Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]#[N:8])=[N:4][NH:5][CH:6]=1.[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=1)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([N:5]2[CH:6]=[C:2]([Br:1])[C:3]([C:7]#[N:8])=[N:4]2)=[CH:15][CH:14]=1)[CH3:10]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: N#Cc1n[nH]cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cc(Br)c(C#N)n2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
A suspension of 4-bromo-1H-pyrazole-3-carbonitrile (0.52 g), 4-fluoro-benzoic acid ethyl ester (0.56 g) and cesium carbonate (1.5 g) in N,N-dimethylformamide (10 mL) was stirred at 100° C. for 2 hours. After cooling to ambient temperature, this reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The organic layer was through an aminopropyl silica gel, and this filtrate was concentrated under reduced pressure. This obtained residue was washed with a mixed solvent of n-hexane/diethyl ether=5/1 to give the title compound (0.25 g).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][OH:7])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:14](Cl)(=[O:16])[CH3:15].Cl.N1C=CC=CC=1>O.C(Cl)Cl>[C:14]([O:7][CH2:6][CH2:5][CH2:4][C:1](=[O:3])[CH3:2])(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: CC(=O)CCCO
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)CCCOC(C)=O
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a 1 liter 3-neck round bottom flask equipped with a stirrer, thermometer, condenser and addition funnel, was added 102 grams (1 mole) of 3-acetylpropanol, 125 mls of pyridine and 600 mls of methylene chloride. With ice cooling and good agitation, 78.5 grams (1 mole) of acetyl chloride was added slowly from the addition funnel while holding the temperature at 25° C. or below. Pyridine hydrochloride began coming out of solution about 1/3 of the way through the addition. After the addition was complete, the reaction mixture was stirred an additional 15 minutes at 20°-25° C. and then warmed to 40° C. and stirred an hour at 40° C. Then 150 mls of water were added to dissolve the pyridine hydrochloride and the aqueous layer was separated. The organic layer was washed twice with 200 mls of 10% HCl, once with water and saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and the methylene chloride stripped off on a rotary evaporator under reduced pressure. The light yellow liquid weighed 104 grams (72% crude yield). The infrared spectrum of the product contained two strong carbonyl bands at 1720 cm-1 and 1745cm-1 and there was no OH band.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C@@H:3]([NH2:5])[CH3:4].[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1.C(O)(=O)C.O>CO>[CH3:1][CH:2]([CH3:6])[C@@H:3]([NH:5][C:10](=[O:11])[CH2:9][C:8](=[O:12])[CH3:7])[CH3:4]
Reactant: CC(C)[C@H](C)N
Reactant: C=C1CC(=O)O1
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)CC(=O)N[C@@H](C)C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (2S)-3-methylbutan-2-amine (30 g, >99% ee, Aldrich) in methanol (180 mL) was added dropwise diketene (29 mL) under ice bath, and the mixture was stirred at room temperature for 20 hr. The mixture was neutralized with acetic acid (120 mL) under ice bath, water was added thereto, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (56.6 g).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][C:24]([CH3:42])([C:26]2[N:30]([CH3:31])[C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:41])([F:40])[F:39])=[N:28][N:27]=2)[CH3:25])=[C:18]([CH:22]=1)[C:19]([OH:21])=O.C1CCN2C(=NCCC2)CC1.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56]>CN(C=O)C.O>[ClH:13].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][C:24]([CH3:25])([C:26]2[N:30]([CH3:31])[C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:41])([F:39])[F:40])=[N:28][N:27]=2)[CH3:42])=[C:18]([CH:22]=1)[C:19]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:21]
Reactant: CS(N)(=O)=O
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cl
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)NS(C)(=O)=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
CDI (180 mg) was added to a solution of 5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoic acid (300 mg) in DMF, followed by stirring at 50° C. for one hour. DBU (325 mg) and methanesulfonamide (200 mg) were added to the reaction solution, followed by stirring at 50° C. for 1.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate three times, with chloroform once and then with chloroform-methanol (4:1) mixed solution twice. The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1), ethyl acetate (3 ml) and methanol (1.5 ml) were added to the resulting amorphous, and a 4M hydrogen chloride-ethyl acetate solution (150 μl) was added thereto. The solvent was evaporated under reduced pressure and was powdered with diisopropylether to obtain, as a colorless solid, 5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)-N-(methylsulfonyl)benzamide monohydrochloride (143.8 mg).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:6]2[C:7](=[O:16])[CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[CH:23][CH:22]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1Cc2ccccc2-c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)Cc3ccccc3-c3ccccc32)cc1
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a solution of 0.82 g (4 mmol) of 5H,7H-dibenzo[b,d]azepin-6-one in 15 ml of dimethylformamide at room temperature 0.20 g (5 mmol) of sodium hydride 55% in oil was added. After stirring for 30 min at room temperature 0.75 g (5 mmol) of p-methoxybenzyl chloride were added and stirring was continued at room temperature for 2 hours. For workup the mixture was distributed between water and ethyl acetate. The organic layer was re-extracted with 1 N hydrochloric acid and the aqueous layers were washed with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (hexane/ethyl acetate=1:1) to yield 1.175 g (91%) of 5-(4-methoxybenzyl)-5H,7H-dibenzo[b,d]azepin-6-one as a colourless oil; MS: m/e: 330.4 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:24]>>[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:24][C:17](=[O:19])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10].[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:24]
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Temperature: 38 °C
Reaction time: 20 h

