Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[C:3](=[O:45])[C:4]1[CH:44]=[CH:43][CH:42]=[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]=2[C:22]2[CH:27]=[C:26]([C:28](=[O:41])[NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:25]=[CH:24][N:23]=2)=[O:8])[CH:5]=1.C(N(CC)CC)C.[CH3:61][S:62](Cl)(=[O:64])=[O:63]>ClCCl>[CH3:1][N:2]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([S:62]([CH3:61])(=[O:64])=[O:63])[CH2:50][CH2:49]1)[C:3](=[O:45])[C:4]1[CH:44]=[CH:43][CH:42]=[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]=2[C:22]2[CH:27]=[C:26]([C:28](=[O:41])[NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=3)[CH:25]=[CH:24][N:23]=2)=[O:8])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCN1CCNCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN1CCN(S(C)(=O)=O)CC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 49.5 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N1-methyl-N1-(2-(piperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide (100 mg, 0.14 mmol, 1.00 equiv) in dichloromethane (3 mL), triethylamine (42 mg, 0.42 mmol, 3.00 equiv), and methanesulfonyl chloride (17 mg, 0.15 mmol, 1.05 equiv). The resulting solution was stirred for 40 min at 25° C. The reaction was then quenched by the addition of 3 mL of water. The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×5 mL of water and 1×5 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (90 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 55.8 mg (50%) of a light yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.97 (d, J=5.1 Hz, 1H), 8.764 (d, J=9.0 Hz, 1H), 8.45 (s, 1H), 8.16˜8.10 (m, 3H), 7.89˜7.87 (m, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.72˜7.67 (m, 4H), 7.62˜7.53 (m, 2H), 4.72 (s, 2H), 4.00 (s, 2H), 3.68˜3.55 (m, 14H), 3.11 (s, 3H), 2.96 (s, 3H), 2.04 (d, J=4.8 Hz, 1H), 1.83 (d, J=5.1 Hz, 1H). MS (ES, m/z): 806 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH2:15](N)[CH3:16]>C1COCC1>[CH2:15]([NH:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])[CH3:16]
Reactant: CCN
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CCNc1cccc([N+](=O)[O-])c1C#N
Yield: 88 %

Procedure:
Prepared as in Example 90c from 2,6-dinitrobenzonitrile and a 2M ethylamine solution in THF in 88% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.13 (t, J=7.6 Hz, 3H), 3.26-3.33 (m, 2H), 6.59 (bt, J=5.2 Hz, NH), 7.22 (d, J=9.2 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.60 (t, J=8.4 Hz, 1H). MS 162 (M-Et).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:7][C:6]=12.[CH2:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)[CH3:26]>>[CH2:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:7][C:6]=12)[CH3:26]
Reactant: CCc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2ncc(Br)c2n1
Product: CCc1ccccc1-c1cnn2ccc(NC[C@@H]3CCCN3C(=O)OC(C)(C)C)nc12
Yield: 77 %

Procedure:
The Suzuki coupling of (S)-tert-butyl 2-(((3-bromopyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)pyrrolidine-1-carboxylate with (2-ethylphenyl)boronic acid under the same conditions as described in example 5.6.5 to give 77% of the titled compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20 (t, J=7.58 Hz, 3 H) 1.49 (s, 9 H) 1.79-1.95 (m, 3 H) 1.95-2.05 (m, 1H) 2.82 (q, J=7.58 Hz, 2 H) 3.34-3.44 (m, 3 H) 3.44-3.53 (m, 1 H) 4.15 (br. s., 1 H) 6.08 (d, J=6.82 Hz, 1 H) 7.23-7.31 (m, 3 H) 7.32-7.38 (m, 1 H) 7.51 (dd, J=7.20, 1.39 Hz, 1 H) 7.91 (s, 1 H) 8.20 (d, J=6.32 Hz, 1H); LRMS (ESI) m/e 422.0 [(M+H)+, calcd for C24H31N5O2 421.0].
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[N:31]=1>CN(C)C=O>[CH3:37][O:36][C:32]1[N:31]=[C:30]([CH2:29][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: COc1cccc(CCl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc(COc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 85.9 %

