Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:15][CH:16]=2)[C:11]([CH3:26])=[CH:10][C:9]1([CH3:28])[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Se](=O)=[O:30]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:15][CH:16]=2)[C:11]([CH:26]=[O:30])=[CH:10][C:9]1([CH3:28])[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1-c1ccc2c(c1)C(C)=CC(C)(C)N2C(=O)OC(C)(C)C
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccc2c(c1)C(C=O)=CC(C)(C)N2C(=O)OC(C)(C)C
Yield: 60.3 %

Procedure:
A mixture of 1.6 g of 6-(2-methoxyphenyl)-2,2,4-trimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester, 20 mL of 1,4-dioxane, and 1.4 g of selenium dioxide was refluxed for half an hour. Another 1.4 g portion of selenium dioxide was added. The reaction was allowed to reflux for 6 hours. The reaction mixture was then filtered through diatomaceous earth and the residue was rinsed with EtOAc. The solvent was evaporated in vacuo and the residue was purified by flash chromatography to yield 1 g of 4-formyl-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][O:33][CH2:34][CH2:35][NH:36][CH2:37][CH2:38][O:39][CH3:40].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:32][O:33][CH2:34][CH2:35][N:36]([CH2:27][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]2)[CH:26]=[CH:25][CH:24]=1)[CH2:37][CH2:38][O:39][CH3:40]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: COCCNCCOC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN(CCOC)CCOC)c4)cc23)CC1
Yield: 16.8 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(methyloxy)-N-[2-(methyloxy)ethyl]ethanamine (114.3 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (10.5 mg, 16%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CC(OO)=[O:14].CC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N+:4]([O-:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC(=O)OO
Reactant: Brc1cnc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: [O-][n+]1cc(Br)cc2ccccc21
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a solution of 3-Bromoquinoline 5 (2.08 g, 10 mmol) in CHCl3 (5 ml) was added CH3CO2OH (5 ml, 32% solution in dilute HOAc, 20 mmol) and the mixture was stirred overnight. Acetone (3 ml) was added and the mixture was stirred an additional 15 min then poured into saturated NaHCO3 (aq) and extracted with CH2Cl2. The combined extracts were dried (K2CO3) and concentrated to yield pure 6 (2.26 g, 100%) as a tan solid. 1H NMR d (d=delta) (ppm): 7.7 dd (CH atom), 7.8 m (2 CH atom), 7.9 s (CH atom), 8.6 s (CH atom), 8.7 d (CH atom).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[CH:17]=O.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[CH2:17][NH:23][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Cn1c(=O)c(C=O)c(N)n(-c2ccccc2)c1=O
Reactant: CCCCN
Product: CCCCNCc1c(N)n(-c2ccccc2)c(=O)n(C)c1=O

Procedure:
Reductive amination of 6-amino-5-formyl-3-methyl-1-phenyl-2,4 (1H, 3H)-pyrimidinedione with N-butylamine was performed in substantially the same manner as Example 18 to thereby give an intermediate, 6-amino-5-(N-butylaminomethyl)-3-methyl-1-phenyl-2,4 (1H, 3H)-pyrimidinedione. The intermediate was reacted with 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid by a conventional condensation method to give the title compound (yield 36%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[CH3:18][C:19]([O:22][C:23]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])([CH3:21])[CH3:20]>C(O)C>[C:19]([O:22][C:23](=[O:24])[NH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:28][CH2:27]1)([CH3:21])([CH3:18])[CH3:20]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 80 °C
Yield: 37.4 %

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (74 mg, 0.48 mmol) in ethanol (1 ml) was added triethylamine (200 μl, 1.43 mmol) and 4-N-Boc-aminopiperidine (106 mg, 0.53 mmol). The solution was heated at 80° C. for 4 hours, and then cooled to room temperature. The precipitate was collected by filtration and washed with ethanol (2 ml), then dried under vacuum to yield the product (57 mg, 36%). LC/MS (LCT) Rt 4.57 [M+H]+ 318
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH:6][S:12]([CH3:11])(=[O:14])=[O:13])=[C:4]([F:10])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1c(F)cc(Br)cc1F
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1c(F)cc(Br)cc1F
Temperature: 50 °C
Reaction time: 6 h
Yield: 98.3 %

