Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[CH3:32][O:33][CH2:34][C:35]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:36]
Reactant: COCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A155) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:15]3[C:10]([C:11]([NH2:16])=[N:12][CH:13]=[N:14]3)=[C:9]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:21]=4)[CH:8]=2)[CH2:3][CH2:2]1.Cl[CH2:34][C:35](N(C)C)=[O:36]>>[C:35]([N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[N:15]3[C:10]([C:11]([NH2:16])=[N:12][CH:13]=[N:14]3)=[C:9]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:21]=4)[CH:8]=2)[CH2:5][CH2:6]1)(=[O:36])[CH3:34]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5cccnc5)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Product: CC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5cccnc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 40 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 7-piperidin-4-yl-5-[2-(pyridin-3-ylmethyl)-2H-indazol-6-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting acetyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 20 mg (40%) of the desired product was isolated. 1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1 H) 7.47-7.87 (m, 2 H) 7.82-7.86 (m, 3 H) 7.67 (s, 1 H) 7.43 (dd, 1 H) 7.26 (d, 1 H) 6.61 (s, 1 H) 5.75 (s, 2 H) 4.76 (dd, 1 H) 4.02 (dd, 1 H) 3.21-3.50 (m, 2 H) 2.82 (dd, 1 H) 2.14-2.26 (m, 5 H) 1.88 (dt, 2 H). LC-MS [M+H]*=467.4, RT=0.44 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5](/[CH:9]=[CH:15]/[N:16]([CH3:18])[CH3:17])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 96 %

Procedure:
A solution of 10.3 g (50 mmol) of 4,5-dichloro-2-nitrotoluene (Helv. Chim. Acta 1936, 19, 434-439) in a mixture of 11.9 g (100 mmol) N,N-dimethylformamide dimethylacetal in DMF (25 ml) was heated at 100° C. for 16 h. The dark reaction mixture was concentrated in vacuo, the residue diluted with methylene chloride and washed twice with water. The organic solution was dried over MgSO4, then concentrated in vacuo affording 12.6 g (48 mmol, yield 96.5%) of the crude title compound as dark red crystals.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:20][C:19]4[CH:21]=[C:22]([N:25]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]5)[CH:23]=[CH:24][C:18]=4[O:17]3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].C(O)(C(F)(F)F)=O.FC1C2OC(C3(O)CCN(C4N=CC(CCC)=CN=4)CC3)CC=2C=C(C2CCNCC=2)C=1>>[N:25]1([C:22]2[CH:23]=[CH:24][C:18]3[O:17][CH:16]([CH:13]4[CH2:12][CH2:11][N:10]([C:7]5[N:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][N:8]=5)[CH2:15][CH2:14]4)[CH2:20][C:19]=3[CH:21]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: CCCc1cnc(N2CCC(C3Cc4cc(N5CCN(C(=O)OC(C)(C)C)CC5)ccc4O3)CC2)nc1
Agent: CCCc1cnc(N2CCC(O)(C3Cc4cc(C5=CCNCC5)cc(F)c4O3)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cnc(N2CCC(C3Cc4cc(N5CCNCC5)ccc4O3)CC2)nc1

Procedure:
Compound 9D was prepared from Compound 9C and TFA by in a similar manner to the procedure described for Compound 1J in Example 1. LC/MS (m/z)=408 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1.[N+](C1C=CC(OC(=O)[NH:59][C:60]2[CH:65]=[CH:64][C:63]([O:66][CH:67]([CH3:69])[CH3:68])=[CH:62][CH:61]=2)=CC=1)([O-])=O>N1C=CC=CC=1>[CH:67]([O:66][C:63]1[CH:64]=[CH:65][C:60]([NH:59][C:6]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][C:28]5[NH:32][N:31]=[N:30][N:29]=5)=[CH:21][CH:22]=4)[N:17]=[CH:16][N:15]=3)[CH2:12][CH2:13]2)=[O:7])=[CH:61][CH:62]=1)([CH3:69])[CH3:68]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCc4nnn[nH]4)ccc23)CC1
Reactant: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: c1ccncc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4cc(OCCCc5nnn[nH]5)ccc34)CC2)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 13.8 %