Procedure:
Tetrahydrofuran (3 mL) and a 5N sodium hydroxide aqueous solution (22.4 μL, 0.11 mmol) were added to 4-(5-(2-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was then concentrated under a reduced pressure, which gave a white solid. To a suspension of this solid in N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of the 2-chloromethyl-6-methoxy-pyridine (21.2 mg, 0.13 mmol) described in Manufacturing Example 99-1-2, which was stirred for 12 hours at 60° C. This reaction mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and this residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (36.7 mg, 84%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[Cl:35])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5Cl)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-chlorophenylboronic acid.
Reaction SMILES: N#N.[Br:3][C:4]1[N:8]2[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH3:33][C:34]([CH3:40])([CH3:39])[CH2:35][C:36](Cl)=[O:37].CCN(C(C)C)C(C)C>C(OCC)(=O)C>[Br:3][C:4]1[N:8]2[N:9]=[C:10]([N:13]3[CH2:14][CH2:15][N:16]([C:36](=[O:37])[CH2:35][C:34]([CH3:40])([CH3:39])[CH3:33])[CH2:17][CH2:18]3)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1
Reactant: Brc1cnc2ccc(N3CCNCC3)nn12
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl
Agent: N#N
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Temperature: 25 °C

Procedure:
To a rapidly stirred, ambient temperature, N2 blanketed, suspension of 3-bromo-6-piperazin-1-yl-imidazo[1,2-b]pyridazine (dihydrochloride (400.5 mg, 1.1 mmol) and 3,3-dimethylbutanoyl chloride [7065-46-5] (0.2 mL, 1.4 mmol) in ethyl acetate (50 mL) was added Hunig's base [7087-68-5] (0.8 mL, 4.6 mmol) and the reaction allowed to stir over night. Once complete, the reaction was washed with brine, dried (MgSO4), and crystallized from chilled ethyl acetate/heptane to afford 392.5 mg of white crystalline powder, mp. 170-171° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (s, 9H) 2.30 (s, 2H) 3.57 (d, J=7.06 Hz, 4H) 3.63-3.72 (m, 4H) 7.26 (d, J=9.92 Hz, 1H) 7.63 (s, 1H) 7.91 (d, J=9.92 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 29.57, 30.81, 40.12, 43.50, 45.26, 45.34, 99.17, 110.56, 125.96, 131.44, 136.42, 154.89, 169.49. LRMS (ESI) m/z 380.1/382.1 [(M+H)]+, calc'd for C16H22BrN5O: 380.28.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:25])[C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][S:13]2(=[O:19])=[O:18])[N:9]=[C:8]([NH:20][CH:21]([CH2:23][CH3:24])[CH3:22])[CH:7]=1>C1COCC1>[CH:21]([NH:20][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][S:13]2(=[O:19])=[O:18])[N:9]=1)[C:5]([OH:25])=[O:4])([CH2:23][CH3:24])[CH3:22]
Reactant: CCC(C)Nc1cc(C(=O)OC)cc(N2CCCCS2(=O)=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(C)Nc1cc(C(=O)O)cc(N2CCCCS2(=O)=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Add 1 N lithium hydroxide (4.0 mL, 3.88 mmol) to a solution of 2-sec-butylamino-6-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-isonicotinic acid methyl ester (0.590 g, 1.80 mmol) in THF (5 mL) at 0° C. Stir for 2 h at room temperature and acidify the mixture to about pH =2 and concentrate. Extract the residue with ethyl acetate (3×40 mL) and wash the combined extract with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound (0.377 g, 74%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4]1)[CH3:2].[N+:21]([O-])([OH:23])=[O:22].S(=O)(=O)(O)O>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([N+:21]([O-:23])=[O:22])=[C:10]([O:13][CH3:14])[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2nc(OC)ccc2c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cn(CC)c2nc(OC)c([N+](=O)[O-])cc2c1=O
Temperature: 0 °C

