Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:21][C:22]1[C:27](Cl)=[N:26][C:25]([Cl:29])=[CH:24][N:23]=1)(=[O:20])=[O:19]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:27]2[C:22]([NH:21][S:18]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=3[Cl:10])(=[O:20])=[O:19])=[N:23][CH:24]=[C:25]([Cl:29])[N:26]=2)[CH:5]=[N:6][CH:7]=1
Reactant: OCc1cncc(Br)c1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1cncc(Br)c1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using (5-bromo-3-pyridinyl)methanol (0.2 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.25 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]3[O:11][C:10]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:9]([CH3:17])[C:8]=3[CH:18]=2)[CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.CO>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]3[O:11][C:10]([CH:12]([OH:16])[CH:13]([CH3:14])[CH3:15])=[C:9]([CH3:17])[C:8]=3[CH:18]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(C3CC3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(O)C(C)C)oc2ccc(C3CC3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
1-(5-Cyclopropyl-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (0.80 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (10 mL) and methanol (1 mL), and sodium borohydride (90%, 0.34 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (1 mL) and 1N hydrochloric acid (5 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (0.4 g, 50%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([N:26]3[CH2:27][CH2:28][CH2:29][CH:25]3[CH3:24])[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: CC1CCCN1
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CS(C)=O
Product: CC1CCCN1c1cc(NC(=O)c2ccc(C(C)(C)O)cc2)nc2ccnn12
Temperature: 25 °C
Yield: 29.7 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol) and 2-methylpyrrolidine (26 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 25-50% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a orange solid (34 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (d, J=6.06 Hz, 3 H) 1.45 (s, 6 H) 1.71-1.81 (m, 1 H) 1.90-2.01 (m, 1 H) 2.03-2.26 (m, 2 H) 3.75-3.91 (m, 1 H) 3.96-4.12 (m, 1 H) 4.96 (br. s., 1 H) 6.27 (d, J=2.27 Hz, 1 H) 6.98 (s, 1 H) 7.61 (d, J=8.34 Hz, 2 H) 7.91-8.09 (m, 3 H) 10.81 (s, 1 H). ESI-MS: m/z 380.3 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>ClCCl>[C:27]([N:1]1[CH2:2][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:4]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.8 %

Procedure:
To a stirred solution of 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (100 mg, 0.42 mmol) in dichloromethane (10 mL) cooled to 0° C. was added diisopropylethylamine (160 mg, 1.26 mmol) and acetic anhydride (45 mg, 0.51 mmol). The resulting mixture was stirred at RT for 3 h before it was quenched by addition of water (10 ml). The aqueous layer was extracted with dichloromethane (3×10 ml) and the combined organic layers were washed with saturated aqueous NaHCO3 (10 ml), dried (Na2SO4), filtered and concentrated. Purification by silica FCC (using a gradient of eluents; 100:0 to 99:1 DCM:2M NH3 in MeOH) followed by purification by preparative HPLC (Method 2) gave the title compound (35 mg, 30% yield) as colourless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=2[C:32]#[N:33])=[N:18]S(C(C)(C)C)=O)[CH:14]=[CH:15][CH:16]=1>>[Br:10][C:11]1[CH:12]=[C:13]([C:17]2([C:2]3[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=3)[C:25]3[C:26](=[C:27]([F:31])[CH:28]=[CH:29][CH:30]=3)[C:32]([NH2:33])=[N:18]2)[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cc(Br)nc(C)n1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1cccc(F)c1C#N
Product: Cc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)nc(C)n1
Yield: 35 %

Procedure:
The title compound was synthesized as described for Example 35i in 35% yield, starting from of 4-bromo-2,6-dimethylpyrimidine (507 mg, 2.71 mmol) and N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (850 mg, 2.09 mmol). MS (ES+) m/z 411, 413 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].Br[C:11]1[C:12](=[O:24])[N:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([CH3:17])=[CH:15][N:16]=1>[N+](C1C=CC=CC=1)([O-])=O>[CH2:1]([C:3]1[C:8]([NH:9][C:11]2[C:12](=[O:24])[N:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([CH3:17])=[CH:15][N:16]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncccc1N
Reactant: CCOC(=O)Cn1c(C)cnc(Br)c1=O
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOC(=O)Cn1c(C)cnc(Nc2cccnc2CC)c1=O
Temperature: 200 °C

