Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5](C(OCC)=O)[CH2:4][CH:3]1[CH2:13][CH3:14]>[OH-].[Na+]>[NH2:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH2:13][CH3:14]
Reactant: CCOC(=O)N1CCC(N)C(CC)C1
Agent: [Na+]
Agent: [OH-]
Product: CCC1CNCCC1N
Temperature: 120 °C
Reaction time: 120 h

Procedure:
Ammonium acetate (33 g) was added to the stirred solution of 1-carbethoxy-3-ethyl-4-piperidinone (8.2 g, 41 mmol) in methanol (125 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (2.5 g, 39 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH ˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish crude 4-amino-1-carbethoxy-3-ethylpiperidine, which was used as such in the next step. 4-Amino-1-carbethoxy-3-ethylpiperidine was suspended in 5 M NaOH solution (36 ml), stirred at 120° C. for 120 hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated to dryness to afford 4-amino-3-ethylpiperidine. Yield 3.1 g (59.6%), C7H16N2, m/z 129 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41]([OH:43])=[O:42])O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([N:12]([CH2:15][CH3:16])[CH2:11][CH2:10][CH2:9][NH:8][C:6]1[N:7]=[C:2]([C:38]2[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41]([OH:43])=[O:42])[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=1)[CH3:14]
Reactant: CC1(C)OB(c2cccc(C(=O)O)c2)OC1(C)C
Reactant: CCN(CC)CCCNc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 150 °C
Yield: 184 %

Procedure:
To the compound 4-chloro-2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (210.5 mg, 0.50 mmol) in dioxane (15 mL) and water (5 mL) were added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (125 mg, 0.75 mol), potassium carbonate (210 mg, 1.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol). The mixture was heated with microwave at 150° C. for 15 min. The mixture was concentrated, then mixed with DMSO (0.75 mL) and water (0.25 mL). Separation by HPLC afforded the title compound (467 mg, 32%). LC-MS m/z 508 (M+H)+.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][CH:7]=[C:6]([Br:12])[CH:5]=2.S(=O)(=O)(O)[OH:14].O1CCOCC1>O>[Br:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]([CH3:11])[C:2](=[O:14])[NH:3]2)=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1c(Br)[nH]c2cc(Br)ccc12
Solvent: C1COCCO1
Solvent: O
Product: CC1C(=O)Nc2cc(Br)ccc21

Procedure:
To 2,6-dibromo-3-methyl-1H-indole (15.7 g) were added 3N aqueous sulfuric acid solution (100 ml) and dioxane (100 ml), and the mixture was refluxed for 5 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound (11.2 g) as a brown crystal.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH3:13])=[CH:7][CH:6]=1.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:11]([C:8]1[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:16])([F:15])[F:1])=[CH:6][CH:7]=1)[CH2:12][CH3:13])=[O:22])([CH3:20])[CH3:19]
Reactant: CCC(=O)c1ccc(OCC(F)(F)F)nc1
Reactant: CC(C)(C)[S@](N)=O
Product: CCC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)(F)F)nc1
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (0.39 g, colorless oil) from 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-1-one (0.54 g, 2.29 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [CH3:1][C:2]([OH:29])([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH:19]=[CH:20]2)=[CH:15][CH:14]=3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C1(N2C(=[O:41])N=NC2=O)C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]([OH:29])([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][C@@H:20]2[OH:41])=[CH:15][CH:14]=3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C1N=NC(=O)N1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h

