Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]([CH2:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=1.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][NH:28][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=3)[CH2:11][N:12]([CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=2)=[CH:32][CH:33]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CS(=O)(=O)N(CCc1cccnc1)Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CS(=O)(=O)N(CCc1cccnc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 19 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 504. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.4 (d, 1H) 8.3 (s, 2H) 8.0 (s, 1H) 7.9 (d, 1H) 7.5 (m, 3H) 7.2 (m, 1H) 7.0 (d, 2H) 6.9 (d, 1H) 6.7 (d, 2H) 5.5 (m, 1H) 4.4 (s, 2H) 3.7 (m, 2H) 3.4 (m, 2H) 2.8 (m, 7H).
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C[Si]([C:17]#[N:18])(C)C>[I-].[Zn+2].[I-]>[OH:10][CH:9]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:12][CH:11]=1)[C:17]#[N:18]
Reactant: CC(C)Cc1ccc(C=O)cc1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Product: CC(C)Cc1ccc(C(O)C#N)cc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 107.5 %

Procedure:
Zinc iodide (0.21 g) was added to a mixture of 4-isobutylbenzaldehyde (6.5 g) and trimethylsilylcyanide (5.0 g). The mixture was stirred at room temperature for 3 minutes and partitioned between ethyl acetate and 7% hydrochloric acid. The organic layer was washed with 7% hydrochloric acid and water and dried over magnesium sulfate. The solvent was removed in vacuo to give 2-hydroxy-2-(4-isobutylphenyl)acetonitrile as a yellow oil (8.15 g).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:6]([CH2:7][CH2:8][O:9]S(C2C(C)=CC=CC=2)(=O)=O)[NH:5][C:4]1=[O:20])[CH3:2].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=CC=1.[K]>C(O)C>[CH2:1]([C@H:3]1[C@@H:6]([CH2:7][CH2:8][O:9][C:24]2[S:27][CH:21]=[CH:26][CH:25]=2)[NH:5][C:4]1=[O:20])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CC[C@@H]1C(=O)N[C@@H]1CCOS(=O)(=O)c1ccccc1C
Agent: [K]
Solvent: CCO
Product: CC[C@@H]1C(=O)N[C@@H]1CCOc1cccs1

Procedure:
To 8 mg of the titled product of Example 10 Step C in 1 ml of absolute ethanol was added a small amount of potassium thiophenol. The resulting mixture was refluxed for 1/2 hour and the product purified by preparative TLC (30% EtOAc in hexane). 1H NMR (CDCl3): δ1.04(3H, t), 1.46-1.98(4H, m), 2.97(2H, t), 3.06-3.16(1H, m), 3.77-3.85(1H, m), 5.99 (1H, broad), 7.16-7.36(5H, m).
Reaction SMILES: [N:1]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])=[O:8])=[O:4].CC(O)=O.[H][H]>CO.[Pd]>[N:1]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])=[O:4]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)N1CCC[C@H]1C(=O)O

Procedure:
8 g (17.4 mmol) of Boc-Pro-Gly-Pro-OBzl were dissolved in 100 ml of methanol, 0.5 ml of CH3COOH and palladium black were added, while stirring on a magnetic stirrer, and hydrogen was passed through for 2 hours. The solution was filtered, evaporated, evaporated 3 times with benzene and 2 times with ethyl acetate. Then, it was precipitated with ether hexane from acetone, and the precipitate formed in the flask was dried in a desiccator over P2O5/KOH and paraffin.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[C:5]([C:4]1[C:3]([CH3:10])=[C:2]([NH:1][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: Cc1c(N)cccc1C#N
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: Cc1c(C#N)cccc1NC(C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 56.5 %