Procedure:
A mixture of 2-ethyl-3-aminopyridine (0.35 g, 2.8 mMol, 2 eq) from step 2 above and 3-bromo-6-methyl-1-(ethoxycarbonylmethyl)pyrazinone (0.39 g, 1.4 mMol) in 1 mL of nitrobenzene was heated at 200 ° C. for 2 h. The reaction was concentrated in vacuo and the residue purified by flash silica gel chromatography using 1% methanol in methylene chloride as an eluent to afford the title compound as a yellow oil that crystallizes upon sitting. (0.058 g; HPLC RT=4.45 min, method A).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=[O:13].[Br:14]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:14][C:11]1[N:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]([CH:12]=[O:13])=[CH:9][CH:10]=1
Reactant: O=Cc1cccn1-c1ncccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Br)n1-c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a solution of 0.5 g of 1-(2-pyrimidinyl)-1H-pyrrole-2-carbaldehyde in 10 ml of N,N-dimethylformamide was added 0.6 g of N-bromosuccinimide. The resulting mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.43 g of 5-bromo-1-(2-pyrimidinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12](OCC)=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][C:5]=3[C:4]=2[C:3]=1[Cl:29].[Li+].[BH4-].[OH-].[Na+].CCOC(C)=O>C1COCC1.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][OH:13])[C:6]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21][C:5]=3[C:4]=2[C:3]=1[Cl:29]
Reactant: CCOC(=O)Cn1c2c(c3c(Cl)c(Cl)ccc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3ccc(Cl)c(Cl)c23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.7 %

Procedure:
A solution of tert-butyl 9,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.0 g, 2.3 mmol) in dry THF (10 mL) was cooled to 0° C. Then, LiBH4 (0.15 g, 6.8 mmol) was added and the reaction was allowed to warm slowly to rt. After 4 h, the reaction was diluted with H2O followed by addition of 10% aqueous NaOH and extraction with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M, SIM) with heptane/EtOAc (1:1) followed by crystallization from EtOAc/heptane gave 0.19 g (21%) of a white solid: mp 174.5-176.0° C.; IR (diffuse reflectance) 3419, 1662, 1466, 1447, 1424, 1370, 1359, 1275, 1248, 1170, 1157, 1120, 1078, 933, 799 cm−1; MS (EI) m/z 398 (M+), 400, 398, 344, 342, 341, 268, 86, 84, 57, 51; Anal. Calcd for C19H24Cl2N2O3: C, 57.15; H, 6.06; N, 7.01; found: C, 57.13; H, 6.13; N, 6.95.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][CH2:28][C:29]1([NH:33]CC2C=CC=CC=2)[CH2:32][O:31][CH2:30]1>>[NH2:33][C:29]1([CH2:28][CH2:27][NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:32][O:31][CH2:30]1
Reactant: NCCC1(NCc2ccccc2)COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCC3(N)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-(aminoethyl)-N-benzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95-7.89 (t, 1 H), 7.89-7.87 (t, 1 H), 7.64-7.60 (m, 2 H), 7.49-7.45 (m, 1 H), 7.31 (d, J=8.4 Hz, 1 H), 7.24-7.21 (m, 1 H), 6.87 (t, J=10.4 Hz, 1 H), 6.05 (s, 1 H), 5.08 (s, 2 H), 4.39 (m, 6 H), 3.63 (t, J=9.2 Hz, 2 H), 3.41-3.36 (m, 2 H), 2.41 (s, 2 H), 2.35 (s, 3 H), 2.08 (t, J=14.4 Hz, 2 H).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].N[C@H](C(O)=O)[C@H](CC)C.N[C@@H](C(O)=O)[C@@H](CC)C.N[C@H](C(O)=O)CC(C)C.N[C@@H](C(O)=O)CC(C)C.N[C@H](C(O)=O)C(C)C.N[C@@H](C(O)=O)C(C)C>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCC[C@@H](N)C(=O)O
Agent: CC(C)C[C@@H](N)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CC(C)[C@@H](N)C(=O)O
Product: CSCC[C@H](N)C(=O)O

Procedure:
replace with: D-Met, S-Me-Cys, Ile, D-Ile, Leu, D-Leu, Val, D-Val;
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C)C=O>[C:6]1([S:5][CH2:4][CH2:3][CH2:2][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCCCSc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCSc1ccccc1
Yield: 63.8 %

