Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCC.C1(OC#[N:28])C=CC=CC=1>CCOCC>[C:2](#[N:28])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C#CCCCCCCCCCCCC
Reactant: N#COc1ccccc1
Reactant: [Li]CCCC
Solvent: CCOCC
Product: CCCCCCCCCCCCC#CC#N
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
n-BuLi (2.2 M, 24.3 mL, 53.5 mmol) was added dropwise to a cooled (-78° C.) slurry of tetradecyne (10.3 g, 52.7 mmol) in anhydrous ether (60 mL) at a rate not allowing the temperature to rise above -40° C. The resulting slurry was stirred (5 minutes, 70° C.), then phenyl cyanate (6.9 g, 58.0 mmol) was added dropwise at a rate not allowing the temperature to rise above -60° C. The resulting slurry was stirred (45 minutes, -78° C.) then warmed (25° C.). The resulting solution was diluted with ether (140 mL), washed with 1.5 N NaOH (2×100 mL), washed with brine (1×100 mL), then dried (MgSO4), and concentrated in vacuo. The resulting oil was chromatographed on silica (pentane to 95:5 pentane:ether) to yield 9.0 g (77.8%) of 2-pentadecynenitrile as a pale yellow liquid.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])C)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)=[O:4].Cl.[OH2:20].[CH2:21](O)[CH3:22]>[Pd]>[CH3:1][N:2]([CH2:13][CH2:21][CH2:22][N:6]([CH3:7])[CH3:5])[C:3]([C:15]1[NH:16][CH:18]=[C:13]([N:2]([CH3:1])[C:3]([C:5]2[NH:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=2)=[O:4])[CH:14]=1)=[O:20]
Reactant: CCO
Reactant: CN(C)CCCN(C)C(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: O
Agent: [Pd]
Agent: Cl
Product: CN(C)CCCN(C)C(=O)c1cc(N(C)C(=O)c2cc([N+](=O)[O-])c[nH]2)c[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of example 1 (3.4 g) was dissolved in ethanol (40 ml) and diluted hydrochloric acid (20 ml) and reduced over a Pd catalyst (5% on carbon) under H2 pressure (50 psi) in a Parr apparatus. Water (20 ml) was added and the catalyst filtered off. The resulting solution was concentrated and the residue was dissolved in water (40 ml). Sodium bicarbonate (4 g) was added, followed by a solution of N-methyl-4-nitropyrrole-2-carboxylic acid chloride (2.8 g) in 20 ml of benzene. The resulting mixture was stirred for about 2 hours at room temperature and then was extracted with chloroform. The dried organic extracts were concentrated in vacuo and the residue was purified by column chromatography (CHCl3 75, EtOH95% 25, NH4OH 0.6) to give 4.7 g of 3-[N-methyl-4-(N-methyl-4-nitropyrrole-2-carboxamido)pyrrole-2-carboxamido]propyl-dimethylamine as a yellow solid, m.p. 178°-180° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][C@H:15]([CH3:17])[C@@H:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:13]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1.[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55](O)=[O:56])=[O:40])([CH3:37])([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:29]([O:28][C:27]([NH:26][C@H:13]1[C@H:14]([O:18][Si:19]([C:22]([CH3:23])([CH3:25])[CH3:24])([CH3:20])[CH3:21])[C@@H:15]([CH3:17])[CH2:16][N:11]([C:3]2[C:2]([NH:1][C:55]([C:43]3[N:44]=[C:45]([C:47]4[C:48]([F:54])=[CH:49][CH:50]=[CH:51][C:52]=4[F:53])[S:46][C:42]=3[NH:41][C:39](=[O:40])[O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:56])=[CH:7][N:6]=[C:5]3[O:8][CH2:9][CH2:10][C:4]=23)[CH2:12]1)=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.2 %

Procedure:
To a mixture of tert-butyl ((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (67.8 mg, 0.142 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (65.4 mg, 0.184 mmol) and HATU (168.1 mg, 0.4421 mmol) was added DMF (2.0 mL) followed by DIPEA (144.5 mg, 1.118 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to afford the sub-title compound as a brown solid (29.2 mg, 25%). LCMS calc. for C39H55F2N6O7SSi (M+H)+: m/z=817.4. found 817.3.