Procedure:
3-amino-2-methylbenzonitrile (108 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-cyano-2-methylphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (52 mg, 55%) as a white solid. Mass Spectrum: M+H+ 461.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[N:38][C:37]([NH2:40])=[CH:36][N:35]=2)[CH2:30][CH2:29]1)=O)(C)(C)C>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:40][C:37]3[N:38]=[CH:39][C:34]([N:31]4[CH2:30][CH2:29][NH:28][CH2:33][CH2:32]4)=[N:35][CH:36]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(N)cn2)CC1
Product: CN(C)C(=O)c1cc2cnc(Nc3cnc(N4CCNCC4)cn3)nc2n1C1CCCC1
Yield: 55.1 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.342 mmol) and 5′-amino-2,3,5,6-tetrahydro-[1,2]bipyrazinyl-4-carboxylic acid tert-butyl ester (114 mg, 0.408 mmol), followed by deprotection using General Procedure A to give 7-cyclopentyl-2-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (82 mg, 45%). MS (ESI) m/z 436.3 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]3[N:19]([C:20]=2[CH:21]=O)[C:18]2[CH2:23][CH2:24][CH2:25][CH2:26][C:17]=2[S:16]3)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:27]([NH:35][NH2:36])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]3[N:19]([C:20]=2[CH:21]=[N:36][NH:35][C:27]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:34])[C:18]2[CH2:23][CH2:24][CH2:25][CH2:26][C:17]=2[S:16]3)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2nc3sc4c(n3c2C=O)CCCC4)cc(OC)c1OC
Reactant: NNC(=O)c1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2nc3sc4c(n3c2C=NNC(=O)c2cccnc2)CCCC4)cc(OC)c1OC

Procedure:
Next, 0.37 g of 5,6,7,8-tetrahydro-2-(3,4,5-trimethoxyphenyl)-3-formylimidazo[2,1-b]benzothiazole, 0.15 g of nicotinohydrazide, and 0.1 g of potassium hydroxide were heated and stirred in 20 ml of methanol at 90° C. for 1.5 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was extracted with chloroform. The extract was washed with water and dried, then the solvent was distilled off and the residue was crystallized from methanol to obtain the desired substance in an amount of 0.40 g (yield of 81.6%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:10]([CH2:12][NH2:13])[OH:11]>C(O)C>[CH2:2]([NH:13][CH2:12][CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: NCCO
Solvent: CCO
Product: OCCNCCc1ccccc1
Temperature: 75 °C
Yield: 84.1 %

Procedure:
A mixture of 2-bromoethyl benzene (2.0 g, 10.8 mmol) and ethanolamine (3.96 g, 64.8 mmol) in ethanol (11 mL) was heated at 75° C. for 16.5 hours at which time LC/MS showed the reaction was complete. The reaction mixture was then concentrated to remove ethanol and the resulting residue was diluted with DCM (100 mL). The organic layer was partitioned with water (100 mL) and the aqueous layer was extracted with DCM (50 mL). The combined organic layers were washed with water (2×5 mL), dried over sodium sulfate, filtered, and concentrated to give the title intermediate as a light yellowish oil (1.5 g). (m/z): [M+H]+ calcd for C10H15NO, 166.13; found, 166.2) 1H NMR (d6-DMSO, 300 MHz) δ (ppm): 7.13-7.29 (m, 5H), 4.4 (br, 1H), 3.42 (t, J=5.7 Hz, 2H), 2.61-2.76 (m, 4H), 2.55-2.59 (t, J=5.7 Hz, 2H), 1.55 (br, 1H).
Reaction SMILES: [CH2:1]([Li])[CH3:2].[F:4][C:5]1[CH:26]=[CH:25][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.[Cl-].[NH4+]>CCOCC>[F:4][C:5]1[CH:26]=[CH:25][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)([OH:10])[CH2:1][CH3:2])=[CH:7][CH:6]=1
Reactant: [Li]CC
Reactant: O=C(c1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC(O)(c1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1
Temperature: -20 °C

