Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)C(O)=O)[N:16]=2)[CH:12]=[N:11]1)[CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)#[N:2].C1C=CC(OP(OC2C=CC=CC=2)([N:40]=[N+]=[N-])=O)=CC=1.C(N(CC)CC)C.O>O1CCOCC1>[NH2:40][C:24]1[CH:23]=[C:22]([NH:21][C:17]2[N:16]=[C:15]([C:13]3[CH:12]=[N:11][N:10]([CH:4]([CH:5]4[CH2:9][CH2:8][CH2:7][CH2:6]4)[CH2:3][C:1]#[N:2])[CH:14]=3)[CH:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: N#CCC(C1CCCC1)n1cc(-c2ccnc(Nc3cccc(C(=O)O)c3)n2)cn1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: N#CCC(C1CCCC1)n1cc(-c2ccnc(Nc3cccc(N)c3)n2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)benzoic acid (228 mg, 0.566 mmol), and diphenylphosphonic azide (0.18 mL, 0.85 mmol), triethylamine (0.16 mL, 1.1 mmol) in 1,4-dioxane (4.2 mL) was stirred at room temperature overnight. To the resulting mixture was added water (0.36 mL). The reaction was refluxed overnight. The crude racemic mixture was used directly in next step. An analytically pure sample was obtained by RP-HPLC (pH 2). LCMS (M+H) 374.1.
Reaction SMILES: [C:1](O)(=O)[C:2]([OH:4])=[O:3].[CH3:7][N:8]([CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[C:9](=[O:12])[CH2:10][NH2:11].C(=O)([O-])[OH:33].[Na+]>C(Cl)(Cl)Cl>[C:30]([OH:33])(=[O:29])[CH2:31][CH2:1][C:2]([OH:4])=[O:3].[CH3:7][N:8]([CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[C:9](=[O:12])[CH2:10][NH2:11].[CH3:7][N:8]([CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[C:9](=[O:12])[CH2:10][NH2:11]
Reactant: O=C(O)C(=O)O
Reactant: O=C([O-])O
Agent: CN(Cc1cccc(-c2ccc(N3CCOCC3)cc2)c1)C(=O)CN
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(O)CCC(=O)O
Reaction time: 0.17 h

Procedure:
To N-methyl-N-{[4′-(morpholin-4-yl)biphenyl-3-yl]methyl}glycinamide oxalate (100 mg) were added CHCl3 (10 ml) and a saturated aqueous sodium hydrogen carbonate solution (10 ml), followed by stirring for 10 minutes. The aqueous layer was extracted with chloroform (10 ml). The combined organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in EtOH (2 ml), and succinic acid was added thereto, followed by stirring for 3 hours. The resulting crystal was filtered and washed with EtOH. The product residue was dried under reduced pressure and dried to obtain N-methyl-N-{[4′-(morpholin-4-yl)biphenyl-3-yl]methyl}glycinamide hemisuccinate (85 mg) as a colorless crystal.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][SH:24])=[CH:19][CH:18]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:24][C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:19][CH:18]=1
Reactant: COc1ccc(CS)cc1
Reactant: CCOC(=O)COc1ccccc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccccc1SCc1ccc(OC)cc1
Yield: 79 %

Procedure:
To a solution of ethyl 2-(2-bromophenoxy)acetate (3.0 g, 0.0116 mol) in dioxane (30 mL) was added (4-methoxyphenyl)methanethiol (2.14 g, 0.0139 mol), Pd2(dba)3 (20 mg), xantphos (20 mg) and DIEA (3 mL). The mixture was degassed 4 times (N2) and heated at reflux for 3 h, concentrated, and the crude product was purified by column chromatography. (3 g, yield 79%) MS (ESI+) e/z: 355.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][P:3](CC(CC(C)C)C(O)=O)([CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=[O:4].NC1CCCCCCCCCCC(=O)N1>>[CH3:1][O:2][PH:3]([CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=[O:4]
Reactant: COP(=O)(CC(CC(C)C)C(=O)O)CN1C(=O)c2ccccc2C1=O
Agent: NC1CCCCCCCCCCC(=O)N1
Product: CO[PH](=O)CN1C(=O)c2ccccc2C1=O

