Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH2:15][C:16]([OH:18])=O)[CH:14]=2)[S:3]1.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[F:21][C:22]([F:30])([F:31])[C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:16](=[O:18])[CH2:15][C:13]2[CH:14]=[C:9]([CH:8]=[C:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])[CH:10]=[CH:11][C:12]=2[O:19][CH3:20])=[CH:28][CH:29]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(C=C2SC(=O)NC2=O)cc1CC(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C=C2SC(=O)NC2=O)cc1CC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 72.1 %

Procedure:
2-[5-[(2,4-Dioxothiazolidin-5-ylidene)methyl]-2-methoxyphenyl]-acetic acid (440 mg, 1.50 mmol), 4-(trifluoromethyl)aniline (242 μL, 1.50 mmol), triethylamine (210 μL, 1.51 mmol) and dehydrated N,N-dimethylformamide (5 mL) were mixed, and, under an atmosphere of argon, diethyl cyanophosphate (228 μL, 1.50 mmol) was added under cooling with ice and stirring. After stirring for 1 hour at room temperature, the mixture was allowed to stand for 3 days. The reaction mixture was poured into ice water and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate, and then dried to obtain 472 mg (72%) of the title compound as yellow crystals.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17]>[OH-].[Li+].CN(C)C=O>[Cl:17][CH2:16][C@@H:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClC[C@@H]1CO1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and lithium hydroxide (48 mg, 2 mmol) were added to 100 mL N,N-dimethyl formamide. The mixture was stirred at 25° C. for 30 minutes. (S)-epichlorohydrin (18.6 g, 0.2 mol) was then added and the mixture was stirred at 0° C. for 8 hours. The mixture was filtered and the solvent was evaporated to provide 52 g colorless oil with 90% yield. HPLC: 99.0%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O.O.NN>CO>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH2:10]
Reactant: COc1ccc(I)c([N+](=O)[O-])c1
Agent: NN
Solvent: O
Solvent: CO
Product: COc1ccc(I)c(N)c1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a solution of 4-iodo-3-nitroanisole (5 g, 17.9 mmole) in 100 ml methanol was added FeCl3 (50 mg, 0.3 mmole) and activated carbon (40 mg). The mixture was heated to reflux and hydrazine hydrate (1.75 g, 35 mmole) was added dropwise. The mixture was refluxed for an additional 8 hours and cooled to room temperature, filtered through Celite. The filtrate was concentrated and purified by column chromatography (eluting with 10% EtOAc in hexanes) to give 4.05 g product as pale yellow oil (91% yield). 1H NMR (300 MHz, CDCl3) δ 7.47 (1H, d, J=8.7 Hz), 6.31 (1H, d, J=2.8 Hz), 6.13 (1H, dd, J=2.8, 8.7 Hz), 3.73 (3H, s).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[C:5](=[O:7])=[O:6]>P.[Pd]>[CH:2](=[C:3]1[CH2:4][CH:1]([CH:2]=[CH:3][CH3:4])[O:7][C:5]1=[O:6])[CH3:1]
Reactant: O=C=O
Reactant: C=CC=C
Agent: [Pd]
Agent: P
Product: CC=CC1CC(=CC)C(=O)O1
Yield: 0.4 %

Procedure:
Inoue et al., Chem Comm. 1976, 65 describes a process in which butadiene is reacted with carbon dioxide in a polar aprotic solvent in the presence of certain palladium-phosphine complexes (e.g. Pd (Ph2PCH2CH2PPh2)2) to give a five membered lactone, 2-ethylidene-hept-5-en-4-olide, in small yields (0.4 to 12.3% yield based on butadiene), together with much higher yields of butadiene oligomers (60-85% yield).
