Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH2:6].C([O-])(=O)C.[K+].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:14]1([NH:6][C@@H:5]([C:4]([O:3][CH3:2])=[O:8])[CH3:7])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)[C@@H](C)N
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](C)NC1CCCCC1
Temperature: 10 °C
Yield: 80 %

Procedure:
To a suspension of D-Alanine methyl ester hydrochloride (16.0 g, 114.6 mmol) in dry dichloromethane (150 mL) was added potassium acetate (11.2 g, 114.6 mmol) and the reaction mixture stirred for ten minutes. The reaction mixture was then cooled to 10° C., cyclohexanone (11.8 mL, 114.6 mmol) was added, followed by sodium triacetoxyborohydride (30.3 g, 143.2 mmol) in portions over a period of ten minutes. Reaction mixture was stirred at room temperature for 16 h after which saturated sodium bicarbonate solution (60 mL) was added and stirred for another 30 minutes. The reaction mixture was further basified with aqueous sodium carbonate to pH=˜10. The organic layer was separated and the aqueous layer extracted with dichloromethane (3×75 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and evaporated to give titled compound (yield: 80%). 1HNMR (300 MHz, CDCl3): δ 0.97-1.21 (m, 4H), 1.26 (d, J=6.9 Hz, 3H), 1.57-1.59 (m, 2H), 1.75-1.67 (m, 3H), 1.89-1.84 (m, 1H), 2.36-2.29 (m, 1H), 3.48 (q, J=6.9 Hz, 1H), 3.70 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][NH:6]1)[CH3:3].[CH:21](O)=[O:22]>C1(C)C=CC=CC=1>[CH:21]([N:6]1[CH2:7][CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]1[CH2:4][N:2]([CH3:1])[CH3:3])=[O:22]
Reactant: CN(C)CC1NCC(c2ccccc2)c2ccccc21
Reactant: O=CO
Solvent: Cc1ccccc1
Product: CN(C)CC1c2ccccc2C(c2ccccc2)CN1C=O
Yield: 120 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-1-dimethylaminomethyl-4-phenylisoquinoline base (Example 2) (9.5 g, 0.035 m) in toluene (100 ml) under nitrogen was added formic acid (8.05 g, 0.175 m) and the mixture heated to reflux in a Dean and Stark apparatus. After 3 ml of water were collected, the mixture was cooled, treated with 250 ml of 5% NaOH, and extracted with ether (1×150 ml) and then chloroform (3×100 ml) and the combined organic extracts dried over MgSO4. Evaporation of the solvents gave 12.6 g of 1,2,3,4-tetrahydro-2-formyl-1-dimethylaminomethyl-4-phenylisoquinoline as a yellow oil. This material was used directly for additional chemical processing without further purification.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:15]([C:12]2[CH:13]=[C:14]3[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]3[CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:10][CH:11]=2)=[O:17])[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)O)ccc12
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3cccc(Cl)c3)ccc12
Yield: 98.7 %