Procedure:
140.3 g of the 1α,2α-epoxide of the 1,4-cyclic adduct of cholesta-1,5,7-triene-3β,25-diol and 4-phenyl-1,2,4-triazoline-3,5-dione obtained in Example 2 was dissolved in 15 ml of tetrahydrofuran, and 142 mg of lithium aluminum hydride was added little by little to the solution under agitation. Then, the mixture was mildly refluxed and boiled for 1 hour and cooled, and 20 ml of tetrahydrofuran was added to the reaction mixture. A saturated aqueous solution of Glauber salt was added to the reaction mixture until generation of bubbles was stopped, whereby excessive lithium aluminum hydride was decomposed. The reaction mixture was then filtered, and the residue was washed 3 times with 10 ml of tetrahydrofuran. The organic solvent layer was dried and the solvent was distilled off. The residue was purified by using a column packed with 20 g of Sephadex LH 20, and a fraction eluted by chloroform-hexane (65 : 35 V/V ratio) was collected and recrystallized from ether-hexane to obtain 49.9 mg of cholesta-5,7-diene-1α,3β,25-triol in the form of needles melting at 149° to 152° C.
Reaction SMILES: [N:1]([C@@H:4]([C:7]1[CH:8]=[N:9][C:10]([CH:13]([F:15])[F:14])=[CH:11][CH:12]=1)[CH2:5][OH:6])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.Cl>C1COCC1>[NH2:1][C@@H:4]([C:7]1[CH:8]=[N:9][C:10]([CH:13]([F:15])[F:14])=[CH:11][CH:12]=1)[CH2:5][OH:6]
Reactant: [N-]=[N+]=N[C@H](CO)c1ccc(C(F)F)nc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N[C@H](CO)c1ccc(C(F)F)nc1
Reaction time: 3 h
Yield: 84.2 %

Procedure:
To a stirred solution of (S)-2-azido-2-(6-(difluoromethyl)pyridin-3-yl)ethanol (1 g, 4.67 mmol) in 15 mL of THF was added PPh3 (2.45 g, 9.39 mmol). The resulting reaction mixture was stirred for 3 h, treated with 0.5 mL of water and stirred for 16 h. After completion of the reaction, the reaction mixture was treated with 2N HCl (15 mL) and extracted with EtOAc. The aqueous layer was treated with aq. NH3 and the volatiles were evaporated to afford a residue. Purification of the residue by column chromatography (small pad of neutral Al2O3, aq. NH3/MeOH/CH2Cl2, 1:14:85) afforded the title compound (0.74 g, 85% yield). MS: 189 [M+1]+; 1H-NMR (300 MHz, CD3OD): 8.72 (s, 1H), 8.09 (d, 1H, J=8.3 Hz), 7.75 (d, 1H, J=8.3 Hz), 6.73 (t, 1H, J=55.0 Hz), 4.39-4.43 (m 1H), 3.90 (dd, 1H, J=10.9, 4.7 Hz), 3.80 (dd, 1H, J=10.9, 6.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([NH2:8])=[S:7].Cl[CH2:17][C:18](=O)[CH3:19]>C1C=CC=CC=1>[CH3:15][O:14][C:10]1[CH:9]=[C:5]([C:6]2[S:7][CH:17]=[C:18]([CH3:19])[N:8]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13]
Reactant: CC(=O)CCl
Reactant: COc1cc(C(N)=S)cc(OC)c1OC
Solvent: c1ccccc1
Product: COc1cc(-c2nc(C)cs2)cc(OC)c1OC
Temperature: 25 °C
Yield: 62 %

Procedure:
Into 200 ml of benzene, 22.7 g (0.1 mol) of 3,4,5-trimethoxythiobenzamide and 11.1 g (0.12 mol) of chloroacetone were dissolved, and the solution was heated under a reflux condenser for 5 hours. After cooling to room temperature, the crystals which separated out were collected by filtering and recrystallized from methanol. The product consisting of pale yellow needle-like crystals, and amounting to 16.5 g was thus obtained, melting at 105° to 106.5° C. The yield was 62%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][Si:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][O:20][CH2:19][N:10]1[C:11]2[C:18]3[CH:17]=[CH:16][S:15][C:14]=3[CH2:13][C:12]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)=[CH:3][CH:4]=2)=[N:9]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(-c3ccc(O)cc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 52 %