Procedure:
A solution of 32.86 g (0.177 mole) of 1-chloro-3-(phenylthio)propane and 33.7 g (0.182 mole) of potassium phthalimide in 500 ml of dimethylformamide was stirred at 80° C. for 19 hr. The dimethylformamide was removed in vacuo. The residue was dissolved in methylene chloride and the resulting solution extracted with several portions of dilute sodium hydroxide solution. The methylene chloride layer was dried over magnesium sulfate, filtered, and the filtrate evaporated in vacuo. The resulting solid residue was recrystallized from methylene chloride-hexane to give 33.56 g (63.8%) of white crystalline product, m.p. 83°-85° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:11][C:10]2[C:5](=[CH:6][C:7]([CH3:12])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:13].Cl[C:16]([O:18][C:19]([CH3:21])=[CH2:20])=[O:17].O>N1C=CC=CC=1>[C:19]([O:18][C:16]([N:11]1[C:10]2[C:5](=[CH:6][C:7]([CH3:12])=[CH:8][CH:9]=2)[NH:4][C:3](=[O:13])[C:2]1([CH3:14])[CH3:1])=[O:17])([CH3:21])=[CH2:20]
Reactant: Cc1ccc2c(c1)NC(=O)C(C)(C)N2
Reactant: C=C(C)OC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: C=C(C)OC(=O)N1c2ccc(C)cc2NC(=O)C1(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3,3,7-Trimethyl-3,4-dihydroquinoxalin-2(1H)-one (0.4 g, 2.1 mmol) were dissolved in 10 ml of anhydrous pyridine, and the stirred solution was treated at room temperature with 0.24 ml (2.2 mmol) of isopropenyl chloroformate. The mixture was stirred for 6 hours at room temperature and treated with water, the precipitate which formed was filtered off with suction, washed with water and dried. This gave 0.4 g (69%) of colorless crystals of melting point 185° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Br[C:20]1[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[O:22][N:21]=1>>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[O:22][N:21]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: O=C(O)c1cc(Br)no1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)on3)CC2)c(Cl)c1Cl
Yield: 33.6 %

Procedure:
The title compound was prepared via the procedure described in Example 1 from 182 mg (0.5 mmol) of 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1) and 103 mg (0.54 mmol) of 3-bromoisoxazole-5-carboxylic acid (Intermediate 120), to afford the title compound as a white solid, (65 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([N:15]([CH3:26])[C:16]2[C:17]3[CH:25]=[CH:24][NH:23][C:18]=3[N:19]=[C:20](Cl)[N:21]=2)[CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].O>[CH3:26][N:15]([C@@H:10]1[C@H:11]([CH3:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[C:16]1[C:17]2[CH:25]=[CH:24][NH:23][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1N(C)c1nc(Cl)nc2[nH]ccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Product: C[C@@H]1CCNC[C@@H]1N(C)c1ncnc2[nH]ccc12
Temperature: 72.5 °C

Procedure:
To a clean, dry, nitrogen-purged 500 ml hydrogenation reactor were charged 20 wt % Pd(OH)2/C (palladium hydroxide on carbon) (5.0 g, 50% water wet), water (200 ml), and N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-2-chloro-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50.0 g, 0.135 mol). The reactor was purged three times at 50 psi with nitrogen and three times at 50 psi with hydrogen. Once purging was complete, the reactor was heated to 70-75° C. and pressurized to 50 psi with hydrogen through a continuous feed. The hydrogen uptake was monitored until no hydrogen was consumed for a minimum of 1 hour. The reactor was cooled to 20-30° C. and purged three times at 50 psi with nitrogen. The reaction mixture was filtered through water-wet Celite and transferred to a clean, dry, nitrogen-purged 500 ml reactor for subsequent processing.
Reaction SMILES: [N:1]1N=N[N:4]2[CH:9]=[C:8]([CH:10]3[O:15][CH2:14][C:13](=[O:16])[N:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11]3)[CH:7]=[CH:6][C:5]=12.O.O.Cl[Sn]Cl.Cl>CO>[NH2:1][C:5]1[N:4]=[CH:9][C:8]([CH:10]2[O:15][CH2:14][C:13](=[O:16])[N:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11]2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)N1CC(c2ccc3nnnn3c2)OCC1=O
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)N1CC(c2ccc(N)nc2)OCC1=O
Yield: 88.7 %

Procedure:
A solution of 2-(tetrazolo[1,5-a]pyrid-6-yl)-4-(1,1-dimethylethyl)-5-oxo-morpholine (550 mg), SnCl2.2H2O (968 mg) and 0.2 ml of 12N hydrochloric acid in 60 ml of methanol was heated at reflux for 14.5 hours under nitrogen. The reaction mixture was concentrated under reduced pressure and then poured into ice water containing 5N sodium hydroxide. The basic aqueous mixture was repeatedly extracted with methylene chloride. The combined organic fractions were washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. Concentration gave 603 mg of crude product which was chromatographed on silica gel (95:5:1 methylene chloride:ethanol:ammonium hydroxide) to give 442 mg of product. Mass spectrum (FAB) 250 (M+1). 13C NMR (CDCl3) 27.9 49.5 57.7 69.2 74.3 108.5 123.6 135.8 146.3 158.7 167.4 ppm.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:8]2[N:9]=[C:10]([NH:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[CH:12][C:7]=2[CH:6]=1.N[C@@H]1CC[O:34]C[C@H]1O.C(OCC)(=O)C>CN1CCCC1=O>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:8]2[N:9]=[C:10]([NH:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH:15]3[OH:34])[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: N[C@@H]1CCOC[C@H]1O
Reactant: CCn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(NC3CCOCC3)nc21
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(NC3CCOCC3O)nc21
Yield: 21.9 %