Procedure:
This compound was prepared according to the method of Example 11, using 150 mg (0.581 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid and 68 μL (0.639 mmol, 1.1 equiv) 3-chloro-aniline as starting materials to give 211 mg (99%) of a clear oil; HRMS calcd for C21H22N3OCl+H: 368.1532. Found: 368.1567.
Reaction SMILES: COCN1C=CC=N1.C([Li])CCC.ClC1C2OC(C([O-])=O)OC=2C=C(C=O)C=1Cl.[Li+].[Cl:31][C:32]1[C:40]2[O:39][CH:38]([C:41]([OH:43])=[O:42])[O:37][C:36]=2[CH:35]=[C:34]([CH:44]([C:46]2[N:50]([CH2:51][O:52][CH3:53])[N:49]=[CH:48][CH:47]=2)[OH:45])[C:33]=1[Cl:54]>CN(C)P(=O)(N(C)C)N(C)C.C(OCC)(=O)C.O1CCCC1>[Cl:31][C:32]1[C:40]2[O:39][CH:38]([C:41]([OH:43])=[O:42])[O:37][C:36]=2[CH:35]=[C:34]([C:44]([C:46]2[N:50]([CH2:51][O:52][CH3:53])[N:49]=[CH:48][CH:47]=2)=[O:45])[C:33]=1[Cl:54]
Reactant: COCn1nccc1C(O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)O2
Agent: COCn1cccn1
Agent: O=Cc1cc2c(c(Cl)c1Cl)OC(C(=O)[O-])O2
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCn1nccc1C(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 1.12 g of 1-methoxymethyl-pyrazole, 25 ml of tetrahydrofuran, 6.88 ml of 1.6M n-butyl lithium and a solution of 2.69 g of lithium 4,5-dichloro-6-formyl-1,3-benzodioxole-2-carboxylate in 12 ml of hexamethylphosphoric triamide is treated in the same manner described in Example 11-(1) to give an ethyl acetate solution containing 4,5-dichloro-6-[(1-methoxymethyl-pyrazol-5-yl)hydroxymethyl)-1,3-benzodioxole-2-carboxylic acid. The ethyl acetate solution is washed with water, dried and evaporated to remove solvent under reduced pressure. The residue (crude 4,5-dichloro-6-[(1-methoxymethyl-pyrazol-5-yl)hydroxymethyl]-1,3-benzodioxole-2-carboxylic acid) is dissolved in 100 ml of methylene chloride, 10 g of pyridinium dicromate are added thereto and the mixture is stirred at room temperature for 17 hours. Insoluble materials are filtered off and washed with methylene chloride. The filtrate and the washing solution are combined and evaporated under reduced pressure to remove solvent. Ethyl acetate is added to the residue and insoluble materials are filtered off. The filtrate is washed, dried and evaporated under reduced pressure to remove solvent. The residue is recrystallized from ethyl acetate-n-hexane to give 1.57 g of 4,5-dichloro-6-(1-methoxymethyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:23].[Na+]>CO>[NH2:23][CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2]1([CH3:16])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N)C(C)(C)C1
Temperature: 0 °C
Reaction time: 22 h
Yield: 193.4 %

Procedure:
A slurry of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (12.90 g, 56.8 mmol) and ammonium acetate (26.2 g, 341 mmol) in anhydrous methanol (40 mL) was stirred at room temperature under nitrogen for 3 h. After cooling to 0° C., sodium cyanoborohydride (1.783 g, 28.4 mmol) was added. The mixture was stirred at 0° C. for 5 min and at ambient temperature for 22 h. After removal of solvent in vacuo, the residue was treated with water (120 mL), stirred for 20 min, and extracted with dichloromethane (3×60 mL). The combined extracts were dried (MgSO4), concentrated and pumped under vacuum over weekend to give crude tert-butyl 4-amino-3,3-dimethylpiperidine-1-carboxylate (12.54 g). The purity of the product was not determined because of the lack of strong UV chromaphore in LCMS or HPLC, and presence of Boc rotamers in 1H NMR. The material was taken to the next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:4]=2[C:5](I)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:25]([Cu])#[N:26].[OH-].[NH4+].Cl>CCOC(C)=O.CN1CCCC1=O>[C:25]([C:5]1[C:4]2[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:15][O:16][C:3]=2[C:2]([OH:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)#[N:26]
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccc(OC)cc3)noc2c1O
Reactant: N#C[Cu]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2c(-c3ccc(OC)cc3)noc2c1O
Temperature: 110 °C
Yield: 58.9 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-(4-methoxyphenyl)isoxazolo[4,5-c]pyridine-6-carboxylate (390 mg, 0.89 mmol) and CuCN (238 mg, 2.66 mmol) were added to 6 mL of N-methyl-2-pyrrolidone. The resulting suspension was heated in an oil bath (T=110° C.) for 1 h. The reaction mixture was cooled slightly and poured into a vigorously stirring mixture of ammonium hydroxide (100 mL, 30% aqueous solution) and EtOAc (100 mL). The mixture was acidified with concentrated hydrochloric acid to pH 3 and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated, and the residue was purified flash chromatography (0-100% EtOAc/hexanes) to afford 178 mg of the title compound. MS: (+) m/z 340.42 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12].Cl[CH2:16][CH2:17][CH2:18][O:19][CH3:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:10](=[O:14])[CH:11]([CH3:12])[CH3:13]
Reactant: COCCCCl
Reactant: Cc1ccc(Br)c(NC(=O)C(C)C)c1
Product: COCCCN(C(=O)C(C)C)c1cc(C)ccc1Br

Procedure:
Analogously to Example 8c, 16.50 g of N-(2-bromo-5-methylphenyl)isobutyramide and 8.59 ml of 1-chloro-3-methoxypropane are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.13 (1:1 EtOAc-heptane); Rt=18.54 (II).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([N:13]2[CH2:17][CH2:16][S:15][CH2:14]2)(=[O:12])=[O:11])[C:3]=1[C:4]#[N:5].I([O-])(=O)(=O)=[O:19].[Na+]>CO.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([N:13]2[CH2:17][CH2:16][S:15](=[O:19])[CH2:14]2)(=[O:12])=[O:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1S(=O)(=O)N1CCSC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1c(F)cccc1S(=O)(=O)N1CCS(=O)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 70 %