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[CH2:12][C@H:11]([N:13]([CH3:15])[CH3:14])[CH2:10][NH:9]1)=O)CCC.[NH3:16]>CO>[CH3:14][N:13]([CH3:15])[C@@H:11]1[CH2:10][NH:9][C@H:8]([C:6]([NH2:16])=[O:5])[CH2:12]1
Reactant: N
Reactant: CCCCOC(=O)[C@@H]1C[C@H](N(C)C)CN1
Solvent: CO
Product: CN(C)[C@@H]1CN[C@H](C(N)=O)C1

Procedure:
A solution of (2S,4S)-4-Dimethylamino-pyrrolidine-2-carboxylic acid butyl ester (326 mg) and 7M ammonia in methanol (8 ml) is stood for 18 hours at room temperature in a sealed vessel. Filtration, evaporation and trituration with diethyl ether/methanol gives the title compound as a beige solid.
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:11])[CH2:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])[CH3:3].[CH:12]([O-])([O-])[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>>[CH2:14]([O:13][CH:12]=[C:5]([C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])[C:4](=[O:11])[CH:2]([CH3:1])[CH3:3])[CH3:15]
Reactant: CC(C)C(=O)CC(=O)C(C)C
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)C(C)C)C(=O)C(C)C
Yield: 49.2 %

Procedure:
A mixture comprising 17.2 g (110 mmol) of 2,6-dimethyl-3,5-heptanedione, 22.8 g (153 mmol) of ethyl orthoformate and 31.5 g (309 mmol) of acetic anhydride, was reacted for 2 hours at 110° C. The solvent was distilled off under reduced pressure to obtain 11.5 g (yield: 49%) of 4-ethoxymethylene-2,6-dimethyl-3,5-heptanedione.
Reaction SMILES: [Br:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH:12]([F:14])[F:13])=[CH:8][CH:9]=2)[C:4](=[O:15])[O:3]1.[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[Br-:1].[F:13][CH:12]([F:14])[O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:2]([P+:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[O:3][C:4]2=[O:15]
Reactant: O=C1OC(Br)c2ccc(OC(F)F)cc21
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C1OC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(OC(F)F)cc21
Product: [Br-]
Yield: 94.9 %

Procedure:
Under N2, a solution of 3-bromo-6-difluoromethoxy-3H-isobenzofuran-1-one (6.2 g, 22.2 mmoles), prepared as described in example 95, in dry acetonitrile (30 ml) was added with triphenylphosphine (6.4 g, 24.4 mmoles). After 4 hours under reflux the mixture was dried to give a foam which was triturated in ethyl ether overnight, then filtered, washed with ethyl ether and dried to give 11.4 g of the title compound (yield: 95%).
Reaction SMILES: CC([N:5]([C@H:9]([CH3:30])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:25]3[C:26]([CH3:29])=[N:27][O:28][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:29][C:26]1[C:25]2[C:20]([O:19][C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:30])[NH2:5])=[CH:14][CH:15]=3)=[CH:21][CH:22]=[CH:23][C:24]=2[O:28][N:27]=1
Reactant: Cc1noc2cccc(Oc3ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cc3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc2cccc(Oc3ccc(NC(=O)[C@@H](C)N)cc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
1,1-dimethylethyl[(1R)-1-methyl-2-({4-[(3-methyl-1,2-benzisoxazol-4-yl)oxy]phenyl}amino)-2-oxoethyl]carbamate (Intermediate 13, 587 mg) was dissolved in 10.0 ml of DCM and then TFA (5.0 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. After the removal of the volatiles, the residue was purified with an SCX cartridge and eluted with DCM/MeOH/NH3 (2.0 M solution in MeOH). Evaporation afforded 337 mg of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[C:5]=2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([CH3:23])=[C:16]([C:20](O)=[O:21])[N:17]([CH3:19])[N:18]=3)=[CH:10][C:9]=2[CH3:24])[CH2:3][CH2:2]1.O1CCCC1.C(Cl)(=O)C([Cl:44])=O>CN(C)C=O>[CH:1]1([C:4]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[C:5]=2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([CH3:23])=[C:16]([C:20]([Cl:44])=[O:21])[N:17]([CH3:19])[N:18]=3)=[CH:10][C:9]=2[CH3:24])[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2nn(C)c(C(=O)O)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(-c2nn(C)c(C(=O)Cl)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Reaction time: 2 h