Procedure:
To a solution of 4-bromo-2,6-difluoroaniline (3.0 g, 14.4 mmol) in pyridine (20 ml) was added methanesulfonyl chloride (2.23 ml, 28.8 mmol) at room temperature. Then the mixture was stirred at 50° C. for 6 hours. After cooing to room temperature, the mixture was concentrated in vacuo. The resulting residue was dissolved in THF (40 ml). To this solution was added 2M aqueous sodium hydroxide solution (40 ml) and the reaction was stirred at room temperature for 4 hours. The mixture was acidified with 2M aqueous HCl solution and the whole was extracted with EtOAc. The organic layer was washed with 2M aqueous HCl solution, brine, and dried over sodium sulfate. After concentration in vacuo, the title compound (4.05 g, 98% yield) was obtained as orange solids.
Reaction SMILES: [CH2:1]([NH:7][C:8]1[CH:40]=[CH:39][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[NH:30][C:29]5=[O:34])=[CH:25][CH:24]=4)[N:18]([CH3:37])[C:17]=3[CH:38]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46]([N:49]=[C:50]=[O:51])=[CH:45][CH:44]=1>O1CCCC1>[O:33]=[C:31]1[NH:30][C:29](=[O:34])[CH:28]([CH2:27][C:26]2[CH:35]=[CH:36][C:23]([O:22][CH2:21][C:19]3[N:18]([CH3:37])[C:17]4[CH:38]=[C:13]([O:12][C:11]5[CH:39]=[CH:40][C:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:50]([NH:49][C:46]6[CH:45]=[CH:44][C:43]([C:42]([F:41])([F:52])[F:53])=[CH:48][CH:47]=6)=[O:51])=[CH:9][CH:10]=5)[CH:14]=[CH:15][C:16]=4[N:20]=3)=[CH:24][CH:25]=2)[S:32]1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCNc1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Solvent: C1CCOC1
Product: CCCCCCN(C(=O)Nc1ccc(C(F)(F)F)cc1)c1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Reaction time: 48 h

Procedure:
A mixture of 5-[4-[6-(4-n-hexylaminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.39 g), α,α,α-trifluoro-p-tolyl isocyanate (0.15 g) and anhydrous tetrahydrofuran (20 ml) was allowed to stand at room temperature for 2 days. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and then concentrated. The residue was reprecipitated from a mixture of ether and diisopropyl ether to afford the title compound (0.37 g, Rf=0.49: thin layer chromatography on a silica gel plate using ethyl acetate:n-hexane=2:1 as the eluant).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:28])([CH3:27])[CH:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:7])=[O:6].[N-:29]=[N+:30]=[N-:31].[Na+]>CS(C)=O>[N:29]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:28])([CH3:27])[CH:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:7])=[O:6])=[N+:30]=[N-:31]
Reactant: CCOC(=O)C(OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, ethyl (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoate (23a) (0.31 g, 0.71 mmol) dissolved in 10 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.11 g (1.8 mmol) of sodium azide (NaN3). After work-up, the crude title compound (23b) was used in the next step without further purification. MS (ESI) m/z 466.07 (M+Na)+.
Reaction SMILES: [Na].[C:2]([O:9][CH3:10])(=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[O-]CC.[Na+:14].Br[CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17]>C(O)C>[O-:5][CH2:4][CH3:3].[Na+:14].[CH3:17][CH:16]([CH:3]([C:2]([O:9][CH3:10])=[O:8])[C:4]([O:6][CH3:7])=[O:5])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(C)Br
Reactant: COC(=O)CC(=O)OC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCC(C)C(C(=O)OC)C(=O)OC
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Sodium ethoxide was prepared from sodium metal (7.61 g) and absolute ethanol (200 ml). Dimethyl malonate (50.3 ml) was added dropwise to the ethanol containing sodium ethoxide. After heating to 80° C., 2-bromopentane (50 g) was added and the mixture was reflued for 24 h. Dimethyl (2-pentyl)malonate (62.7 g) was obtained after the usual work-up. Dimethyl (2-pentyl)malonate was added to a 50% potassium hydroxide solution and the mixture was heated for 3 h while water/ethanol being distilled off. After cooling, the solution was acidified with concentrated hydrochloric acid. Then, the solution was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the resulting product was heated to 180° C. until bubbling ceased. After distillation, colorless 3R,S-methy-caproic acid was obtained. Yield: 27.7 g (35%), b.p. 200° C./760 mmHg.
Reaction SMILES: C[Li].[CH3:3]COCC.[C:8]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl>[CH3:3][C:14]1[CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:17]=[CH:16][N:15]=1
Reactant: CC(C)(C)c1ccncc1
Reactant: CCOCC
Agent: [Li]C
Solvent: ClCCl
Product: Cc1cc(C(C)(C)C)ccn1
Yield: 74.2 %

