Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=O.Cl>CO>[CH3:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C=O)cc1C
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1C
Temperature: 25 °C
Yield: 39.9 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methyl-4-methoxybenzaldehyde 1.11 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.75 g.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Br:24])=[CH:22][C:5]2[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])[O:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>ClCCl>[Br:24][C:23]1[C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:3][C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2F)oc2cc(N)c(Br)cc12
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(-c2ccc(F)cc2F)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a solution of ethyl 6-amino-5-bromo-2-(2,4-difluorophenyl)benzofuran-3-carboxylate (310 mg, 0.78 mmol) and pyridine (185 mg, 2.35 mmol) in dichloromethane (10 mL) was added dropwise methanesulfonyl chloride (179 mg, 1.56 mmol) at 0° C., then the mixture was stirred at 25° C. overnight. 10% HCl (aq) was added, then the mixture was extracted with dichloromethane (30 mL*3), dried over Na2SO4, and concentrated to provide ethyl 5-bromo-2-(2,4-difluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylate (350 mg, yield: 94%). 1H-NMR (CDCl3, 400 MHz) δ 8.32 (s, 1H), 7.91 (s, 1H), 7.64˜7.90 (m, 1H), 7.06 (d, J=3.0 Hz, 1H), 7.03 (d, J=3.0 Hz, 1H), 6.88 (s, 1H), 4.38 (q, J=7.2 Hz, 2H), 3.02 (s, 3H), 1.33 (t, J=7.6 Hz, 3H). MS (M+H)+: 474/476.
Reaction SMILES: [H-].[Na+:2].[CH3:3][N:4]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5]1.Cl[C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C([O-])(=O)C.[Na+]>CS(C)=O>[CH3:3][N:4]1[CH2:8][CH2:7][CH:6]([O:9][C:11]2[C:12]([C:13]([O-:15])=[O:14])=[CH:16][CH:17]=[CH:18][N:19]=2)[CH2:5]1.[Na+:2]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CN1CCC(O)C1
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCC(Oc2ncccc2C(=O)[O-])C1
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 6.4 g (0.13 mole) of 50% sodium hydride (mineral oil) in 50 ml of dimethylsulfoxide was added dropwise 6.4 g (0.063 mole) of 1-methyl-3-pyrrolidinol. During addition, the temperature rose from 25° C. to 31° C. After 10 minutes, a solution of 10 g (0.063 mole) of 2-chloronicotinic acid in 50 ml of dimethylsulfoxide was added dropwise causing the temperature to rise. When the temperature reached 55° C., it was maintained there by the intermittent use of an ice bath until addition was complete. The mixture was then heated to 55°-60° C. for 1.5 hr., cooled and filtered. The filter cake was suspended in 100 ml of ethyl acetate and filtered. The solid was recrystallized from ethyl acetatemethanol. Yield of product was 5 g., dec. 240° C. The NMR analysis showed that the compound contained 1/3 mole of sodium acetate as impurity.
Reaction SMILES: ClC(Cl)C.[CH3:5][O:6][C:7]1[CH:44]=[CH:43][C:10]([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:13]2[N:18]=[CH:17][C:16]([C:19]3[C:20]4[CH2:33][CH2:32][NH:31][C:21]=4[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=3)=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[I:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([N:52]=[C:53]=[O:54])[CH:47]=1>CN(C1C=CN=CC=1)C.ClCCl>[I:45][C:46]1[CH:47]=[C:48]([NH:52][C:53]([N:31]2[C:21]3[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=[C:19]([C:16]4[CH:15]=[N:14][C:13]([N:12]([CH2:11][C:10]5[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:44][CH:43]=5)[CH2:34][C:35]5[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=5)=[N:18][CH:17]=4)[C:20]=3[CH2:33][CH2:32]2)=[O:54])[CH:49]=[CH:50][CH:51]=1
Reactant: O=C=Nc1cccc(I)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3cccc(I)c3)cn2)cc1
Temperature: 25 °C