Procedure:
54 mg of 2-Fluoro-6-(thiazolidine-3-sulfonyl)-benzonitrile in 10 ml of methanol and 1 ml of water are treated with 45 mg of sodium periodate, and the mixture is stirred for 14 hours at room temperature. The reaction mixture is poured into water, and the aqueous layer is extracted three times with ethyl acetate. The combined organic layers are dried over sodium sulfate, filtered and concentrated in vacuo. Purification by reverse phase HPLC affords 40 mg of 2-Fluoro-6-(1-oxo-1 lambda*4*-thiazolidine-3-sulfonyl)-benzonitrile.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.Cl.[NH2:35][CH:36]([C:38]1[NH:39][C:40]([C:46]2[CH:55]=[CH:54][CH:53]=[C:52]3[C:47]=2[N:48]=[C:49]([NH:57][C:58]([CH3:62])([CH3:61])[CH2:59][OH:60])[C:50]([CH3:56])=[N:51]3)=[CH:41][C:42]=1[C:43](O)=[O:44])[CH3:37].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[OH:60][CH2:59][C:58]([NH:57][C:49]1[C:50]([CH3:56])=[N:51][C:52]2[C:47]([N:48]=1)=[C:46]([C:40]1[NH:39][C:38]3[CH:36]([CH3:37])[NH:35][C:43](=[O:44])[C:42]=3[CH:41]=1)[CH:55]=[CH:54][CH:53]=2)([CH3:62])[CH3:61]
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)c(C(C)N)[nH]3)c2nc1NC(C)(C)CO
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(C)NC4=O)c2nc1NC(C)(C)CO
Yield: 29.1 %

Procedure:
Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (AK Scientific, Inc., Union City, Calif.) (226 mg, 0.43 mmol) was added to a solution of 2-(1-aminoethyl)-5-(3-((1-hydroxy-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (302d) (140 mg, 0.33 mmol) and DIPEA (0.23 mL, 1.33 mmol) in CH2Cl2 (8 mL) and DMF (8 mL) at RT. After 30 min the reaction mixture was concentrated. The residue was put into solution with EtOAc and the organic layer was washed with water, saturated NaHCO3 (aq.) and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to provide 2-(3-((1-hydroxy-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (302e) (35 mg, 0.096 mmol, 28% yield) as a yellow foam. The mixture of enantiomers was separated by chiral SFC (Chiralcel OJ (Sepax) (21×250, 5 μm); additive in supercritical fluid CO2 was 15% MeOH with 20 mM NH3; 75 mL/min; column temperature 40° C.; outlet pressure 100 bar) to give Example 302: (R)-2-(34(1-hydroxy-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (22 mg, 0.06 mmol, 18% yield, >99% ee). 1H NMR (400 MHz, CDCl3) δ ppm 7.92 (dd, J=7.63, 1.56 Hz, 1H), 7.69 (dd, J=8.02, 1.56 Hz, 1H), 7.39 (t, J=7.82 Hz, 1H), 6.87 (d, J=1.56 Hz, 1H), 4.60-4.69 (m, 1H), 3.80-3.91 (m, 2H), 2.59 (s, 3H), 1.63-1.64 (m, 3H), 1.61-1.62 (m, 3H), 1.53 (d, J=6.65 Hz, 3H). m/z (ESI, +ve) 366.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[O:11][CH2:12][C:13](=[O:19])[C:14]=1[C:15]([O:17][CH3:18])=[O:16].ClCC(=O)CC(OC)=O.FC1C=C(F)C=CC=1N=C=O.[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][N:47]=2)[C:42]([CH:49]=O)=[CH:41]1.N1CCC[C@H]1C(O)=O>CC(O)C>[NH:40]1[C:48]2=[N:47][CH:46]=[CH:45][CH:44]=[C:43]2[C:42]([CH:49]=[C:12]2[O:11][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:13]2=[O:19])=[CH:41]1
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2F)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: COC(=O)CC(=O)CCl
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C=Nc1ccc(F)cc1F
Solvent: CC(C)O
Product: COC(=O)C1=C(Nc2ccc(F)cc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 75.5 %