Procedure:
In an analogous manner to that described in Example 1(A)(iv), from 0.367 g of 2(RS)-[[(RS)-(methoxy)(phthalimidomethyl)phosphinyl]methyl]-4-methylvaleric acid and 0.2 g of (-)-3-amino-2-azacyclotridecanone there was obtained 0.21 g of [(RS)-4-methyl-2-[[(R or S) -2-oxoazacyclotridecyl]carbamoyl]pentyl](phthalimidomethyl)phosphinic acid methyl ester in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:30][CH:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[C:4]([CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].C([BH3-])#N.[Na+].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(O)(=O)C>CO.O>[F:1][C:2]1[C:3]([NH:30][CH:31]2[CH2:32][CH2:33][CH:34]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH2:35][CH2:36]2)=[C:4]([CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cc(F)c(NC4CCC(=O)CC4)c(C(=O)N(C)C)c3)cc12
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cc(F)c(NC4CCC(N5CCOCC5)CC4)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-2-(4-oxo-cyclohexylamino)-benzamide (91 mg, 0.14 mmol), sodium cyanoborohydride (17.5 mg, 0.28 mmol), and morpholine (37 μL, 0.41 mmol) were dissolved in 1.7 mL methanol, containing 5% v/v of glacial acetic acid and 2% v/v of water. The reaction was stirred for 2 hrs at ambient temperature and quenched with a saturated sodium bicarbonate solution. The mixture was concentrated, suspended in a minimal amount of water and loaded onto a 5 g C18 functionalized silica gel cartridge. The cartridge was washed with 1 N aqueous potassium hydrogensulfate and water. Elution with acetonitrile and evaporation of the solvent afforded a brown oil which was purified by reverse-phase HPLC to afford 10.4 mg (0.014 mmol, 10%) of both diastereoisomers of 3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-2-(4-morpholin-4-yl-cyclohexylamino)-benzamide as a white powder. More polar diastereoisomer (4.5 mg) 1H NMR (500 MHz, DMSO-d6) δ13.75 (bs, 1H), 8.81 (d, J=2 Hz, 1H), 8.27 (d, J=2 Hz, 1H), 8.16 (s, 1H), 7.62 (dd, J=7.5 Hz, J2=1.5 Hz, 1H), 7.58 (dd, J=13.5 Hz, J2=2 Hz, 1H), 7.45 (ddd, J=8 Hz, J2=7 Hz, J3=1.5 Hz, 1H), 7.30 (d, J=2 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.08 (td, J=7.5 Hz, J2=1 Hz, 1H), 4.56 (d, J=9 Hz, 1H), 3.82 (s, 3H), 3.53 (t, J=4.5 Hz, 4H), 3.11 (m, 1H), 2.99 (bs, 3H), 2.90 (s, 3H), 2.43 (t, J=4.5 Hz, 4H), 2.14 (m, 1H), 1.88 (m, 2H), 1.82 (m, 2H), 1.17 (m, 4H). MS: m/z 573.4 (M+H+). Less polar diastereoisomer (5.9 mg) 1H NMR (500 MHz, DMSO-d6) δ13.77 (bs, 1H), 8.82 (s, 1H), 8.30 (s, 1H), 7.61 (m, 2H), 7.45 (t, J=8 Hz, 1H), 7.34 (m, 1H), 7.20 (d, J=8 Hz, 1H), 7.08 (t, J=8 Hz, H), 4.87 (d, J=9 Hz, 1H), 3.82 (s, 3H), 3.56 (m, 5H), 2.96 (m, 6H), 2.41 (m, 4H), 2.14 (m, 1H), 1.65 (m, 2H), 1.51 (m, 2H), 1.48 (m, 4H). MS: m/z 573.3 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([NH:14][S:15]([C:18]([Cl:22])=[C:19]([Cl:21])[Cl:20])(=[O:17])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl:23][C:24]([Cl:30])([S:28]Cl)[CH:25]([Cl:27])[Cl:26]>ClCCl>[CH:8]1([N:14]([S:28][C:24]([Cl:30])([Cl:23])[CH:25]([Cl:27])[Cl:26])[S:15]([C:18]([Cl:22])=[C:19]([Cl:20])[Cl:21])(=[O:17])=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=S(=O)(NC1CCCCC1)C(Cl)=C(Cl)Cl
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C(Cl)=C(Cl)Cl)N(SC(Cl)(Cl)C(Cl)Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A 4.0 g (0.04 mol) sample of triethylamine was added dropwise to a cooled (-10° to 0° C.) solution of 9.5 g (0.0324 mol) N-(cyclohexyl)trichlorovinylsulfonamide, m.p. 152°-153° C., and 7.6 g (0.0324 mol) 1,1,2,2-tetrachloroethylsulfenyl chloride in 200 ml dichloromethane. The reaction mixture was then stirred at about 25° C. for 3 hours, washed with water, dried over magnesium sulfate and evaporated to give an oil. The oil was chromatographed on silica gel. The N-cyclohexyl-N-(1,1,2,2-tetrachloroethylthio)trichlorovinylsulfonamide product, 11 g (72% yield), was eluted from the silica gel with 30% ether/20% hexane. The infrared spectrum of the product showed strong absorption bands at 1385 cm-1 and 1160 cm-1. The elemental analysis for the product is tabulated in Table I under Compound No. 6.
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]([OH:24])[CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(OCC)(=O)C>[NH3:20].[CH:25]1([NH:31][C:4]([C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]([OH:24])[CH2:19][NH:20][CH:21]([CH3:22])[CH3:23])[C:9]=3[C:10]=2[CH3:11])=[O:5])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1oc2cccc(OCC(O)CNC(C)C)c2c1C
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NC2CCCCC2)oc2cccc(OCC(O)CNC(C)C)c12
Product: N
Yield: 25 %