Procedure:
Ethyl 1-ethyl-7-methoxy-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (82 g) was added to a mixture of fuming nitric acid (200 ml) and concd. sulfuric acid (330 ml), then the mixture was heated at 80° C. for 2 hours with stirring. The mixture was poured into 500 ml of ice-water. The precipitate was collected, washed with water, and dried. Recrystallization from ethanol gave 93.5 g of ethyl 1-ethyl-1,4-dihydro-7-methoxy-6-nitro-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 223.5°-227° C.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(N)(=[S:13])C.Cl>CN(C)C=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([NH2:10])=[S:13])=[CH:3][CH:4]=1
Reactant: COc1ccc(C#N)cc1
Reactant: CC(N)=S
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(N)=S)cc1
Yield: 75.4 %

Procedure:
A mixture of 53.26 g of anisonitrile and 60.10 g of thioacetamide in 600 ml of dimethylformamide was saturated with dry hydrogen chloride gas while being cooled in an ice bath. The mixture was then distilled on an oil bath at 100° C. After the liquid had been removed, aqueous sodium bicarbonate was added and the solid was collected and recrystallized from toluene, giving 50.47 g of 4-methoxythiobenzamide as a yellow solid.
Reaction SMILES: [C:1]([C:3](=[C:8](SC)[S:9][CH3:10])[C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH3:13][C:14]([CH3:19])([CH3:18])[C:15]([NH2:17])=[O:16].[H-].[Na+].Cl>CC(N(C)C)=O>[C:1]([C:3](=[C:8]([NH:17][C:15](=[O:16])[C:14]([CH3:19])([CH3:18])[CH3:13])[S:9][CH3:10])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: CC(C)(C)C(N)=O
Reactant: COC(=O)C(C#N)=C(SC)SC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)C(C#N)=C(NC(=O)C(C)(C)C)SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
Methyl 2-cyano-3,3-bis(methylsulfanyl)prop-2-enoate (4.06 g) and 2,2-dimethylpropanamide (2.02 g) were dissolved in DMA (200 ml), and sodium hydride (1.92 g) was added under ice-cooling. The mixture was stirred at room temperature overnight, and poured into ice. The mixture was acidified with 1 N aqueous hydrochloric acid solution. The precipitated crystals were collected by filtration, and dried to give the object compound (2.4 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH:15](C(OCC)=O)[C:16]([O:18]CC)=[O:17])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl>C1COCC1.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][C:16]([OH:18])=[O:17])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cnc(-c2ccnc(C)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ncc(CC(=O)O)cc2C)ccn1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A mixture of diethyl 2-(2′,3-dimethyl-2,4′-bipyridin-5-yl)malonate 156-4 (935 mg, 3 mmol) and NaOH (480 mg, 12 mmol) in THF (1.8 mL) and water (1.8 mL) was stirred at 65° C. for 3 hours. After cooled down to room temperature, the mixture was treated with 3N HCl aqueous solution to adjust the pH around 3, and then stirred for 15 minutes. The resulting solution was evaporated to dryness and the remaining solid was extracted with 20% methanol in ethyl acetate. The organic extraction was concentrated to give 2-(2′,3-dimethyl-2,4′-bipyridin-5-yl)acetic acid 156-5 as white solid. MS m/z 243.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:2][C:3](=[O:4])[N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(CCl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
To the solution of morpholine (10 mmol, 0.872 mL) and Et3N (15 mmol, 2.09 mL) in THF (20 mL) at 0° C. was dropped in chloroacetyl chloride 1 (12 mmol, 0.956 mL). The mixture was stirred at 0° C. for 4 h and then r.t. overnight. The reaction was quenched with H2O and evaporated to dryness. Purification by column chromatography (CH2Cl2/CH3OH=50/1) gave 2-chloro-1-morpholin-4-yl-ethanone 2 (1.62 g, 100%). 2 (1.6 g, 0.98 mmol) was treated with piperazine-1-carboxylic acid t-butyl ester (10 mmol, 1.86 g) in DMF (20 mL) at 70° C. for 12 h in the presence of K2CO3 (3 mmol, 4.14 g). Solvents were evaporated and the crude product was purified by flash chromatography (CH2Cl2/CH3OH=30/1) to give 4-(2-morpholin-4-yl oxo-ethyl)-piperazine-1-carboxylic acid t-butyl ester 4, which was treated with TFA (5 mL) in CH2Cl2 (5 mL) at r.t. for 2 h. Evaporation of all solvents furnished the TFA salt of 1-morpholin-4-yl-2-piperazin-1-yl-ethanone 4 (4.1 g, 93%).
Reaction SMILES: [CH:1]1([CH:6]([CH2:16][CH3:17])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][N:19]([CH3:30])[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=1.Cl>C(O)C>[CH:1]1([CH:6]([CH2:16][CH3:17])[C:7]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][N:19]([CH3:30])[CH3:18])=[CH:24][CH:25]=2)([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(C(=O)c1ccc(O)cc1)C1CCCC1
Reactant: CN(C)CCOc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: CCC(C1CCCC1)C(O)(c1ccc(O)cc1)c1ccc(OCCN(C)C)cc1

