Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]1[N:19]=[C:18]([N:20]2C(=O)C3C(=CC=CC=3)C2=O)[CH:17]=[CH:16][CH:15]=1.O.NN>C1COCC1>[NH2:3][O:12][CH2:13][C:14]1[N:19]=[C:18]([NH2:20])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1cccc(N2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: NOCc1cccc(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(6-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}pyridin-2-yl)-1H-isoindole-1,3(2H)-dione (50 g, 125 mmol) in THF (350 mL) was added dropwise hydrazine hydrate (61 mL, 1.25 mol) at room temperature. After stirring overnight at room temperature, the reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo. Purification of the residue on silica gel afforded 6-[(aminooxy)methyl]pyridin-2-amine as a colourless oil [10.0 g; 57% of theory; HPLC/MS: m/z=140 (M+H); log P(HCOOH)<−0.23].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([CH:20]3[CH2:25][CH2:24][CH2:23][O:22][CH2:21]3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:26].[I-].N.CCO>>[NH2:26][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([CH:20]3[CH2:25][CH2:24][CH2:23][O:22][CH2:21]3)[CH2:10]2)[N:12]=1
Reactant: [NH4+]
Reactant: CSC1=NC2(CC(C3CCCOC3)Oc3ccc(Br)cc32)C(=O)N1C
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N=C1N
Yield: 107.9 %

Procedure:
A solution of 6-bromo-1′-methyl-2′-(methylthio)-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.047 mmol), NH4I (54.5 mg, 0.37 mmol) in a solution of NH3/EtOH (2 mL, 8 N) was heated at 120° C. in a tube in a microwave reactor for 3 h. After cooling, the mixture was concentrated in vacuo to give 2′-amino-6-bromo-1′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C1(S(O[CH2:21][CH2:22][Cl:23])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:23][CH2:22][CH2:21][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCCCl)c1ccccc1
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: NC(=O)c1ccc(OCCCl)cc1

Procedure:
A mixture of 4-hydroxybenzamide (194 g, 1.25M), 2-(benzenesulphonyloxy)ethyl chloride (359 g, 1.8M), and potassium carbonate (172.8 g, 1.25M) in butan-2-one (2.16 1) was stirred at reflux for 24 hours. After cooling, distilled water (2.0 1) was added and the resultant precipitate filtered off, washed with water, and dried. Crystallisation from ethanol gave the title compound, yield (232.0 g), m.p. 66°.
Reaction SMILES: [CH2:1]([N:3]([C@H:47]1[CH2:52][CH2:51][C@H:50]([C:53]([O:55]C)=[O:54])[CH2:49][CH2:48]1)[S:4]([C:7]1[CH:8]=[C:9]([CH:44]=[CH:45][CH:46]=1)[C:10]([NH:12][C:13]1[S:14][C:15]2[CH2:43][CH2:42][CH2:41][CH2:40][C:16]=2[C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1)=[O:19])=[O:11])(=[O:6])=[O:5])[CH3:2].CO.[OH-].[Na+]>C1COCC1>[C:53]([C@H:50]1[CH2:51][CH2:52][C@H:47]([N:3]([CH2:1][CH3:2])[S:4]([C:7]2[CH:8]=[C:9]([CH:44]=[CH:45][CH:46]=2)[C:10]([NH:12][C:13]2[S:14][C:15]3[CH2:43][CH2:42][CH2:41][CH2:40][C:16]=3[C:17]=2[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=3)=[CH:23][CH:22]=2)=[O:19])=[O:11])(=[O:6])=[O:5])[CH2:48][CH2:49]1)([OH:55])=[O:54]
Reactant: CCN([C@H]1CC[C@H](C(=O)OC)CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN([C@H]1CC[C@H](C(=O)O)CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a mixture of 230 mg of methyl 4-(3-{4-[({2-[(3-{ethyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}propyl)benzoate, 2 mL of methanol, and 2 mL of THF was added 2 mL of a 1 M aqueous NaOH solution, followed by stirring at 60° C. for 2 days. The reaction mixture was cooled and then concentrated under reduced pressure. The obtained residue was diluted with water and then neutralized with 1 M hydrochloric acid. To the reaction mixture was added 0.5 mL of THF and the precipitate was collected by filtration. The obtained solid was suspended in 10 mL of ethanol, and then the precipitate was collected by filtration to obtain 147 mg of 4-{3-[4-({[2-({3-[(trans-4-carboxycyclohexyl)(ethyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]propyl}benzoic acid as a beige crystal.
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25].CCN(C(C)C)C(C)C>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:25][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Reactant: NCc1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCc2cccc(F)c2)S/C1=C\c1ccc2ncncc2c1

