Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:14][C:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([Cl:26])=[CH:21][CH:22]=2)[N:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:16]=1[C:33]1[O:34][CH:35]=[CH:36][N:37]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:8][CH2:14][C:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][C:20]([Cl:26])=[CH:21][CH:22]=3)[N:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:16]=2[C:33]2[O:34][CH:35]=[CH:36][N:37]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=c1c(CBr)c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc12
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A 5 mL round-bottomed flask was charged with 6-chloronicotinamide (14 mg, 0.091 mmol), sodium hydride (60% suspension in mineral oil, 5.0 mg, 0.013 mmol) and DMF (1 mL) to give a slightly white suspension. This mixture was stirred at 50° C. for 15 min. During this time, the reaction mixture became more cloudy and difficult to stir. The reaction mixture was cooled to room temperature. A solution of 3-(bromomethyl)-7-chloro-2-(oxazol-2-yl)-1-phenylquinolin-4(1H)-one (38 mg, 0.091 mmol) in DMF (1 mL) was added dropwise to the room temperature reaction mixture. The reaction was stirred at 50° C. over 1 hr. LC/MS at this time suggested formation of the desired product. The reaction mixture was allowed to cool gradually to room temperature, then it was stirred at room temperature overnight. The reaction was quenched via addition of 1 mL water slowly. The quenched reaction mixture was then partitioned between 20 mL ethyl acetate and 20 mL water. The organic phase was dried (MgSO4), filtered, then concentrated over silica gel. The silica gel supported crude product was loaded onto a 40 gram silica gel column. Flash chromatography (75% ethyl acetate-hexanes ramped to 100% ethyl acetate) was used to partially purify the desired product 6-chloro-N-(7-chloro-2-(oxazol-2-yl)-4-oxo-1-phenyl-1,4-dihydroquinolin-3-ylmethyl)nicotinamide from the side product 6-chloro-N,N-bis((7-chloro-2-(oxazol-2-yl)-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methyl)nicotinamide. Homogeneous fractions were concentrated to provide 6-chloro-N-(7-chloro-2-(oxazol-2-yl)-4-oxo-1-phenyl-1,4-dihydroquinolin-3-ylmethyl)nicotin-amide as 1 mg (2% yield) of a white solid. 1H NMR (chloroform-d) δ ppm 8.75 (d, J=2.4 Hz, 1H) 8.42 (d, J=8.6 Hz, 1H) 7.99 (dd, J=8.2, 2.7 Hz, 1H) 7.68 (bs, 1H), 7.58 (s, 1H), 7.45 (m, 3H), 7.39 (dd, J=8.5, 2.0 Hz, 1H) 7.34 (d, J=8.2 Hz, 1H) 7.28 (m, 2H) 7.13 (s, 1H) 6.85 (d, J=2.0 Hz, 1H) 4.47 (d, J=5.5 Hz, 2H). MS calcd. for C25H16C12N4O3 [(M+H)+] 490.1, obsd. 490.9.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]2[C:10]([C:29]3[CH:28]=[N:27][N:26]([CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25][O:20]4)[CH:30]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2cnn(C3CCCCO3)c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: C[Si](C)(C)CCOCn1cc(-c2cnn(C3CCCCO3)c2)c2c(Cl)ncnc21

Procedure:
A mixture of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C1) (2.0 g, 4.9 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (C17) (1.91 g, 6.87 mmol), potassium phosphate (4.0 g, 19 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.10 g, 87 μmol) was degassed several times with nitrogen and irradiated in a microwave synthesizer at 130° C. for 1.5 hours. The reaction mixture was partitioned between ethyl acetate (400 mL) and water (60 mL), and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Chromatography on silica gel (Gradient: 10% to 80% ethyl acetate in petroleum ether) afforded the product as a brown oil. Yield: 1.33 g, 3.06 mmol, 62%. 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.87 (s, 1H), 7.76 (s, 1H), 7.38 (s, 1H), 5.68 (s, 2H), 5.46 (dd, J=9.4, 2.9 Hz, 1H), 4.08-4.15 (m, 1H), 3.71-3.79 (m, 1H), 3.57 (dd, J=8.3, 8.0 Hz, 2H), 2.04-2.24 (m, 3H), 1.61-1.79 (m, 3H), 0.94 (dd, J=8.3, 8.3 Hz, 2H), −0.03 (s, 9H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15](O)[CH:16]=[CH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:17][CH:16]=[CH2:15])=[O:13]
