Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([CH:11]2[CH2:16]CC[CH2:13][CH2:12]2)[C:5](=[O:10])[N:6](C)[C:7]=1[CH3:8].C1CCC(N2C(=O)NC3CCCC=3C2=O)CC1.BrC1C(=O)N(C(C)C)C(=O)NC=1C.C(N1C(=O)C(Cl)=C(C)NC1=O)(C)(C)C>>[Br:1][C:2]1[C:3](=[O:17])[N:4]([CH:11]([CH2:12][CH3:13])[CH3:16])[C:5](=[O:10])[NH:6][C:7]=1[CH3:8]
Reactant: Cc1c(Br)c(=O)n(C2CCCCC2)c(=O)n1C
Agent: Cc1[nH]c(=O)n(C(C)(C)C)c(=O)c1Cl
Agent: Cc1[nH]c(=O)n(C(C)C)c(=O)c1Br
Agent: O=c1[nH]c2c(c(=O)n1C1CCCCC1)CCC2
Product: CCC(C)n1c(=O)[nH]c(C)c(Br)c1=O

Procedure:
5-bromo-3-cyclohexyl-1,6-dimethyluracil; 3-cyclohexyl-5,6-trimethyleneuracil; 5-bromo-3-isopropyl-6-methyluracil; 3-tert-butyl-5-chloro-6-methyluracil;
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:14][C:13]2=[N:15][NH:16][C:17](=[O:18])[C:10]3[C:11]4[C:12]2=[C:4]([NH:5][C:6]=4[CH:7]=[CH:8][CH:9]=3)[CH2:3]1.Cl[CH2:21][CH:22]1[CH2:24][O:23]1.CN(C)CCN1C2CC(C)(C)CC3=NNC(=O)C4C(C=23)=C1C=CC=4>>[CH3:1][C:2]1([CH3:19])[CH2:14][C:13]2=[N:15][NH:16][C:17](=[O:18])[C:10]3[C:11]4[C:12]2=[C:4]([N:5]([CH2:21][CH:22]2[CH2:24][O:23]2)[C:6]=4[CH:7]=[CH:8][CH:9]=3)[CH2:3]1
Reactant: ClCC1CO1
Reactant: CC1(C)CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Agent: CN(C)CCn1c2c3c4c(cccc41)C(=O)NN=C3CC(C)(C)C2
Product: CC1(C)CC2=NNC(=O)c3cccc4c3c2c(n4CC2CO2)C1

Procedure:
Compound 41 was prepared from 2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one and 2-(chloromethyl)oxirane according to the procedures similar to those for Compound 28. 1H NMR (DMSO-d6) δ 9.96 (s, 1H), 7.65 (d, 1H, J=8.4 Hz), 7.49 (d, 1H, J=7.8 Hz), 7.18 (dd, 1H, J=8.4, 7.8 Hz), 4.60-4.63 (m, 1H), 4.21-4.24 (m, 1H), 3.27-3.29 (m, 1H), 2.76-2.77 (m, 1H), 2.75 (s, 2H), 2.46-2.48 (m, 1H), 2.26 (s, 2H), and 0.92 (s, 6H). MS (ESI) m/e [M+1]+ 310.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH:45]([C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][N:48]=1)[NH2:46].C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([NH:46][NH:45][C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][N:48]=1)=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: NNc1nccc2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NNc1nccc2ccccc12)Cc1cc(F)ccc1F
Reaction time: 0.29 h