Procedure:
A mixture of the sulfone (see example 95 for preparation) (0.50 g, 1.31 mmol) and trans-4-amino-3-hydroxy-tetrahydropyran (0.23 g, 1.97 mmol) (see following ref for preparation: (a) Marquis, Robert W et al J. Med. Chem. (2001), 44(5), 725-736. (b) Gribble, Andrew D et al PCT Int. Appl. (1998), 74 pp. (c) Mochalin, V. B et al Zh. Org. Khim. (1971), 7(4), 825-8). in 2 mL of 1-methyl-2-pyrrolidinone was heated at 100° C. for 12 h. The reaction mixture was cooled, ethyl acetate (15 mL) was added and the organic solution was washed with water (3×, 15 mL), brine and then dried (MgSO4). Evaporation of the solvent under reduced pressure and column chromatography (CH2Cl2/methanol—97/3) afforded 120 mg of product (mpt. 174.9-176.3° C., MS (M+H)=419)
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.Cl.[NH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][NH:15][C:16]2[N:17]([CH2:30][CH2:31][CH3:32])[N:18]=[C:19]3[C:28]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=[C:20]3[NH2:29])[CH2:9][CH2:8]1.C(N(CC)CC)C.CN1CCCC1=O>ClCCl>[C:1]([N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][CH2:14][NH:15][C:16]2[N:17]([CH2:30][CH2:31][CH3:32])[N:18]=[C:19]3[C:28]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=[C:20]3[NH2:29])[CH2:11][CH2:12]1)(=[O:3])[CH3:2]
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1NCCC1CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nc2c(N)nc3ccccc3c2c1NCCC1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.7 %

Procedure:
Acetyl chloride (0.27 g, 0.24 mL, 3.39 mmol) was added to a stirring suspension of N1-(2-piperidin-4-ylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine dihydrochloride (1.2 g, 2.83 mmol) and triethylamine (2.9 g, 3.9 mL, 28.3 mmol) in dichloromethane (100 mL). After 10 minutes, 1-methyl-2-pyrrolidinone (15 mL) was added and the resulting suspension was stirred at ambient temperature 16 hours. Additional acetyl chloride (0.27 g, 0.24 mL, 3.39 mmol) was added and the suspension was stirred at ambient temperature 4 hours. The dichloromethane was removed under reduced pressure and water (100 mL) was added to the resulting oil. The solution was transferred to a separatory funnel and extracted with ethyl acetate (2×50 mL) and dichloromethane (50 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Methanol (20 mL) and sodium hydroxide (10 mL, 1 N in water) were added to the resulting oil and the suspension was stirred one hour. The methanol was removed under reduced pressure and the aqueous layer was neutralized with hydrochloric acid (1 N in water) and extracted with dichloromethane (3×50 mL). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated under reduced pressure to 7.5 g of a yellow oil. Sodium carbonate (75 mL, 10% w/w in water) was added to this oil and a brown gum crashed out and stuck to the sides of the flask. The liquid was decanted off and the remaining gum was crystallized from hot acetonitrile (50 mL) and isolated by filtration to yield 242 mg of N1-[2-(1-acetylpiperidin-4-yl)ethyl]-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine as a tan solid. mp 203-206° C. Anal. calcd for C22H30N6O: C, 66.98; H, 7.66; N, 21.30. Found: C, 66.92; H, 7.92; N, 21.57.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([NH:19][C:20]([CH:22]3[CH2:25][CH2:24][N:23]3C(OC(C)(C)C)=O)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[N:4][NH:3]1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[O:1]=[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([NH:19][C:20]([CH:22]3[CH2:25][CH2:24][NH:23]3)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[N:4][NH:3]1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCC1C(=O)Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1)C1CCN1

Procedure:
A solution of EXAMPLE 112A (64 mg) in dichloromethane (4 mL) was treated with trifluoroacetic acid (2 mL) at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 339 (M+H)+; 1H NMR (300 MHz, CD3OD): δ 1.64-1.73 (m, 4H), 2.36-2.44 (m, 2H), 2.46-2.53 (m, 2H), 2.57-2.69 (m, 1H), 2.81-2.93 (m, 1H), 3.94-4.04 (m, 1H), 3.98 (s, 2H), 4.08-4.20 (m, 1H), 5.07 (dd, J=9.49, 7.80 Hz, 1H), 7.03 (d, J=8.14 Hz, 1H), 7.30 (t, J=7.80 Hz, 1H), 7.41 (t, J=1.70 Hz, 1H), 7.49 (dd, J=7.97, 1.53 Hz, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([OH:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH2:38]([O:46][C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCO
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CCCCCCCCOC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with octanol, mp 56°-58° C.