Procedure:
A 267.2 mg (1 m mol) of N-benzyloxycarbonyl-L-aspartic acid and 537.6 mg (3 m mol) of L-phenylalanine methyl ester were dissolved in 5 ml of McIlvain's buffer solution (pH:7.0). The resulting solution was admixed with 100 mg of Thermoase and 100 mg of potato inhibitor and shaken at 38° C. for 20 hours. The precipitate was collected and washed with water and dried to obtain 580 mg of a crude crystalline addition compound of N-benzyloxycarbonyl-L-aspartyl-L-phenylalanine methyl ester and L-phenylalanine methyl ester (1:1) (melting point: 123 to 125° C.; Yield: 95.5 % based on N-benzyloxycarbonyl-L-aspartic acid).
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=2)[CH:10]=[C:9]([Cl:24])[CH:8]=1)[CH3:6].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([CH2:48][OH:49])[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1>ClCCl.C1CCCCC1>[Cl:24][C:9]1[CH:8]=[C:7]([CH:5]([O:49][CH2:48][C:35]2([C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=3)[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:39][CH2:40]2)[CH3:6])[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:14]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-1-(5-Chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (1.1 g, 2.33 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.79 g, 2.57 mmol) were combined in a dichloromethane/cyclohexane mixture (1:1, 10 mL) and cooled to 0° C. The reaction was treated with tetrafluoroboric acid-diethyl ether complex (64 μL, 0.47 mmol), stirred at 0° C. for 1 h, quenched by addition of saturated sodium bicarbonate, and diluted with diethyl ether. The layers were separated. The ethereal was washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 0.81 g (56%) as a clear film. 1H-NMR (CDCl3, 500 MHz) δ 8.00 (s, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.30-7.33 (m, 2H), 7.01-7.05 (m, 2H), 6.77 (m, 1H), 5.62-5.68 (s, 2H), 4.93 (q, J=6.4 Hz, 1H), 3.72 (m, 2H), 3.58-3.61 (m, 2H), 3.33-3.39 (m, 2H), 3.03-3.08 (m, 2H), 2.08-2.22 (m, 2H), 1.87-1.97 (m, 2H), 1.44 (s, 9H), 1.43 (d, J=6.4 Hz, 3H), 0.91-0.92 (m, 2H), 0.05 (s, 9H). Mass spec.: 618.86 (MH)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5](=[O:17])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[N+:18]([C:21]1[CH:32]=[CH:31][C:24]([O:25][CH:26]([CH3:30])[C:27](O)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]([O:4][CH2:3][CH2:2][O:1][C:27](=[O:28])[CH:26]([O:25][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:32][CH:31]=2)[CH3:30])=[O:17])=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)OCCO
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.8 %

