Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH:29]3[CH2:31][CH2:30]3)[CH2:24][CH2:23]2)[C:9]2[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(=O)C1C=CC([C@@H](N2CCN(CC=C)CC2)C2C=CC=C(N[CH2:50][C:51]3[S:52][CH:53]=[CH:54][CH:55]=3)C=2)=CC=1)C>CO>[CH:29]1([CH2:28][N:25]2[CH2:26][CH2:27][N:22]([C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:50][C:51]4[S:52][CH:53]=[CH:54][CH:55]=4)[CH:3]=3)[C:9]3[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=3)[CH2:23][CH2:24]2)[CH2:30][CH2:31]1
Reactant: C=CCN1CCN([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(NCc3cccs3)c2)CC1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(N)c2)N2CCN(CC3CC3)CC2)cc1
Solvent: CO
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(NCc3cccs3)c2)N2CCN(CC3CC3)CC2)cc1

Procedure:
Synthesized using COMPOUND 68 and the method described for COMPOUND 69. Purity (HPLC): >99%; Optical purity (Chiral HPLC): >99%; (400 MHz, CD3OD) 0.39-0.44 (m, 2H), 0.72-0.78 (m, 2H), 1.04-1.10 (m, 1H), 1.07-1.11 (m, 3H), 1.22 (t, J=6.99 Hz, 3H), 2.20-2.36 (m, 2H), 2.91-3.08 (m, 2H), 3.04 (d, J=7.49 Hz, 2H), 3.06-3.19 (m, 2H), 3.21-3.30 (m, 2H), 3.46-3.60 (m, 4H), 4.33 (s, 1H), 4.52 (s, 2H), 6.62 (dd, J=8.00, 2.44 Hz, 1H), 6.77 (d, J=7.58 Hz, 1H), 6.83 (t, J=1.81 Hz, 1H), 6.94 (dd, J=5.04, 3.53 Hz, 1H), 6.98-7.00 (m, 1H), 7.07 (t, J=7.80 Hz, 1H), 7.25 (dd, J=5.00, 122 Hz, 1H), 7.30 (d, J=8.17 Hz, 2H), 7.50 (d, J=8.16 Hz, 2H). Found. C, 53.58; H, 5.46; N, 7.10. C31H40N4OS×0.70H2O 2.4CF3COOH has C, 53.55; H, 5.50; N, 6.98%. [a]D20=−19.74 deg [c 0.947, MeOH]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:34](=[CH:35][CH:36]=1)[C:7]1=[CH:8][C:9]3[C:10]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(O)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(O)[C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:38])[CH3:37].[I-].[K+].[PH2]([O-])=O.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:34](=[CH:35][CH:36]=1)[C:7]1=[CH:8][C:9]3[C:10]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[C:11]4[C:16](=[C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:38])[CH3:37])[CH:15]=[CH:14][CH:13]=[CH:12]4
Reactant: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)C(O)(c1ccccc1)c1ccccc1C3(O)c1ccccc1
Agent: O=[PH2][O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)c2cc(Br)ccc2-c2cc3c(-c4ccccc4)c4ccccc4c(-c4ccccc4)c3cc21
Reaction time: 5 h
Yield: 73.6 %

Procedure:
2-bromo-13,13-dimethyl-6,11-diphenyl-11,13-dihydro-6H-indeno[1,2-b]anthracene-6,11-diol (4.19 g, 0.0075 mol), Potassium iodide (12.45 g, 0.075 mol), and Sodium hypophosphite (6 g, 0.037 mol) were placed in a flask, and were suspended in acetic acid (200 ml). The reaction mixture was stirred for five hours while heating. After the reaction was terminated, the reaction solution was added to an excess of distilled water. The resultant solid was washed with distilled water, filtered, and purified by column chromatography to give 2-bromo-13,13-dimethyl-6,11-diphenyl-13H-indeno[1,2-b]anthracene (2.9 g, yield=74%).
Reaction SMILES: C(O[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:4][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)Nc1ccccc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccccc1-c1ccccc1
Reaction time: 1 h