Procedure:
At room temperature, to the mixture of 5-{4-[2-Cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-2,4-dimethyl-2H-pyrazole-3-carboxylic acid (described in Reference Preparation example 116) and tetrahydrofuran 50 ml was added oxalyl dichloride 0.5 g and N,N-dimethylformamide 0.1 ml. The mixture was stirred for two hours and concentrated under reduced pressure to give 5-{4-[2-Cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-2,4-dim ethyl-2H-pyrazole-3-carbonylchloride 1.3 g.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[OH:22])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].CN(C)C1C=CC=CC=1.[Br:32][C:33]([CH3:38])([CH3:37])[C:34](Br)=[O:35].C(OCC)(=O)C>ClCCl>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:34](=[O:35])[C:33]([Br:32])([CH3:38])[CH3:37])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1O
Reactant: CC(C)(Br)C(=O)Br
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)C(C)(C)Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In 30 ml of dichloromethane are dissolved 3.2 g of 16β-ethyl-17β-hydroxy-4-estren-3-one and 1.2 ml of dimethylaniline and, with stirring at room temperature (15°-25° C.), 1.0 ml of 2-bromo-2-methylpropionyl bromide is added to the above solution. The mixture is stirred at room temperature (15°-25° C.) for 16 hours, followed by addition of 300 ml of ethyl acetate. The mixture is washed with 10% phosphoric acid, water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride in that order and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 400 ml of diisopropyl ether-n-hexane (1:1), elution is carried out with 800 ml of the same solvent system. The eluate is evaporated under reduced pressure to remove the solvent, giving 2.6 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:11][C:12]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[N:24]([C:30](=[O:32])[CH3:31])[N:23]=3)[C:18](Br)=[CH:17][N:16]=2)=[CH:13][CH:14]=1)=[O:9])(=[O:3])[CH3:2].CCN(CC)CC.[C:41]([Si:43]([CH3:46])([CH3:45])[CH3:44])#[CH:42]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:11][C:12]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[N:24]([C:30](=[O:32])[CH3:31])[N:23]=3)[C:18]([C:42]#[C:41][Si:43]([CH3:46])([CH3:45])[CH3:44])=[CH:17][N:16]=2)=[CH:13][CH:14]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCNC(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)n(C(C)=O)n3)n2)s1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCNC(=O)c1ccc(-c2ncc(C#C[Si](C)(C)C)c(Nc3cc(C4CC4)n(C(C)=O)n3)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
Step 5 A mixture of N-(2-acetamidoethyl)-5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-bromopyrimidin-2-yl)thiophene-2-carboxamide (294.0 mg, 0.5 mmol, 1.0 eq), Pd(PPh3)2Cl2 (40.8 mg, 0.5 mmol, 0.1 eq) and CuI (9.5 mg, 0.05 mmol, 0.1 eq) was flushed with nitrogen. Anhydrous THF (10 mL) and Et3N (154.5 mg, 1.5 mmol, 3.0 eq) were added and the reaction mixture was flushed with nitrogen. Ethynyltrimethylsilane (149.9 mg, 1.5 mmol, 3.0 equiv.) was added and the reaction mixture was stirred at room temperature for 1 h. Then, the reaction mixture was concentrated to 5 mL. The conc. liquid was extracted with EtOAc and washed with water, brine. The organic layers were concentrated to afford the residue, which was purified by silica gel chromatography (PE/EA/MeOH=2:1:0.06 as eluant) to afford N-(2-acetamidoethyl)-5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-((trimethylsilyl)ethynyl) pyrimidin-2-yl)thiophene-2-carboxamide (96.1 mg, 35.2%) as pale yellow solid. LC-MS (m/z)=549.9 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[N+:11]([O-:13])=[O:12].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]2=[N:10][N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])Nc1ccccn1