Procedure:
To 125 ml. of a 0.8 molar ethereal ethyl lithium solution a solution of 12.25 g. of 4-fluoro-4'-benzyloxy-benzophenone in 180 ml. of dry ether is added dropwise, in argon atmosphere, with stirring at -20° C. The reaction mixture is allowed to warm up to room temperature and stirred for further 90 minutes. It is then poured into saturated aqueous ammonium chloride solution under cooling. The aqueous phase is extracted with ether, the organic phases are combined and washed to neutral with water. After drying over anhydrous magnesium sulfate ether is distilled off under reduced pressure. The solid residue is crystallized from a mixture of ethyl acetate and n-heptane to yield 7.4 g. of the named compound, melting at 56°-57° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][CH:6]=1)(=[O:4])=[O:3].[Br:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]=[O:19]>C1C=CC=CC=1>[Br:13][CH2:14][CH2:15][N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][N:7]=1)=[O:12]
Reactant: O=CCNCCBr
Reactant: CS(=O)(=O)c1cnc(N=C=O)s1
Solvent: c1ccccc1
Product: CS(=O)(=O)c1cnc(NC(=O)N(CC=O)CCBr)s1
Reaction time: 1 h

Procedure:
5-Methylsulfonylthiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-β-bromoethylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-β-bromoethyl-3-(5-methylsulfonylthiazol-2-yl)ureido]acetaldehyde as the residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[C:16]1([CH:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:23]2[CH2:26][CH:25](S(C)(=O)=O)[CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH:22]([N:23]1[CH2:26][CH:25]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:24]1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1NC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C
Yield: 14.5 %

Procedure:
To a solution of 4.1 g (0.033 mol) of o-anisidine in 20 mL DMF, 4.6 g (0.033 mol) of K2CO3 was added, followed by 9.5 g (0.030 mol) of 1-(diphenylmethyl)-3-methane sulfonyl azetidine. The reaction was heated at 80° C. for 5 h. Water was added and the product was extracted with ether. The organic phase was dried and the solvent was removed under vacuo. The residue was filtered through silica gel, starting with 100% methylene chloride, then 25% ethyl acetate/hexane to give 1.5 g of the desired product: mp 75-77° C. 1H NMR (300 MHz, CDCl3) δ 2.89 (dd, 2H), 3.70 (dd, 2H), 3.84 (s, 3H), 4.13 (m, 1H), 4.40 (m, 1H), 4.38 (s,1H), 6.42 (dd,1H), 6.69 (dd, 1H), 6.79 (m, 2H), 7.20 (m, 2H), 7.26 (m, 4H), 7.42 (m, 4H); MS (ES) m/z (relative intensity): 345 (M++H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[OH:23]>C(O)(=O)C>[Cl:1][C:15]1[CH:16]=[N:17][C:18]2[C:13]([C:14]=1[OH:23])=[CH:12][C:11]([O:10][CH3:9])=[C:20]([O:21][CH3:22])[CH:19]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc2nccc(O)c2cc1OC
Solvent: CC(=O)O
Product: COc1cc2ncc(Cl)c(O)c2cc1OC
Temperature: 20 °C

Procedure:
5.45 g of N-chlorosuccinimide were added to a solution of 6,7-dimethoxyquinolin-4-ol in 300 cm3 of acetic acid, with stirring and at a temperature in the region of 20° C. The reaction mixture was heated at a temperature in the region of 50° C. for 6 hours. After cooling to about 20° C. and stirring for 18 hours at this same temperature, the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. One hundred cm3 of sodium hydrogen carbonate solution were added dropwise to the evaporation residue and the suspension was then stirred for 24 hours in the region of 20° C. The insoluble material was filtered off and then dried in an oven under reduced pressure (20 Pa). 5.39 g of 3-chloro-4-hydroxy-6,7-dimethoxyquinoline were obtained in the form of a dark green solid.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH3:21])[CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:23][CH2:24][C@H:25]([NH:33][S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>>[C:29]([O:28][C:26](=[O:27])[C@@H:25]([NH:33][S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35])[CH2:24][NH:23][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:21])=[CH:20][CH:19]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: C[C@@H](COc1ccc(C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Agent: Cl
Product: C[C@@H](COc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C