Procedure:
Cool a solution of methyl lithium in ether (200 mL, 1.6 M, 320.00 mmol) in an ice bath and add 4-tert-butyl-pyridine (20.28 g, 150.00 mmol) drop wise. Once the substrate is added, warm the reaction to ambient temperature for 3 hours. Concentrate the reaction to near dryness to remove the ether and then add anhydrous toluene (200 mL) and heat to reflux for 20-21 hours. Cool in an ice bath while slowly and cautiously adding ice to quench the reaction. Add water (200 mL) and then extract the aqueous with ethyl acetate (3×250 mL) and separate the layers. Pool, desiccate, filter and concentrate the organic extracts to an oil. Chromatograph the oil on silica using a gradient of 0→50% ethyl acetate hexanes over 25 minutes to yield the title compound (16.60 g, 111.23 mmol). MS(ESI), m/z 150 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].CO>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([CH2:5][OH:6])=[CH:8][CH:9]=[CH:10][N:11]=1
Reactant: COc1ncccc1C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ncccc1CO
Temperature: 70 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
To a 100-mL round-bottomed flask was added 2-methoxynicotinic acid (1.52 g, 9.93 mmol, Aldrich, St. Louis, Mo.) and borane methyl sulfide complex (3.77 mL, 39.7 mmol, Aldrich, St. Louis, Mo.) in tetrahydrofuran (30 mL). The reaction mixture was stirred at 70° C. for 16 h. The mixture was cooled to 0° C. and MeOH (10 mL) was added dropwise. After the addition was completed, the reaction mixture was stirred for further 20 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 60% EtOAc/hexanes to give (2-methoxy-3-pyridinyl)methanol (1.15 g) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][CH:11]([C:15]1[O:16][C:17]2[C:22]([C:23](=[O:32])[C:24]=1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:21][CH:20]=[C:19]([Cl:33])[CH:18]=2)[CH:12]([CH3:14])[CH3:13])(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:7][CH2:8][CH2:9][NH:10][CH:11]([C:15]1[O:16][C:17]2[C:22]([C:23](=[O:32])[C:24]=1[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[CH:21][CH:20]=[C:19]([Cl:33])[CH:18]=2)[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)C(NCCNC(=O)OC(C)(C)C)c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NCCN)c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1
Yield: 90.9 %

Procedure:
A solution of {2-[1-(3-benzyl-7-chloro-4-oxo-4H-chromen-2-yl)-2-methyl-propylamino]-ethyl}-carbamic acid tert-butyl ester (5.7 g, 12 mmol) in 4:1 methylene chloride/trifluoroacetic acid (250 mL) was maintained at room temperature for 1.5 hours, at which time it was concentrated. The residue was dissolved in methylene chloride (200 mL), washed with 10% sodium carbonate, saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and concentrated. The residue (4.2 g, 91% yield) was used without further puification.
Reaction SMILES: FC1C=C(CCC(O)=O)C=C[C:7]=1[O:8]C.Br[C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]3[CH:26]=[C:27]([CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])[CH:28]=[CH:29][C:30]=3[O:31][CH2:32][CH:33]3[CH2:38][CH2:37][CH2:36]C[CH2:34]3)[CH:22]=[CH:21][C:19]=2[N:20]=1>[OH-].[Na+]>[CH:33]1([CH2:32][O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:26][C:25]=2[C:23]2[CH:22]=[CH:21][C:19]3[N:20]=[C:16]([O:8][CH3:7])[S:17][C:18]=3[CH:24]=2)[CH2:34][CH2:36][CH2:37][CH2:38]1
Reactant: COc1ccc(CCC(=O)O)cc1F
Reactant: CCOC(=O)CCc1ccc(OCC2CCCCC2)c(-c2ccc3nc(Br)sc3c2)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1nc2ccc(-c3cc(CCC(=O)O)ccc3OCC3CCCC3)cc2s1
Reaction time: 18 h