Procedure:
A solution of 158 mg (0.5 mmol) of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1), 96 mg (0.5 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 89 mg (0.63 mmol based on 95% purity) of 1-hydroxybenzotriazole (HOBT) in 4 mL of anhydrous dichloromethane was stirred at room temperature in a stoppered flask. After 15-20 min, this solution was added dropwise by syringe through a septum to a second solution of 95.5 mg (0.6 mmol) of 1-hydrazinoisoquinoline (Intermediate 8) and 0.261 mL (194 mg, 1.5 mmol) of N,N-diisopropylethylamine in 2 mL of anhydrous dichloromethane and 2 mL of anhydrous DMF. Stirring under nitrogen was continued for 4 h. The solution was then concentrated under vacuum. The residue was partitioned between ethyl acetate and 5% aqueous citric acid solution. The organic phase was washed with more 5% citric acid, then with water, and finally with saturated sodium carbonate aqueous solution. The organic solution was dried over magnesium sulfate, filtered and concentrated. The residue contained the title compound along with some material that had already undergone ring closure. LC-MS 457 (M+1 for title compound), 439 (M+1 for ring-closed product).
Reaction SMILES: [CH3:1]C1C=C(O)C=CC=1O.C[O-].[Na+].CC1C(C)=C(C=CC=1O)O.[CH3:23][C:24]1[C:25]([OH:33])=[C:26]([CH3:32])[C:27]([CH3:31])=[C:28]([CH:30]=1)[OH:29]>CO>[CH3:23][C:24]1[C:25]([OH:33])=[C:26]([CH3:32])[C:27]([CH3:31])=[C:28]([OH:29])[C:30]=1[CH3:1]
Reactant: Cc1cc(O)ccc1O
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: C[O-]
Agent: Cc1c(O)ccc(O)c1C
Agent: [Na+]
Solvent: CO
Product: Cc1c(C)c(O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into an autoclave (inner volume: 9 ml, made of SUS 316, equipped with a manometer) were charged 0.108 g of methylhydroquinone, 3.573 g of methanol and 0.2 mg of sodium methylate. The reaction was started by elevating the temperature up to 350° C. with sand bath. The pressure during the reaction was 16 MPa. After 4 hours, the autoclave was quickly cooled and the reaction solution was taken out from the autoclave when the temperature was cooled back to the room temperature. The measurement according to the process described above revealed that the conversion of methylhydroquinone was 86% by mole, the selectivity of dimethylhydroquinone was 38% by mole, the selectivity of trimethylhydroquinone was 37% by mole and no tetramethylhydroquinone was produced. As byproducts, methyl ethers of monomethylhydroquinone, dimethylhydroquinone and trimethylhydroquinone, represented by the formulae shown above, were formed with a selectivity of 6%, 4% and 3%, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7]2.C(O[C:31]1(O[Si](C)(C)C)[CH2:33][CH2:32]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH:31]1([NH:1][C:2]2[CH:3]=[C:4]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:5]=[C:6]3[C:10]=2[N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7]3)[CH2:33][CH2:32]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CCOC(=O)C1Cc2cc(OCCOC)cc(N)c2N1C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1Cc2cc(OCCOC)cc(NC3CC3)c2N1C(=O)OC(C)(C)C
Yield: 75 %