Reaction SMILES: [CH:1]([NH:4][C@H:5]1[CH2:10][C@@H:9]([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C@@H:8]([NH:17][C:18](=[O:33])[CH2:19][NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:7][CH2:6]1)([CH3:3])[CH3:2].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:38](C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH:1]([N:4]([CH3:38])[C@H:5]1[CH2:10][C@@H:9]([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C@@H:8]([NH:17][C:18](=[O:33])[CH2:19][NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:7][CH2:6]1)([CH3:2])[CH3:3]
Reactant: CC(C)N[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](C(=O)OC(C)C)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)OC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
A solution of (1R,2S,5R)-isopropyl 5-(isopropylamino)-2-(2-(3-trifluoromethyl-benzamido)acetamido)cyclohexanecarboxylate (210 mg, 0.45 mmol; Example 11l) in 10 ml of CH2Cl2 is treated with 37% aqueous formaldehyde (0.5 ml) and NaBH(OAc)3 (0.3 g, 1.4 mmol) powder and stirred at room temperature for 2 hours. The mixture was treated with 1 N NaOH and stirred at room temperature for 1 hr and extracted into CH2Cl2. The extract was washed with water, brine, dried over Na2SO4, filtered and the solvent evaporated to give 200 mg of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ(TMS): 8.16 (s, 1 H), 8.06 (d, J=7.8 Hz, 1 H), 7.86 (bt, 1 H), 7.75 (d, J=7.8 Hz, 1 H), 7.55 (t, J=7.8 Hz, 1 H), 7.21 (bs, 1 H), 4.91 (m, 1 H), 4.51 (m, 1 H), 4.12 (d, J=5.2 Hz, 2 H), 3.01 (m, 1 H), 2.58 (m, 1 H), 2.57 (m, 2 H), 2.21 (s, 3 H), 2.02-1.40 (m, 7 H), 1.16 (m, 6 H), 1.02 (m, 6 H). MS found: (M+H)+=486.46.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:25]3[C:26](=[O:45])[N:27]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[F:44])[C:28](=[O:36])[N:29]([CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:30]=3[NH2:31])=O)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CO>[CH:33]1([CH2:32][N:29]2[C:30]3[N:31]=[C:22]([CH2:21][C:18]4[CH:19]=[CH:20][C:15]([NH:14][S:11]([C:7]5[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=5[CH3:10])(=[O:12])=[O:13])=[CH:16][CH:17]=4)[NH:24][C:25]=3[C:26](=[O:45])[N:27]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[F:44])[C:28]2=[O:36])[CH2:34][CH2:35]1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Nc2ccc(CC(=O)Nc3c(N)n(CC4CC4)c(=O)n(Cc4ccccc4F)c3=O)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)Nc2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)s1
Temperature: 50 °C
Reaction time: 6 h
Yield: 29.7 %

Procedure:
A solution of 2-[4-(2-acetylamino-4-methyl-thiazole-5-sulfonylamino)-phenyl]-N-[6-amino-1-cyclopropylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetamide (56 mg, 0.085 mmol) in methanol warmed to 50° C. was treated with a 10% aqueous sodium hydroxide solution (0.34 mL, 0.085 mmol). The reaction was stirred at 50° C. for 6 h. At this time, the reaction was concentrated in vacuo, diluted with water, and acidified to pH=2 with a 1.0N aqueous hydrochloric acid solution (0.9 mL). This mixture was cooled in an ice-bath. The resulting solids were collected by filtration, washed with water, and dried in vacuo. HPLC (20–80% acetonitrile/water) afforded N-(5-{4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenylsulfamoyl}-4-methyl-thiazol-2-yl)-acetamide (16.1 mg, 29.7%) as a white solid; FAB-HRMS m/e calculated for C29H28FN7O5S2 (M+H)+ 638.1656, found 638.1641; and 2-amino-4-methyl-thiazole-5-sulfonic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide trifluoro-acetic acid salt (5.4 mg, 10%) as a white solid; FAB-HRMS m/e calculated for C27H26FN7O4S2 (M+H)+ 596.1550, found 596.1547.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[NH:11][C:10](=[O:15])[N:9]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[N:18]=[C:8]3[C:7]=2[CH2:6]1.[H-].[Na+].[C:32](Cl)(=[O:34])[CH3:33]>CN(C=O)C.C(OCC)(=O)C>[C:32]([N:11]1[C:12]2[CH2:13][CH2:14][N:5]([CH2:4][C:3]3[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=3[F:1])[CH2:6][C:7]=2[C:8]2=[N:18][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[CH:16][N:9]2[C:10]1=[O:15])(=[O:34])[CH3:33]
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CN(Cc1ccccc1F)CC2
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)n1c2c(c3nc(-c4ccccc4F)cn3c1=O)CN(Cc1ccccc1F)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 9-(2-fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (392 mg, 1 mmol) and 50% sodium hydride (144 mg, 3 mmol) in DMF (5 mL) was stirred at room temperature for 15 min. Acetyl chloride (1 mL) was added and stirring was continued for 30 min. The reaction was diluted with ethyl acetate and washed with water. After drying over magnesium sulfate, the solvent was removed in vacuo and the residue was subjected to flash chromatography on silica gel with 30% ethyl acetate in hexane as the eluent to afford 6-acetyl-9-(2-fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (compound 55) and 5-acetoxy-9-(2-fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2c]pyrido[3,4-e]pyrimidine (compound 56) as white solids.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]COC)=[C:4]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:3]=1.Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH:3]=1