Procedure:
A solution of 18 g (0.075 mol) of 2-ethoxycarbonylaminobiphenyl in 100 ml of THF is added dropwise to a suspension of 14.2 g (0.373 mol) of lithium aluminum hydride in 300 ml of THF. The mixture is stirred for another 1 hour and then refluxed for 3 hours. Subsequently, while cooling in ice, 28 ml of water are firstly added dropwise and 18 ml of 15% strength aqueous sodium hydroxide are then added. After the precipitate has been separated off, it is washed a number of times with ether. The combined filtrates are dried over sodium sulfate, and the reddish liquid obtained after evaporation of the solvent is fractionated at 0.01 mbar. Bp.: 65–67° C. Yield: 10.64 g=77%.
Reaction SMILES: C1(C([O:14][C:15](=[O:33])[C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:21][C:20]=2[NH2:32])=[N:17][OH:18])C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+:35]>CO>[Na+:35].[C:25]([C:22]1[CH:23]=[CH:24][C:19]([C:16](=[N:17][OH:18])[C:15]([O-:33])=[O:14])=[C:20]([NH2:32])[CH:21]=1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)c1ccc(C(=NO)C(=O)OC(c2ccccc2)c2ccccc2)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(C(=NO)C(=O)[O-])c(N)c1
Temperature: 0 °C

Procedure:
50 g of 2-(4-BOC-aminophenyl)-2-hydroxyiminoacetic acid diphenylmethyl ester are boiled under reflux in a mixture of 1660 ml of methanol and 250 ml of 2N aqueous NaOH for 11/2 hours under nitrogen. The reaction mixture is concentrated to 300 ml, diluted with ethyl acetate and washed three times with water. The aqueous washings are combined, cooled to 0° C. and adjusted to a pH of 3 with 2N aqueous hydrochloric acid. Extraction is carried out with ethyl acetate and the organic phase is washed neutral with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated by evaporation in vacuo. 250 ml of water are mixed with the evaporation residue and the pH is adjusted to 7 with 2N aqueous sodium hydroxide solution. The aqueous solution is then extracted with ethyl acetate, the organic phase is washed three times with water, the aqueous washings are combined and filtered through sand, the filtrate is concentrated in vacuo to approximately 50 ml and the product is precipitated by adding 150 ml of ethanol and 500 ml of ether. After filtering off and drying, 2-(4-BOC-aminophenyl)-2-hydroxyiminoacetic acid sodium salt (syn-anti mixture) is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH2:36]([N:38]([C:46]([CH3:50])([CH3:49])[CH:47]=O)[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH3:37].N1CCCCC1>O1CCOCC1.CC(O)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:50][C:46]([N:38]([CH2:36][CH3:37])[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:47])[CH3:49])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CCN(C(=O)OC(C)(C)C)C(C)(C)C=O
Solvent: C1CCNCC1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCN(C(=O)OC(C)(C)C)C(C)(C)C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
To a solution of 3-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (236 mg, 0.5 mmol, 1 equiv) and tert-butyl ethyl(2-methyl-1-oxopropan-2-yl)carbamate (2.15 g, 10 mmol, 20 equiv) in dioxane (30 mL) was added 0.5 mL piperidine, 1 drop AcOH and 2 g of 4A molecular sieves. The resulting mixture was stirred for 2 h at 110° C. The solids was filtered out, the filtrate was diluted with 200 mL of ethyl acetate, washed with brine, dried over Na2SO4, concentrated and purified on silica gel column (ethyl acetate/MeOH 10/1) to give 60 mg (19%) of tert-butyl 5-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl(ethyl)carbamate as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=2)[N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CC(N(C)C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:3][C:4]=2[C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cnc2c(-c3cnc(N)nc3)nc(Cl)nc21
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Product: CC(C)n1cnc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Temperature: 94 °C
Yield: 58 %