Procedure:
A mixture of the corresponding inteimmediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.3 g, 0.9 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.33 g, 1.5 mmol), Na2CO3 (2 M, 2.7 mL), and Pd(PPh3)2Cl2 (8 mg, 0.075 mmol) in toluene/ethanol (1:1, 6 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give 4′-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pe ntalen-6-yl]-biphenyl-4-ol as brown solid in 52% yield.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[I:19]CI.N(OCCC(C)C)=O>C(#N)C>[I:19][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: ICI
Reactant: CCOC(=O)c1cnn(-c2cccc(F)c2)c1N
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(F)c2)c1I
Temperature: 50 °C
Yield: 78.8 %

Procedure:
Ethyl 5-amino-1-(3-fluorophenyl)-1H-pyrazole-4-carboxylate (518 mg, 2.08 mmol) was suspended in acetonitrile (5 mL) at ambient temperature. Diiodomethane (675 μL, 8.38 mmol) was added followed by isopentyl nitrite (565 μL, 4.21 mmol). The reaction was heated at 50° C. for one hour and was then partitioned between water and ethyl acetate. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After removal of solvents under reduced pressure, the crude material was purified using silica gel column chromatography (10-25% ethyl acetate in hexanes) to afford ethyl 5-iodo-1-(3-fluorophenyl)-1H-pyrazole-4-carboxylate (589 mg, 1.64 mmol, 79% yield).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:38])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[N:30][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=45)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:37])[CH2:9]1.CC#N>C(Cl)Cl>[CH3:38][N:7]([CH3:6])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[N:30][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=45)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:37][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Solvent: ClCCl
Solvent: CC#N
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4c3CCCC4)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.1 %

Procedure:
A solution of acryloyl chloride (32 mg, 0.36 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 134, 152 mg, 0.34 mmol) in CH2Cl2 (15 mL), which was cooled in an ice/water bath. The solution was stirred for 10 minutes while cooled by the ice bath, and was then allowed to warm to r.t. then stirred for 1 h. The mixture was then diluted with CH2Cl2 and washed with sat. NaHCO3 and then brine. The organic solution was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave crude product (100 mg) as a beige solid after trituration with diethyl ether. CH3CN (˜3 mL) was then added to the crude product and the resulting slurry was stirred at 50° C. for 4 h. After cooling to r.t. the suspended solid was collected by filtration, washed with CH3CN and dried at 45° C. overnight to give the title compound (72 mg, 42%) as a yellow solid; 1H NMR: 1.68-1.81 (3H, m), 1.89-1.98 (2H, m), 2.03-2.11 (1H, m), 2.17 (6H, s), 2.66-2.74 (1H, m), 3.00-3.05 (2H, m), 3.13-3.21 (3H, m), 3.31-3.38 (1H, m), 3.86 (3H, s), 4.09 (2H, t), 5.70 (1H, dd), 6.21 (1H, dd), 6.48-6.56 (2H, m), 6.96 (1H, d), 7.72 (1H, s), 8.03 (2H, d), 8.27 (1H, d), 9.30 (1H, s); m/z: ES+ MH+ 503.67.
Reaction SMILES: [NH2:1][C:2]([CH3:12])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[Na].Br[CH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[C:19]([NH:21][C@@H:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH3:23])=[O:20]>CN(C=O)C.C1COCC1>[NH2:1][C:2]([CH3:12])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][O:4][CH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[C:19]([NH:21][C@@H:22]([C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[CH3:23])=[O:20]
Reactant: C[C@@H](NC(=O)c1cc(CBr)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Reactant: CC(N)(CO)Cc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)c1cc(COCC(C)(N)Cc2ccccc2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-amino-2-methyl-3-phenylpropan-1-ol I (28 mg, 0.17 mmol) in 0.5 nL DMF cooled to 0° C. was added sodium hexamethyldisylazide (0.17 mL, 0.17 mmol, 1 M in THF). The reaction mixture was stirred at 0° C. for 5 min and intermediate III 3-(bromomethyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (25 mg, 0.06 mmol) in 0.5 mL DMF was added dropwise. The reaction mixture was stirred at 0° C. for 0.5 h and purified by preparative HPLC (5%->95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) to afford 3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide. 1H NMR (400 MHz, d4-MeOH) δ 8.87 (d, J=8 Hz, 1H), 7.86-7.80 (m, 2H), 7.66 (s, 1H), 7.45-7.40 (m, 2H), 7.36-7.24 (m, 3H), 7.22-7.16 (m, 2H), 7.10-7.02 (m, 2H), 5.30-5.20 (m, 1H), 4.73-4.64 (m, 2H), 3.44 (A of AB, d, J=10 Hz, 1H), 3.39 (B of AB, d, J=10 Hz, 1H), 3.35 (s, 3H), 3.09 (A of AB, d, J=13.2 Hz, 1H), 2.94 (s, 3H), 2.87 (B of AB, d, J=13.2 Hz, 1H), 1.59 (d, J=7.2 Hz, 3H), 1.25 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C[O-].[Na+].ClC1C=CC=CC=1.Cl[CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40]>CO>[CH2:37]([N:38]([CH2:41][CH3:42])[CH2:39][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH:9]2[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:4][CH:3]=1)[CH3:36]
Reactant: Oc1ccc(N2c3ccccc3CCC2c2ccc(Cl)cc2)cc1
Reactant: CCN(CC)CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CO
Product: CCN(CC)CCOc1ccc(N2c3ccccc3CCC2c2ccc(Cl)cc2)cc1