Procedure:
To a mixture of [4-nitrophenoxy]-acetic acid-2-hydroxyethyl ester 23 (100 grams, 410 mmol) and 2-(4-nitrophenoxy)-propionic acid 29 (95 g, 450 mmol) in anhydrous dichloromethane (1000 ml) under nitrogen atmosphere was added dropwise a solution of 1,3-dicyclohexyl carbodiimide (240 g, 1160 mmol) in anhydrous dichloromethane (600 ml). The reaction mixture was stirred at room temperature for 12 hrs. The solids were filtered off and dichloromethane distilled off to get crude 38. The crude 38 was purified by column chromatography on silica gel using benzene as eluant to give pure 38 (53 grams, 29%) as a yellow low melting solid.
Reaction SMILES: N[C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[S:8].[ClH:25].N([O-])=O.[Na+].[S:30](=[O:32])=[O:31]>[Cu](Cl)Cl.C(O)(=O)C>[CH2:12]([S:11][C:4]1[CH:5]=[C:6]([CH:10]=[C:2]([S:30]([Cl:25])(=[O:32])=[O:31])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:7]([OH:9])=[S:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cc(C(O)=S)cc(SCc2ccccc2)c1-c1ccccc1
Reactant: Cl
Reactant: O=S=O
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S(=O)(Cl)c1cc(C(O)=S)cc(SCc2ccccc2)c1-c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
5-Amino-3-benzylthio-4-phenylthiobenzoic acid (1.1 g), acetic acid (10 ml), and concentrated hydrochloric acid (10 ml) is stirred and cooled to 5°C. At this temperature a concentrated solution of sodium nitrite (0.21 g) is added slowly while stirring. The resultng diazonium mixture is poured into acetic acid (20 ml), saturated with sulphur dioxide and containing copper chloride (0.2 g CuCl2, 2 H2O). The reaction mixture is allowed to reach room temperature while stirring. After 30 minutes, the precipitated 3-benzylthio-5-chlorosulfonyl-4-phenylthiobenzoic acid is collected, washed with aqueous acetic acid and dried in vacuo at room temperature.
Reaction SMILES: C[N:2](C)[CH:3]=[N:4][C:5]([C:7]1[N:16]=[C:15]2[N:9]([CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([Cl:21])[N:18]=[CH:17][C:14]=32)[CH:8]=1)=O.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31]N>>[Cl:21][C:19]1[N:18]=[CH:17][C:14]2[C:15]3[N:9]([CH2:10][CH2:11][O:12][C:13]=2[CH:20]=1)[CH:8]=[C:7]([C:5]1[N:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[Cl:24])[N:2]=[CH:3][N:4]=1)[N:16]=3
Reactant: NNc1ccccc1Cl
Reactant: CN(C)C=NC(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Agent: Cl
Product: Clc1cc2c(cn1)-c1nc(-c3ncnn3-c3ccccc3Cl)cn1CCO2

Procedure:
Following the procedures of Example 378, 8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylic acid 1-dimethylamino-methylideneamide was reacted with 2-chlorophenylhydrazine hydrochloride to give 8-chloro-2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (MS(ESI+) 399.1/401.1) which was reacted with L-prolineamide to give 410. MS(ESI+) 477.1. 1H NMR (400 MHz, DMSO) δ 8.26 (s, 1H), 8.15 (s, 1H), 7.79 (s, 1H), 7.72 (dd, J=8.0, 1.1 Hz, 1H), 7.66-7.52 (m, 3H), 7.29 (br, 1H), 6.91 (br, 1H), 5.83 (s, 1H), 4.45-4.38 (m, 4H), 4.23 (d, J=7.7 Hz, 1H), 3.61-3.53 (s, 1H), 3.40-3.32 (m, 1H), 2.23-2.06 (m, 1H), 2.02-1.84 (m, 3H)
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[CH3:3].[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26]([Cl:30])=[CH:25][N:24]=1.C([N:33](CC)CC)C>CCCCO>[NH2:33][C:23]1[N:28]=[C:27]([NH:1][C@H:2]([C:4]2[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6](=[O:15])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:14])[CH3:3])[C:26]([Cl:30])=[CH:25][N:24]=1.[Cl:22][C:23]1[N:28]=[C:27]([NH:1][C@H:2]([C:4]2[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6](=[O:15])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:14])[CH3:3])[C:26]([Cl:30])=[CH:25][N:24]=1
Reactant: Cc1cccc2cc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCN(CC)CC
Solvent: CCCCO
Product: Cc1cccc2cc([C@H](C)Nc3nc(Cl)ncc3Cl)n(-c3ccccc3)c(=O)c12
Product: Cc1cccc2cc([C@H](C)Nc3nc(N)ncc3Cl)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C

Procedure:
A mixture of 3-(1-aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 4704) (150 mg, 0.54 mmol), 2,4,5-trichloropyrimidine (119 mg, 0.65 mmol) and triethylamine (137 mg, 1.35 mmol) in n-BuOH (10 mL) was stirred at reflux for 2 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (MeOH:CH2Cl2=1:100) to afford the desired product, (S)-3-(1-(2,5-dichloropyrimidin-4-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (2H)-one (compound 5101) (170 mg, 74% yield as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:20]2=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]2[N:18]=1.C(OC)(OC)OC.O=[C:40]1[CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[NH:42]1[CH2:43][CH:40]([N:11]2[CH2:10][CH2:9][CH:8]([C:7]3[C:2]([Cl:1])=[C:3]([NH:16][C:17]4[N:22]=[C:21]([NH:23][CH:24]5[CH2:25][CH2:26]5)[C:20]5=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]5[N:18]=4)[CH:4]=[C:5]([C:14]#[N:15])[CH:6]=3)[CH2:13][CH2:12]2)[CH2:41]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: COC(OC)OC
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CCN(C3CNC3)CC2)c1
Reaction time: 0.02 h