Reactant: COCOc1ccc(F)cc1CCc1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Oc1ccc(F)cc1CCc1ccc(F)cc1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
1785 mg of methoxymethyl {4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenyl} ether [prepared as described in step (a) above] were dissolved in 8 ml of ethyl acetate, and then 8 ml of a 4N solution of hydrogen chloride in ethyl acetate were added to the resulting solution, whilst ice-cooling. The resulting mixture was allowed to stand at room temperature for 2 hours, after which it was concentrated by evaporation under reduced pressure, and purified by silica gel column chromatography, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1483 mg (yield 99%) of the title compound as an oily substance.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17]([OH:19])=[O:18])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[Na][Na].F[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N+:49]([O-:51])=[O:50].C(N(CC)CC)C.Cl>O.C1C=C(C([N-]C(C2N=CC=CC=2)=O)=O)N=CC=1.O.O.[Cu+2]>[C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[N+:49]([O-:51])=[O:50])[CH:13]([C:17]([OH:19])=[O:18])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [Cu+2]
Agent: Cl
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1ccccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
To a solution of 4-carbobenzyloxypiperazine-2-carboxylic acid, copper chelate in 750 ml water was added ethylenediaminetetracetic acid, disodium salt, dihydrate (7.9 g, 21 mmol). The mixture was heated to 80° C. for 3 h. The reaction mixture was then cooled to rt and concentrated to dryness. The residue was dissolved in 100 ml DMSO. 2-Fluoronitrobenzene (4.9 g, 35 mmol) and triethyl amine (20 ml, 143 mmol) were added and the solution was heated to 60° C. for 16 h. The dark reaction mixture was cooled to rt. Concentrated HCl was added to bring the pH to 3. The solution was then diluted with 500 ml water and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with water, dried over MgSO4 and concentrated to afford 4-carbobenzyloxy-1-(2-nitrophenyl) piperazine-2-carboxylic acid used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[CH3:13][C:14]1([CH3:32])[C:19](=[O:20])[CH:18]=[C:17]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:16][CH2:15]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:18]3[C:19](=[O:20])[C:14]([CH3:32])([CH3:13])[CH2:15][CH2:16][C:17]=3[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)[C:10](=[O:11])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C=NC(Cl)c1ccc(Br)cc1
Reactant: CC1(C)CCC(Nc2cccc(C(F)(F)F)c2)=CC1=O
Solvent: ClCCl
Product: CC1(C)CCC2=C(C1=O)C(c1ccc(Br)cc1)NC(=O)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (569 mg, 2.31 mmol) in dichloromethane (5 mL) is added to a solution of 6,6-dimethyl-3-(3-(trifluoromethyl)-phenylamino)cyclohex-2-enone (intermediate 6, 654 mg, 2.31 mmol) in dichloromethane (15 mL), and the resulting mixture is heated at reflux for 4 h and stirred at room temperature over night. Another portion of 1-bromo-4-(chloro(isocyanato)methyl)benzene (283 mg, 1.15 mmol) is added and the mixture is heated at reflux for 24 h. The mixture is cooled to room temperature and all volatiles are evaporated. The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 90:10 to 60:40). Yield: 372 mg; ESI mass spectrum: [(79Br)-M+H]+=493, [(81Br)-M+H]+=495; Retention time HPLC: 1.37 min (Z005—001).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]>>[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: COCCCN
Product: COCCCNc1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 3-methoxy-propylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 1.81 (m, 2H); 2.98 (m, 2H); 3.24 (s, 3H); 3.41 (m, 4H); 3.56 (m, 2H); 7.19 (m, 2H); 7.28 (bs, 1H); 7.50 (m, 2H); 7.92 (m, 2H); 8.18 (m, 3H); 8.38 (bs, 1H); 8.68 (bs, 1H); 12.13 (bs, 1H). MS (ion spray) m/z 455 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:21])(=[O:3])[CH3:2].[CH3:22][CH2:23][O:24][C:25](OCC)(OCC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][CH:11]=2)[C:6](=[C:25]([O:24][CH2:23][CH3:22])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:5]1=[O:21])(=[O:3])[CH3:2]
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: CC(=O)N1C(=O)Cc2cc(C(=O)c3ccccc3)ccc21
Product: CCOC(=C1C(=O)N(C(C)=O)c2ccc(C(=O)c3ccccc3)cc21)c1ccccc1

Procedure:
Prepared from 1-acetyl-5-benzoyl-2-indolinone and triethyl orthobenzoate
