Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH:22]([C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1)([CH3:24])[CH3:23]>ClC(Cl)C>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:31]([C@H:28]1[CH2:29][CH2:30][C@H:25]([CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27]1)=[O:32]
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Reactant: CC(C)[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](C(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
D-Phenylalanine methyl ester hydrochloride (20 g, 0.092 mol) was suspended in a solution of triethylamine (66 mL) in dichloroethane (100 mL) and the mixture was stirred for 1 hour at room temperature. The organic layer was separated after washing with water and dried over anhydrous sodium sulphate. Trans-4-isopropylcyclohexane carboxylic acid (15.8 g, 0.092 mol) was added to the organic layer followed by LiOH—Al2O3 (5.5 g of LiOH adsorbed on 40.5 g aluminum oxide) and the resulting mixture heated at for 24 hours. The reaction mixture was filtered through a celite bed and washed with 1.5 N HCl, 5% sodium bicarbonate solution and brine. The organic layer was concentrated to yield 15.5 g of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.C(N(CC)CC)C.[CH:22]([NH2:25])([CH3:24])[CH3:23]>ClCCl.C(OCC)(=O)C>[CH:22]([NH:25][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CC(C)N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cnc(SC)nc1NC(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 10.0 g (43.0 mmol) of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate and 7.2 mL (51.6 mmol) of triethylamine in 100 mL of dichloromethane is added 4.4 mL (51.6 mmol) of isopropylamine. The reaction solution is stirred at 0° C. for 2 hours then allowed to warm to room temperature. The reaction mixture is diluted with ethyl acetate, washed twice with aqueous HCl, twice with water, once with a saturated solution of sodium bicarbonate, and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated to give 11.1 g (quant.) of the title compound as an oil which solidified on standing: mp 159-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:9][CH:10]=[CH:11][C:12]([NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)=[O:13])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:9][CH:10]=[CH:11][C:12]([NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)=[O:13])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C=CC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=CC=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)Nc1ccc(C(=O)O)cc1

Procedure:
A mixture of 4.0 g. of p-[5,5-bis(p-chlorophenyl)-2,4-pentadienamido]benzoic acid, ethyl ester, 40 ml. of ethanol, and 10 ml. of 1N sodium hydroxide is heated at reflux for 4 hours, filtered while hot, 15 ml. of 1N hydrochloric acid are added, and the mixture is cooled in ice. The solid is collected, washed with water, dried and recrystallized from ethanol, giving 3.1 g. of the desired product, m.p. 273°-276° C.
Reaction SMILES: [C:1]1([C:17]([O:19][CH3:20])=[O:18])[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:5]=12.C1C(=O)N([Br:28])C(=O)C1>C(#N)C>[Br:28][C:3]1[N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:6][C:5]2=[C:1]([C:17]([O:19][CH3:20])=[O:18])[N:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncn2c1CN(C(=O)OC(C)(C)C)CC2
Solvent: CC#N
Product: COC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a stirred solution of Intermediate 1G (2 g, 7.11 mmol) in anhydrous acetonitrile (30 mL) at room temperature, NBS (1.30 g, 7.11 mmol) was added in one portion. The resulting mixture was stirred at room temperature in the dark for 24 hours. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. A saturated aqueous solution of sodium sulfite was added and the biphasic mixture was stirred vigorously at room temperature for 30 minutes. The aqueous phase was separated and the organic layer was washed twice with brine, dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica), eluting with ethyl acetate/hexane mixtures to give Intermediate 1H as a white solid at 60% yield. 1H-NMR (400 MHz, CDCl3) δ: 1.52 (s, 9H), 3.85 (m, 2H), 3.89 (s, 3H), 3.93 (m, 2H), 4.89 (s, 2H). LCMS (+ESI) m/z 362.16 [M+H]+, 360.16 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH3:10][N:11]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[CH3:32])[C:12]([C:14]1[S:25][C:17]2=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]2[CH:15]=1)=[O:13].N>>[CH3:10][N:11]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[CH3:32])[C:12]([C:14]1[S:25][C:17]2=[N:18][C:19]3[CH:24]=[CH:23][C:22]([N+:1]([O-:4])=[O:2])=[CH:21][C:20]=3[N:16]2[CH:15]=1)=[O:13]