Procedure:
According to the procedure described in the synthesis method of Intermediate 9 provided that the reaction was carried out for 18 hours, Intermediate 76 (169 mg) and 2 N aqueous sodium hydroxide (500 μl) were reacted and treated to obtain the title compound (Compound No. V-88, 114 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a cooled (0° C.) solution of 4-bromo-2-methylbenzoic acid (15.1 g, 0.070 mol) in tetrahydrofuran (180 mL) and methanol (45 mL) was slowly added (trimethylsilyl)diazomethane (2.0M in hexanes, 42 mL, 0.084 mol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h, at which time it was concentrated in vacuo to afford methyl 4-bromo-2-methylbenzoate (16 g, 100%) as a yellow oil. The residue was taken to the next step without further purification. 1H NMR (400 MHz, CDCl3): 7.78 (d, 1H), 7.42 (s, 1H), 7.38 (d, 1H), 3.88 (s, 3H), 2.58 (s, 3H). MS (EI) for C9H9BrO2: 230 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])=[O:2].C(N(CC)CC)C.[CH3:18][O:19][P:20]([O-:23])[O:21][CH3:22]>C(OCC)(=O)C>[CH3:18][O:19][P:20]([CH:1]([C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([C:6]#[N:7])[CH:4]=1)[OH:2])(=[O:23])[O:21][CH3:22]
Reactant: N#Cc1cccc(C=O)c1
Reactant: COP([O-])OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COP(=O)(OC)C(O)c1cccc(C#N)c1
Yield: 74 %

Procedure:
A mixture of 3-formyl-benzonitrile (10 g, 76.26 mmol), triethylamine (9.26 g, 91.05 mmol) and dimethyl-phosphite (10.91 g, 99.14 mmol) was stirred in ethyl acetate at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate (50 ml), washed with a saturated ammonium chloride solution (1×50 ml), dried (Na2SO4) and the filtrate was evaporated affording the crude [(3-cyanophenyl-hydroxymethyl]-phosphonic acid dimethyl ester as a yellow solid (13.60 g, 56.43 mmol, 74%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][CH3:14].CO.[H][H]>[Pt]=O.O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)ccc1OC

Procedure:
A 2 liter Parr Bottle was charged with 11.6 grams (55 mmol) methyl-2-methoxy-5-nitrobenzoate, 450 mL of methanol and 150 mL of tetrahydrofuran (THF). Platinum oxide was added (460 mg) and the mixture was hydrogenated under 45 psi hydrogen for 1 hour. The reaction mixture was filtered through Celite® (diatomaceous earth) and evaporated. The reaction mixture was diluted with 500 mL of methylene chloride, and then washed with water and brine. The organic phase was dried and evaporated (9.9 grams). This material was used without further purification.
Reaction SMILES: C[O:2][C:3]([CH2:5][S:6][C:7]1[S:8][C:9]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:11]=1[N+:12]([O-])=O)=O>C(O)(=O)C.O.[Fe]>[CH3:18][O:17][C:15]([C:9]1[S:8][C:7]2[S:6][CH2:5][C:3](=[O:2])[NH:12][C:11]=2[CH:10]=1)=[O:16]
Reactant: COC(=O)CSc1sc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(s1)SCC(=O)N2
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
To a solution of 2-methoxycarbonylmethylthio-5-methoxycarbonyl-3-nitrothiophene (26.1 g) in acetic acid (360 ml) and water (36 ml) was added portionwise iron (36.5 g) at 80° C. After stirring for 3 hours at 80° C., the hot reaction mixture was filtered and the filtrate was poured into ice-water. The resulting precipitate was collected by filtration and washed with water to give 2,3-dihydro-6-methoxycarbonyl-2-oxothieno[2,3-b][1,4] thiazine (11.12 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][C:9]([OH:11])=O)[CH:3]=1.[N+]([O-])(O)=O.[O:16]([CH2:20][CH2:21][NH2:22])[N+:17]([O-:19])=[O:18].C(OC(C)C)(C)C>>[O:16]([CH2:20][CH2:21][NH:22][C:9](=[O:11])[CH2:8][O:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)[N+:17]([O-:19])=[O:18]
Reactant: Cc1cc(OCC(=O)O)no1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: Cc1cc(OCC(=O)NCCO[N+](=O)[O-])no1
Yield: 36.9 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.40 g of 5-methyl-3-isoxazolyloxyacetic acid and 0.43 g of nitroxyethylamine nitrate, 0.23 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: C(OC(=O)C)(=O)C.C[O:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[NH2:17])=O.C([O-])=O.[NH4+].[CH:22]([NH2:24])=O>C(O)=O>[N:17]1[C:16]2[CH:15]=[CH:14][S:13][C:12]=2[C:10](=[O:9])[NH:24][CH:22]=1
Reactant: COC(=O)c1sccc1N
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=c1[nH]cnc2ccsc12
Temperature: 25 °C
Yield: 160.2 %