Procedure:
2-cyclopentyl-1-[p-(N,N-dimethyl-2-aminoethoxy)phenyl]-1-(p-hydroxyphenyl)-1-butanol, which was prepared from α-cyclopentyl-p-hydroxybutyrophenone and p-(N,N-dimethyl-2-aminoethoxy) bromobenzene according to the procedure of example 3, was dehydrated in ethanol in the presence of hydrochloric acid. The product was recrystallized from n-hexane, mp. 112°-120° C. and was found to be an 1:1 mixture of E- and Z-isomers.
Reaction SMILES: [NH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][CH2:5][C:4]=2[CH:3]=[N:2]1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:41])=[C:27]([CH:40]=1)[C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1)=[O:29]>ClCCl>[NH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:37]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=4[CH3:41])=[N:36][CH:35]=3)=[O:38])[CH2:6][CH2:5][C:4]=2[CH:3]=[N:2]1
Reactant: c1ccc2c(c1)NCCc1cn[nH]c1-2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3ccccc32)cn1
Reaction time: 16 h

Procedure:
To a solution of 0.20 mol of 1,4,5,6-tetrahydropyrazolo[4,3-d][1]benzazepine, 0.80 mol of triethylamine is added 0.42 mol of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride in 15 ml of dichloromethane. The mixture is stirred under argon for 16 hours and diluted with dichloromethane (25 ml). The mixture is washed with H2 O), 1MNaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue in methanol-tetrahydrofurane(1:1) stirred with 1NNaOH for 5 hours. The mixture is neutralized with acetic acid and the solvent removed. To the residue is added H2O and the mixture extracted with ethyl acetate. The extract is washed with H2O, 1NHCl, 1MNaHCO3 and dried (Na2SO4). The solvent removed under vacuum and the residue chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>COC(C)(C)C>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[N:9][C@@H:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:24][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: C[C@H](N)c1ccccc1
Solvent: COC(C)(C)C
Product: C[C@H](N=Cc1ccc(OCc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.8 %

Procedure:
0.11 g (0.93 mmol) of (S)-α-methylbenzylamine and 0.26 g (1.23 mmol) of 4-benzyloxybenzaldehyde are mixed in 4 ml of t-butyl methyl ether and stirred for three days at room temperature, and then evaporated under reduced pressure to give a residue, which was then washed with 5 ml of n-hexane, filtered, and dried to give 0.24 g (0.77 mmol) of (S)-N-(4-benzyloxybenzylidene)-α-methylbenzylamine (Yield: 83%, purity 90%).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH3:13][CH:14]1[NH:18][C:17](=[O:19])[CH2:16][CH2:15]1>>[CH3:13][CH:14]1[CH2:15][CH2:16][C:17](=[O:19])[N:18]1[C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CC1CCC(=O)N1
Product: CC1CCC(=O)N1c1ccc(C(=O)O)cc1

Procedure:
Using ethyl 4-iodobenzoate (1.70 mL) and 5-methylpyrrolidin-2-one (0.98 g) and by the reaction and treatment in the same manner as in Preparation Example 15, the title compound (1.80 g) was obtained.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:40])[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1.[CH2:41]([C:48]1[CH:53]=[C:52](Cl)[N:51]=[C:50]([Cl:55])[N:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:41]([C:48]1[N:49]=[C:50]([Cl:55])[N:51]=[C:52]([NH:40][C:30]2[CH:31]=[CH:32][C:33]([N:34]3[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]3)=[C:28]([O:27][CH3:26])[CH:29]=2)[CH:53]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Clc1cc(Cc2ccccc2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Nc2cc(Cc3ccccc3)nc(Cl)n2)ccc1-n1cnc(C)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 7.4 %