Procedure:
A solution of 4-{7-[3-(1H-Tetrazol-5-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid tert-butyl ester (6.1 mg, 14 μmol), as prepared in the previous step, in 9:1 TFA/anisole (100 μL) was stirred at 100° C. for 10 min. The solution was then concentrated. Pyridine (100 μL) and (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (5.8 mg, 18 μmol), as prepared in Example 1a, were added, and the solution was stirred at 80° C. for 15 min. The reaction was concentrated, taken up in 1M NaH2PO4 (2 mL), and extracted with 95:5 DCM/MeOH (2×2 mL). The combined organic layers were dried (Na2SO4), concentrated, and purified by flash silica cartridge chromatography (EtOAc→acetone eluent) to provide the title compound (1.0 mg, 14%). 1H-NMR (400 MHz, 95:5 CDCl3/CD3OD) δ 9.09 (s, 1H), 8.08 (s, 1H), 7.30-7.21 (m, 4H), 6.85 (m, 2H), 4.49 (septet, 1H), 4.27 (m, 2H), 4.24 (t, 2H), 3.70 (tt, 1H), 3.19 (t, 2H), 3.12 (td, 2H), 2.40 (m, 2H), 2.17-1.92 (m, 4H), 1.32 (d, 6H). LC/MS (ESI) calcd mass 516.3, found 517.2 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][CH:11]([O:16][CH2:17][CH3:18])[CH2:12][N:13]=[C:14]=[NH:15])[CH3:9].CS(O)(=O)=O.[OH-].[Na+]>C(O)C>[CH2:17]([O:16][CH:11]([O:10][CH2:8][CH3:9])[CH2:12][NH:13][C:14]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[NH:15])[CH3:18]
Reactant: Nc1ccccc1
Reactant: CCOC(CN=C=N)OCC
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(CNC(=N)Nc1ccccc1)OCC
Yield: 73.8 %

Procedure:
Aniline (1.66 g, 17.8 mmol) was dissolved in ethanol (25 mL), and N-(2,2-diethoxyethyl)carbodiimide (a), (2.82 g, 17.8 mmol), was added dropwise. Then methanesulfonic acid (1.71 g, 17.8 mmol) was added, and the mixture was warmed at reflux for 24 h. The reaction mixture was poured into NaOH (0.5 M) and extracted with CH2Cl2. Drying and concentration afforded a product that was subjected to flash chromatography to give the intermediate guanidine (b) (3.3 g, 73.8%). NMR (500 MHz, DMSO-d6) δ 7.27-6.90 (m, 5H), 4.55 (t, 1H), 3.76-3.70 (m, 2H), 3.60-3.54 (m, 2H), 3.35-3.34 (d, 2H), 1.22 (pent, 6H). MS: 249.8 (M−H)−; 252.1 (M+H)+.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]2)[CH2:2]1.[NH3:13]>>[NH2:13][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1
Reactant: COC(=O)N1CCCC2(CO2)C1
Reactant: N
Product: COC(=O)N1CCCC(O)(CN)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.1 g (53.2 mmol) of methyl 5-aza-1-oxaspiro[2,5]octane-5-carboxylate are added dropwise to 50 ml of ammonia solution (25%) and the mixture is stirred overnight at room temperature. It is then concentrated and the residue is distilled.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:15]2[N:14]=[C:13]3[CH:18]=[N:19][N:20]([CH3:21])[C:12]3=[C:11](Cl)[C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:25])C>>[CH2:1]([C:8]1[CH:17]=[CH:16][C:15]2[NH:14][C:13]3[CH:18]=[N:19][N:20]([CH3:21])[C:12]=3[C:11](=[O:25])[C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ncc2nc3ccc(Cc4ccccc4)cc3c(Cl)c21
Reactant: CC(=O)O
Product: Cn1ncc2[nH]c3ccc(Cc4ccccc4)cc3c(=O)c21
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of 7-benzyl-9-chloro-1-methyl-1H-pyrazolo[4,3-b]quinoline (EXAMPLE 11, step 2, 1.00 g, 3.25 mmol) in 50% aqueous acetic acid (20 ml) was refluxed for 6 h. After cooling to room temperature, the formed solid was collected by filtration to give 905 mg (96%) of the title compound as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.CN(C)C(=[O:10])C.[C:12]1(=[O:45])[N:16]([CH:17]2[C:38](=[O:39])[N:19]3[CH:20]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:27])[C:21]([CH3:25])([CH3:24])[S:22](=O)[C@H:18]23)[C:15](=[O:40])[C:14]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:13]12>C(OCC)(=O)C>[C:12]1(=[O:45])[N:16]([CH:17]2[C:38](=[O:39])[N:19]3[CH:20]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:27])[C@:21]([CH3:24])([OH:10])[CH2:25][S:22][C@H:18]23)[C:15](=[O:40])[C:14]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:13]12
Reactant: COc1ccc(COC(=O)C2N3C(=O)C(N4C(=O)c5ccccc5C4=O)[C@H]3S(=O)C2(C)C)cc1
Reactant: CC(=O)N(C)C
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C2N3C(=O)C(N4C(=O)c5ccccc5C4=O)[C@H]3SC[C@@]2(C)O)cc1
Yield: 62 %