Reactant: O=C(O)CCCCCCCCCCS
Reactant: C=CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C=CCOC(=O)CCCCCCCCCCS
Yield: 77.2 %

Procedure:
1.09 g (5 mmol) 11-mercaptoundecanoic acid was placed along with 3 g (51.7 mmol) allyl alcohol, 0.57 g p-toluenesulfonic acid and 40 ml benzene in a round bottom flask and heated for 25 minutes with azeotropic removal of water using a Dean-Stark apparatus. The reaction mixture was then cooled and washed with 10% aqueous sodium bicarbonate solution (3×20 ml). The benzene layer was dried over anhydrous MgSO4, and removal of solvent yielded a colorless oil (0.997 g, 77%). 1H-NMR (300 MHz, CDCl3) 1.27, m, 12 H; 1.60, m, 5 H; 2.33, t, 2 H, J=7.5 Hz; 2.51, q, 2 H, J=7.4 Hz; 4.59, dt, 2 H, J=5.7, 1.4 Hz; 5.20-5.39, m, 2 H; 5.85-6.00, m, 1 H; IR (film) 2560 (SH), 1730 (C=O), 1640 cm-1 (C=C); EI-MS; 258 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:35]2[CH2:34][CH2:33][N:32]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=3)[CH2:37][CH2:36]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1cc(N2CCN(C(=O)Nc3nc4cc(C)ccc4nc3OC)CC2)cc(OC)c1OC
Yield: 94 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(3, 4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 94%). 1H NMR (300 MHz, CDCl3): δ 2.44-2.49 (m, 3H), 3.18-3.25 (m, 4H), 3.80-3.86 (m, 12H), 4.04-4.13 (m, 4H), 6.20 (s, 2H), 7.02-7.20 (m, 1H), 7.31-7.40 (m, 1H), 7.46-7.63 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[S:5])[CH3:2].[NH2:7][C:8]1[CH:9]=[C:10]([NH:18][C:19]2[N:28]=[CH:27][C:26]3[N:25]([CH3:29])[C:24](=[O:30])[CH2:23][N:22]([CH:31]([CH3:33])[CH3:32])[C:21]=3[N:20]=2)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.O>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[S:5])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([NH:18][C:19]2[N:28]=[CH:27][C:26]3[N:25]([CH3:29])[C:24](=[O:30])[CH2:23][N:22]([CH:31]([CH3:33])[CH3:32])[C:21]=3[N:20]=2)[CH:9]=1)[CH3:2]
Reactant: CCOC(=S)Cl
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(C(F)(F)F)c3)nc21
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=S)Nc1cc(Nc2ncc3c(n2)N(C(C)C)CC(=O)N3C)cc(C(F)(F)F)c1
Yield: 68 %

Procedure:
Ethylchlorothioformate (0.754 ml; 7.230 mmol) was added dropwise to a cooled (0° C.) suspension of 2-(3-Amino-5-trifluoromethyl-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (2.5 g; 6.573 mmol) in 10 ml of dry Pyridine. The reaction mixture was allowed to reach room temperature and maintained at that temperature 2 h. Water was added to the reaction mixture and the precipitated formed was filtered washed with water and dried in vacuo. 2.1 g (4.48 mmol; 68% yield) of a yellow powder were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[N:3]=1.S1C(C2C=C(N)C=C3C=2N[N:23]=C3)=CC2C=CC=CC1=2.CCN(CC)CC>COCCOC>[CH3:11][S:8]([C:4]1[N:3]=[C:2]([NH2:23])[CH:7]=[CH:6][N:5]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1nccc(Cl)n1
Reactant: Nc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CS(=O)(=O)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
To a mixture of 4-chloro-2-methanesulfonyl-pyrimidine (2.54 g, 13.2 mmol) in DME (20 mL) was added a mixture of 7-benzo[b]thiophen-2-yl-1H-indazol-5-ylamine (Example #F.8.1, 1.95 g, 7.35 mmol) and Et3N (1.43 mL, 10.3 mmol) in DME (160 mL). The reaction mixture was stirred at room temperature for about 16 hours then filtered, then filtrate was adsorbed onto alumina. The mixture was purified by flash column chromatography over alumina using CH2Cl2/MeOH (99:1) as an eluent to yield the initial crop of product. A second crop was obtained by triturating the alumina in CH2Cl2/MeOH (8:2) and combined with the first to afford 7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-(2-methanesulfonyl-pyrimidin-4-yl)-amine (1.09 g, 36% yield): LC/MS (method e) Rt 1.8 min; m/z (ESI−): (M−H)+ 419.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)c1