Procedure:
Similar procedure as described in example 1d was used, starting from 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one, 3-fluoro-benzylamine and DIEA to give 2-(3-fluoro-benzylamino)-5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one: LC-MS m/e observed. LC-MS m/e 379 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C@@H](NS(C(C)(C)C)=O)CC)=[CH:4][CH:3]=1.Cl.[O:19]1[CH2:24][CH2:23]OCC1.[CH3:25][CH2:26]OCC>CO>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:24]([OH:19])[CH2:23][CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1ccc(Br)nc1
Reactant: C1COCCO1
Reactant: CCOCC
Agent: Cl
Solvent: CO
Product: CCCC(O)c1ccc(Br)nc1
Reaction time: 2 h

Procedure:
To a mixture of 2-methyl-propane-2-sulfinic acid [(S)-1-(6-bromopyridin-3-yl)-propyl]-amide (5.35 g, 16.8 mmol) in methanol (25 mL) is added a solution of 4 N HCl in dioxane (10 mL, 40 mmol). After 2 hour, the mixture is concentrated to near dryness to afford a white solid. The solid is diluted with ether and collected by filtration to afford the title compound.
Reaction SMILES: O.C(O)(=O)C.[CH:6]([C:9]1[CH:25]=[CH:24][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1)([CH3:8])[CH3:7].C(=O)([O-])[O-].[Na+].[Na+]>[Fe].C(O)C>[CH:6]([C:9]1[CH:25]=[CH:24][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1)([CH3:8])[CH3:7]
Reactant: CC(C)c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)c1ccc(C(=O)c2ccc(N)cc2)cc1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
800 parts of water, 250 parts of iron chips and 28 parts of acetic acid are initially introduced, and the mixture is heated to 95° C. and stirred for 1 hour at 95° C. It is then cooled to 90° C., 800 parts of ethanol are added, and 55 parts of 4-isopropyl-4'-nitrobenzophenone are added in a solid form in small portions in the course of 30 minutes. The mixture is heated for 8 hours under reflux, its pH is adjusted to 9 by means of 44 parts of sodium carbonate solution, 600 parts of ethanol are added, heating under reflux is carried out for 15 hours, the mixture is filtered hot and the residue is washed three times with 200 parts each of hot ethanol. Ethanol is distilled off from the combined filtrates and the aqueous bottom is cooled down. The precipitated crystals are then filtered off and dried in vacuo. 45.5 parts of 4-isopropyl- 4'-aminobenzophenone having a melting point of 110° C. are obtained. The valuable dyestuff of the formula VI ##STR7## can be prepared from 4-isopropyl-4'-aminobenzophenone as indicated in German Offenlegungsschrift No. 2,001,821, Table 1, Example 15.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([C:11]3[N:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=3)[C:6]=2[CH:18]=1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C@:25]([OH:29])([C:27]#[CH:28])[CH3:26])[CH:21]=1>N1CCCCC1.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.[Cu]I>[NH2:17][C:13]1[N:14]=[CH:15][N:16]=[C:11]([N:7]2[C:6]3[CH:18]=[C:2]([C:28]#[C:27][C@:25]([C:22]4[CH:21]=[C:20]([CH3:19])[O:24][N:23]=4)([OH:29])[CH3:26])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[CH3:10])[N:12]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: Cc1nc2ccc(Br)cc2n1-c1ncnc(N)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3nc(C)n(-c4ncnc(N)n4)c3c2)no1
Temperature: 95 °C
Yield: 39.4 %

Procedure:
To a solution of 4-(6-bromo-2-methyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-amine (160 mg, 0.52 mmol) in piperidine (2 mL) was introduced tetrakis(triphenylphosphine)palladium(0) (60.59 mg, 0.05 mmol), copper(I) iodide (9.99 mg, 0.05 mmol) and (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (118.9 mg, 0.79 mmol). The reaction was then warmed to 95° C. for 40 minutes (75 W, microwave heating). The reaction mixture was then cooled to RT and concentrated in vacuo. Purification of the residue by flash column chromatography (4-8% MeOH gradient in DCM) gave the title compound as a pale brown solid (77 mg): 1H NMR (500 MHz, DMSO) delta 1.81 (3H, s), 2.41 (3H, s), 2.90 (3H, s), 6.37 (1H, s), 6.51 (1H, s), 7.33 (1H, dd, J=8.28, 1.50 Hz), 7.60 (1H, d, J=8.20 Hz), 8.01 (1H, br. s.), 8.06 (1H, br. s.), 8.40 (1H, s), 8.66 (1H, s); LC-MS: m/z=+376.45 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/I)=[CH:9]/[CH2:10][N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH3:12])=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:20]2[CH:21]=[CH:22][S:18][CH:19]=2)=[CH:9]/[CH2:10][N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH3:12])=[CH:4][CH:3]=1
Reactant: CN(C/C=C(\I)c1ccc(Br)cc1)CC(=O)O
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CN(C/C=C(/c1ccc(Br)cc1)c1ccsc1)CC(=O)O
Temperature: 90 °C
Reaction time: 4.5 h

