Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C@H:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C@@H:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: C[C@@H]1NCCc2ccccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: C[C@H]1c2ccccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-(S)-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: N#N.[H-].[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:15]([CH3:17])[CH3:16])[C:13]#N)=[CH:8][CH:7]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23](CCl)=[CH:22][CH:21]=1>O.CN(C)C=O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:15]([CH3:17])[CH3:16])=[CH:13][C:23]2[CH:26]=[CH:27][C:20]([C:19]([F:29])([F:28])[F:18])=[CH:21][CH:22]=2)=[CH:8][CH:7]=1
Reactant: CN(C)C(C#N)c1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=Cc1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Yield: 88.3 %

Procedure:
Into a 200 ml four-necked flask equipped with a thermometer, a stirrer, a dropping funnel and a N2 gas supply tube, a N2 gas was introduced so that the interior of the flask became a N2 atmosphere. 40 ml of dimethylformamide and 2.4 g (61.6 mmol) of sodium hydride (62% oil suspension) were charged, and a solution comprising 10 g (56 mmol) of 2-(4-fluorophenyl)-2-(N,N-dimethylamino)acetonitrile and 10.9 g (56 mmol) of 4-(trifluoromethyl)benzyl chloride, was dropwise added over a period of one hour at from 5 to 10° C. under cooling with ice water and then further reacted at from 20 to 30° C. for one hour. After completion of the reaction, 200 ml of water was added, and the mixture was extracted with 200 ml of ethyl acetate. The extract was washed with a 5% sodium hydrogen carbonate aqueous solution and water and then dried over anhydrous sodium sulfate. Ethyl acetate was distilled off, and the obtained oily substance was distilled under reduced pressure to obtain 15.3 g (yield: 88.3%) of the desired compound (boiling point: 130-135° C./0.6 KPa). The NMR spectrum data thereof were as follows.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[CH:4][C:3]=1[C:21]#[C:22][CH2:23][OH:24].CCO.[Cl-].[NH4+]>[Fe].O>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])=[CH:4][C:3]=1[CH:21]=[CH:22][CH2:23][OH:24]
Reactant: Nc1c(C#CCO)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccccc2C(F)(F)F)cc(C=CCO)c1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
3-(4-Amino-5-nitro-2′-trifluoromethyl-biphenyl-3-yl)-prop-2-yn-1-ol (131 mg, 0.390 mmol, as prepared in Example 10, step A) was placed in an 8 mL vial equipped with a magnetic stir bar, and EtOH (4 mL) was added via syringe followed by water (1 mL). Ammonium chloride (10 eq., 209 mg, 3.90 mmol) and Fe powder (5 eq., 109 mg, 1.95 mmol) were added as solids. The vial was tightly capped, placed in a heated block, and stirred at 80° C. for 16 h. The reaction was cooled to RT, filtered, and the solids were washed three times with MeOH (5 mL). The filtrate was concentrated under reduced pressure, the residue was dissolved in EtOAc (20 mL) and washed with water (20 mL), and the aqueous layer was extracted three times with EtOAc (10 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure, yielding 95 mg of the title compound as a 1:1 mixture with 3-(4,5-diamino-2′-trifluoromethylbiphenyl-3-yl)-prop-2-yn-1-ol. The mixture was carried through to the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C@@H:15]([CH3:31])[C:16](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[BH4-].[Li+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C@@H:15]([CH3:31])[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](CO)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
A solution of 156 mg (0.36 mmol) of (3-(1-t-butoxycarbonyl-piperidin-4-yl)-2-(R)methylpropyl)-4-(S)-benzyloxazolidin-2-one (from EXAMPLE 99, Step A) in 3 mL of THF at O° C. was treated with 0.03 mL (0.73 mmol) of MeOH followed by 16 mg (0.73 mmol) of lithium borohydride. The cooling bath was removed, the mixture was warmed to rt and stirred for 3 h. The reaction was quenched with H2O and sat'd sodium potassium tartrate. The quenched mixture was diluted with CH2Cl2 and stirred for 1 h, then extracted 3× with CH2Cl2. The combined organic layers were washed with sat'd NaCl, dried over Na2SO4, filtered and the filtrate concentrated. Purification by silica gel column chomatography with 0-25% EtOAc/hexanes (v/v) provided 72 mg (77%) of the title compound: 1H NMR (500 MHz) δ 0.92 (d, J=6.8,33H). 1.01-1.12 (3H), 1.27-1.33 (m, 1H), 1.45 (s, 9H), 1.46-1.50 (m, 1H), 1.61-1.75 (4H), 2.69 (bq, 2H), 3.41 (dd, J=3.9,6.6 Hz, 1H). 3.49 (dd, J=4.8, 5.7, 1H). 4.07 (bd, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C@:8]23[CH2:16][O:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:7]=1.FC(F)(F)C([NH2:31])=O.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>[Cu]I.O.CO>[NH2:31][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C@:8]23[CH2:16][O:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:7]=1
Reactant: NC(=O)C(F)(F)F
Reactant: O=C(NC1=N[C@@]2(c3cc(Br)ccc3F)COC[C@H]2CS1)c1ccccc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: Nc1ccc(F)c([C@]23COC[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Temperature: 22 °C
Reaction time: 19 h
Yield: 49.9 %