Yield: 87 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) furnished 0.062 g (87%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-3-carboxamide as a white solid.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=3[F:29])[CH:13]=2)=[N:10][CH:11]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:43])[CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[F:29][C:23]1[CH:24]=[C:25]([NH:26][C:40](=[O:41])[CH2:39][C:38]([NH:37][C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)=[O:43])[CH:27]=[CH:28][C:22]=1[O:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH:2]=[O:3])=[CH:11][N:10]=3)[S:20][C:19]=12
Reactant: O=C(O)CC(=O)Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccc(F)cc5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To intermediate 38 (0.40 g, 0.98 mmol) in dry DMF (20 mL) was added 3-(4-fluorophenylamino)-3-oxopropanoic acid (47) (0.39 g, 2.0 mmol) [U.S. 2007/0004675 A 1], and EDC.HCl (0.38 g, 2.0 mmol) and the mixture was stirred at r.t. for 2 h. The mixture was then partitioned between ethyl acetate and water resulting in precipitate. The precipitate was isolated by suction filtration and combined with the organic phase from the filtrate, concentrated, and dried in vacuum. The residue was dissolved in acetone (50 mL) to give a colorless solution. The solution was diluted with water (20 mL) and TFA (2 mL), heated to reflux for 3 h, then cooled and concentrated. The precipitated product was isolated by suction filtration, and dried in vacuum to afford intermediate 48 (0.35 g, 66%, presumably as the trifluoroacetate salt). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.59 (s, 1H), 10.29 (s, 1H), 10.14 (s, 1H), 9.15 (s, 1H). 8.59 (s, 1H), 8.58 (m, 1H), 8.52 (d, J=8.2 Hz, 1H), 8.39 (dd, J=8.2, 2.0 Hz, 1H), 7.90 (dd, J=13.1, 2.2 Hz, 1H), 7.65-7.60 (m, 2H), 7.54-7.44 (m, 2H), 7.17 (t, J=8.8 Hz, 2H), 6.75 (d, J=5.5 Hz, 1H), ˜3.50 (s, 2H, obscured by water peak). MS (m/z): 545.2 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][CH:7]=1)C.[OH-].[Na+]>CO>[C:16]([O:15][C:13]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:20])=[O:3])=[CH:11][CH:10]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)Cc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
To 20 mL of a methanol solution containing 0.7 g of ethyl-4-tert-butoxycarbonylaminophenylacetate, 13 mL of 1M aqueous sodium hydroxide solution was added and stirred at room temperature for a day and night. The reaction liquid was concentrated under reduced pressure, and rendered acidic with 2M aqueous citric acid solution. The precipitated crystal was recovered by filtration under cooling with ice, to provide 0.40 g of 4-t-butoxycarbonylaminophenylacetic acid as pale yellow crystal. The compound was dissolved in 13 mL of THF, and to which 0.40 g of CDI was added, followed by 2 hours' stirring at room temperature. Then 13 mL of a THF solution containing 0.71 g of DBU and 0.26 g of 5-amino-3-(4-fluorophenyl)-4-pyrimidinylisoxazole were added and stirred for a night at room temperature. The solvent was distilled off of the reaction solution under reduced pressure and water was added to the residue, followed by extraction with ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate and removed of the solvent by distillation under reduced pressure. The residue was purified on 30 g silica gel chromatography (eluent, chloroform:methanol=100:1), and the crystalline residue was washed with ether-hexane to provide 0.364 g (yield: 46%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:2]