Procedure:
To a solution of 5-(2-chloro-9-isopropyl-9H-purin-6-yl)-pyrimidin-2-ylamine (2.84 mmol) in dimethyl acetamide (18 ml) was added morpholine (2.84 mmol). The reaction mixture was stirred while being heated on an oil bath maintained at 94° C. for 12 h. The reaction was monitored for the absence of starting material by LC-MS. The crude material was directly loaded onto a preparative HPLC column and purified by chromatography to give 5-(9-isopropyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine in a yield of 58%. 1H NMR, DMSO-d6: 9.53 (s, 2H), 8.32 (s, 1H), 7.30 (bs, 2H), 4.72 (m, 1H), 3.78 (m, 4H), 3.73 (m, 4H), 1.55 (d, 6H). m/z: 341.17 [MH]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=O)=[C:9]([O:16][CH3:17])[CH:8]=2)[C:4]([CH3:18])=[N:3]1.CS(C1[N:24]=[CH:25][C:26]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=2[N:28]=1)(=O)=O>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:24]=[CH:25][C:26]4[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=4[N:28]=3)=[C:9]([O:16][CH3:17])[CH:8]=2)[C:4]([CH3:18])=[N:3]1
Reactant: COc1cc(-c2cn(C)nc2C)ccc1NC=O
Reactant: CC(C)(C)CNc1nccc2cnc(S(C)(=O)=O)nc12
Product: COc1cc(-c2cn(C)nc2C)ccc1Nc1ncc2ccnc(NCC(C)(C)C)c2n1
Yield: 21 %

Procedure:
The title compound was prepared according to Example 40 using N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide (Preparation 76) and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 47). The residue was purified by silica gel column chromatography eluting with 50-100% EtOAc in cyclohexane to give the title compound (4 mg, 21%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8]O)[CH:7]=1.[Br:12]P(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][Br:12])[CH:7]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(Br)cc1CO
Solvent: ClCCl
Product: COc1ccc(Br)cc1CBr
Reaction time: 0.25 h

Procedure:
To a solution of (5-bromo-2-methoxyphenyl)methanol (1.0 g, 4.6 mmol) in dichloromethane (10 mL) at 0° C. was added tribromophosphine (1 M in dichloromethane, 9.2 mL, 9.2 mmol). The ice bath was removed and the reaction stirred for 15 min. The reaction was concentrated, poured onto cold saturated sodium bicarbonate, extracted with pentane, dried over magnesium sulfate, and concentrated to give 1.15 g (89%) as a white crystalline solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.44 (d, J=2.5 Hz, 1H), 7.38 (dd, J=8.9, 6.1 Hz, 1H), 4.47 (s, 2H), 3.87 (s, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 156.7, 133.6, 132.8, 128.4, 112.8, 112.7, 56.0, 27.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:19]2[C:24](=[O:25])[NH:23][C:22](=[O:26])[CH:21]=[N:20]2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([NH2:17])[CH:10]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.O>N1C=CC=CC=1>[Cl:18][C:6]1[CH:5]=[C:4]([N:19]2[C:24](=[O:25])[NH:23][C:22](=[O:26])[CH:21]=[N:20]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([NH:17][S:34]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1N
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-[3,5-dichloro-4-(3-amino-4-methoxy-phenoxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (100 mg) in pyridine (1 mL) was added 4-fluorobenzenesulfonyl chloride (59 mg) and the resulting solution was allowed to stir at room temperature for 1 h. The reaction solution was poured over water, extracted with ethyl acetate, the organic layer washed with 1N hydrochloric acid, water, brine, dried (Na2SO4), concentrated in vacuo and flash chromatographed on silica gel (40% acetone/hexanes) to afford the title compound of Step B as a light-yellow colored solid, 115 mg. m.p. 90-96° C., MS Calc.:553.4; Found:550.9.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[O:22]=[C:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([C:23]4([OH:22])[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:26]4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Product: COC(=O)c1nc2n(c1C1(O)CN(C(=O)OC(C)(C)C)C1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (0.3 g) was reacted with tert-butyl 3-oxoazetidine-1-carboxylate similar to as described in example 8 with non-critical modifications to produce methyl 10-bromo-3-(1-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. This crude intermediate was reacted via General Procedure L then deprotected with 4N HCl in dioxane (5 eq) at room temperature to provide 10-bromo-9-fluoro-3-(3-hydroxyazetidin-3-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. 10-bromo-9-fluoro-3-(3-hydroxyazetidin-3-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with cyclopropane carboxylic acid similar to as described in Example 2 with non-critical modifications to afford crude 10-bromo-3-(1-(cyclopropanecarbonyl)-3-hydroxyazetidin-3-yl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was then reacted with 2-Methyl-3-butyne-ol via General Procedure F to afford 7.9 mg (71.8%) 3-[1-(cyclopropanecarbonyl)-3-hydroxy-azetidin-3-yl]-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[C:18]([O:21][CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([Cl:32])[N:31]=1)[C:26](O)=[O:27])(=[O:20])[CH3:19]>>[C:18]([O:21][CH2:22][C:23]1[CH:24]=[C:25]([C:26](=[O:27])[NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:14])([F:12])[F:13])=[C:3]([CH3:2])[CH:4]=2)[CH3:16])[CH:29]=[C:30]([Cl:32])[N:31]=1)(=[O:20])[CH3:19]
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)F
Reactant: CC(=O)OCc1cc(C(=O)O)cc(Cl)n1
Agent: Cl
Product: CC(=O)OCc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)cc(Cl)n1
Yield: 21 %