Procedure:
A mixture of 4-(2-hydroxy-3-isopropylamino-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (A. N. Grinev et al., Otkrytiya, Izobret. 1986, (43), 275) (10 mg) and cyclohexylamine (50 μl) was heated at 175° C. for 11 hours. The reaction mixture was dissolved in ethyl acetate and washed with 0.1 N HCl solution and water. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by preparative thin layer chromatography (using dichloromethane:MeOH:ammonia solution (25-28%)=10:1:0.2 as a developing solvent) to give 4-(2-hydroxy-3-isopropylamino-propoxy)-3-methyl-benzofuran-2-carboxylic acid cyclohexylamide (7 mg) as a white powder. FAB-MS: m/z 389 (MH+); 1H-NMR (CDCl3): δ 1.10 (6H, d, J=6 Hz), 1.20-2.04 (10H, m), 2.78 (3H, s), 2.83 (1H, m), 2.87 (1H, dd, J1=12.5 Hz, J2=6 Hz), 2.97 (1H, dd, J1=12.5 Hz, J2=3 Hz), 3.97 (1H, m), 4.08 (3H, m), 6.45 (1H, br d, J=8 Hz), 6.64 (1H, d, J=8 Hz), 7.04 (1H, d, J=8 Hz), 7.27 (1H, t, J=8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([Cl:13])[N:7]=[C:6]1Cl.[C:16]([O:20][C:21](=[O:29])[NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([Cl:13])[N:7]=[C:6]1[N:26]1[CH2:25][CH2:24][CH:23]([NH:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:29])[CH2:28][CH2:27]1
Reactant: COC(=O)Cn1c(Cl)nc(Cl)c(Cl)c1=O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(Cl)c(Cl)c1=O
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a solution of (2,4,5-trichloro-6-oxo-6H-pyrimidin-1-yl)-acetic acid methyl ester (6.0 g, 22.4 mmol) and piperidin-4-yl-carbamic acid tert-butyl ester (4.9 g, 24.4 mmol) in DMF (50 mL) was added DIPEA (5.7 g, 44.3 mmol) dropwise at RT, and the mixture was stirred overnight. The reaction mixture was diluted with water (500 mL), and the solids were collected by filtration. The solids were then dissolved in DCM (100 mL), washed with water (100 mL, 3×), washed with brine (100 mL), dried (Na2SO4) and concentrated. The residue was purified by silica chromatography (1:2 to 1:1, DCM:PE) to give 6.3 g of the title product (64%). 1H NMR (400 MHz, CDCl3): δ 1.22-1.34 (m, 2H), 1.45 (s, 9H), 1.97-2.03 (m, 2H), 2.96-3.09 (m, 2H), 3.68-3.69 (m, 1H), 3.75 (s, 3H), 4.42-4.44 (m, 3H), 4.84 (s, 2H). [M+H] Calc'd for C17H24Cl2N4O5, 435. Found, 435.
Reaction SMILES: [H-].[Na+].CS(C)=O.[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:35])[CH2:16][CH2:17][CH2:18][N:19]2[CH2:26][CH:25]3[CH2:27][CH:21]([CH2:22][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]3)[CH2:20]2)=[CH:11][CH:10]=1)#[N:8].[N:36]1[CH:41]=[CH:40][C:39]([CH2:42]Cl)=[CH:38][CH:37]=1>CN(C=O)C.O>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH:15]([O:35][CH2:42][C:39]2[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=2)[CH2:16][CH2:17][CH2:18][N:19]2[CH2:20][CH:21]3[CH2:27][CH:25]([CH2:24][N:23]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:22]3)[CH2:26]2)=[CH:13][CH:14]=1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CC2CC(CN(CCCC(O)c3ccc(C#N)cc3)C2)C1
Reactant: ClCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CCCC(OCc3ccncc3)c3ccc(C#N)cc3)C2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
NaH (0.059 g; 55% suspension in oil; 1.35 mmol) was washed with petroleum ether (fraction 40/60). 2 mL of DMSO was added. tert-Butyl 7-[4-(4-cyanophenyl)-4-hydroxybutyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (see Example 1(x) above; 0.54 g; 1.05 mmol) dissolved in 10 mL of DMF was added dropwise at 0° C. After 15 minutes, 4-pyridinylmethyl chloride (0.17 g; 1.05 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 30 minutes, then at rt overnight. The reaction mixture was diluted with water and extracted with ethyl acetate:toluene (1:1). The organic layer was separated and washed with brine and water. Evaporation in vacuo gave 0.56 g of crude product. Purification on silica (DCM:10% MeOH) gave 0.17 g (26%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:10]=1)=[N:7][O:8][N:9]=2.C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][N:18]([CH3:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>COCCOC.O>[N:9]1[O:8][N:7]=[C:6]2[CH:10]=[C:2]([C:22]3[CH:23]=[CH:24][C:19]([N:18]([CH3:28])[CH3:17])=[CH:20][CH:21]=3)[CH:3]=[CH:4][C:5]=12
Reactant: Brc1ccc2nonc2c1
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN(C)c1ccc(-c2ccc3nonc3c2)cc1
Temperature: 25 °C