Procedure:
To a suspension of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 208)(60 mg, 0.138 mmol) in a mixture solvent of methanol (0.7 ml)/CH2CL2 (0.7 ml) was added trimethyl orthoformate (0.7 mL, 6.33 mmol), (The suspension converted to a clear solution within 1 min.), tert-butyl 3-oxoazetidine-1-carboxylate (237 mg, 1.383 mmol), and acetic acid (0.032 mL, 0.553 mmol). The mixture was stirred at Rt for 40 min and then sodium cyanoborohydride (87 mg, 1.383 mmol) was added and stirred at room temperature for overnight. The reaction mixture was partitioned between EtOAc and diluted aq. NaHCO3, The aqueous layer was extracted with EtOAc; the combined organic layer was washed with brine and concentrated. The crude intermediate was purified by prep HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; solvent B=90% Methanol, 10% H2O, 0.1% TFA, Flow rate 42 ml per min, 20-100% B, over 20 min). The HPLC fractions containing the intermediate were applied onto a cartridges of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with 2 N solution of ammonia in methanol/DCM (1:1). Removal of the solvents left 46 mg intermediate as a white solid which was dissolved in DCM (2 ml) and TFA (1 ml) was added. The resulting mixture was stirred at room temperature for 0.5 hour. Removal of the solvent and the residue was taken in MeOH/DCM and applied onto a cartridges of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with 2 N solution of ammonia in methanol/DCM (1:1). Removal of the solvents left the product (39 mg) as a white solid
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Si:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6](Br)[CH:7]=1.[CH:28]1[C:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[O:33][C:32]=2[C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:1][C:2]1[CH:3]=[C:4]([Si:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[C:6]([C:40]2[C:34]3[O:33][C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:36]=4[C:35]=3[CH:37]=[CH:38][CH:39]=2)[CH:7]=1
Reactant: Brc1cc(Br)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: OB(O)c1cccc2c1oc1ccccc12
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: O
Solvent: Cc1ccccc1
Product: Brc1cc(-c2cccc3c2oc2ccccc23)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 63.8 %

Procedure:
A solution of (3,5-dibromophenyl)triphenylsilane (4.66 g, 9.43 mmol), dibenzo[b,d]furan-4-ylboronic acid (1.00 g, 4.72 mmol), Pd(PPh3)4 (0.109 g, 0.094 mmol) and potassium carbonate (1.304 g, 9.43 mmol) in toluene (150 mL) and water (25 mL) was refluxed under nitrogen overnight. The organic phase was isolated, filtered and evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (4/1, v/v) as eluent to yield (3-bromo-5-(dibenzo[b,d]furan-4-yl)phenyl)triphenylsilane (1.75 g, 64% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.CCN(C(C)C)C(C)C.Cl[C:31]1[N:36]=[CH:35][N:34]=[C:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:32]=1[CH3:44].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:31]4[N:36]=[CH:35][N:34]=[C:33]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C:32]=4[CH3:44])[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1c(Cl)ncnc1C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc2c(c1)CCN(C1CCN(c3ncnc(C(=O)OC(C)(C)C)c3C)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.20 g (0.73 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 0.14 mL (0.80 mmol) DIPEA were placed in 3.0 mL DMF. 0.17 g (0.74 mmol) tert. butyl 6-chloro-5-methyl-pyrimidine-4-carboxylate were added and the reaction mixture was stirred for 3 h at RT. The reaction mixture was mixed with water and extracted with DCM. The organic phase was dried, filtered and concentrated to dryness by rotary evaporation. The residue was combined with diisopropylether and the precipitated solid was suction filtered and dried.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C(C([O-])=O)=NN=N1)C1C=CC=CC=1.[K+].[CH3:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH2:41])[C:36]=1[OH:42])=[O:34].N1C=CC=CC=1>C(Cl)Cl>[C:33]([C:35]1[C:36]([OH:42])=[C:37]([CH:38]=[CH:39][CH:40]=1)[NH:41][C:13]([C:12]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[N:10][N:11]=1)=[O:14])(=[O:34])[CH3:32]
Reactant: CC(=O)c1cccc(N)c1O
Reactant: O=C(Cl)c1nnnn1Cc1ccccc1
Agent: O=C([O-])c1nnnn1Cc1ccccc1
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1cccc(NC(=O)c2nnnn2Cc2ccccc2)c1O
Reaction time: 8 h

Procedure:
A solution of crude 1-benzyl-1H-tetrazole-5-carbonyl chloride (prepared from 2.4 g of potassium 1-benzyl-1H-tetrazole-5-carboxylate in the manner hereinbefore described in Reference Example 3) in dry methylene chloride (50 ml) was added to a stirred solution of 3-amino-2-hydroxyacetophenone (1.5 g) and pyridine (0.9 g) in dry methylene chloride (40 ml) at 10° C. After standing at room temperature overnight, the solution was evaporated in vacuo and the resulting solid residue was recrystallised from a large volume of ethanol to give 3'-acetyl-1-benzyl-2'-hydroxy-1H-tetrazole-5-carboxanilide (1.5 g), in the form of pale yellow needles, m.p. 155°-157° C.