Reactant: CCOC(=O)CCCBr
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(C#N)c1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
3-cyanophenol (2 000 mg; 16.79 mmol; 1 eq.) was dissolved in DMF (40 mL). Then ethyl 4-bromobutyrate (3 602.35 mg; 18.47 mmol; 1.10 eq.) and K2CO3 (3 480.55 mg; 25.18 mmol; 1.50 eq.) were added to the reaction mixture. The reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was cooled to RT and diluted with EtOAc. The organic layer was washed with water (3×), brine, dried over MgSO4 and concentrated affording the title compound as a colourless liquid (3.92 g, 96%). 1H NMR (DMSO-d6, 300 MHz) δ 7.51-7.38 (m, 3H), 7.29-7.26 (m, 1H), 4.10-4.03 (m, 4H), 2.48-2.43 (t, J=7.37 Hz, 2H), 2.02-1.93 (m, 2H), 1.20-1.15 (t, J=7.10 Hz, 3H). HPLC (Method A) Rt 4.49 min (Purity: 97.9%).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.Cl[C:18]1[N:19]([C:23]2[CH2:27][CH2:26][CH2:25][N:24]=2)[CH2:20][CH2:21][CH:22]=1>>[ClH:1].[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:18]3[N:19]([C:23]4[CH2:27][CH2:26][CH2:25][N:24]=4)[CH2:20][CH2:21][CH:22]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: ClC1=CCCN1C1=NCCC1
Reactant: Clc1cccc2c1Oc1ccccc1N2
Agent: Cl
Product: Clc1cccc2c1Oc1ccccc1N2C1=CCCN1C1=NCCC1

Procedure:
Reaction of 4-chlorophenoxazine with 2-chloro-(1-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 4-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOXAZINE HYDROCHLORIDE, m.p. 278°-282° C. (dec.), from ethanol-ether.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:15][CH2:14][C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][C:7]=2[CH2:6]1)=[O:4].O.[NH2:17][NH2:18]>>[CH3:1][O:2][C:3]([N:5]1[CH2:15][CH2:14][C:8]2[N:9]=[N:10][C:11]([NH:17][NH2:18])=[CH:12][C:7]=2[CH2:6]1)=[O:4]
Reactant: COC(=O)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Solvent: O
Product: COC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
16.5 g of 3-chloro-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid methyl ester and 70 cc of hydrazine hydrate are heted in a water bath for 1 hour. The title compound has a M.P. of 178°-180° (decomp., from acetonitrile).
Reaction SMILES: [C:1]1(C2SCC(C(O)=O)N=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC(C#N)=CC=2)C=C1.[NH:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35]3[S:36][CH2:37][C@@H:38]([C:40]([OH:42])=[O:41])[N:39]=3)=[CH:32][CH:33]=2)[CH:28]=[CH:27]1.[OH-].[Na+].[S:45](Cl)(Cl)(=[O:47])=[O:46].Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[NH:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35]3[S:36][CH2:37][C@@H:38]([C:40]([OH:42])=[O:41])[N:39]=3)=[CH:32][CH:33]=2)[CH:28]=[CH:27]1.[C:1]1([S:45]([N:26]2[C:34]3[C:29](=[CH:30][C:31]([C:35]4[S:36][CH2:37][C@@H:38]([C:40]([OH:42])=[O:41])[N:39]=4)=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)(=[O:47])=[O:46])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(O)C1CSC(c2ccccc2)=N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: N#Cc1ccc2[nH]ccc2c1
Solvent: Cc1ccccc1
Product: O=C(O)[C@@H]1CSC(c2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2)=N1

Procedure:
(R)-2-(1H-indol-5-yl)-4,5-dihydrothiazole-4-carboxylic acid 63a was synthesized using the same method as used for 42a from 1H-indole-5-carbonitrile and used without further purification. To a vigorously stirring solution of 63a (1 mmol) and tetrabutylammonium hydrogen sulfate (0.15 mmol) in toluene (10 mL) at 0° C. was added 50% aqueous sodium hydroxide (10 mL) and sulfonyl chloride (2 mmol). The resultant solution was stirred at RT for 6 h. Then 1 N HCl was added to acidify the mixture to pH=2 and extracted with CH2Cl2, the organic layer was separated and dried (MgSO4); then evaporated to dryness to yield 64a, which were used in subsequent steps without further purification.