Procedure:
To a mixture of 1-tert-butyl 2-ethyl 7-amino-5-(2-methoxyethoxy)indoline-1,2-dicarboxylate (2.76 g), [(1-ethoxycyclopropyl)oxy](trimethyl)silane (7.29 mL), acetic acid (4.19 mL) and ethanol (70 mL) was added sodium cyanoborohydride (122 mg), and the mixture was refluxed for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give the title compound (2.30 g, yield 75%) as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][C:33](=[C:36]=[O:37])OC)[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40].ClCCl.[CH2:51]([OH:53])C>>[C:2]1([N:8]([CH2:32][CH2:33][C:36]([O:53][CH3:51])=[O:37])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH:27][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCOC(=O)Cl
Reactant: CCO
Reactant: COC(=C=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccc4)ccc3n2C)cc1
Yield: 54 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxy-carbonylethyl)amide hydrochloride and n-hexyl chloroformate. Yield: 54% of theory, C34H40N6O5 (612.7); Rf value: 0.45 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=613.
Reaction SMILES: S(O[CH:6]([CH3:35])[CH2:7][C:8]1[C:16]([C:17]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[N:18][NH:19][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=1)(=O)(=O)C.[OH-].[Na+]>ClCCl.CO>[CH3:35][CH:6]1[CH2:7][C:8]2[CH:9]=[C:10]3[O:14][CH2:13][O:12][C:11]3=[CH:15][C:16]=2[C:17]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[N:18][N:19]1[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CC(Cc1cc2c(cc1C(=NNc1ncccn1)c1ccc([N+](=O)[O-])cc1)OCO2)OS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1c1ncccn1)OCO3
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
A mixture of 3.13 g (6.27 mmol) of the compound obtained in Step B, 60 ml of a 1:1 mixture of dichloromethane-methanol and 0.52 ml (6.90 mmol) of 50% sodium hydroxide solution was stirred at room for 1.5 h. After filtration the reaction mixture was concentrated, the residue was treated with water and recrystallized from three fold dimethylformamide containing 10% water to yield 1.96 g (77%) of the title compound; Mp.: 261-263° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[N:16]([C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21](OC)=[O:22])=[C:17]=[O:18].C(N(CC)CC)C>C(#N)C.O>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([N:14]3[C:21](=[O:22])[C:20]4[C:19](=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:16][C:17]3=[O:18])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: COC(=O)c1ccccc1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]c3ccccc3c2=O)cn1
Yield: 18 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (75 mg, 0.33 mmol), methyl 2-isocyanatobenzoate, and triethylamine (200 mg, 2 mmol) in acetonitrile (3 mL) were irradiated in the microwave reactor at 100° C. for 30 minutes. The reaction was cooled, diluted with H2O (75 mL), and extracted with ethyl acetate (3×, 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated on the rotovap. The residue was purified by silica gel chromotography (75% ethyl acetate in hexanes) to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)quinazoline-2,4(1H,3H)-dione (20 mg, 18%) as a light pink solid. 1H NMR (DMSO-d6, 400 MHz): δ2.16 (s, 3H), 2.40 (s, 3H), 5.17 (s, 2H), 7.17-7.22 (m, 2H), 7.50 (s, 1H), 7.66 (dt, J=8, 1.2 Hz, 1H), 7.92 (d, J=6.8 Hz, 1H), 7.95 (s, 1H), 11.52 (bs, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.5 μM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2>CO.CS(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH2:13][CH2:14][N:15]([CH2:20][C@H:19]([OH:18])[CH2:21][O:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)[CH2:16][CH:17]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: COc1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CO
Solvent: CS(C)=O
Product: COc1ccc2c(C3=CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.80 g, 3.5 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.66 g, 3.5 mmol). The resulting free base was recrystallized from methanol to yield a white crystalline solid. Yield 0.63 g (43%). mp 155°-160° C. FDMS m/e=417 (M+ of free base). α[D]589 =+4.30 (c=0.98, methanol/dimethylsulfoxide).
Reaction SMILES: C(OC1[CH:14]=[C:13]([O:15][CH2:16][C:17]2C=CC=CC=2)[CH:12]=CC=1[C@H]1[C@H](CC=C)CCC(=O)C1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33](O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:16]([O:15][CH:13]([CH3:12])[CH3:14])([CH3:17])[CH3:33].[CH3:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: OCCO
Reactant: C=CC[C@@H]1CCC(=O)C[C@H]1c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)OC(C)C
Product: CCCCCC

