Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:15][C@@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([C:28](OC)=[O:29])[CH2:17]2)=[O:14])=[N:5]1)([CH3:3])[CH3:2].[Cl-].[Li+].[BH4-].[Na+]>O1CCCC1CO>[OH:29][CH2:28][C@@H:18]1[CH2:17][C@H:16]([NH:15][C:13]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=2)=[O:14])[CH2:20][N:19]1[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22]
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: OCC1CCCO1
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CO)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Reaction time: 20 h
Yield: 92.9 %

Procedure:
To a stirred solution of 1-tert-butyl 2-methyl (2S,4S)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidine-1,2-dicarboxylate (135 mg, 0.313 mmol, step 1 of Example 7) in tetrahydrofuran-methanol (2 mL-2 mL) were added lithium chloride (81 mg, 1.92 mmol) and sodium borohydride (73 mg, 1.92 mmol) at room temperature. The resulting mixture was stirred at the same temperature for 20 h. Another lithium chloride (81 mg, 1.92 mmol) and sodium borohydride (73 mg, 1.92 mmol) were added to the mixture at room temperature. After stirring for 3 h, the mixture was quenched with water (10 mL), extracted with ethyl acetate (100 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (1:1) to give 117 mg (93%) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2O)cc1
Reactant: OCc1ccccc1
Product: COc1ccc(CC(=O)c2ccc(OCc3ccccc3)cc2O)cc1
Yield: 94.7 %

Procedure:
Using the previous procedure and starting from 1-(2,4-dihydroxyphenyl)-2-(4-methoxyphenyl)ethanone (8.0 g, 31.0 mmol) and benzyl alcohol (3.37 mL, 32.55 mmol), 10.23 g (95%) of the title compound was obtained as a white solid: mp 97-98° C. (lit. 93-95° C.); IR (KBr) 1635, 1611, 1512, 1496, 1387, 1351, 1289, 1227, 1173, 1131, 1029, 994, 948, 842, 830, 791, 745, 725, 695, 535 cm−1; 1H NMR (250 MHz, CDCl3) δ 12.73 (s, 1H), 7.75 (d, J=9.6 Hz, 1H), 7.33-7.40 (m, 5H), 7.18 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 6.53-6.49 (m, 2H), 5.07 (s, 2H), 4.14 (s, 2H), 3.78 (s, 3H); 13C NMR (69.3 MHz, CDCl3) δ 202.77, 166.19, 165.63, 159.10, 136.26, 132.51, 130.82, 129.15, 128.77, 127.97, 126.71, 114.63, 113.73, 108.71, 102.48, 70.6.5, 55.69, 44.38; HRMS calculated for C22H20NaO4 (M+Na)+ 371.1259; found 371.1265.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([CH:33]=2)[C:31]#[N:32])O1>>[C:31]([C:30]1[CH:33]=[C:26]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:6][N:7]=2)[CH:27]=[N:28][CH:29]=1)#[N:32]
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)nc1
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2cncc(C#N)c2)nc1
Yield: 47 %

Procedure:
Prepared in a similar manner to Example 23 from 2-(6-bromopyridin-3-yl)-N-isobutyl-2-methylpropanamide (example 40a) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile. Yield: 47%. 1H NMR (400 MHz, dMSO): δ 0.72-0.74 (d, 6H), 1.51 (s, 6H), 1.66-1.69 (m, 1H), 2.82-2.86 (m, 2H), 7.62-7.64 (m, 1H), 7.82-7.85 (m, 1H), 8.10-8.12 (d, 1H), 8.65-8.66 (d, 1H), 8.89-8.90 (t,1H), 9.05-9.06 (d, 1H), 9.50-9.51 (d, 1H); MS+H (323).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)sc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1sc(-c2ccc(F)cc2)cc1C(=O)O

Procedure:
A mixture of ethyl 2-amino-5-(4-fluorophenyl)- 3-thiophene carboxylate (2g), sodium hydroxide (1g) and ethanol (20 ml) was refluxed for 5 hours, cooled and then concentrated. The solid residue was dissolved in water, filtered and acidified at 0°C. The light brown precipitate was collected by filtration to give pure 2-amino-5-(4-fluorophenyl)- 3-thiophene carboxylic acid, m.p. 172°-4°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccc(F)cc4)c3)c2c1
Yield: 23.9 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 4-fluorophenylacetic acid (0.11 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 52 mg (23% yield) of the title compound. 1H NMR (DMSOd6) δ 13.2 (br s, 1H), 10.2 (s, 1H), 8.6 (s, 1H), 8.23 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.73 (m, 1H), 7.6 (d, 1H), 7.5 (t, 1H), 7.47–7.34 (m, 3H), 7.17 (m, 2H), 3.7 (s, 2H); ES-MS (m/z) 389 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH2:26][CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([O:21][CH2:26][CH:27]=[CH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: BrCC=Cc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Product: Cc1c(C)c2c(c(C)c1OCC=Cc1ccccc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 71 %