Procedure:
The title compound is prepared in 21% yield (100 mg, a yellow solid) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (295 mg, 1.1 mmol, Amine-17, single enantiomer) and 2-(acetoxymethyl)-6-chloroisonicotinic acid (500 mg, 1.1 mmol, Step-1) by the similar manner in Step-1 of Example 8.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].CCN(C(C)C)C(C)C.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>ClCCl>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:23]([CH:20]1[CH2:22][CH2:21]1)=[O:24]
Reactant: NCc1cccc(Br)c1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cccc(Br)c1)C1CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
3-Bromo-benzylamine hydrochloride (437.3 mg, 2.0 mmol) was dissolved in dichloromethane (15 mL), and the solution was cooled to 0° C. DIEA (688.0 μL, 3.9 mmol) was then added, and the reaction was stirred at 0° C. for 5 minutes. Then cyclopropanecarbonyl chloride (180.0 μL, 2.3 mmol) was added, and the reaction was stirred at 0° C. for 20 minutes. The reaction was quenched with distilled water, and the solvents were removed. The resulting mixture was redissolved in DMF (10 mL) and purified by reverse phase HPLC to give the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.[Cl:23][C:24]1[CH:34]=[CH:33][C:27](/[CH:28]=[CH:29]/B(O)O)=[CH:26][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:24]1[CH:34]=[CH:33][C:27](/[CH:28]=[CH:29]/[C:2]2[N:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=3)[C:4](=[O:22])[CH:3]=2)=[CH:26][CH:25]=1
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Reactant: COc1cc(-n2cnc(Cl)cc2=O)ccc1OCC(C)(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-n2cnc(/C=C/c3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 55 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A mixture of 6-chloro-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one Part A of Procedure 11 (40 mg, 0.12 mmol), (E)-4-chlorostyrylboronic acid (56 mg, 0.30 mmol), potassium phosphate, tribasic (78 mg, 0.37 mmol), and palladiumtetrakis (7 mg, 6.16 μmol) in DMF (1 mL) was stirred under nitrogen at 55° C. for 1 hour. The mixture was diluted with DCM, washed with water, sat. NaHCO3 and brine, then dried (Na2SO4) and concentrated to afford the crude product. The crude product was purified using ISCO flash chromatography (silica gel/hexanes-ethyl acetate 100:0 to 0:100 gradient). The product was re-purified using HPLC (C18 column/10:90 to 90:10 MeOH—H2O) to afford the desired product (E)-6-(4-chlorostyryl)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one J-1 (16.8 mg, 0.039 mmol, 31% yield) as a light yellow solid. LC/MS 427 (M+H)+, tR 0.97 min (method 5); 1H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (1H, s), 7.76 (1H, d, J=15.56 Hz), 7.53 (2H, d, J=8.28 Hz), 7.38 (2H, d, J=8.28 Hz), 7.01 (1H, d, J=8.03 Hz), 6.82-6.98 (3H, m), 6.46 (1H, s), 3.89 (5H, br. s.), 1.37 (6H, s).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[N:15]([CH3:24])[C:14]4=[O:25])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1.[C:54]([OH:60])([C:56]([F:59])([F:58])[F:57])=[O:55]>C(Cl)Cl>[F:57][C:56]([F:59])([F:58])[C:54]([OH:60])=[O:55].[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:24])[C:14](=[O:25])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:34]3[CH:35]=[CH:36][C:37]([N:40]4[CH2:41][CH2:42][NH:43][CH2:44][CH2:45]4)=[CH:38][CH:39]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCNCC5)cc4)n[nH]c3c1)C(=O)N2C
Yield: 42 %