Procedure:
A mixture of 5.0 g. (11.73 mmole) of trans-3-(2,4-dibenzyloxyphenyl)-4-(2-propenyl)cyclohexanone, 6.5 ml. (117 mmole) of ethylene glycol and 223 mg. (1.17 mmole) of p-toluenesulfonic acid in 50 ml. of benzene was heated at reflux for 1.5 hours. Water was removed via a soxhlet extractor filled with molecular sieves. The reaction was cooled and added to 500 ml. saturated sodium bicarbonate and 300 ml. ether. The ether phase was separated, dried over magnesium sulfate and evaporated. Trituration with diisopropyl ether-hexane gave 5.31 g. (96%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].N1C=CC=CC=1.[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](Cl)=[O:46])=[O:41]>ClCCl>[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40](=[O:41])[C:42]1[CH:50]=[CH:49][CH:48]=[C:44]([C:45]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4](=[O:5])[NH:6][C:7]2[N:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[N:8]=2)=[O:46])[CH:43]=1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ncn(-c2cccc(C(F)(F)F)c2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ncn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 2.5 °C
Yield: 14.9 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzamide (150 mg, 0.35 mmol, 1.00 equiv) in dichloromethane (20 mL), and pyridine (83 mg, 1.05 mmol, 3.01 equiv). This was followed by dropwise addition of a solution of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoyl chloride (130 mg, 0.42 mmol, 1.20 equiv) in dichloromethane (10 mL) with stirring at 0-5° C. The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 30 mL of dichloromethane. The resulting mixture was washed with 1×20 mL of NH4Cl and 2×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 36.7 mg (15%) of a yellow solid. 1H-NMR (400 MHz, DMSO, ppm): δ 11.43-11.33(m, 2H), 9.70(s, 1H), 9.43(s, 1H), 8.77(s, 1H), 8.26-8.18 (m, 3H), 8.06-7.93 (m, 2H), 7.86-7.79(m, 2H), 7.68-7.62(m, 2H), 7.52(s, 1H), 7.30-7.28(d, J=6.9 Hz, 1H), 4.59-4.57(m, 1H), 4.18-3.83(m, 27H), 3.44(s, 3H), 3.27-3.26 (m, 5H), 3.18 (s, 3H), 2.96(s, 4H), 1.69(s, 4H), 1.59-1.52(m, 3H). MS (ES, m/z): 705 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[S:16]1C2C=CC=CC=2[N:18]=[C:17]1NC(=O)C(O)=O>>[NH2:18][C:17]1[S:16][C:3]2[C:4]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=2[N:1]=1
Reactant: O=C(O)C(=O)Nc1nc2ccccc2s1
Reactant: COc1ccc(-c2ccccc2)cc1N
Product: COc1ccc(-c2ccccc2)c2sc(N)nc12

Procedure:
The title compound was prepared from 3-amino-4-methoxy-biphenyl, according to the patent literature N-(Benzothiazol-2-yl)oxamic acid derivatives. W. Winter, M. Thiel, A. Roesch and O. H. Wilhelms, German Patent, DE 2656468, 1978. and is obtained as a white solid, MS: m/e=256 (M+), mp. 207-208° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[C:33]=2[F:39])=[O:11])=[C:5]([O:40][CH3:41])[CH:4]=1)#[N:2].[OH:42]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[C:33]=2[F:39])=[O:11])=[C:5]([O:40][CH3:41])[CH:4]=1)(=[O:42])[NH2:2]
Reactant: OO
Reactant: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Br)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Br)c1F
Temperature: 10 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide (0.16 g, 0.26 mmol) prepared in Example 116 in DMSO (1 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.43 g, 3.8 mmol), then aqueous solution (1N) of NaOH (1.3 mL, 1.3 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide as a white solid (Yield 0.11 g, 67%)
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:16][C@:14]2([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:34]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:16][C@:14]2([C:29]2[S:30][C:31]([Br:34])=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1=N[C@@]2(c3cccs3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC1=N[C@@]2(c3ccc(Br)s3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 91.9 %