Procedure:
To a solution of (Z)-N-(1-(4-bromophenyl)-1-iodoprop-1-en-3-yl)sarcosine, tbutyl ester D (29.86 g, 64.06 mmol) in dimethoxyethane (300 mL) was added 3-thiopheneboronic acid (9.02 g, 70.47 mmol), Pd(PPh3)4 (3.70 g, 3.20 mmol), and 2M Na2CO3 (300 mL). The reaction was warmed to 90° C. with vigorous mechanical stirring for 4.5 hours. The mixture was cooled, and partitioned between EtOAc and water. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated. Column chromatography (2-5% acetone/hexanes) provided (Z)-N-(1-(4-bromophenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine, tbutyl ester E(i) (27.06 g, 78%) as a yellow oil. 1H NMR (300 MHz, CDCl3) 1.43 (s, 9H), 2.36 (s, 3H), 3.14 (s, 2H), 3.28 (d, 2H), 6.16 (7, 1H), 6.86 (d, 1H), 7.12-7.14 (m, 3H), 7.32 (collapsed dd, 1H), 7.41 (d, 2H).
Reaction SMILES: C([C:4]1([O:18][C@H:17]([CH2:19][Cl:20])[C@H:16]([Cl:21])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])[OH:5])(=O)C.C(O)(=O)C.NN>CN(C=O)C.ClCCl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:16]([Cl:21])[C@@H:17]([CH2:19][Cl:20])[O:18][CH:4]1[OH:5])(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@H]1[C@@H](Cl)[C@@H](CCl)OC(O)(C(C)=O)[C@@H]1OC(C)=O
Agent: NN
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@@H](Cl)[C@@H](CCl)OC(O)[C@@H]1OC(C)=O
Yield: 105.8 %