Procedure:
Following the procedure for coupling 19-6 to 2-1, 22-4 (295 mg, 1.0 mmol) was coupled to 2-1 (336 mg, 1.0 mmol) to give 22-5 as a beige solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([Cl:17])=[CH:6][C:7]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15].[C:18](=O)([O:20]CC)[NH2:19]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:3]2[S:4][C:5]([Cl:17])=[CH:6][C:7]=2[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[N:19][C:18]1=[O:20]
Reactant: CCOC(N)=O
Reactant: CNc1sc(Cl)cc1C(=O)c1ccccc1F
Agent: [Cl-]
Agent: [Zn+2]
Product: Cn1c(=O)nc(-c2ccccc2F)c2cc(Cl)sc21
Temperature: 200 °C

Procedure:
A mixture of 700 mg of 2-methylamino-3-(o-fluorobenzoyl)-5-chlorothiophene, 700 mg of ethyl carbamate and 50 mg of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is extracted with chloroform. The extracts are combined, washed with water, dried over sodium sulfate and concentrated under reduced pressure to give a residue, which is chromatographed on silica gel using chloroform as an eluent to give crystals of 1-methyl-4-(o-fluorophenyl)-6-chloro-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 192° - 194°C (after recrystallization from ethanol).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][N:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:36][N:37]1[CH:41]=[C:40]([S:42](Cl)(=[O:44])=[O:43])[N:39]=[C:38]1[CH3:46]>CN(C1C=CN=CC=1)C>[CH3:36][N:37]1[CH:41]=[C:40]([S:42]([N:24]2[CH2:25][CH2:26][CH:21]([C:12]3[C:11]4[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][CH:7]=5)[CH:10]=4)[NH:14][N:13]=3)[CH2:22][CH2:23]2)(=[O:44])=[O:43])[N:39]=[C:38]1[CH3:46]
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: NC(=O)c1cc(-c2ccc(CO)cc2)cc2c(C3CCNCC3)n[nH]c12
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5ccc(CO)cc5)cc34)CC2)cn1C
Yield: 30.9 %

Procedure:
Following the general procedure of Example 11, 5-[4-(hydroxymethyl)phenyl]-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Example 73) (0.07 mmol), diisopropylethylamine (100 uL, 0.56 mmol), DMAP (25 mg, 0.014 mmol) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (33 mg, 0.17 mmol) were reacted to give the title compound (11 mg, 31% for 3 steps).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:16]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([N+:22]([O-])=O)[CH:7]=1.[H][H]>[Pt].CO>[NH2:22][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[C:16]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Temperature: 25 °C
Yield: 92.3 %

Procedure:
In a 20 L-volume glass reaction vessel equipped with a stirrer, a thermometer and a reflux condenser, 2,328 g (6.78 moles) of the ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate prepared in the Synthesis Example 2, 2 wt. % platinum per 118 g of carbon (50 wt. % product, N.E. Chemcat Corporation, 6.0 mmoles in terms of platinum metallic atom) and 9,440 mL of methanol were placed. The mixture was allowed to react at 50 to 60° C. for 6 hours in an atmosphere of hydrogen while stirring. After the reaction was complete, the reaction solution was cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure to obtain 1,960 g of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate as an orange liquid (isolation yield: 92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: NCCN1CCOCC1
Reactant: N#Cc1cc(Br)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1cc(Br)ccc1NCCN1CCOCC1
Yield: 49.7 %