Procedure:
To a solution of methyl 2-[(2,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.27 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and 2,4-difluorophenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in 2-propanol (5.0 mL), L-proline (0.023 g, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 12 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (0.30 g, y. 75%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1(C)C=CC=CC=1.[F:19][C:20]1[C:25]([F:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:21]=1[OH:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.O>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([O:29][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[C:25]([F:26])[C:20]=2[F:19])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(O)c(F)c1F
Reactant: O=C(O)c1cc(Br)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2ccc(Br)cc2C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.4 %

Procedure:
To a 500 mL flask charged with 2,5-dibromobenzoic acid (14 g, 50.0 mmol) and copper (I) trifluoromethanesulfonate toluene complex (1.29 g, 2.50 mmol) were added toluene (100 mL, 50.0 mmol) followed by EtOAc (0.25 mL, 2.50 mmol) and 2,3-difluoro-4-methoxyphenol (8.41 g, 52.5 mmol). To the resulting green mixture was added cesium carbonate (34.2 g, 105 mmol) in two portions. The mixture was stirred at rt for 5 minutes before being placed in a 110° C. oil bath where it was maintained for 12 h. The reaction was cooled to rt and poured into a separatory funnel containing 1 L of water. The layers were separated and the aqeuous layer was washed with ethyl acetate (2×200 mL). The aqeuous layer was acidified with 6 N HCl and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to provide a brown oil. The derived oil was triturated with ethyl acetate (100 mL) and hexanes (1000 mL). The slurry was cooled to −10° C. for 4 hours then filtered to provide 5-bromo-2-(2,3-difluoro-4-methoxyphenoxy)benzoic acid (11.55 g, 32.2 mmol, 64.3% yield) as a light tan solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH2:7][OH:8].[H-].[Na+].I[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:37]=[CH:36][C:19]([O:20][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=3)[O:25][CH:26]=2)=[CH:18][CH:17]=1.O>CN(C=O)C>[Br:35][C:32]1[CH:31]=[CH:30][C:29](/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:20][C:19]3[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:1]4[CH:5]=[CH:4][N:3]=[C:2]4[CH2:6][CH2:7][OH:8])=[CH:37][CH:36]=3)[N:23]=2)=[CH:34][CH:33]=1
Reactant: Brc1ccc(/C=C/c2nc(COc3ccc(CCCCI)cc3)co2)cc1
Reactant: OCCc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Br)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of 2-(1H-imidazol-2-yl)-ethanol (449 mg) in DMF (10 ml), 60% oily sodium hydride (176 mg) was added under ice cooling. After stirring at room temperature for 30 minutes, 4-[[4-(4-iodobutyl)phenoxy)methyl]-2-[(E)-2-(4-bromophenyl)ethenyl]-1,3-oxazole (2.15 g) was added under ice cooling. After stirring overnight at room temperature, water was added under ice cooling. The reaction mixture was extracted with a mixture of ethyl acetate-THF. The extract was dried over magnesium sulfate, after which it was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to yield the titled compound (2.09 g) as a light-yellow crystal.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([C:15]2[S:19][CH:18]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O.O1CCCC1.O>[Br:1][C:18]1[S:19][C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:16][C:17]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1csc(-c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccccc2)sc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
N-Bromosuccinimide (360 mg, 2.02 mmol) was added to a solution of methyl 5-phenylthiophene-3-carboxylate (11b) (440 mg, 2.02 mmol) in a mixture of N,N-dimethylformamide (4 mL) and tetrahydrofuran (4 mL). The reaction mixture was stirred at room temperature for 1 hour. N-Bromosuccinimide (72 mg, 0.40 mmol) was added and the stirring was maintained for 1 hour. The mixture was poured in water (10 mL) and extracted with dichloromethane (2×15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to provide the desired product (11c) (390 mg, 1.3 mmol, 65%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[C:3]1=[O:18].CC1(C)C2C(=CC=CC=2)C(=O)NC1=O>N.[Ni].O>[CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[C:3]1=[O:18]
Reactant: CC1(C)C(=O)N(CCCC#N)C(=O)c2ccccc21
Agent: [Ni]
Agent: CC1(C)C(=O)NC(=O)c2ccccc21
Agent: N
Solvent: O
Product: CC1(C)C(=O)N(CCCCN)C(=O)c2ccccc21
Reaction time: 2 h