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[C:21]([O:20][CH:15]([C:8]1[N:9]([CH3:14])[C:10](=[O:13])[C:11]2[C:6]([C:7]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[CH:12]=2)[C:16]([O:18][CH3:19])=[O:17])([CH3:22])([CH3:23])[CH3:24]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN)cc2c(=O)n1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CNS(C)(=O)=O)cc2c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
An ice cold solution of methyl 2-(7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate (17 mg, 0.039 mmol) in dichloromethane (DCM) (750 μl) was treated with Et3N (8.14 μl, 0.058 mmol) and MsCl (3.64 μl, 0.047 mmol), stirred for 1 hour, and then warmed to rt for 1 hour. Additional Et3N (8 uL) and MsCl (4 uL) were added at 00° C., the reaction was stirred at rt for 1 hour, and then concentrated. The residue was purified by column chromatography (0-10% MeOH/DCM) to afford methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-7-(methylsulfonamidomethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (17 mg, 0.033 mmol, 85% yield) as yellow solid. The methyl ester was hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-7-(methylsulfonamidomethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetic acid (14 mg, 0.027 mmol, 88% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.44 (s, 1 H), 7.59-7.50 (m, 1 H), 7.40-7.29 (m, 1 H), 7.29-7.24 (m, 1 H), 7.17 (dd, J=8.4, 12.5 Hz, 1 H), 7.08-6.99 (m, 1 H), 5.35 (s, 1 H), 5.15-5.03 (m, 1 H), 4.44 (d, J=5.7 Hz, 2 H), 3.67 (s, 3 H), 2.97-2.89 (m, 3 H), 2.37 (s, 3 H), 2.32 (s, 3 H), 1.09-1.02 (m, 9 H); LCMS (m/z) ES+=501 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1
Agent: [Pd]
Product: COc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 15e), from palladium (10 mol %) on carbon and 2-(3-nitro-6-methoxyphenyl)-5-phenylbenzoxazole (450 mg, 1.3 mmol) the subtitle compound was obtained (420 mg, 99%). The product was used directly in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][N:35]([C:2]2[CH:3]=[CH:4][C:5]3[C:9]4[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=4[N:7]([CH3:22])[C:6]=3[N:23]=2)[C:34](=[O:38])[CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CCC2
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
A suspension of tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (0.15 g, 0.40 mmol), 4-benzyloxypyridinone (80 mg, 0.40 mmol), and Cs2CO3 (0.14 g, 0.44 mmol) in DMSO (2.3 mL) was placed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (91 mg, 0.48 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (40 mL) and washed with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (2×30 mL). The resulting organic solution was dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) gave the title compound (141 mg, 70%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.98-7.95 (m, 1H), 7.81-7.79 (m, 1H), 7.49-7.37 (m, 5H), 7.30-7.27 (m, 1H), 6.15 (dd, J=7.8, 2.7 Hz, 1H), 5.98 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.58 (br s, 2H), 3.71 (s, 3H), 3.66 (t, J=5.4 Hz, 2H), 3.03-3.01 (m, 2H), 1.98-1.93 (m, 2H), 1.35-1.27 (m, 9H); ESI MS m/z 501 [M+H]+.
Reaction SMILES: CC([O-])(C)C.[K+].[O:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[C:15]([C:19]([N+:22]([O-:24])=[O:23])=[CH:20][N:21]=2)[C:16]([OH:18])=[O:17])[CH2:9][CH2:8]1.[NH2:25]C.Cl>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH2:25][C:20]1[C:19]([N+:22]([O-:24])=[O:23])=[C:15]([CH:14]=[C:13]([N:10]2[CH2:11][CH2:12][O:7][CH2:8][CH2:9]2)[N:21]=1)[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1cc(N2CCOCC2)ncc1[N+](=O)[O-]
Reactant: CN
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Product: Nc1nc(N2CCOCC2)cc(C(=O)O)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of Cu(OAc)2 (1.01 g, 5.6 mmol) and t-BuOK (21.95 g, 196 mmol) in DMF (200 mL) was added a solution of 2-morpholino-5-nitroisonicotinic acid (5.66 g, 28 mmol) and NH2CH3.HCl (4.65 g, 56 mmol) in DMF (100 mL) at 60° C. dropwise. The mixture was then stirred at 60° C. for 16 h. LCMS showed the desired product. It was cooled to room temperature and filtered. The filter cake was dissolved with water (250 mL) and acidified with aq. HCl solution to pH=1. It was then extracted with DCM/MeOH (400/100 mL×8). The organic layer was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with MeOH/DCM=1/10 to afford the crude product as a black oil (4.5 g); LC/MS: MS (ES+) m/e 269 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1)=[O:2].C(O)C.[BH4-].[Na+].O>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(CO)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a solution of 3-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (20.0 g) in tetrahydrofuran (300 mL)-ethanol (30 mL) was gradually added sodium borohydride (1.09 g) at 0° C. After stirring at room temperature for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile as colorless crystals (19.2 g, yield 96%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 113-115° C.