Procedure:
Using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and 3-bromo-1-phenyl-1-propene, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]I)=[CH:5][CH:4]=1)#[N:2].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[K]>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CCCI)cc1
Reactant: C1CNCCN1
Agent: [K]
Solvent: C1CCOC1
Product: N#Cc1ccc(CCCN2CCNCC2)cc1
Yield: 66.2 %

Procedure:
A solution of 250 mg of 3-(4-cyanophenyl)propyl iodide, 0.85 g of anhydrous piperazine and 0.5 g of potassium carbonated in 10 ml of tetrahydrofuran was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and, after addition of saturated aqueous solution of sodium chloride, the residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 140 mg of 1-[3-(4-cyanophenyl)propyl]piperazine.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:18]([CH3:19])=[O:20])=[CH:7][CH:6]=1
Reactant: CCCCc1ccc(O)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
4-n-Butylphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (783 mg) and acetyl chloride (675 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using chloroform to give 4-n-butylphenyl acetate (1.03 g, yield 80%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[C:28]([CH:38]([CH3:40])[CH3:39])[NH:27][N:26]=1)(=[O:3])[CH3:2].[N+](C1C=C(S(O[CH2:54][C@@H:55]2[O:57][CH2:56]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:54][C@@H:55]3[O:57][CH2:56]3)=[CH:35][CH:36]=2)=[C:28]([CH:38]([CH3:40])[CH3:39])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OC[C@H]3CO3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.1 %

Procedure:
A mixture of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-hydroxyphenyl)methyl]-5-isopropyl-1H-pyrazole (0.55 g), (R)-1-(3-nitrobenzenesulfonyloxy)-2,3-epoxypropane (0.38 g) and cesium carbonate (0.57 g) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate 10=2/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(R)-2,3-epoxypropoxy]phenyl}methyl)-5-isopropyl-1H-pyrazole (0.4 g). This material (43 mg) was dissolved in ethanol (1.5 mL). To the solution was added 2-amino-2-methyl-1,3-propanediol (51 mg), and the mixture was stirred at 75° C. for 14 hours. To the reaction mixture was added 1 mol/L aqueous sodium hydroxide solution (0.28 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μm, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/methanol=90/10-10/90) to give the title compound (12 mg).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][SiH:18]([Cl:20])[Cl:19]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:17][Si:18]([Cl:20])([Cl:19])[CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH:9]=[CH:8][CH:7]([Si:18]([Cl:20])([Cl:19])[Cl:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: C(C=Cc1ccccc1)=Cc1ccccc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cl[Si](Cl)(Cl)C(C=CC(c1ccccc1)[Si](Cl)(Cl)Cl)c1ccccc1
Temperature: 180 °C
Yield: 26 %

Procedure:
As in Example 1, 1,4-diphenyl-1,3-butadiene (2.00 g, 9.70 mmol), trichlorosilane (5.25 g, 38.76 mmol), tetrabutylphosphonium chloride (0.29 g, 0.98 mmol) and 5 mL of toluene (solvent) were added in a 25 mL stainless steel tube under nitrogen atmosphere. After sealing the cylinder with a cap, the reactor was maintained at 180° C. for 8 hours. After removing the solvent and unreacted trichlorosilane and tetrachlorosilane through simple distillation, this reaction mixture was distilled under reduced pressure to separate the catalyst and the product. The product was recrystallized from 10 mL of n-hexane for 4 days to yield 1.51 g (yield: 51%) of 2,5-diphenyl-1,1-dichlorosilacyclo-3-pentene and 1.20 g (yield: 26%) of 1,4-bis(trichlorosilyl)-1,4-diphenyl-2-butene.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:36][CH3:37])(=[O:35])[CH2:33]O.[NH:38]1[C:42]([CH:43]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]2)=[N:41][N:40]=[N:39]1>ClCCl>[CH3:37][O:36][C:32](=[O:35])[CH2:33][N:41]1[C:42]([CH:43]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]2)=[N:38][N:39]=[N:40]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnn[nH]2)CC1
Reactant: COC(=O)CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cn1nnnc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Triphenylphosphine (1.28 g, 4.89 mmol), DEAD (804 μL, 4.89 mmol), and methyl glycolate (378 μL, 4.89 mmol) were added to a solution of tert-butyl 4-(1H-tetraazol-5-yl)piperidine-1-carboxylate (619.7 mg, 2.447 mmol) in dichloromethane (20 mL). The reaction mixture was stirred for 16 h at rt and then concentrated under reduced pressure. Purification by MPLC (silica gel, 10-50% EtOAc/hexanes) afforded tert-butyl 4-[1-(2-methoxy-2-oxoethyl)-1H-tetraazol-5-yl]piperidine-1-carboxylate. ESI-MS calculated for C14H23N5O4: 325.36, found 348 (M+Na).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.N(CC1C2C(=CC=CC=2)NC=1)C1C=CC=CC=1.N1CCCC1=O.C(N(CC)CC)C.N1CCCC=1N(CC1C2C(=CC=CC=2)NC=1)C1C=CC=CC=1.C.[C:59]1([N:65]=[C:66]2[CH2:70][CH2:69][CH2:68][N:67]2[CH2:71][C:72]2[C:80]3[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=3)[NH:74][CH:73]=2)[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>C(O)C.ClCCCl>[C:59]1([NH:65][CH:66]2[CH2:70][CH2:69][CH2:68][N:67]2[CH2:71][C:72]2[C:80]3[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=3)[NH:74][CH:73]=2)[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1
Reactant: c1ccc(N=C2CCCN2Cc2c[nH]c3ccccc23)cc1
Agent: O=C1CCCN1
Agent: c1ccc(N(Cc2c[nH]c3ccccc23)C2=NCCC2)cc1
Agent: c1ccc(NCc2c[nH]c3ccccc23)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: c1ccc(NC2CCCN2Cc2c[nH]c3ccccc23)cc1