Procedure:
500 mg (2.5 mmol) 5-bromo-benzo[1,2,5]oxadiazole and 313 mg (0.1 eq.) tetrakis-(triphenylphosphine)palladium are stirred for 30 minutes at room temperature in 10 mL 1,2-dimethoxyethane. 533 mg (2 eq.) sodium carbonate are dissolved in 1.8 mL water and added to the reaction mixture, followed by 663 mg (1.6 eq.) 4-(dimethylamino)phenylboronic acid. After stirring at reflux for 18 h, the reaction mixture is cooled to room temperature and extracted with ethyl acetate and water. The organic phases are combined, dried with magnesium sulfate, filtered and evaporated. The residue is column chromatographed (hexane, then hexane/ethyl acetate 8:1 then 5:1) to yield the desired product as a yellow solid. MS(ES+): 240 (M+1).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH2:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:6][CH:5]=1.Cl.C[CH:26]([NH2:41])[C:27]1C=[CH:31][C:30](CCC2C=CC=CC=2)=[CH:29][CH:28]=1>>[ClH:1].[CH3:2][CH:3]([N:23]=[C:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:41]1)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:6][CH:5]=1
Reactant: CCCCCCCCCCCCCc1ccc(C(C)N)cc1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Agent: Cl
Product: CCCCCCCCCCCCCc1ccc(C(C)N=C2CCCCCN2)cc1

Procedure:
Following essentially the same procedure described in Example IV but substituting α-methyl-ρ-tridecylbenzylamine hydrochloride for the α-methyl-ρ-phenethylbenzylamine hydrochloride above, results in the formation of 2-(α-methyl-ρ-tridecylbenzylimino)hexahydroazepine hydrochloride having a M.P. 183°-5° C.
Reaction SMILES: FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.C(C[NH:26][C:27](=[O:52])[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH2:38][C:37]([C:43]3[CH:48]=[C:47]([Cl:49])[CH:46]=[C:45]([Cl:50])[CH:44]=3)([C:39]([F:42])([F:41])[F:40])[O:36][N:35]=2)=[CH:30][C:29]=1[CH3:51])(=O)N.O.Cl.[C:55](#[N:57])C.O>>[ClH:49].[NH2:57][CH2:55][NH:26][C:27](=[O:52])[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH2:38][C:37]([C:43]3[CH:48]=[C:47]([Cl:49])[CH:46]=[C:45]([Cl:50])[CH:44]=3)([C:39]([F:40])([F:41])[F:42])[O:36][N:35]=2)=[CH:30][C:29]=1[CH3:51]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(N)=O
Reactant: CC#N
Agent: Cl
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCN
Temperature: 25 °C