Procedure:
To a dichloroethane solution (10 ml) of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (540 mg), DMAP (12.2 mg) and 1-iodo-3-isocyanato-benzene (490 mg) were added, followed by refluxing for 17 hours. This was cooled to room temperature, and dichloromethane (40 ml) was added. After washing with saturated aqueous ammonium chloride solution (30 ml), the organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, followed by silica gel column chromatography (hexane/dichloromethane/ethyl acetate=4/4/1 to 1/2/1), to obtain the desired compound as a crude product (404 mg, 51%).
Reaction SMILES: O1C=[CH:4][CH:3]=[C:2]1P(C1OC=CC=1)C1OC=CC=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27](=[O:28])[C:26](I)=[C:25]([O:30][CH3:31])[C:24](=[O:32])[NH:23][C:22]=2[CH:33]=1.C([Sn](CCCC)(CCCC)CCCC)C=C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:4]([C:26]1[C:27](=[O:28])[C:21]2[CH:20]=[CH:19][C:18]([Cl:17])=[CH:33][C:22]=2[NH:23][C:24](=[O:32])[C:25]=1[O:30][CH3:31])[CH:3]=[CH2:2]
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Agent: [Pd]
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=CCc1c(OC)c(=O)[nH]c2cc(Cl)ccc2c1=O
Reaction time: 0.17 h
Yield: 831.6 %

Procedure:
A solution of tri(2-furyl)phosphine (0.019 g) and tris-(dibenzylideneacetone)dipalladium(O) (0.020 g) in toluene (25 mL) was allowed to stir for 10 minutes. To this solution was added 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.750 g), followed by allyltributyltin (0.83 g). The reaction mixture was heated to reflux for 16 hours, was allowed to cool, and the toluene was evaporated. The residue was dissolved in ethyl acetate, and the resulting solution was filtered through silica gel and stirred over an equal volume of 1 molar aqueous potassium fluoride for 0.5 hour. The organic portion was separated, washed (water, brine), dried, filtered through diatomaceous earth and evaporated. The resulting orange solid was triturated with hexanes and subsequently chromatographed, with ethyl acetate:hexanes (5:1) as the eluent, to afford the title compound (0.189 g); mp 135°-136° C.; NMR: 11.43 (broad s,1), 7.63 (d,1, J=8.5), 7.36 (d,1, J=2.0), 7.29 (dd,1, J=8.6, 1.9), 5.85-5.72 (m,1), 5.00-4.96 (m,1), 4.94 (m,1), 3.80 (s,3), 3.28 (m,2). Analysis for C14H12ClNO3 0.25 H2O.: Calculated: C, 59.58; H, 4.46; N, 4.96; N, 4.96; Found C, 59,74; H, 4.39; N, 4.93.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[C:10]1([C:16](=O)[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: NNc1ccccc1Br
Product: O=C(C(=NNc1ccccc1Br)c1ccccc1)c1ccccc1

Procedure:
1,2-Diphenylethane-1,2-dione (2-bromophenyl)hydrazone was prepared from 2-bromophenyl hydrazine and 1,2-diphenyl-ethane-1,2-dione according to the procedure of Step 1 Example 2. MS m/z 379;
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]([CH3:8])[O:6][C:5](=[O:9])[C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16](Cl)(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C1COCC1>[C:16]([O:1][CH2:2][C:3]1[CH:7]([CH3:8])[O:6][C:5](=[O:9])[C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC1OC(=O)C(c2ccccc2)=C1CO
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OCC1=C(c2ccccc2)C(=O)OC1C

Procedure:
4-Hydroxymethyl-5-methyl-3-phenyl-2(5H)-furanone (Compound 7), (73 mg, 0.36 mmol), lauroyl chloride (117 mg, 0.54 mmol), triethylamine (47 mg, 0.47 mmol) and dimethylaminopyridine (1 mg, 0.01 mmol) were stirred in anhydrous THF (2 mL) at ambient temperature under argon for 2 hours. The crude reaction mixture was concentrated, the organics were extracted into diethyl ether and solids were filtered off. The ether was removed by rotary evaporator and the resulting oil was purified by flash chromatography on silica to give the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:16]=[C:17]1O[C:19](=[O:20])[CH2:18]1.C(Cl)Cl>CCOCC>[CH3:1][N:2]1[C:17]([CH3:16])=[CH:18][C:19](=[O:20])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C=C(NC)c1ccccc1
Reactant: C=C1CC(=O)O1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccccc2)n(C)c(C)cc1=O
Reaction time: 117 h