Procedure:
To a 2 L round bottom flask is added N-((4aS,7aS)-7a-(5-bromo-2-fluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (35.0 g, 80.4 mmol), trifluoroacetamide (16.2 g, 143 mmol), copper(I) iodide (2.66 g, 13.7 mmol), sodium iodide (21.3 g, 141 mmol) and potassium carbonate (21.5 g, 153 mmol). The flask is capped with a septum, vacuum and back filled with nitrogen. 1,4-dioxane (731 mL) (previously degassed with vacuum-nitrogen) is added via cannula, and N,N′-dimethyl-, trans (+/−) 1,2-cyclohexanediamine (10.1 g, 70.8 mmol) is added. The mixture is placed in a preheated oil bath at 100° C. and stirred at this temperature for 19 h. The septum is replaced by a reflux condenser and a mixture of methanol (154 mL) and water (154 mL) is added through the condenser. The mixture is stirred at 100° C. for 3.5 h, cooled to 22° C., and concentrated partially under reduced pressure (to 0.6 L volume). Aqueous ammonium hydroxide (25%, 154 mL) is added and the mixture is stirred for 10 min. The mixture is extracted three times with ethyl acetate (3×500 mL) and the solvent is removed under reduced pressure. A residue is obtained that is purified by flash chromatography with a linear gradient of 50% to 75% ethyl acetate in hexane to give the title compound (14.9 g, 47%). ES/MS m/e: 372 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH:30]([C:33](=[O:34])[NH:1][CH2:2][C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:4]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)C1

Procedure:
3-[(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared starting from intermediate D and 1-(tert-butoxycarbonyl)-pyrrolidine-3-carboxylic acid. MS calcd. for C26H29ClN3O4 [(M+H)+] 481.3, obsd. 482.0.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([Cl:8])=[CH:6][NH:5][N:4]=1.[CH3:9][C:10]1[N:15]=[C:14]([SH:16])[N:13]=[C:12]([OH:17])[CH:11]=1>>[Cl:8][C:7]1[C:3]([CH2:2][S:16][C:14]2[N:13]=[C:12]([OH:17])[CH:11]=[C:10]([CH3:9])[N:15]=2)=[N:4][NH:5][CH:6]=1
Reactant: Clc1c[nH]nc1CBr
Reactant: Cc1cc(O)nc(S)n1
Product: Cc1cc(O)nc(SCc2n[nH]cc2Cl)n1

Procedure:
This example was synthesized from 3-(bromomethyl)-4-chloro-1H-pyrazole and 6-methyl-2-sulfanylpyrimidin-4-ol following general procedure as described in the last step of Example 22. The title compound was obtained as a white solid (500 mg, 20% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 3.17 (s, 1H), 4.40 (s, 2H), 6.00 (bs, 1H), 7.93 (s, 1H); M+257.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].O>COCCOC>[CH3:25][S:26]([C:29]1[CH:34]=[C:33]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:11]\[OH:12])=[CH:4][CH:3]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: O/N=C(\CC(c1ccccc1)c1ccc(Br)cc1)c1ccncc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CS(=O)(=O)c1cccc(-c2ccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)cc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 175.4 %

Procedure:
To a stirred solution of (E)-3-(4-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 5, 10 mg), (3-methylsulfonylphenyl)boronic acid (58 mg), tetrakis-(triphenylphosphine)palladium (0) (30 mg) in 1,2-dimethoxyethane (2 mL) was added potassium carbonate (90 mg). The mixture was stirred at 80° C. overnight. Water was added, the phases were separated and the inorganic one was extracted with diethyl ether (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 2:1 to EtOAc) to yield (E)-3-(3′-methanesulfonyl-biphenyl-4-yl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (21 mg, 18%) as a light yellow foam, MS (ESI+): m/z=457.2 ([M+H]+).
Reaction SMILES: O[C@@H:2]1[CH2:7][C@@H:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@H:5]([CH3:13])[CH2:4][CH2:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:38]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C(C)=CC=CC=1C.II.[Cl-]>C(Cl)(Cl)(Cl)Cl>[I:38][C@H:2]1[CH2:7][C@@H:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@H:5]([CH3:13])[CH2:4][CH2:3]1
Reactant: II
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CC[C@H]1C
Agent: [Cl-]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@H](I)CC[C@H]1C