Procedure:
To a stirred clear and colorless solution of benzyl (4aR,7aR)-2-benzamido-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (1.67 g, 3.50 mmol) in dimethylformamide (35 mL) at room temperature, under an atmosphere of nitrogen is added N-bromosuccinimide (747 mg, 4.20 mmol). The resulting pale yellow solution is stirred at room temperature for 50 minutes. The solution is diluted with ethyl acetate (150 mL) and washed with water (3×50 mL) and brine (50 mL). The organic phase is separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography eluting with a hexanes/ethyl acetate, gradient from 80:20 to 0:100, to give the title compound (1.79 g, 92%) as a white solid: ES/MS (m/z): 557.8 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:18])[N:3]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:34])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[ClH:18].[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:34])[CH2:21][CH2:20]2)[N:3]=1
Reactant: COc1cc2c(N)nc(Cl)nc2c(OC)c1OC
Reactant: O=C1c2ccccc2CN1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(N)nc(N3CCC(N4Cc5ccccc5C4=O)CC3)nc2c(OC)c1OC
Product: Cl
Reaction time: 16 h

Procedure:
The mixture of 5.39 g of 4-amino-2-chloro-6,7,8-trimethoxy-quinazoline, 4.32 g of 2-(4-piperidinyl)-isoindolin-1-one, 4.24 g of anhydrous sodium carbonate and 75 ml of dimethylformamide is stirred under nitrogen at 125°-130° for 16 hours. It is filtered, the filtrate evaporated, the residue dissolved in methylene chloride and the solution washed with aqueous sodium bicarbonate. The organic layer is separated, dried, and evaporated. The residue is suspended in refluxing isopropanol and acidified with hydrogen chloride to pH=1. The precipitate formed is filtered off and triturated with warm ethanol to yield the 2-[1-(4-amino-6,7,8-trimethoxy-2-quinazolinyl)-4-piperidinyl]-isoindolin-1-one monohydrochloride melting at 234° (dec.).
Reaction SMILES: CN(C)[C:3]([C:5]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1)=[O:4].C[Mg]Br.Cl.[O:21]1CC[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[C:10]1([C@@H:8]2[O:7][N:6]=[C:5]([C:3]([C:22](=[O:21])[CH3:23])=[O:4])[CH2:9]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)C(=O)C1=NO[C@@H](c2ccccc2)C1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)C(=O)C1=NO[C@@H](c2ccccc2)C1
Temperature: -15 °C

Procedure:
A solution of (5R)-4,5-dihydro-N,N-dimethyl-5-phenyl-3-isoxazole-carboxamide (i.e. the product of Example 12, Step D) (3.5 g, 16.0 mmol) in a mixture of tetrahydrofuran (5 mL) and toluene (10 mL) was cooled to −15° C., and methyl magnesium bromide (3.0M solution in tetrahydrofuran, 8.8 mL, 26.4 mmol) was added over 1 h at −15° C. Then the reaction mixture was poured over a mixture of 20 g of concentrated hydrochloric acid and 80 g of ice, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (100 mL), and the combined extract was washed with brine (40 mL) and concentrated under reduced pressure to give 3.2 g of 1-[(5R)-4,5-dihydro-5-phenyl-3-isoxazoyl]ethanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]([O:20][CH3:21])(=[O:19])[C:12]([CH2:14][C:15](OC)=[O:16])=[CH2:13].Cl.CCOCC>CO>[CH3:21][O:20][C:11]([CH:12]1[CH2:14][C:15](=[O:16])[N:8]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:13]1)=[O:19]
Reactant: COc1ccc(CN)cc1
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 4-metoxybenzylamine (42 g, 0.306 mol) in methanol (40 mL) at 0° C. was added the dimethyl itaconate (48 g, 0.306 mol) in methanol (13 mL). The solution was stirred at room temperature for 4 days. 1N HCl was added to the solution followed by ether. The two layers were separated and the aqueous phase extracted with ether. The combined organic phases were dried (MgSO4). Upon filtration of the drying agent the desired material 79 precipitated from solution that was collected and dried under vacuum. 23.26 g, 29%. MS, m/z (relative intensity): 264 [M+H, 100%]. Anal. Calcd for C14H17N1O4: C, 63.87; H, 6.51; N, 5.32. Found: C, 63.96; H, 6.55; N, 5.29.