Procedure:
10.25 gms of ethyl beta-methylaminocinnamate, 9.4 gms of technical grade diketene and 25 mls dry methylene chloride are mixed in a flask fitted with a calcium chloride drying tube. The reaction mixture is stored at room temperature for 117 hours. Approximately 75 ml of dry ether is added and the resulting crystalline solid is filtered to yield 8.5 gms of ethyl 1,6-dimethyl-2-phenyl-4-oxonicotinate. mp (toluene)=244-8.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C-:12]#[N:13].[Na+].O>CN(C)C=O>[CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][C:12]#[N:13])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)c1ccc(CCl)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CC#N)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 102.2 %

Procedure:
To a stirred solution of 100 g of 4-isopropylbenzyl chloride in 1500 mL of N,N-dimethylformamide was added 32.0 g of sodium cyanide under ice-cooling. The mixture was stirred at 70° C. for 4 hours, and water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 96.5 g of (4-isopropylphenyl)acetonitrile.
Reaction SMILES: CN1CCCCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]([C:20]([OH:22])=O)[CH:17]([CH3:19])[CH3:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([NH2:41])[CH3:40])=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([NH:41][C:20](=[O:22])[C@H:16]([CH:17]([CH3:18])[CH3:19])[NH:15][C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[CH3:40])=[CH:35][CH:34]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc(C(C)N)cc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: COc1ccc(C(C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)cc1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 217.1 %

Procedure:
2.3 g (0.023 mol) of N-methylpiperidine are added to 5.0 g of t-butoxycarbonyl-L-valine (0.023 mol), dissolved in 50 ml of CH2Cl2, at -20° C. 3.2 g (0.023 mol) of isobutyl chloroformate are then rapidly added dropwise at -20° C., the mixture is subsequently stirred at the same temperature for 10 minutes and cooled to -60° C. and 3.5 g (0.023 mol) of 4-methoxy-1-phenylethylamine are allowed to run in, the temperature being kept below -15° C. After 2 hours at -15° C., the mixture is subsequently stirred at room temperature for 15 hours, the solid is filtered off and rinsed with CH2Cl2, the filtrate is concentrated, the residue is introduced into water, the mixture is extracted twice with ethyl acetate and the combined ethyl acetate phases are washed with NaHCO3 solution and water, dried and concentrated. 17.5 g (85% of theory) of N-(t-butoxycarbonyl)-L-valine 4-methoxy-1-phenylethylamide of melting point 126°-127° C. are obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[F:12].CCN(C(C)C)C(C)C.[CH3:22][C@H:23]1[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[F:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][N:27]1[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@@H:23]([CH3:22])[CH2:28]1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CBr)c(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of 2-fluoro-4-nitrotoluene (1.55 g, 10 mmol), N-bromosuccinimide (1.96 g, 11 mmol) and benzoyl peroxide (0.121 g, 0.5 mmol) in CCl4 (60 mL) was irradiated with a 500 W lamp overnight. The reaction mixture was filtered, concentrated and eluted through a silica column with EtOAc/pentane to give a crude product mixture (2.34 g) which was used in step 2. Step 2: A mixture of crude 4-(bromomethyl)-3-fluoro-1-nitrobenzene (2.11 g) from step 1, Hunig's base (1.9 mL, 10.913 mmol) and 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (2 g, 10 mmol) in DMF (15 mL) was stirred at room temperature for 40 minutes. The reaction mixture was concentrated, re-dissolved in DCM and washed with water (×2) and brine, then dried and concentrated. The crude product was purified by column chromatography. Elution with EtOAc/pentane yielded the title compound as a yellow gum which crystallised on standing (2.11 g). δH (CDCl3, 400 MHz) 8.03 (1H, dd), 7.91 (1H, dd), 7.70 (1H, m), 4.22 (1H, br.s), 3.84 (1H, d), 3.61 (2H, m), 3.12 (1H, td), 2.74 (1H, m), 2.57 (1H, m), 2.27 (1H, dd), 2.11 (1H, m), 1.46 (9H, s), 1.25 (3H, d). MS (ES): MH+ 354.1. Description 66
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][CH2:32][OH:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][CH2:32][OH:33])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCCO)ccc21
Yield: 88.7 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (40.0 mg, 0.0974 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 2-aminoethanol (0.024 mL, 0.39 mmol), acetic acid (0.112 mL, 1.96 mmol) and sodium triacetoxyborohydride (103 mg, 0.486 mmol), followed by purification by preparative thin-layer chromatography (hexane/ethyl acetate=1/2) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[(2-hydroxyethyl)aminomethyl]indol-2-yl)isoindolinone (39.4 mg, yield 871).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([CH2:16][CH2:17][CH2:18][NH2:19])[CH:15]=[CH:14][N:13]=[CH:12]1.C(N(CC)CC)C>COCCOC>[N:11]1([CH2:16][CH2:17][CH2:18][NH:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCCn1ccnc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(NCCCn2ccnc2)cc1
Temperature: 0 °C