Procedure:
A solution of acetyl 2,3-di-O-acetyl-4,6-dichloro-4,6-dideoxy-D-galactopyranose (compound 82) (2.24 g, 6.5 mmol) and hydrazine acetate (903 mg) in DMF (22 mL) was stirred for 2 hours at room temperature. The reaction mixture was then diluted with dichloromethane (250 mL) and washed 4 times with water (4×250 mL), dried over anhydrous sodium sulfate and evaporated. Flash chromatography using hexane-ethyl acetate (1:1) as an eluent gave 2,3-di-O-acetyl-4,6-dichloro-4,6-dideoxy-D-galactopyranose (~6.88 mmol). This compound was then dissolved in dichloromethane (20 mL) cooled to 0° C., and trichloroacetonitrile (3.35 mL, 34.4 mmol) was added. After stirring at 0° C. for 40 minutes, the solvent was evaporated and the residue was chromatographed on a silica gel column, eluting with hexane-ethyl acetate (5:1), to give imidate 83 (1.14 g, 39%) as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][CH2:17][C@@:18]([CH3:33])([S:29]([CH3:32])(=[O:31])=[O:30])[C:19]([NH:21][O:22]C2CCCCO2)=[O:20])[CH:12]=1>O1CCOCC1.ClCCl.O>[C:19]([NH2:21])(=[O:20])[CH2:18][CH2:17][CH3:16].[F:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][CH2:17][C@@:18]([CH3:33])([S:29]([CH3:32])(=[O:31])=[O:30])[C:19]([NH:21][OH:22])=[O:20])[CH:12]=1
Reactant: COc1cccc(-c2cc(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)no2)c1F
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCC(N)=O
Product: COc1cccc(-c2cc(CC[C@](C)(C(=O)NO)S(C)(=O)=O)no2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
Hydrochloric acid (4.0 M in 1,4-dioxane, 0.13 mL, 0.51 mmol, 4 equiv) was added to a solution of (2R)-4-[5-(2-fluoro-3-methoxyphenyl)isoxazol-3-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.60 g, 0.13 mmol, 1.0 equiv) in 1,4-dioxane-dichloromethane-water (2:2:1, 2.5 mL), and the reaction was allowed to stir at room temperature for 2 h. The solvent was removed under reduced pressure, and the resulting crude material purified by preparative HPLC (Sepax 2-ethyl pyridine 250×21.2 mm 5 μm, heptane-ethanol solvent system as eluent) to provide (2R)-4-[5-(2-Fluoro-3-methoxyphenyl)isoxazol-3-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide butanamide (0.01 g, 20%). MS (LCMS) m/z 385.0 (M−1). 1H NMR (400 MHz, METHONAL-d4) δ1.59-1.71 (m, 3H) 2.13-2.29 (m, 1H) 2.61-2.81 (m, 2H) 2.80-2.99 (m, 1H) 3.07 (s, 3H) 3.92 (s, 3H) 6.65-6.84 (m, 1H) 7.16-7.30 (m, 2H) 7.37-7.52 (m, 1H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH3:11][C:8]1[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:10][CH:9]=1
Reactant: CCOC(=O)C1CC=C(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=CCC(C(=O)O)C1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A solution of the 3-Methyl-cyclopent-3-enecarboxylic acid ethyl ester (255 mg, 1.65 mmol) in MeOH (4.0 mL) and 10% aq. NaOH (3.3 mL, 8.25 mmol) was heated at 50° C. for 16 h, reaction mixture was cooled to room temperature, solvent was evaporated, diluted with water. The aqueous solution was washed with ether, and acidified with aq. 1 N HCl, extracted with ether. The ethereal solution was washed with brine and dried. Evaporation of the solvent furnished the 3-Methyl-cyclopent-3-enecarboxylic acid (200 mg, 97% yield). 1H NMR (CDCl3, 400 MHz) 5.27 (brs, 1H), 3.26-3.17 (m, 1H), 2.7-2.55 (m, 4H), 1.74 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[CH:6]=[CH:7][CH2:8]Cl)([O-:3])=[O:2].[NH2:14][C:15]1[S:16][C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][C:23]=2[N:24]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:14][C:15]1[S:16][C:17]2[CH2:18][CH2:19][N:20]([CH2:8][CH:7]=[CH:6][C:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:21][CH2:22][C:23]=2[N:24]=1
Reactant: O=[N+]([O-])c1ccccc1C=CCCl
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Nc1nc2c(s1)CCN(CC=Cc1ccccc1[N+](=O)[O-])CC2
Yield: 57 %

Procedure:
Prepared from 2-nitro-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform. Yield: 57% of theory, Melting point: 125°-128° C. (ether).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:27][C:26](=O)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]\[C:57]([OH:59])=[O:58]>ClCCCl.C(O)C>[C:54]([O-:61])(=[O:60])/[CH:55]=[CH:56]\[C:57]([O-:59])=[O:58].[C:54]([O-:61])(=[O:60])/[CH:55]=[CH:56]\[C:57]([O-:59])=[O:58].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:27][CH:26]([NH+:33]4[CH2:34][CH2:35][NH+:30]([CH3:29])[CH2:31][CH2:32]4)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[C:3]=12.[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:27][CH:26]([NH+:33]4[CH2:34][CH2:35][NH+:30]([CH3:29])[CH2:31][CH2:32]4)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: O=C(O)/C=C\C(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CC(=O)C1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCO
Product: C[NH+]1CC[NH+](C2CC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)C2)CC1
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 40 °C
Yield: 0.1 %

Procedure:
A mixture of 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclobutanone (0.300 g, 0.00081 mol), N-methylpiperazine (0.243 g, 0.00242 mol) and acetic acid (0.146 g, 0.00242 mol) in 1,2-dichloroethane (20 ml) was stirred for twenty min at 40° C. and sodium triacetoxyborohydride (0.223 g, 0.00105 mol) was added in three portions over one hour. The mixture was stirred for eighteen hours at 40° C. The solvent was removed under reduced pressure and the residue partitioned between aqueous saturated sodium bicarbonate solution (30 ml) and chloroform (15 ml). The organic layer was separated and the aqueous layer was further extracted with chloroform three times (15 ml each). The combined organic extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to yield yellow oil that was purified by flash chromatography on silica gel using dichloromethane/methanol (97:3) as a mobile phase. The solvent was removed in vacuo and the residue (0.120 g, 0.000263 mol) was dissolved in absolute ethanol (10 mL). A solution of maleic acid (0.122 g, 0.001053 mol) in absolute ethanol (5 mL) was added and the mixture was stirred at reflux for fifteen minutes. The solution was cooled to room temperature and the precipitate was filtered, washing with absolute ethanol (3×5 mL). The solvent was removed in vacuo to give 1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutyl}-4-methylhexahydropyrazinediium dimaleate (0.181 g, 0.000397 mmol) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[C:13]([C:16]1[S:20][C:19](B(O)O)=[CH:18][CH:17]=1)([OH:15])=[O:14].C(N(CC)CC)C>CN(C=O)C>[CH:11]([C:10]1[CH:9]=[N:8][N:5]2[CH:6]=[CH:7][C:2]([C:19]3[S:20][C:16]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=3)=[N:3][C:4]=12)=[O:12]
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=Cc1cnn2ccc(-c3ccc(C(=O)O)s3)nc12
Temperature: 100 °C
Yield: 22 %