Procedure:
reacting said ethyl (1R,2R,5S)-5-hydroxy-2-methylcyclohexane-1-carboxylate (12) with Ph3P-imidazole-I2 (or Ph3P-2,6-lutidine-I2) in a carbon tetrachloride/methlylene chloride mixture to produce ethyl (1R,2R,5R)-5-iodo-2-methylcyclohexane-1-carboxylate (4a).
Reaction SMILES: ClC1CCC2C(=CC(OC)=CC=2)C1.C(OC(=O)C)C.[CH2:20]([O:22][C:23](=[O:38])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[CH2:28][CH2:27][C:26]=1[Cl:37])[CH3:21].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1.CO>[CH2:20]([O:22][C:23](=[O:38])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[CH:28]=[CH:27][C:26]=1[Cl:37])[CH3:21]
Reactant: CCOC(=O)CC1=C(Cl)CCc2ccc(OC)cc21
Agent: COc1ccc2c(c1)CC(Cl)CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(Cl)ccc2ccc(OC)cc12
Temperature: 25 °C

Procedure:
A mixture of [2-Chloro-7-methoxy-3,4-dihydro-2H-naphthalen-(1 E/Z)-ylidene]-acetic acid ethyl ester and of (2-Chloro-7-methoxy-3,4-dihydro-naphthalen-1-yl)-acetic acid ethyl ester (26.82 g, 95.52 mmol) is dissolved under an atmosphere of argon in dioxane (280 ml). 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ, 47.70 g, 210.16 mmol) is added, and the reaction mixture is refluxed for 2 h. TLC analysis indicates complete conversion of starting material. After cooling to RT, addition of MeOH renders the reaction mixture homogeneous. Silica gel (250 g) is added, and the solvent is removed by rotary evaporation. Purification by FCC (hexane/EtOAc 9:1) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.24 (t, J=8.8 Hz, 3H), 3.95 (s, 3H), 4.19 (q, J=8.8 Hz, 2H), 4.28 (s. 2H), 7.16-7.19 (m, 1H), 7.22 (s, 1H), 7.38 (d, J=10 Hz, 1H), 7.68 (d, J=10 Hz, 1H), 7.75 (d, J=10 Hz, 1H). ES+-MS: 279.2, 281.2 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)=[CH:5][CH:4]=1)=[O:2].[CH3:38][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)=[CH:36][CH:37]=1)[CH3:38]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(C=O)cc2)c2ncnn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(C(C)O)cc2)c2ncnn12
Temperature: 0 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
4′-{[4-(4-Formylbenzyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.3 g) was dissolved in tetrahydrofuran (30 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 2.8 mL) was added at −78° C. The reaction mixture was warmed to 0° C., and stirred for 6 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.2 g, 90%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([O:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([O:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1OC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1OC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A solution of tert-butyl (Z)-4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yloxy}piperidine-1-carboxylate (0.020 g, 0.041 mmol) in methylene chloride (3.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3.0 mL), and then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was azeotroped twice with toluene under reduced pressure. The residual solid was added with water, and then the mixture was adjusted to pH 9 with saturated aqueous sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(piperidin-4-yloxy)benzofuran-3(2H)-one (0.016 g, 100%).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[CH3:25])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]1([CH2:29][NH2:30])[CH2:28][CH2:27]1>CN1C(=O)CCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH:26]1([CH2:29][NH:30][C:2]2[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:15][C:14]=4[CH3:25])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:28][CH2:27]1
Reactant: Cc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Reactant: NCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NCC3CC3)c2n1
Temperature: 120 °C
Yield: 9.6 %

Procedure:
To a solution of 8-chloro-N-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Preparation 113, 40 mg, 0.114 mmol) in NMP (3 mL) was added cyclopropanemethylamine (0.1 ml, 1.140 mmol). The reaction mixture was heated to 120° C. for 18 hours. The reaction mixture was diluted with aqueous saturated NaHCO3 (20 mL) and EtOAc (2×20 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-5% MeOH in EtOAc to give the title compound (4.2 mg, 10%).
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[C:8]([NH2:14])(=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11].O>C1(C)C=CC=CC=1>[C:8]([NH:14]/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4])(=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CCC(=O)C(=O)O
Reactant: CC(C)CC(N)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C/C=C(\NC(=O)CC(C)C)C(=O)O
Reaction time: 5 h