Procedure:
2.56 gm of 4,4-dimethyl-2-(3-cyano-propyl)-1,2,3,4-tetrahydro-isoquinoline-1,3-dione prepared from 4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-1,3-dione and 4-chlorobutyric acid nitrile) were dissolved in 50 ml of methanolic ammonia, and the solution was hydrogenated in the presence of 1 gm of Raney nickel at 50° C and 5 atmospheres pressure for 2 hours. The reaction mixture was then diluted with water, acidified and extracted with chloroform. The aqueous phase was made alkaline, extracted with chloroform, and the chloroform extract was evaporated. The residue was used as the starting compound in the following step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C(O)C>[NH2:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[N:4][C:3]=1[NH:17][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(CNc2ncnc(Cl)c2N)cc1

Procedure:
Part A. A solution of 5-amino-4,6-dichloropyrimidine (24.6 g, 150 mmol), 4-methoxybenzylamine (20.0 mL, 150 mmol) and diisopropylethylamine (30.0 mL, 172 mmol) in ethanol (200 mL) was heated to ref lux for 4 days. After cooling, the solution was evaporated and the residue partitioned between water and ethyl acetate. The organic layer was washed with more water and brine, and the three aqueous phases were back-extracted in sequence with ethyl acetate. The extracts were combined, dried over sodium sulfate, filtered and evaporated. The resulting solid was triturated with ether, collected by filtration and dried under vacuum to afford pure product, 5-amino-4-chloro-6-(4-methoxybenzylamino)pyrimidine. m.p. 187-188° C. TLC RF 0.11 (30:70 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): Δ 8.12 (1H, s), 7.33 (2H! d, J=9.0 Hz), 6.89 (2H, d, J=9.0 Hz), 5. 01 (1H, br), 4. 61 (2H, d, J=5. 1 Hz), 3. 81 (3H, s), 3.35 (2H, br). MS (NH3-CI): m/e 268 (4), 267 (31), 266 (15), 265 (100).
Reaction SMILES: Cl[C:2]1[C:12]2[C:11]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:10]=3[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:8][CH2:7][C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1.[CH3:25][OH:26].C[O-].[Na+]>O1CCCC1>[Cl:17][C:15]1[CH:14]=[CH:13][C:11]2[C:12]3[C:2]([O:26][CH3:25])=[N:3][C:4]([CH3:24])=[N:5][C:6]=3[CH2:7][N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]=2[CH:16]=1
Reactant: Cc1nc(Cl)c2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C)nc2c1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.0 g (2.8 mmol) of 1,9-dichloro-3-methyl-7-phenyl-5H-pyrimido[4,5-d][2]benzazepine and 1.0 mL of a 4.2M methanol solution of sodium methoxide in 20 mL of a 1:1 mixture of methanol and tetrahydrofuran was stirred at room temperature for 1 hr. The solvent was removed at reduced pressure and the residue was triturated with water to give an off-white solid. Recrystallization from a mixture of ether and petroleum ether gave colorless prisms, mp 185°-187°.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[C:6]([CH3:14])=[CH:5][C:4]1([CH3:16])[CH3:15])[CH3:2].[Cl:17][C:18]1[C:19]([Cl:31])=[C:20]([Cl:30])[C:21]([Cl:29])=[C:22]2[C:27](=[O:28])[O:26][C:24](=[O:25])[C:23]=12>ClCCCl>[C:27]([C:22]1[C:21]([Cl:29])=[C:20]([Cl:30])[C:19]([Cl:31])=[C:18]([Cl:17])[C:23]=1[C:24]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[OH:13])[N:3]([CH2:1][CH3:2])[C:4]([CH3:15])([CH3:16])[CH:5]=[C:6]2[CH3:14])=[O:25])([OH:28])=[O:26]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CCN1c2cc(O)ccc2C(C)=CC1(C)C
Solvent: ClCCCl
Product: CCN1c2cc(O)c(C(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c3C(=O)O)cc2C(C)=CC1(C)C

Procedure:
24 g (0.11 mol) N-ethyl-7-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline and 31.6 g (0.11 mol) tetrachloro-phthalic acid anhydride were dissolved in 200 ml 1,2-dichloroethane and refluxed for 3 h. After cooling, the solution was filtered and evaporated to dryness in a rotary evaporator. The residue was suspended in ca. 500 ml chloroform and heated to boiling. The solid (=product) was filtered. In order to increase the yield, the mother liquor was rotary evaporated to dryness and purified by column chromatography. For this ca. 100 g silica gel (ICN silica 32-63, 60A) was used as a separation material for ca. 3 g crude product. A mixture of chloroform +5% ethanol serve as a flow agent. The filtered solid was dissolved in ca. 1 l diethyl ether. After filtering the solvent was removed by distillation and the residue was dried to form a yellow solid.