Procedure:
A procedure was followed similar to that described in Example 1 but using 18 g. 1-(4-hydroxyphenyl)-2-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoline, 3.8 g. sodium methoxide, 160 ml. chlorobenzene, 15 ml. dry methanol and 8.8 g. N-(2-chloroethyl) diethylamine. The crude material was chromatographed on 700 g. activated magnesium silicate (60-100 mesh) using benzene, benzene containing increasing amounts of ether, and ether as eluants and there was thus eluted with 7 - 50% ether in benzene and with ether 15 g. 1-{4-[2-(diethylamino)ethoxy]phenyl}-2-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoline which was converted to the cyclohexanesulfamate salt; m.p. 161°-163°C. (isopropyl alcohol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[CH3:22][S:23]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCNCC1
Product: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(OC(F)(F)F)cc2)CC1

Procedure:
Intermediate 42 (152 mg, 0.5 mmol) was reacted with methanesulfonyl chloride by Method E. Recrystallization from EtOAc:acetone afforded compound 55 (160 mg, 84%) as a white solid: Mp 233-234° C. 1H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.22 (d, J=8.6 Hz, 2H), 6.29 (d, J=7.5 Hz, 1H), 3.64-3.55 (m, 1H), 3.47 (d, J=12.2 Hz, 2H), 2.91-2.84 (m, 5H), 1.94-1.88 (m, 2H), 1.50-1.40 (m, 2H). Purity 98%. HRMS calculated for C14H18F3N3O4S−H+ 380.0892. found (ESI(−), [M−H]) 380.0931.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl.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>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:25]3[CH:30]=[N:29][C:28]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)=[CH:27][CH:26]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
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: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccc(N4CCOCC4)nc3)nc12
Temperature: 110 °C
Reaction time: 0.42 h
Yield: 56.4 %