Procedure:
A solution of 1.07 g (10.5 mmole) of 2-keto-butyric acid and 0.71 g (7.0 mmole) of isovaleramide in 15 ml of toluene was stirred under reflux with collection of H2O in a small Dean-Stark trap. After 5 hrs, the solution was cooled, resulting in fairly heavy crystallization. After standing, the solid was collected on a filter and washed with toluene and then with CH2Cl2. Yield of white crystals=0.47 g, mp 172°-174° (slight prelim. softening). The material was recrystallized from diisopropyl ketone. Tlc (4:1 toluene-AcOH) now showed only a faint trace of the other isomer. Yield of white crystals=0.32 g (25%), mp 175° (slight prelim. softening). NMR indicated essentially exclusively Z-isomer.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>CCOCC>[C:26]([N:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)(=[O:28])[CH3:27]
Reactant: c1ccc(Oc2ccc(C3CCCN3)cc2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)N1CCCC1c1ccc(Oc2ccccc2)cc1

Procedure:
To a solution of 10 parts of 2-(4-phenoxyphenyl) pyrrolidine in 200 parts of anhydrous ether and 4.2 parts of triethylamine, there was added a solution of 3.3 parts of acetyl chloride in 30 parts of ether. The reflux was maintained for one hour, then the reaction mixture was filtered off on cooling and the filtrate was distilled. There were obtained 13 parts of 1-acetyl-2-(4-phenoxyphenyl) pyrrolidine.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[C:10]1([Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:2]2[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([Cl:9])[N:1]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: Clc1nc(Cl)nc(-c2ccccc2)n1

Procedure:
One mole of cyanuric chloride was treated with one mole of phenylmagnesium bromide in Step I to form 6-phenyl-2,4-dichloro-s-triazine. This reaction is described in detail in a paper by Hirt, et al., Helvetica Chimica Acta 33, pages 1365-9 (1950). In Step II, the product of the reaction of Step I (0.025 mole) was dissolved in chloroform (35 ml) and stirred in an oil bath at 50° C. To this solution was added dropwise with stirring a solution of sodium hydroxide (0.05 mole), 3-ethynylphenol (0.05 mole), and water (25 ml) during one hour. The reaction was continued overnight and yielded an organic phase which was subsequently separated and dried over sodium sulfate. Removal of solvent under reduced pressure gave a solid product, 6-phenyl-2,4-bis(3-ethynylphenoxy)-s-triazine, mp 139°-144° C., which thermally cured at 260° C. to a heat stable polymer.
Reaction SMILES: [Cl-].C[Al+]C.CCCCCC.[F:11][C:12]([F:16])([F:15])[CH2:13][NH2:14].[C:17]([O:21][C:22](=[O:51])[NH:23][C@H:24]([C@@H:42]1[CH2:46][C@@H:45]([CH:47]([CH3:49])[CH3:48])[C:44](=[O:50])[O:43]1)[CH2:25][N:26]1[CH2:31][C:30](=[O:32])[N:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[CH2:28][C:27]1([CH3:41])[CH3:40])([CH3:20])([CH3:19])[CH3:18].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl.C(OCC)(=O)C>[C:17]([O:21][C:22](=[O:51])[NH:23][C@@H:24]([CH2:25][N:26]1[CH2:31][C:30](=[O:32])[N:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[CH2:28][C:27]1([CH3:40])[CH3:41])[C@@H:42]([OH:43])[CH2:46][C@H:45]([C:44](=[O:50])[NH:14][CH2:13][C:12]([F:16])([F:15])[F:11])[CH:47]([CH3:49])[CH3:48])([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Reactant: NCC(F)(F)F
Agent: C[Al+]C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2ccccc2Cl)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
2 ml of a solution of dimethylaluminum chloride in n-hexane (1.0 mol/l) (2 mmol) was added to a solution of 160 μl of (2,2,2-trifluoroethyl)amine (2 mmol) in methylene chloride under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for one hour. A solution of 200 mg of {(S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (1m) (0.39 mmol) in methylene chloride (4 ml) was added to the solution obtained above, and the mixture was stirred at room temperature for 26 hours. A 10% potassium sodium tartrate aqueous solution was added to the reaction mixture, followed by dilution with ethyl acetate. Then, the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was extracted with ethyl acetate, and then the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=40/1) to obtain 132 mg of the title compound (yield: 55%).