Reactant: ClCc1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])N=c1ccccn1Cc1ccc(Cl)nc1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
2-Chloro-5-chloromethylpyridine (3.24 g) and 2-nitraminopyridine (2.78 g) were dissolved in anhydrous ethanol (50 ml), and triethylamine (4.04 g) was added to the solution. The mixture was stirred at room temperature for a while. Then, it was heated under reflux conditions for 8 hours. The reaction mixture was cooled to room temperature, and poured into ice water. The precipitated crystals were collected by filtration, and recrystallized from ethanol to give pale yellow 1-(2-chloro-5-pyridylmethyl)-2-nitroimino-1,2-dihydropyridine (2.3 g) as the desired compound. mp. 209-212° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:3]1.C([O:17][C:18](=O)[C:19]([C:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH:22]=1)=O)C.C(O[K])(C)(C)C>C1COCC1>[O:23]1[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:21]([C:19]2[C:18](=[O:17])[NH:14][C:12](=[O:13])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:22]1
Reactant: Cn1cc(CC(N)=O)c2ccccc21
Reactant: CCOC(=O)C(=O)c1coc2ccccc12
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3coc4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a suspension of commercially available 2-(1-Methyl-1H-indol-3-yl)-acetamide (54 mg, 0.28 mmol) and benzofuran-3-yl-oxo-acetic acid ethyl ester (63 mg, 0.28 mmol) in dry THF (2.5 mL) at 0° C. was added dropwise a 1.0 M solution of tert-BuOK in THF (1.15 mL), and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was quenched with 12 N HCl and diluted with EtOAc. The organic solution was washed with saturated NaHCO3, brine, then dried over Na2SO4, evaporated in vacuo and purified by preparative TLC (ethyl acetate:hexane; 2:3) to afford product 3-benzofuran-3-yl-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione (1) (44 mg, 44%) as an orange solid.
Reaction SMILES: CO[CH2:3][N:4]([CH2:11][CH2:12][CH3:13])[CH2:5][CH2:6][Si](C)(C)C.[Br:14][C:15]1[CH:16]=[N:17][C:18]([CH:21]=C)=[N:19][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:14][C:15]1[CH:16]=[N:17][C:18]([CH:21]2[CH2:6][CH2:5][N:4]([CH2:11][CH2:12][CH3:13])[CH2:3]2)=[N:19][CH:20]=1
Reactant: C=Cc1ncc(Br)cn1
Reactant: CCCN(CC[Si](C)(C)C)COC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN1CCC(c2ncc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
Methoxymethyl-propyl-trimethylsilanylethyl-amine (14.13 g, 74.61 mmol) in CH2Cl2 (4 ml) was added dropwise to a 0° C. cooled solution of 5-bromo-2-vinyl-pyrimidine (2 g, 10.80 mmol) and TFA (210 μl, 2.72 mmol) in CH2Cl2 (45 ml) over a period of 20 min. The reaction mixture was then stirred at room temperature for 2 h. The crude material was diluted with CH2Cl2, washed with saturated aqueous NaHCO3 and the organic layer was dried over Na2SO4 and evaporated. The residue was chromatographied on silica gel (CH2Cl2:methanol, 97:3) to afford the title compound (1.03 g, 34%) as a brown oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[CH:18]1([NH:21][C:22](=[O:36])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:20][CH2:19]1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH:18]1([NH:21][C:22](=[O:36])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH2:2][C:3]4[CH:12]=[N:11][C:10]5[N:9]6[CH2:13][CH2:14][CH2:15][C@H:8]6[C:7](=[O:16])[NH:6][C:5]=5[CH:4]=4)[CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:19][CH2:20]1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)c(F)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(F)c1
Temperature: 105 °C