Procedure:
Palladium acetate (2.7 mg, 0.012 mmol) and 2-(dicyclohexylphosphino)-biphenyl (8.5 mg, 0.024 mmol) were dissolved under an atmosphere of nitrogen under stirring in dioxane (1 mL). After 10 min stirring this solution was added to a suspension of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.3 mmol), 4-benzyl-2,6-dichloropyrimidine (71.7 mg, 0.3 mmol) and potassium carbonate (829 mg, 6 mmol) in dioxane (1.7 mL). The reaction was heated to reflux for 16 h. After cooling to 20° C. the reaction was poured onto water and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (9.0 mg, 24%) as a yellow solid.
Reaction SMILES: C(OC(=O)[N:10]([CH2:32][C:33]([CH3:39])([CH3:38])[CH2:34][CH2:35][C:36]#[N:37])[CH2:11][C@@H:12]([OH:31])[C@@H:13]([NH:21][C:22]([O:24][CH:25]1[CH2:30][O:29][CH2:28][O:27][CH2:26]1)=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[O:27]1[CH2:26][CH:25]([O:24][C:22](=[O:23])[NH:21][C@@H:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:12]([OH:31])[CH2:11][NH:10][CH2:32][C:33]([CH3:39])([CH3:38])[CH2:34][CH2:35][C:36]#[N:37])[CH2:30][O:29][CH2:28]1
Reactant: [H][H]
Reactant: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1
Reaction time: 16 h

Procedure:
A solution of (4-Cyano-2,2-dimethyl-butyl)-[(2R,3S)-3-([1,3]dioxan-5-yloxycarbonylamino)-2-hydroxy-4-phenyl-butyl]-carbamic acid benzyl ester (0.420 g, 0.76 mmol) in EtOAc at ambient temperature was treated with palladium on carbon (0.050 g) and stirred under a balloon of hydrogen. After stirring 16 h the mixture was filtered and solvent was removed in vacuo to give desired product as a colorless oil.
Reaction SMILES: CSC.B.[Br:5][CH2:6][C:7]([C:9]1[N:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[S:12][CH:13]=1)=[O:8].C1(B2N3CCC[C@@H]3C(C3C=CC=CC=3)(C3C=CC=CC=3)O2)C=CC=CC=1>O1CCCC1>[Br:5][CH2:6][CH:7]([C:9]1[N:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[S:12][CH:13]=1)[OH:8]
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Agent: B
Agent: c1ccc(B2OC(c3ccccc3)(c3ccccc3)[C@H]3CCCN23)cc1
Solvent: CSC
Solvent: C1CCOC1
Product: OC(CBr)c1csc(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Borane methyl sulfide complex (2M in THF, 50 mL, 100 mmol) and 4-bromoacetyl-2-trifluoromethylthiazole (20.15 g, 73.5 mmol) were added separately and simultaneously over one our to (R)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole (1.2 g, 3.53 mmol) in tetrahydrofuran (50 mL) at ambient temperature. After the reduction was complete the reaction mixture was cooled to 0° C. and quenched with methanol (dropwise addition of 115 mL) while maintaining the temperature at less than or equal to 13° C. The quenched reaction mixture was stirred at 5° to 10° C. for ten minutes and then at ambient temperature for 45 minutes. The solvents were removed in vacuo and the residue was dissolved in methylene chloride (180 mL), washed with pH 4 aqueous phosphate buffer (180 mL), water (180 mL) and dried (MgSO4). The solvent was removed in vacuo to afford 4-(2-bromo-1-hydroxyethyl)-2-trifluoromethylthiazole as an amber oil (20.14 g, 99%, 90% ee). 1NMR (300 MHz, CDCl3 ): δ 7.61 (s, 1H), 5.13 (dd, J=4 Hz, J=7 Hz, 1H), 3.91 (dd, J=4 Hz, J=10 Hz, 1H), 3.70 (dd, J=7 Hz, J=10 Hz, 1H), 2.88 (bs, 1H).