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[C:10]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:11]([CH3:13])[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[I:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:49]=1[CH:48]=[C:47]([S:50]([NH2:53])(=[O:52])=[O:51])[CH:46]=[CH:45]2>>[CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[C:10]([C:14]2[CH:22]=[CH:21][C:17]([C:18](=[O:19])[NH:53][S:50]([C:47]3[CH:46]=[CH:45][C:44]4[C:49](=[C:40]([I:39])[CH:41]=[CH:42][CH:43]=4)[CH:48]=3)(=[O:51])=[O:52])=[CH:16][C:15]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:11]([CH3:13])[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)n1
Reactant: NS(=O)(=O)c1ccc2cccc(I)c2c1
Product: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(I)c4c3)cc2C(=O)N2CCc3ccccc3C2)n1
Yield: 14.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 265, 4-(4-(dibutylcarbamoyl)-1-methyl-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoic acid (Intermediate 264L, 45 mg, 0.09 mmol) and 8-iodonaphthalene-2-sulfonamide (Intermediate 6, 72 mg, 0.21 mmol) were converted to the title compound (11 mg, 15%). 1H NMR (CD3OD, 1:1 mixture of amide rotamers) δ 8.93 (s, 1H), 8.26 (d, J=7.2 Hz, 1H), 8.15 (dd, J=8.8, 1.6 Hz, 2H), 8.05-8.02 (m, 3H), 7.69 (dd, J=15.6, 8.0 Hz, 1H), 7.58 (s, 0.5H), 7.46 (br s, 0.5H), 7.40 (t, J=7.2 Hz, 1H), 7.23-7.11 (m, 3.5H), 6.91 (d, J=7.2 Hz, 0.5H), 4.76 (s, 1H), 4.45 (s, 1H), 3.73 (s, 3H), 3.63-3.52 (m, 6H), 2.82-2.78 (m, 2H), 1.56-1.46 (m, 2H), 1.45-1.27 (m, 4H), 1.20-1.00 (m, 2H), 1.00-0.92 (m, 3H), 0.85-0.75 (m, 3H); MS(ESI+) m/z 832.2 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([Cl:26])=[CH:7][C:8]([F:25])=[C:9]([CH:24]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)(=[O:3])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30]O.C(P(CCCC)CCCC)CCC>C(Cl)Cl>[C:1]([O:4][C:5]1[C:6]([Cl:26])=[CH:7][C:8]([F:25])=[C:9]([CH:24]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH2:30][CH2:29][O:28][CH3:27])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)(=[O:3])[CH3:2]
Reactant: COCCO
Reactant: COc1cc2c(Nc3cc(OC(C)=O)c(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Solvent: ClCCl
Product: COCCOc1cc2ncnc(Nc3cc(OC(C)=O)c(Cl)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
1-1′-(Azodicarbonyl)dipiperidine (413 mg, 1.6 mmol) was added portionwise to a stirred mixture of 4-(5-acetoxy-4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.66 mmol), 2-methoxyethanol (63 ml, 0.8 mmol) and tributylphosphine (405 ml, 1.6 mmol) in methylene chloride at 0° C. The resulting solution was allowed to warm to ambient temperature and stirred for 2 hours. The precipitated solid was removed by filtration, the solvent removed from the filtrate by evaporation and the residue purified by flash chromatography eluting with acetonitrile/methylene chloride (1/9 increasing in polarity to 4/6) to give 4-(5-acetoxy4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline (180 mg, 62%) as a solid.
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][C@@:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1.Br[C:26]1[S:27][C:28]([C:31]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][N:30]=1>>[C:34]([NH:33][C:31]([C:28]1[S:27][C:26]([N:13]2[CH2:14][CH2:15][CH2:16][C@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:24])[CH3:23])([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[O:9][C:8]3=[O:10])[CH2:12]2)=[N:30][CH:29]=1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)NC(=O)c1cnc(Br)s1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCCNC2)C(=O)O1
Product: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCCN(c3ncc(C(=O)NC(C)(C)C)s3)C2)C(=O)O1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one and 2-bromo-N-tert-butylthiazole-5-carboxamide following a procedure analogous to that described in Example 13. LC-MS Method 2 tR=1.23 min, m/z=515.