Procedure:
A mixture of 28.2 g (0.2 mol) of 1-fluoro-4-nitrobenzene, 31.3 g (0.25 mol) of 3-imidazol-1-ylpropylamine and 34.8 ml of triethylamine in 30 ml of 1,2-dimethoxyethane was heated for half an hour with stirring. The mixture was poured into 1.5 liters of ice-cold water and the crystalline precipitate was filtered off, reimpasted in water and then in isopropyl alcohol and dried under vacuum at 40° C. over phosphorus pentoxide. Yellow crystals (36.6 g) which, after purification by recrystallization from refluxing 96° ethanol, melted at 124° C., were obtained, the elemental analysis of which, calculated for C12H14N4O2, was:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4](OS(C)(=O)=O)[C:5]1[S:6][C:7]([CH3:10])=[CH:8][CH:9]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>CC#N>[CH3:1][O:2][C:3](=[O:16])[CH:4]([C:5]1[S:6][C:7]([CH3:10])=[CH:8][CH:9]=1)[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C(OS(C)(=O)=O)c1ccc(C)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(Nc1ccccc1)c1ccc(C)s1
Yield: 24.1 %

Procedure:
A solution of methanesulfonyloxy-(5-methyl-thiophen-2-yl)-acetic acid methyl ester (I266) (2.10 g, 7.94 mmol), aniline (1.09 mL, 11.9 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.04 mL, 11.9 mmol) in MeCN (10 mL) is heated under microwave irradiation at 100° C. for 1 hour. The solvent is removed, DCM is added and the organic phase is washed with water and brine, dried over Na2SO4 and evaporated. The resulting brown oil is purified by silica gel flash chromatography (Hexane/EtOAc=9575 to 90/10) to obtain intermediate I269 as a yellow oil (500 mg, 24% yield).
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH2:22][CH3:23])=[C:4]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[CH:5]=[C:6]([Cl:10])[C:7]=1[C:8]#[N:9].[CH3:24][N:25]([CH3:37])[C:26]([C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([C:31]2[CH:32]=[N:33][C:28]([C:26]([N:25]([CH3:37])[CH3:24])=[O:27])=[CH:29][CH:30]=2)[C:3]([O:21][CH2:22][CH3:23])=[C:4]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[CH:5]=1
Reactant: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C#N)c1Br
Reactant: CN(C)C(=O)c1ccc(B(O)O)cn1
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: C1COCCO1
Solvent: O
Product: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 90 °C
Yield: 84.6 %