Procedure:
A mixture of 4 drops of conc, sulfuric acid in 60 ml. N,N-dimethylacetamide and 80 ml. of benzene was dried azeotropically for 30 minutes. p-Methoxybenzyl 6-phthalimido-2,2-dimethylpenam-3-carboxylate-1-oxide (5.0 g., 10 mmol) was then added. The reaction mixture was refluxed for 30 minutes, cooled and evaporated to near dryness. Ethyl acetate (150 ml.) was added to the product, and the resulting solution was evaporated in vacuo to dryness. A crystalline product formed during evaporation of the solvent. The product was then slurried with 50 ml. of ethyl acetate. Filtration gave 3.1 grams (62 percent) of p-methoxybenzyl 7-phthalimido-3α-methyl-3β-hydroxycepham-4-carboxylate as colorless crystals, mp 216°-217°: nmr (CDCl3) 76 (3, s, 3-CH3), 149 and 205 (2, ABq, J=14 Hz, 2-CH2), 230 (3, s, OCH3), 274 (1, s, 4-H), 300 (1, broad s, OH), 309 (2, s, ester CH2), 324 (1, d, J=4.5 Hz, azetidinone H), 335 (1, d, J=4.5 Hz, azetidinone H), 426 (4, q, p-CH3OC6H4ArH) and 469 Hz (4, m, phthalimido H); ir (mull) 3460 (OH), 1725 (ester C=O), 1739 and 1781 (phthalimido C=O) and 1802 cm-1 (azetidinone C=O, shoulder).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#N)=[CH:9][CH:8]=2)[N:6]=1.[H-].O.O.S([O-])([O-])(=O)=[O:19].[Na+].[Na+]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:19])=[CH:9][CH:8]=2)[N:6]=1
Reactant: O=S(=O)([O-])[O-]
Reactant: Cc1nc(-c2ccc(C#N)cc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(C=O)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
2.95 g of 4-(2-methyl-1,3-thiazol-4-yl)benznitrile was dissloved in 100 ml of benzene and thereto was added dropwise a solution in toluene (1.5M) of diisobutylalminum hydride at the room temperature. Agitation was made for 1 hour. An excess amount of sodium sulfate dihydrate was added to the mixture and the resultant was stirred at the room temperature. A filtrate liquid thereof was concentrated and purified with column chromatography using silica gel and dichloromethane to obtain 1.95 g of the intended compound with a yield of 68%.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]([CH3:22])([OH:21])[CH3:20])=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[C:31]([CH3:32])=[C:30]([C:33](O)=[O:34])[C:29](=[O:36])[N:28]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl.C(OCC)(=O)C>[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:33]([C:30]2[C:29](=[O:36])[N:28]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:27]([CH3:26])[C:31]=2[CH3:32])=[O:34])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]([OH:21])([CH3:22])[CH3:20])=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: CC(C)(O)COc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCC(C)(C)O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 41 °C
Reaction time: 6 h
Yield: 78.1 %