Procedure:
Acetic anhydride (185 mL, 1.96 mol) and formic acid (85 mL, 2.22 mmol) were mixed and stirred. Methyl-3-aminothiophene-2-carboxylate (50 g, 0.16 mol) was added to the reaction mixture, followed by stirring for about 3 hours at room temperature. The reaction solvent was removed under reduced pressure. Separately, ammonium formate (90 g, 1.43 mol) and formamide (150 mL, 3.76 mol) were mixed and stirred for about 30 minutes. The synthesized material in the above was added to the resulting reaction solution, followed by stirring 8 hours at 150° C. The reaction solution was cooled to room temperature and stirred for about 12 hours. The generated solid was filtered, and washed with water to obtain the title compound (39 g, 81%).
Reaction SMILES: Cl[C:2]1[C:3]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[N:4][C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[C:6](Cl)[CH:7]=1.CCOCC>Cl>[CH:25]1([C:23]2[NH:22][N:21]=[C:20]([NH:19][C:3]3[CH:2]=[CH:7][CH:6]=[C:5]([NH:9][C@H:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH3:11])[N:4]=3)[CH:24]=2)[CH2:27][CH2:26]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(Cl)cc1Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCOCC
Product: C[C@H](Nc1cccc(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.5 %

Procedure:
tert-Butyl 5-cyclopropyl-3-[(6-{[(is)-1-(4-fluorophenyl)ethyl]amino}pyridin-2-yl)amino]-1H-pyrazole-1-carboxylate (Method 21; 146 mg) was dissolved in a solution of hydrogen chloride in ether (2.0 M, 2 ml, 4 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed and semi-prep HPLC (Gilson) purification gave the title compound (37 mg, 25%). 1H NMR (CDCl3) δ 0.55 (m, 2H), 0.70 (m, 2H), 1.35 (m, 3H), 1.65 (m, 1H), 4.53 (m, 2H), 4.91 (br s, 1H), 6.10 (br s, 1H), 6.70 (m, 1H), 7.00 (m, 2H), 7.25 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=O)=[C:11]([O:16][CH3:17])[N:10]=[C:9]([S:18][CH3:19])[N:8]=1.[NH2:25][CH2:26][C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.O.ON1C2C=CC=CC=2N=N1.CN(C)C=O>C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:12]([C:13](=[O:15])[NH:25][CH2:26][C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:11]([O:16][CH3:17])[N:10]=[C:9]([S:18][CH3:19])[N:8]=1
Reactant: COc1ccc(CNc2nc(SC)nc(OC)c2C(=O)O)cc1Cl
Reactant: NCc1ncccn1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNc2nc(SC)nc(OC)c2C(=O)NCc2ncccn2)cc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-6-methoxy-2-methylthiopyrimidine (prepared in the above (2)) 183 mg, 2-aminomethylpyrimidine 70 mg, 1-hydroxybenzotriazole hydrate 67 mg and dimethylformamide 4 ml is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimido hydrochloride 114 mg on an ice bath, and the mixture is stirred for 14 hours at room temperature. The reaction mixture is diluted with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; chloroform:ethyl acetate=20:1→10:1) to give 4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]-6-methoxy-2-methylthiopyrimidine as a colorless crystalline powder 208 mg. mp 171-172° C.