Procedure:
A mixture of 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (0.1 g, 0.354 mmol), commercially available 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]morpholine (0.206 g, 0.709 mmol), K2CO3 (0.147 g, 1.063 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.041 g, 35 micomol) in 3 mL of MeOH and 1 mL of DCM was degassed by bubbling argon through the mixture. It was then stirred at 110° C. for 25 minutes under microwave irradiation before being cooled to RT. And evaporated. The residue was adsorbed onto SiO2 and purified twice by SiO2 chromatography (hexanes/EtOAc 0-50% EtOAc, followed by DCM/MeOH 0-4% MeOH) to give 0.073 g of 2,2-Dimethyl-1-[2-(6-morpholin-4-yl-pyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one (56% yield).
Reaction SMILES: [CH2:1]([O:7][C:8]([CH2:10][CH2:11][CH:12]([O:18][C:19](=[O:36])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][Si](C(C)(C)C)(C)C)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:9])[CH2:2][CH:3]=[CH:4][CH2:5][CH3:6].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:7][C:8]([CH2:10][CH2:11][CH:12]([O:18][C:19](=[O:36])/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:9])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6]
Reactant: CCC=CCCOC(=O)CCC(CCCCC)OC(=O)C=Cc1ccccc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC/C=C\CCOC(=O)CCC(CCCCC)OC(=O)/C=C/c1ccccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 10.7 %

Procedure:
To a solution of 6.14 g 3-[2-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acrylic acid 1-(2-hex-3-enyloxycarbonyl-ethyl)-hexyl ester in 50 ml of tetrahydrofuran, a solution of 25 ml of a 1 M tetrabutylammoniumfluoride solution was added at 0° C. After stirring at room temperature for 90 minutes, the solution was quenched with water and extracted with ether. The organic phase was washed with water, dried and evaporated to dryness. The residue was purified by Kugelrohr-distillation and chromatography to yield 0.51 g of a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]([C@@H:9]2[CH2:18][C:17]3[C:12](=[C:13]([F:20])[CH:14]=[C:15]([F:19])[CH:16]=3)[O:11][CH2:10]2)[C:7](=[S:21])[NH:6][CH:5]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>CO.ClCCl>[CH2:22]([NH:1][CH2:2][CH2:3][C:4]1[N:8]([C@@H:9]2[CH2:18][C:17]3[C:12](=[C:13]([F:20])[CH:14]=[C:15]([F:19])[CH:16]=3)[O:11][CH2:10]2)[C:7](=[S:21])[NH:6][CH:5]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CCNCc3ccccc3)c[nH]c1=S)CO2
Temperature: 22.5 °C
Reaction time: 40 h
Yield: 50.9 %

Procedure:
To (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (2.36 g, 7.58 mmol) in a mixture of Methanol (15.00 ml) and Dichloromethane (15 ml) was added BENZALDEHYDE (0.845 ml, 8.34 mmol). To the resulting clear solution SODIUM CYANOBOROHYDRIDE (0.702 g, 10.61 mmol) was added in portions at 20-25° C. to avoid intensive foaming and the solution was stirred at 20-25° C. for 40 h. The solution was quenched at 20-25° C. with 1N HCl (12 ml), neutralised with 3N NaOH (12 ml), the mixture was extracted with DCM (100 ml). The organic phase was washed with brine, dried (MgSO4), evaporated to dryness. The residue was purified on a column with EA-MeOH 9:1 as eluent, fractions collected, concentrated to approx 20 ml, cooled in ice. The precipitate collected, washed with Ethyl Acetate-Petroleum Ether 1:1, dried on air to give (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (1.55 g, 3.86 mmol, 50.9% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[N:4][CH:3]=1>C(#N)C.CO.[Pt]>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][CH2:16][C:17]([CH3:18])([OH:19])[CH3:20])=[N:4][CH:3]=[C:2]([Br:1])[CH:11]=2
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Agent: [Pt]
Solvent: CC#N
Solvent: CO
Product: CC(C)(O)CNc1c(N)cnc2cc(Br)cnc12
Yield: 99.6 %

Procedure:
A Parr vessel was charged with 5% Pt/C (5.8 g) and a suspension of 1-[(7-bromo-3-nitro[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol (58.00 g) in acetonitrile (800 mL) and methanol (400 mL). The vessel was placed under hydrogen pressure (30 psi, 2.1×105 Pa) for 8 hours. The reaction mixture was filtered through a layer of CELITE filter aid. The filtrate was concentrated under reduced pressure to provide 52.70 g of 1-[(3-amino-7-bromo[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol as a yellow foam.