Procedure:
To a solution of 1-((4-(4-amino-2-fluorophenoxy)quinolin-7-yl)oxy)-2-methylpropan-2-ol (5 g, 14.6 mmol), 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (3.46 g, 14.9 mmol) and HOAT (0.39 g, 2.9 mmol) in dichloromethane (30 mL) was added EDCI (3.35 g, 17.5 mmol). The mixture was stirred at 41° C. for 6 hours, cooled to room temperature and diluted with ethyl acetate (30 mL). The resulted suspension was filtered, and the solid was washed with 95% ethanol (50 mL×2). The solid was collected through filtration and dried in vacuo at 45° C. for 6 hours to give the title compound as a white solid (6.35 g, 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:10]=[O:11])[C:7]=1[O:8][CH3:9].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:10]([C:6]1[CH:5]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=[C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[O:8][CH3:9])=[O:11]
Reactant: COc1c(Br)cc(S(N)(=O)=O)cc1C=O
Reactant: OB(O)c1ccccc1
Product: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1ccccc1

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and benzene boronic acid, gave 5-formyl-6-methoxy-biphenyl-3-sulfonic acid amide.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:7]([OH:18])[C:8]2[C:9]([F:17])=[C:10]([OH:16])[CH:11]=[C:12]([CH2:14][CH3:15])[CH:13]=2)[NH:5][CH:6]=1.[C:19]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([CH:7]([C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:19])[C:9]=2[F:17])[OH:18])[NH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(O)c(F)c(C(O)c2nc(Br)c[nH]2)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CCc1cc(OC)c(F)c(C(O)c2nc(Br)c[nH]2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 154.4 %

Procedure:
To a solution of Intermediate 206.2 (394 mg, 0.707 mmol) in 5 mL DMF at rt, were added K2CO3 (117 mg, 0.848 mmol) and iodomethane (132 μL, 2.12 mmol). The mixture was stirred at rt for 3 days, then diluted with EtOAc. The organic phase was washed with H2O (2×), sat. Na2SO3, H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 60% EtOAc/hexanes gradient) to afford 359.4 mg of Intermediate 206.3 as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH:24]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Cl.[F:28][C:29]([F:33])([F:32])[CH2:30][NH2:31]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][C:15]=2[CH2:24][NH:31][CH2:30][C:29]([F:33])([F:32])[F:28])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: NCC(F)(F)F
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and 2,2,2-trifluoroethylamine hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:6][CH2:5]2.[C:17]([Cu])#[N:18]>CN(C=O)C.O>[F:13][C:12]([F:15])([F:14])[C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:17]#[N:18])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:16]
Reactant: O=C(N1CCc2cc(Br)ccc21)C(F)(F)F
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)CCN2C(=O)C(F)(F)F
Temperature: 160 °C
Reaction time: 96 h

Procedure:
1-(5-Bromo-2,3-dihydro-1H-indol-1-yl)-2,2,2-trifluoroethanone (19 g, 0.0646 mol; see step (ii) above) was dissolved in DMF (50 mL). CuCN (8.68 g, 0.0969 mol) was then added and the reaction mixture was stirred at 160° C. for 4 days, before being cooled to RT, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate then concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the sub-title compound as a white solid. Yield: 13 g.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].Br[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[N:11][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCCCCC.CCOC(C)=O>[CH:2]([S:4][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[N:11][CH:12]=1)([CH3:3])[CH3:1]
Reactant: CC(C)S
Reactant: N#Cc1ccc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)SCc1ccc(C#N)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.1 %

Procedure:
Add 2-propanethiol (0.53 mL, 5.6 mmol) to a slurry of 5-bromomethyl-pyridine-2-carbonitrile (1.1 g, 5.6 mmol) and cesium carbonate (1.8 g, 5.6 mmol) in DMF (10 mL) at room temperature under a nitrogen atmosphere. Stir the mixture for 16 h at room temperature. Dilute the mixture with hexane/EtOAc (1:1, 100 mL) and wash with 5% aqueous NaCl (3×30 mL). Collect the organic phase, concentrate in vacuo and purify the residue by chromatography on silica gel (40 g) eluting with hexane/EtOAc (20:1 to 7:3 gradient) to obtain the desired intermediate (0.83 g, 77%). MS (ES+) m/z: 193.2 (M+H)+.
Reaction SMILES: Br[CH:2]([C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=O)[C:3]([NH2:5])=[O:4].[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[NH2:18][C:16]1[S:17][C:2]([C:3]([NH2:5])=[O:4])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:15]=1
Reactant: NC(N)=S
Reactant: NC(=O)C(Br)C(=O)c1ccc(Cl)cc1
Solvent: CCO
Product: NC(=O)c1sc(N)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.5 %