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (590 mg, 3.25 mmol) in DMF was added 5-Carboxythiophene-2-boronic acid (670 mg, 3.9 mmol), triethylamine (1.13 mL, 8.11 mmol) and dichloro-((bis-diphenylphosphino)ferrocenyl)palladium(II) dichloromethane adduct (120 mg, 0.16 mmol). The reaction mixture was degassed with nitrogen then heated at 100° C. for 2 hours. The mixture was cooled to room temperature, diluted with 1N HCl, and filtered. The collected solid was washed with 1N HCl and dried under vacuum. The desired product, 5-(3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid, was recovered in 22% yield and used for the next step without further purification. LCMS (M+1=274)
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[CH:10][CH:9]=1.[CH3:19][C:20]([CH3:22])=O>[Cl-].[Cl-].[Zn+2]>[C:5]([C:20]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[CH:12][CH:13]=1)([CH3:22])[CH3:19])#[N:6]
Reactant: CC(C)=O
Reactant: C[Si](C)(C)C#N
Reactant: N#CCCCc1ccc(N)cc1
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)(C#N)Nc1ccc(CCCC#N)cc1
Yield: 99.7 %

Procedure:
TMSCN (0.3 mL, 2.25 mmol) was added to a mixture of compound 83 (120 mg, 0.75 mmol), acetone (0.33 mL, 4.5 mmol) and ZnCl2 (10 mg, 0.08 mmol) with stirring. The reaction mixture was stirred at room temperature for 1 h, and concentrated in vacuo. The residue was diluted with water, and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give compound 84 (170 mg, 99%) as a light yellow oil. The crude product was used directly for the next step without purification. 1H NMR (400 MHz, CDCl3) δ7.08 (d, 2H, J=8.1 Hz), 6.88 (d, 2H, J=8.1 Hz), 2.72 (t, 2H, J=7.4 Hz), 2.32 (t, 2H, J=7.4 Hz), 1.90-2.00 (m, 2H), 1.69 (s, 6H).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:7]([NH:32][CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)=[N:8][C:9]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=3[N:20]=[C:19]2[CH:29]([F:31])[F:30])=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CC(O)=O.O.O>[F:31][CH:29]([F:30])[C:19]1[N:18]([C:9]2[N:10]=[C:11]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[C:6]3[N:5]=[N:1][N:32]([CH:33]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]4)[C:7]=3[N:8]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=2[N:20]=1
Reactant: O=N[O-]
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c(N2CCOCC2)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2nnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
Aqueous NaNO2 solution (0.5 M, 1.7 mL) was added dropwise to a stirred suspension of tert-butyl 4-{[5-amino-2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4-pyrimidinyl]amino}-1-piperidinecarboxylate (Example 96) (250 mg, 0.435 mmol) in HOAc/H2O (2:1, 12 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1.5 hrs and then diluted with H2O. The resulting precipitate was collected by filtration, washed sequentially with H2O and aqueous NH3, and dried to give tert-butyl 4-[5-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-7-(4-morpholinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-1-piperidinecarboxylate (192 mg, 75%): mp (CH2Cl2/hexanes) 220-222° C.; 1H NMR (CDCl3) δ 7.81 (dd, J=8.4, 0.6 Hz, 1H), 7.42 (t, JHF=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.71 Hz, 1H), 4.92 (tt, J=11.3, 4.1 Hz, 1H), 4.79 (br s, 2H), 4.33 (m, 2H), 4.15 (br s, 2H), 3.92 (dd, J=13.4, 3.0 Hz, 4H), 3.05 (t, J=12.0 Hz, 2H), 2.40 (dq, J=12.0, 4.4 Hz, 2H), 2.18 (dd, J=12.9, 2.5 Hz, 2H), 1.50 (s, 9H); Anal. Calcd. for C27H33F2N9O4: C, 55.4; H, 5.7; N, 21.5. Found: C, 55.5; H, 5.7; N, 21.3%.