Procedure:
Phosphorus oxychloride (7.67 g., 0.05 mole), 3-(anilinomethyl)indole (11.1 g., 0.05 mole), 2-pyrrolidinone (4.26 g., 0.05 mole) and triethylamine (5.06 g., 0.05 mole) in 100 ml. of 1,2-dichloroethane reacted according to the procedure of Example 35 provide a total of 6.4 g. of crude 3-[[N-(1-pyrrolin-2-yl)anilino]methyl]indole as the free base. The crude free base is taken up in ethanol and refluxed for 6 hr., treated with decolorizing charcoal and filtered. Concentration of the ethanol filtrate to about 20 ml. provides on standing a solid which crystallized from ethanol affords 2.75 g. of analytically pure 3-[(2-phenylimino-1-pyrrolidinyl)methyl]indole, m.p. 150°-151° C. (corr.), characterized by the formula: ##STR30##
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][N:14]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])[C:15]2=[O:18])=[CH:10][CH:9]=1.C(OC(=O)C)C>O>[CH3:25][C:24]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][C:8]([NH:7][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[CH:9][CH:10]=2)[C:15]1=[O:18]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccncc1-n1ccc2ccc(N)cc2c1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccncc1-n1ccc2ccc(NC(=O)C3CC3)cc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
TEA (25.1 mL, 0.1792 mmol) and cyclopropanecarbonyl chloride (12 mL, 0.1314 mmol) were added to a solution of 7-amino-2-(4-methyl-pyridin-3-yl)-2H-isoquinolin-1-one (I-24c: 30 mg, 0.1195 mmol) at 0° C. The resulting reaction mixture was stirred at 0° C. for 30 minutes. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was diluted with water and extracted with ethylacetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (70% ethylacetate in hexane) afforded 10 mg of the product (26.2% yield).
Reaction SMILES: C1([C@@H](NCCN[C@H](C2C=CC=CC=2)C)C)C=CC=CC=1.[CH3:21][CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:23]>C([Zn]CC)C>[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:21]
Reactant: CC(O)c1ccccc1
Agent: CC[Zn]CC
Agent: C[C@H](NCCN[C@@H](C)c1ccccc1)c1ccccc1
Product: CC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
The procedure was the same as in Example 11, using diethylzinc (1 mmol) as catalyst and N,N′-bis-(1-(S)-phenylethyl)-1,2-ethylenediamine in a quantity five times less, i.e. 0.2 mmol, as ligand. After the mixture had been stirred at 20° C. for 24 hours, hydrolysis was carried out with a 30% excess of soda, and a mixture of methylphenylcarbinol comprising 88% of the (S) isomer and 12% of the (R) isomer, that is to say, an ee of 74%, was recovered with a yield of 95%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH2:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[CH:24]=[CH:25][CH2:26]Br)=[CH:12][CH:11]=1.O.CCCCCC.C(OCC)(=O)C>CN(C=O)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[CH:24]=[CH:25][CH2:26][NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:12][CH:11]=1
Reactant: NOC1CCCCO1
Reactant: Fc1ccc(Sc2cccc(F)c2C=CCBr)cc1
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Sc2cccc(F)c2C=CCNOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
O-tetrahydropyranylhydroxylamine (2.88 g, 24.6 mmol) is dissolved in 15 ml of dry DMF. A solution of 1-[2-(4-fluorophenylthio)-6-fluorophenyl]3-bromoprop-1-ene (2.80 g, 8.2 mmol) in 6 ml of DMF is added and the reaction is stirred for 4 hours at room temperature. The reaction mixture is poured into 200 ml of water and then extracted twice with diethyl ether. The extracts are washed three times with water and then with brine and dried over MgSO4 to afford the crude product. Chromatography on silica gel eluting with 5:1 hexane/ethyl acetate afforded the subtitle compound.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:47])[O:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([NH:21][C:22]3[N:27]=[C:26]([N:28]([CH:38]4[CH2:40][CH2:39]4)CC4C=CC(OC)=CC=4)[C:25]4=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:24]4[N:23]=3)[C:14]=2[Cl:46])[CH2:8]1)[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([NH:3][C:4](=[O:47])[O:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([NH:21][C:22]3[N:27]=[C:26]([NH:28][CH:38]4[CH2:39][CH2:40]4)[C:25]4=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:24]4[N:23]=3)[C:14]=2[Cl:46])[CH2:8]1)[CH3:2]
Reactant: CCNC(=O)OCC1CN(c2cc(C#N)cc(Nc3nc(N(Cc4ccc(OC)cc4)C4CC4)c4ncc(C#N)n4n3)c2Cl)CCO1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CCNC(=O)OCC1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.5 %