Procedure:
To a mixture of 7.35 g (26.58 mmole) of 2-bromo-3-(4-chloro-phenyl)-3-oxo-propionamide and 300 mL of ethanol was added 2.02 g (26.58 mmole) of thiourea. The mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-dichloromethane (1:3, then 3:1, then 1:0). Recrystallization of the residue gave 1.11 g of 2-amino-4-(4-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.18) as pale yellow crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][O:14][C:15]1[N:20]=[C:19]([CH:21]=O)[CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][O:14][C:15]1[N:20]=[C:19]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: COc1cccc(C=O)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cccc(C=C2N=C(c3cccs3)OC2=O)n1
Temperature: 90 °C
Yield: 44.2 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 6-methoxy-2-pyridinecarboxaldehyde (46 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 38 mg of the above-captioned compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].COC([C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13])=O.[CH3:18][C:19](C)=[O:20].COC1C=C(C=CC=1OC)C(N1CCN(CC(Cl)=O)CC1)=O>O.CC(C)=O>[C:19]([NH:13][C:12]1[CH:11]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:20])[CH3:18]
Reactant: CC(C)=O
Reactant: COC(=O)c1ccccc1N
Agent: COc1ccc(C(=O)N2CCN(CC(=O)Cl)CC2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)Nc1ccccc1
Reaction time: 3 h

Procedure:
8.28 Grams of potassium carbonate was dissolved in 50 ml of water-acetone (1:2), and to this solution was added 15.1 g of o-methoxycarbonylaniline. Under ice-cooled condition, an acetone solution of 34.4 g of [4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetylchloride was added dropwise thereto. After completion of the addition, the reaction was carried out at a room temperature for 3 hours, then acetone was removed by distillation. The residue obtained was extracted with chloroform, then the extract was washed with water, dried and chloroform was removed by distillation. The residue obtained was crystallized by adding ethyl acetate, and the crystals were collected by filtration. Recrystallized from ethanol to obtain 29 g o-methoxycarbonyl-α-[4-3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide in the form of colorless needle-like crystals. Melting point: 167.5°-169.0° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([O:17]CC)=[O:16].[Li+].[OH-]>C1COCC1.CO.O>[O:20]=[S:2]1(=[O:1])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)CN1CCCN(c2ccccc2)S1(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1CCCN(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To ethyl 2-(1,1-dioxido-6-phenyl-1,2,6-thiadiazinan-2-yl)acetate (260 mg, 0.872 mmol) in THF (5 mL) and MeOH (5 mL), was added LiOH (182.9 mg, 4.36 mmol) in H2O (5 mL). The reaction mixture was agitated for 3 hr at room temperature and evaporated. The residue was introduced into ice water, its pH was adjusted down to 1 with 2 N HCl, and extracted with ethyl acetate. The organic layer was dried over MgSO4 to give 2-(1,1-dioxido-6-phenyl-1,2,6-thiadiazinan-2-yl)acetic acid (230 mg, 97%, yellow solid). 1H NMR (300 MHz, DMSO-d6): δ 12.81 (s, 1H), 7.43-7.26 (m, 5H), 3.96 (s, 2H), 3.68-3.62 (m, 4H), 1.92-1.85 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.S(Cl)([Cl:13])=O>ClCCCl>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][Cl:13]
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: ClCc1cccnc1Cl

Procedure:
To 10.24 g (0.065 mole) of 2-chloronicotinic acid were added 20 ml of 1,2-dichloroethane and 9.5 ml of thionyl chloride and the mixture was refluxed for 1 hour. The reaction mixture was concentrated to give 11.9 g of 2-chloronicotinyl chloride as an orange-colored oil. When left standing at room temperature, this product solidified thoroughly.