Procedure:
The boc protected title compound was synthesized according to the method of Example A51B, except substituting (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxy-1′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (600 mg, 1.35 mmol) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (534 mg, 1.37 mmol). The Boc protected compound was purified by column chromatography (silica gel, hexanes/EtOAc, 100:0 to 5:95) which gave 400 mg. This material was dissolved in CH2Cl2 (12 mL) and TFA (3 mL) and the reaction stirred for 3 h at which time the solvent was removed and the residue purified by prep-HPLC which yielded the title product as a pale-yellow solid (339 mg, 42%); 1H NMR (400 MHz, CD3OD) δ 7.90 (d, J=8.2 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.48 (s, 1H), 7.17 (d, J=8.4 Hz, 2H), 7.00 (d J=8.6 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 5.64 (s, 1H), 3.53-3.48 (m, 4H), 3.43-3.37 (m, 5H), 3.31 (s, 3H), 3.29 (s, 3H), 2.29-2.26 (m, 1H), 2.22-2.18 (m, 1H); MS ESI [M+H]+ 480.3, calcd for [C29H29N5O2+H]+ 480.24. Optical Rotation: [α]22D=−113° (c 0.62, MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]=O)[CH:6]=[CH:5]2.C([C:16](CC)(P(=O)([O-])[O-])[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)C.CC(C)([O-])C.[K+]>CS(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:12]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=3)[CH:8]=2)[CH:3]=1
Reactant: O=Cc1ccc2cc(Br)ccc2c1
Reactant: CCC(CC)(c1ccc(Br)cc1)P(=O)([O-])[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Brc1ccc(/C=C/c2ccc3cc(Br)ccc3c2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
6-bromo-2-naphthaldehyde (4.0 g, 17.1 mmol) and diethyl-4-bromobenzylphosphonate (6.3 g, 20.5 mmol) were dissolved in purified dimethylsulfoxide (100 mL) under a nitrogen atmosphere, the reaction solution was cooled down to 0° C., and then potassium t-butoxide (2.5 g, 20.5 mmol) was slowly added thereto. The reaction mixture solution was stirred at room temperature for 12 hours. The reaction mixture solution was subjected to extraction with water and dichloromethane to thereby remove the solvent. The extracted material was sufficiently washed with methanol, and was dried in vacuum to thereby obtain a white solid (6.0 g, yield: 91%).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][C:6](=[N:23][OH:24])[C:5]1=[O:25].[CH2:26]([N:29]=[C:30]=[O:31])[CH2:27][CH3:28].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][C:6](=[N:23][O:24][C:30]([NH:29][CH2:26][CH2:27][CH3:28])=[O:31])[C:5]1=[O:25]
Reactant: CCCN=C=O
Reactant: COCN1C(=O)C(=NO)CN(c2ccccc2)c2ccc(OC)cc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCNC(=O)ON=C1CN(c2ccccc2)c2ccc(OC)cc2N(COC)C1=O
Temperature: 25 °C
Yield: 62.4 %

Procedure:
1-Methoxymethyl-2-oxo-3-hydroxyimino-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.0 g) was dissolved in tetrahydrofuran (10 ml), propyl isocyanate (0.62 g) and triethylamine (0.74 g) were added thereto, the mixture was refluxed for 2 hours and 30 minutes. The reaction mixture was allowed to cool to room temperature, crystals so precipitated were collected by filtration, and the crystals were washed with diisopropyl ether, to thereby obtain 0.78 g of the titled compound as white crystals.