Procedure:
5-Bromo-2-fluorobenzonitrile (1.0 g) and 4-(2-aminoethyl)morpholine (0.65 g) were mixed together in acetonitrile (5 ml) at 70° C. for 4 hours, cooled and poured into a solution of aqueous sodium hydrogen carbonate and was extracted into ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel eluting with 2.5% methanol in dichloromethane containing 1% triethylamine to afford the sub-titled compound as an oil (0.77 g).
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C@@H:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH:7][C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].[C:24]([S:32][CH2:33][C@H:34]([CH3:38])[C:35](Cl)=[O:36])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:1]([N:5]1[CH2:9][C@@H:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:7]([C:35](=[O:36])[C@H:34]([CH3:38])[CH2:33][S:32][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Reactant: C[C@@H](CSC(=O)c1ccccc1)C(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)[C@H](C)CSC(=O)c2ccccc2)C1=O
Yield: 73.4 %

Procedure:
3.0 g of tert.-butyl (4S)-1-n-butyl-2-oxo-imidazolidine-4-carboxylate, 1.4 g of potassium tert.-butoxide, (2S)-3-benzoylthio-2-methylpropionyl chloride (prepared from 2.8 g of (2S)-3-benzoylthio-2-methylpropionic acid and 10 ml of thionyl chloride) and 40 ml of tetrahydrofuran are treated in the same manner as described in Example 2-(2). Then, the oily residue obtained is purified by silica gel chromatography (Solvent, toluene-ethyl acetate (20:1)). 3.8 g of tert.-butyl (4S)-1-n-butyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylate are obtained as colorless syrup.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].I[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36]>C1COCC1>[C:8]1([C:7](=[N:6][C:5]([CH2:15][CH2:14][CH2:7][CH:8]=[CH2:9])([CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[C:4]([O:3][CH2:1][CH3:2])=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=CCCCI
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCCC(CCCC=C)(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A procedure previously described for dialkylation of N-(diphenylmethylene)glycine ethyl ester was used after modifications (see Denmark, S. E.; Stavenger, R. A.; Faucher, A.-M.; Edwards, J. P. J. Org. Chem. 1997, 62, 3375-3389): To a stirred solution of N-(diphenylmethylene)glycine ethyl ester 10 (13.63 g, 51 mmol) in THF (250 mL) was added a solution of KHMDS (11.2 g, 56.1 mmol, 1.1 equiv.) in THF (56 mL) via a cannula at −78° C. over 15 min. After stirring at −78° C. for 1 h, the resulting orange-colored solution was treated with 5-iodo-1-pentene (12 g, 61.2 mmol, 1.2 equiv.). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The resulting suspension was cooled to −40° C. and another solution of KHMDS (15.3 g, 76.5 mmol, 1.5 equiv.) in THF (77 mL) was added via a cannula over 15 min and stirred for 1 h. 5-iodo-1-pentene (16 g, 81.6 mmol, 1.6 equiv.) was then quickly added to the burgundy-colored mixture, and the reaction was left to warm to room temperature overnight (16 h). The reaction was quenched by addition of saturated NH4Cl solution in water (100 mL). The organics were extracted with ethyl acetate (2×150 mL), washed with Na2S2O3 solution and then with brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was dried in vacuo overnight and used for the next reaction without further purification: 1H-NMR (400 MHz, CDCl3) δ 7.83-7.12 (m, 10H), 5.80 (m, 2H), 5.02 (dd, J=17.2, 1.6 Hz, 2H), 4.96 (dd, J=10.4, 1.6 Hz, 2H), 3.74 (q, J=6.8 Hz, 2H), 2.05 (dd, J=14.0, 7.2 Hz, 4H), 1.92 (m, 4H), 1.45 (m, 4H), 1.13 (t, J=6.8 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ 174.8, 166.0, 141.3, 138.9, 128.5, 128.2, 127.9, 115.0, 69.2, 60.5, 37.5, 34.4, 23.3, 14.2; HRMS (ESI) m/z for C27H34NO2 [M+H]+ calcd 404.2589. found 404.2577.