Procedure:
In a solution of 0.47 g of [bis(trifluoroacetoxy)iodo]benzene in 12 ml of acetonitrile-water (1:1), a solution of 0.47 g of N-carbamoylmethyl-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl benzoic acid amide synthesized in Synthetic Example 31 was added with stirring at room temperature, and stirred at room temperature for 5 hours. After the completion of the reaction, 75 ml of water was added in the reaction mixture, 8 ml of concentrated hydrochloric acid was added, then washed with 100 ml of diethyl ether, and the organic phase was subjected to back extraction with 2N hydrochloric acid aqueous solution (20 ml×2). The aqueous phase was combined with the organic phase, water was distilled off, and the residual solid was washed with ethyl acetate to obtain 0.21 g of the aimed product as white crystal. Melting point 155.0 to 157.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][C:41](Cl)=[O:42].[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[CH2:40][NH:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn(C3CCC(N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)CNc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.151 g, 0.356 mmol, 1 equiv), potassium carbonate (0.098 g, 0.711 mmol, 2 equiv), and chloroacetylchloride (0.04 mL, 0.5 mmol, 1.5 equiv) in DMF (1.5 mL) was stirred at ambient temperature for 20 minutes and then aniline (0.32 mL, 3.5 mmol, 10 equiv) was added. The reaction mixture was stirred at ambient temperature for 72 h. The solvent was removed under reduced pressure and the residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was washed with saturated aqueous sodium bicarbonate (10 mL) and then extracted with CH2Cl2 (25 mL). The organic extract was dried over MgSO4, filtered, and concentrated to give cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2-anilinoacetamide as a yellow solid (0.010 g, 0.017 mmol): 1H NMR (d6 DMSO, 400 MHz): δ H 9.30 (1H, s), 8.35-8.38 (1H, m), 8.21 (1H, s), 7.21-7.23 (2H, m), 7.12-7.16 (2H, m), 6.64-6.66 (3H, m), 6.31-6.34 (1H, m), 4.77-4.81 (1H, m), 3.90 (2H, d, J=6.0 Hz), 3.82 (3H, s), 2.21-2.51 (11H, m), 2.16 (3H, s), 2.06-2.08 (2H, m), 1.55-1.70 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 12.37 min. MS: MH+ 570.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O>C1C=CC=CC=1>[Cl:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: Clc1ccccc1
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1Cl
Yield: 50 %

Procedure:
Repeating Example 21 in every detail except that a chlorobenzene solution of 2-chloro-4-nitrobenzoic acid was employed in lieu of the benzene solution of the same, there is obtained a 50% yield of 2,4'-dichloro-4-nitrobenzophenone in good yield and purity having a melting point of 117° - 117.5° C.
Reaction SMILES: [CH2:1]([NH:5][CH3:6])[CH2:2][CH2:3][CH3:4].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19].O>C(Cl)Cl>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18](=[O:20])(=[O:19])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH3:6]
Reactant: O=S(=O)(Cl)CCCCCCCCCCBr
Reactant: CCCCNC
Solvent: O
Solvent: ClCCl
Product: CCCCN(C)S(=O)(=O)CCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
9.63 mmol of n-butylmethylamine is dissolved in 6 ml of absolute CH2Cl2. In a moisture-free environment, 1.85 mmol of 1-bromo-10-decanesulfonyl chloride is now slowly added in drops to 2.5 ml of CH2Cl2 while being cooled with ice. Then, it is stirred for another five hours at room temperature. The mixture is mixed with 10 ml of water, stirred thoroughly for a short time and the organic phase is separated. The aqueous phase is extracted with ether, and the combined organic phases are then washed with saturated NaCl solution and water. After drying on MgSO4, the solvent is removed in a rotary evaporator.
Reaction SMILES: [NH2:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=O.CC1C=[C:25](C)[NH:24]N=1.C([N:30](CC)CC)C>O.C(O)CCC>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([C:3]4[NH:30][C:25]([NH2:24])=[N:1][N:2]=4)[CH:6]=3)[NH:10][N:9]=2)=[CH:15][CH:16]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: CCN(CC)CC
Reactant: NNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Solvent: CCCCO
Solvent: O
Product: Nc1nnc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)[nH]1
Yield: 4.7 %

Procedure:
To a solution of N-amino[3-(4-fluorophenyl)(1H-indazol-5-yl)]carboxamide (440 mg, 1.6 mmol) and 3,5-dimethylpyrazole (321 mg, 1.6 mmol) in water (˜15 mL) was added triethylamine (0.21 mL, 1.6 mmol). The reaction was heated to reflux overnight. The solvent was removed and the crude reaction mixture was taken up in butanol with molecular sieves. The reaction was heated to reflux overnight. The molecular sieves were removed and the solution concentrated. The crude mixture was purified by preparative HPLC. The material was taken up in ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried with magnesium sulfate, filtered and concentrated to yield the title compound (0.022 g, 4.6% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 12.0 (s, 1H), 8.5 (s, 1H), 8.0 (m, 3H), 7.7 (d, 1H), 7.4 (m, 2H), 6.1 (s, 2H), ES-MS (m/z) 295 [M+1]+.