-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.33 step 1) (195 mg, 0.5 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (59 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (101 mg, 53%). MS (ISP) 380.0 [(M+H)+]; mp 213-214° C.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[C:15]([Br:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[Br:17].[CH3:18]O>>[NH2:6][C:7]1[C:8]([Br:17])=[CH:9][C:10]([C:11]([O:13][CH3:18])=[O:12])=[CH:14][C:15]=1[Br:16]
Reactant: Nc1c(Br)cc(C(=O)O)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c(N)c(Br)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
conc. H2SO4 (1.35 mL, 25.48 mmol) was added dropwise to a stirred solution of 4-amino-3,5-dibromobenzoic acid (5.0 g, 16.99 mmol) in MeOH (50 mL) at ambient temperature and the reaction mixture was then stirred at 80° C. for 8 h. The reaction mixture was allowed to cool to ambient temperature, volatiles were evaporated and ice-water was added to the residue and extracted with EtOAc. The organic layer was washed with aqueous NaHCO3 solution followed by brine and water, dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (5.0 g, 95%): 1H NMR (300 MHz, DMSO-d6) δ 7.91 (s, 2H), 6.20 (bs, 2H), 3.78 (s, 3H); ESIMS m/z 307.0 ([M]+); IR (thin film) 3312, 2953, 1726, 595 cm−1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](Cl)=[O:11])=[CH:2]1.[N:13]12[CH2:20][CH2:19][C:16]([CH2:21][NH2:22])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2>C(Cl)Cl>[N:13]12[CH2:20][CH2:19][C:16]([CH2:21][NH:22][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[O:11])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2
Reactant: NCC12CCN(CC1)CC2
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Solvent: ClCCl
Product: O=C(NCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
To a solution of 1H-indole-3-carbonyl chloride (112 mg, 0.625 mmol) in 3 mL of methylene chloride at 0° C. was added (quinuclidin-4-yl)methanamine (86 mg, 0.614 mmol) in 2 mL of methylene chloride. The mixture was stirred at room temperature overnight. The solvent was evaporated and water (20 mL) was added. The water layer was basified to pH 12 with 10% aqueous potassium hydroxide and extracted three times with 25 mL each of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to yield 26 mg of the desired product. 1HNMR: 11.6 (bs, 1H); 8.15 (m, 1H); 8.13 (bs, 1H); 7.65 (bs, 1H); 7.42 (d, 1H); 7.15 (m, 2H); 3.1 (m, 2H); 2.65 (m, 6H); 1.40 (m, 6H). MS (m/e): 284.
Reaction SMILES: [Br:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:21](O)([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[C:21]([O:5][C:4](=[O:6])[CH2:3][CH:2]([Br:1])[CH3:7])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(Br)CC(=O)O
Reactant: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(Br)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The required 3-bromobutyric acid tert-butyl ester was prepared as follows: To a solution of 3-bromobutyric acid (5.0 mL; 47.0 mmol) in tetrahydrofuran (50 mL) was added dropwise trifluoroacetic anhydride (13.7 mL; 98.7 mmol) at −40° C. After 1 hour at −40° C. tert-butyl alcohol (20 mL) was added. The resulting mixture was allowed to warm to RT and stirred overnight. Subsequently, the reaction mixture was concentrated in vacuo. The residue was treated with 2M aqueous NaOH solution and extracted with Et2O. The organic layer was dried (Na2SO4), and concentrated in vacuo to afford 3-bromobutyric acid tert-butyl ester (6.05 g), which was used as such.