Procedure:
The tert-butyl [1-(3-bromo-5-chloro-4-cyano-2-ethoxyphenyl)ethyl]carbamate (0.05 g, 0.1 mmol, Example 179, peak 2) was combined with {6-[(dimethylamino)carbonyl]pyridin-3-yl}boronic acid (0.034 g, 0.17 mmol, Example 179, Step 5) in 1,4-dioxane (3.0 mL) and potassium carbonate (0.034 g, 0.25 mmol) dissolved in water (1.0 mL) in a tube. The reaction was degassed with nitrogen and the tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.02 mmol) was added and degassed again. The tube was sealed and heated in an oil bath to 90° C. After heating for 18 h the reaction was complete. This was allowed to cool to room temperature and partitioned between EtOAc and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the crude as a dark oil. The product was purified by chromatography on silica gel eluting with hexane:EtOAc gradient to give tert-butyl [1-(5-chloro-4-cyano-3-{6-[(dimethylamino)carbonyl]pyridin-3-yl}-2-ethoxyphenyl)ethyl]carbamate as a viscous oil (0.04 g, 66%). LCMS calculated for C24H30ClN4O4 (M+H)+: m/z=473.2. found: 473.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:37])[N:10]([CH2:28][C@H:29]([NH2:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:11](=[O:27])[N:12]([CH2:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:17]=2[F:26])[C:13]=1[CH3:14].[CH2:38]([CH:43]=O)[CH2:39][C:40]([OH:42])=[O:41].N1C=CC=CC=1>CO>[OH:42][C:40]([CH2:39][CH2:38][CH2:43][NH:36][C@H:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][N:10]1[C:9](=[O:37])[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:13]([CH3:14])[N:12]([CH2:15][C:16]2[C:21]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:19]=[CH:18][C:17]=2[F:26])[C:11]1=[O:27])=[O:41]
Reactant: O=CCCC(=O)O
Reactant: Cc1c(-c2ccccc2Cl)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Solvent: c1ccncc1
Solvent: CO
Product: Cc1c(-c2ccccc2Cl)c(=O)n(C[C@H](NCCCC(=O)O)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reaction time: 8 h

Procedure:
To compound 2b (0.03 mmol) in 1 mL MeOH, succinic semialdehyde (0.03 mmol) was added followed by addition of 8 M BH3: Pyridine (0.03 mmol). After overnight shaking, the compound 2-1 was purified by prep. LC-MS. MS (CI) m/z 618.2 (MH+) tR=1.005 (method 1)
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.CN(C)C1C=CC=CC=1.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>C(OCC)(=O)C>[C:21]([NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1)(=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Reactant: CCCC(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nccc(C)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 2-amino-4-methyl-3nitropyridine (5.0 g) and N,N-dimethylaniline (8.5 ml) was heated at 100° C. under nitrogen atmosphere. To the solution was added butyryl chloride (3.5 ml) and the mixture was stirred at 100° C. for 5 hours. After being cooled to room temperature, ethyl acetate was added to the reaction mixture. The organic layer was separated and washed successively with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was washed with n-hexane to give 2-butyrylamino-4-methyl-3-nitropyridine (7.0 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[S:11])SC)(=[O:3])[CH3:2].[N-:12]=[N+:13]=[N-:14].[Na+]>O1CCOCC1.O>[C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:8]([SH:11])=[N:14][N:13]=[N:12]1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCNC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)NCCn1nnnc1S
Yield: 43.2 %

Procedure:
To a solution of methyl N-(2-acetamidoethyl)dithiocarbamate (12.6 g.) in dioxane (40 ml.) was added a solution of sodium azide (6.4 g.) in water (40 ml.), and the mixture was heated under reflux for 4 hours. After dioxane was removed from the resultant mixture under reduced pressure, the residue was washed with ether (350 ml.) and adjusted to pH 1 with 10% hydrochloric acid. After the resultant solution was extracted with ethyl acetate (1.5 l.), the extract was dried over magnesium sulfate and the solvent was evaporated to dryness to give 1-(2-acetamidoethyl)-1H-tetrazole-5-thiol (5.3 g.) having m.p. 137.5° to 139.5° C.