Procedure:
To a vial charged with (+/−)-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)morpholin-2-yl)methyl ethylcarbamate (33.5 mg, 0.051 mmol) in dichlorornethane (204 μl) was added anisole (27.9 μl, 0.255 mmol), followed by trifluoroacetic acid (157 μl, 2.040 mmol). The reaction mixture was stirred at room temperature ON. Excess TFA was removed by concentration in vacuo. The crude residue was taken up in methanol and free based using a 1 g Phenomenex Strata SCX column. The column was flushed with 3 column volumes MeOH and 1 column volume 7 N NH3/MeOH. The ammonia containing fraction was concentrated in vacuo. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 15-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. (+/−)-(4-(2-Chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)morpholin-2-yl)methyl ethylcarbamate (5.9 mg) was isolated.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16]>O1CCCC1>[NH2:1][C:2]1[C:7]([NH:8][C:15](=[O:16])[C:14]([Cl:19])([Cl:18])[Cl:13])=[CH:6][C:5]([C:9]([F:10])([F:12])[F:11])=[CH:4][N:3]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1cc(C(F)(F)F)cnc1N
Solvent: C1CCOC1
Product: Nc1ncc(C(F)(F)F)cc1NC(=O)C(Cl)(Cl)Cl
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
Into 38 ml of dry tetrahydrofuran, 1.5 g of 2,3-diamino-5-trifluoromethylpyridine was dissolved, and a solution mixture comprising 1.54 g of trichloroacetyl chloride and 3.8 ml of dry tetrahydrofuran was dropwise added thereto over a period of 10 minutes. Then, the mixture was reacted at room temperature for 3 hours. After completion of the reaction, precipitated crystals were collected by filtration and washed with tetrahydrofuran to obtain 2.2 g of N-(2-amino-5-trifluoromethyl-3-pyridyl)trichloroacetamide having a melting point of from 210° to 223° C.
Reaction SMILES: [Br-].[C:2]1([C:8]([PH3+])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)C=CC=CC=1.[CH2:22]([Li])[CH2:23][CH2:24]C.C1(=O)CCCCCCCC=CCCCCCC1>C(OCC)C>[CH2:2]=[C:8]1[CH2:9][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:24][CH:23]=[CH:22][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:15]1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Agent: O=C1CCCCCCC=CCCCCCCC1
Agent: [Br-]
Solvent: CCOCC
Product: C=C1CCCCCCC=CCCCCCCC1
Reaction time: 4 h

Procedure:
10.7 g of triphenylmethylphosphoniumbromide are added at room temperature to a mixture of 20 ml of n-butyllithium (1.55 molar in hexane) and 60 ml of diethyl ether. After the mixture has been kept at room temperature for 4 hours, 7.3 g of 8-cyclohexadecen-1-one are added dropwise, and the mixture is refluxed for 18 hours. The mixture is filtered, the solvent is removed by distillation, and the residue is purified by chromatography (SiO2, hexane/ethyl acetate 95:5), giving 2.5 g of 1-methylene-8-cyclohexadecene, identified from the 1H-NMR spectrum: δ=5.2 (t, --CH=CH--); δ=4.75 (s, C=CH2).