Yield: 40.4 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), N-cyclopropyl-3-fluoro-4-(piperazin-1-yl)benzamide hydrochloride (137 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)—N-cyclopropyl-3-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (85.3 mg, 0.184 mmol, 40.3% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.45-0.61 (m, 2 H) 0.61-0.76 (m, 2 H) 1.83-2.05 (m, 3 H) 2.08-2.25 (m, 1 H) 2.44-2.49 (m, 4 H) 2.80 (td, J=7.33, 3.79 Hz, 1 H) 3.08 (br. s., 4 H) 3.54-3.66 (m, 1 H) 3.91-4.06 (m, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.02 (t, J=8.84 Hz, 1 H) 7.49-7.69 (m, 3 H) 8.31 (d, J=4.04 Hz, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C25H29FN6O2, 465; found, 465.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][OH:18])[CH2:3][CH2:2]1.O[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[C:31]([C:36]([O:38][CH3:39])=[O:37])[N:32]=[CH:33]3)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:15])[C:5]=2[CH2:17][O:18][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:35]=[C:34]4[C:29]([CH:30]=[C:31]([C:36]([O:38][CH3:39])=[O:37])[N:32]=[CH:33]4)=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH2:3][CH2:2]1
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Reactant: COC(=O)c1cc2ccc(-c3ccc(O)cc3)cc2cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3)cc2cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of [5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methanol (51 mg, 0.18 mmol), methyl 7-(4-hydroxyphenyl)-3-isoquinolinecarboxylate (50 mg, 0.18 mmol) and triphenylphosphine (52 mg, 0.20 mmol) in dichloromethane (1.5 mL) was added diisopropyl azodicarboxylate (0.035 mL, 0.20 mmol). The solution was heated in a microwave reactor at 90° C. for 10 minutes and then allowed to stand overnight. The mixture was adsorbed onto silica gel and purified by chromatography (silica gel, 0-1.25% methanol in dichloromethane) to afford methyl 7-[4-({[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate (54 mg, 55%). 1H-NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 8.29-8.14 (m, 2H), 7.75 (d, J=9 Hz, 2H), 7.61-7.50 (m, 3H), 6.96 (d, J=9 Hz, 2H), 4.94 (s, 2H), 3.91 (s, 3H), 2.50-2.46 (m, 1H), 1.21-1.14 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)Cc1cccc(N)c1
Yield: 97.2 %

Procedure:
A mixture of ethyl 2-(3-nitrophenyl)acetate (12 g, 57.4 mmol) and Pd/C (1.2 g, 10%) in methanol (100 mL) was hydrogenated (45 psi) at RT for 12 h. The mixture was filtered and the filtrate was concentrated to afford ethyl 2-(3-aminophenyl)acetate (10 g, 97% yield). 1H NMR (400 MHz, DMSO-d6): δ 6.91 (t, J=1.6 Hz, 1 H), 6.42-6.40 (m, 2 H), 6.35 (d, J=7.6 Hz, 1 H), 5.00 (s, 2 H), 4.03 (q, J=7.2 Hz, 2 H), 3.41 (s, 2 H), 1.15 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[CH3:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[CH:14]([N:17]([CH:34]([CH3:36])[CH3:35])[CH2:18][CH2:19][C@@H:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:16])[CH3:15].[OH-].[Na+]>C1COCC1.O>[CH:34]([N:17]([CH:14]([CH3:16])[CH3:15])[CH2:18][CH2:19][C@@H:20]([C:27]1[CH:32]=[C:31]([N:1]=[N:11][C:10]2[CH:12]=[CH:13][C:7]([CH3:6])=[CH:8][CH:9]=2)[CH:30]=[CH:29][C:28]=1[OH:33])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH3:36])[CH3:35]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1ccccc1O)C(C)C
Reactant: Cc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N=Nc2ccc(O)c([C@H](CCN(C(C)C)C(C)C)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
NaNO2 (0.27 g, 4.30 mmol) was added to a mixture of hydrochloric acid (0.64 mL, 7.70 mmol, conc.) and p-methylaniline (0.41 g, 3.80 mmol) in ice-water (20 mL). The mixture was stirred at 0° C. for 10 min. and then added to an ice-cold solution of (R)-N,N-diisopropyl-3-(2-hydroxyphenyl)-3-phenylpropanamine (1.00 g, 3.21 mmol) in THF (3 mL), H2O (12 mL) and sodium hydroxide (0.69 g, 17.32 mmol). After stirring the mixture for 20 minutes, it was extracted with toluene, dried (MgSO4), and evaporated to give an oil, which was chromatographed on (toluene-ethyl acetate-triethylamine 8:1:1) to give 0.83 g, 1.93 mmol, (60%) of the title compound. 1H NMR (CDCl3) δ1.12 (d, 6H), 1.19 (d, 6H), 2.22 (m, 1H), 2.43 (m, 5H), 2.79 (m, 1H), 3.32 (m, 2H), 4.57 (d, 1H), 6.98 (d, 1H), 7.24 (m, 3H), 7.36 (m, 4H), 7.66 (m, 4H).