Reactant: O=[N+]([O-])O
Reactant: C[C@H]1CCCC[C@H]1N(C)C(=O)c1cn2c(nc3ccccc32)s1
Agent: N
Agent: O=S(=O)(O)O
Product: C[C@H]1CCCC[C@H]1N(C)C(=O)c1cn2c(nc3ccc([N+](=O)[O-])cc32)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under ice-cooling, fuming nitric acid (0.28 ml) was added to concentrated sulfuric acid (22 ml) solution of (+)-(1R,2S)-N-methyl-N-(2-methylcyclohexyl)thiazolo [3,2-a]benzoimidazole-2-carboxamide (2.2 g) and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was poured into ice water and neutralized with a 28% aqueous ammonia solution and then the resulting precipitate was collected by filtration to obtain (1R,2S)-N-methyl-N-(2-methylcyclohexyl)-6-nitrothiazolo [3,2-a]benzoimidazole-2-carboxamide. This was treated in the same manner as in Production Example 1 to obtain the title compound (242 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:11])[CH3:10])=[CH:5][C:4]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1>C(O)(C(F)(F)F)=O.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:11])[CH3:10])=[CH:5][C:4]=1[CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: COc1ccc(C(C)C)cc1CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(C)C)cc1CN1CCNCC1
Yield: 126.8 %

Procedure:
A solution of the product from step (a) (1.98 g) in TFA (4 ml) and dichloromethane (2 ml) was stirred for 2 h. The solvent was removed in vacuo and the residue azeotroped with toluene. Aq. potassium carbonate was added and the mixture was extracted with dichloromethane. The organic extracts were dried (MgSO4) and evaporated in vacuo to give the sub-title compound (1.79 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][N:10]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[I:42]I>C1COCC1>[I:42][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:7]1[N:8]=[N:9][N:10]([C:12]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:11]=1
Reactant: II
Reactant: c1ccc(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Ic1ccccc1-c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -10 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of 0.5 g (1.3 mmoles) of 18a in 10 mL dry THF cooled to -20° C. under a nitrogen atmosphere was added dropwise with stirring 0.55 mL of 2.5M n-butyl lithium in hexane (1.4 mmoles). When addition was complete, the reaction was allowed to warm to -10° C. over one hour, held there one hour, then cooled to -78° C. After stirring a few minutes, 0.4 g (1.57 mmole) of I2 was added all at once, and stirring continued. After 1 hour the reaction mixture was allowed to warm to ambient temperature. After removal of the solvent, the residue was partitioned between CHCl3 and 1M KH2PO4. The aqueous phase was extracted two more times, the combined organic phases washed with sufficient aqueous Na2S2O3 to remove excess I2, dried (MgSO4) and the solvent evaporated. The residue was crystallized from CH2Cl2 /ether to give 0.3 g product,
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:8])([CH3:7])[CH:5]=O.Cl.[NH2:10][OH:11].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][O:2][CH2:3][C:4]([CH3:8])([CH3:7])[CH:5]=[N:10][OH:11]
Reactant: COCC(C)(C)C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCC(C)(C)C=NO
Temperature: 40 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
116 parts of methoxypivalaldehyde were dissolved in 600 parts of ethanol, and a solution of 76.5 parts of hydroxylamine hydrochloride and 86 parts of sodium acetate in 500 parts of water was added dropwise to the above, vigorously stirred solution, the temperature increasing temporarily to 40° C. Stirring was continued for 24 hours at room temperature, after which the mixture was poured into 4,000 parts of water and then saturated with sodium chloride and extracted with eight times 400 parts of ether. The combined extracts were dried over sodium sulfate, the solvent was stripped off, and the residue was distilled, giving 90.4 parts of methoxypivalaldoxime as a colourless liquid at 48°-49° C./0.1 mbar. Yield: 69% of theory.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].O.[OH-].[Na+].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]=O)=[CH:21][CH:20]=1>CO>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]=[N:6][OH:7])=[CH:21][CH:20]=1
Reactant: O=CCc1ccc(COc2ccccn2)cc1
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: ON=CCc1ccc(COc2ccccn2)cc1
Reaction time: 0.25 h

Procedure:
To a mixture of hydroxylamine sulfate (19.7 g) and water (250 mL) was added 1N aqueous sodium hydroxide (240 mL) at 0° C., which was stirred at the same temperature for 15 minutes. To the reaction mixture was then added dropwise a mixture of 4-(pyridin-2-yloxymethyl)-phenyl-acetaldehyde described in Manufacturing Example 1-3-3 (27.3 g) and methanol (250 mL), which was stirred overnight at room temperature. The precipitated solids were filtered to obtain the title compound (20.3 g) as an E/Z mixture.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[NH2:7])(=[O:3])[CH3:2].Cl[C:15]1[N:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[N:16]=1.Cl.Cl.C(C1C=C(NC(NC(N)=N)=N)C=C(C(=O)C)C=1)(=O)C>O>[C:1]([C:4]1[CH:5]=[C:6]([NH:7][C:15]2[N:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[N:16]=2)[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Agent: CC(=O)c1cc(NC(=N)NC(=N)N)cc(C(C)=O)c1
Agent: Cl
Solvent: O
Product: CC(=O)c1cc(Nc2nc(N)nc(N)n2)cc(C(C)=O)c1
Yield: 62.5 %

Procedure:
Compound No. 13: A suspension of 3,5-diacetylaniline (1.95 g) in water (10 mL) was treated with 2-chloro-4,6-diamino-1,3,5-triazine (1.455 g) and concentrated HCl (0.1 mL) and heated at reflux for 20 min. After cooling the hydrochloride of Compound No. 13 separated as a white powder. This was filtered out, dissolved in 60 mL of boiling aqueous 75% methanol and treated with triethylamine (1.5 mL). On cooling, off-white flakes separated. Filtration and drying gave 1.79 g of 2-(3,5-diacetylphenyl)amino-4,6-diamino-1,3,5-triazine, mp 271-2° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N:13]1[O:14][N:15]=[C:16]2[CH:21]=[C:20]([C:22]([NH:24][NH2:25])=[O:23])[CH:19]=[CH:18][C:17]=12>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:25][NH:24][C:22]([C:20]1[CH:19]=[CH:18][C:17]2=[N:13][O:14][N:15]=[C:16]2[CH:21]=1)=[O:23]
Reactant: NNC(=O)c1ccc2nonc2c1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc2nonc2c1
Temperature: 100 °C
Yield: 77 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2,1,3-benzoxadiazole-5-carbohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 166 mg of the title compound (77%) as a orange solid in 99.1% purity by HPLC (Rt: 5.65, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)CC1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[C:18]([F:23])[C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:9]([C@H:5]1[C@:4]([OH:12])([CH3:1])[CH2:8][CH2:7][N:6]1[C:20]1[CH:21]=[C:14]([F:13])[C:15]([C:16]#[N:17])=[C:18]([F:23])[CH:19]=1)[CH3:11]
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2cc(F)c(C#N)c(F)c2)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-ethyl-3-methylpyrrolidin-3-ol 0.5 oxalate (200 mg), 2,4,6-trifluorobenzonitrile (270 mg) and lithium carbonate (187 mg), the title compound was obtained as a colorless solid (yield: 187.5 mg, yield: 61%).
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)(CC(=O)C2C=CC=CN=2)C1=O)CCC.[CH3:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[C:29]2=[O:39].[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([C:49](=[O:51])[CH3:50])=[CH:41]1>>[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([C:49](=[O:51])[CH2:50][C:29]2([OH:39])[C:28]3[C:32](=[CH:33][CH:34]=[C:26]([CH3:25])[CH:27]=3)[N:31]([CH2:35][CH2:36][CH3:37])[C:30]2=[O:38])=[CH:41]1
Reactant: CCCN1C(=O)C(=O)c2cc(C)ccc21
Reactant: CC(=O)c1c[nH]c2ccccc12
Agent: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: CCCN1C(=O)C(O)(CC(=O)c2c[nH]c3ccccc23)c2cc(C)ccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-methyl-1-propylindoline-2,3-dione and commercially available 1-(1H-indol-3-yl)ethanone (purchased from Fisher Scientific). 1H-NMR δ 9.02 (bs, 1H), 8.36 (d, 1H), 7.71 (m, 1H), 7.40 (m, 1H), 7.30-7.26 (m, 3H), 7.09 (d, 1H), 6.73 (d, 1H), 5.66 (s, 1H), 3.64 (m, 2H), 3.50 (d, 1H), 3.24 (d, 1H), 2.26 (s, 3H) 1.72 (m, 2H), 0.96 (t, 3H). Calculated mass for C22H22N2O3, 362.16. Observed 385.1 (M+Na).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:15][OH:16])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1.Cl[C:18]1[NH:22][C:21]2[CH:23]=[C:24]([C:36]([F:39])([F:38])[F:37])[CH:25]=[C:26]([C:27]3[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=3)[C:20]=2[N:19]=1>CCO>[CH3:14][C@H:10]1[N:11]([C:18]2[NH:19][C:20]3[C:26]([C:27]4[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=4)=[CH:25][C:24]([C:36]([F:39])([F:38])[F:37])=[CH:23][C:21]=3[N:22]=2)[CH2:12][CH2:13][N:8]([C:7]2[N:6]=[CH:5][C:4]([CH2:15][OH:16])=[CH:3][C:2]=2[C:36]([F:39])([F:38])[F:37])[CH2:9]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Solvent: CCO
Product: C[C@@H]1CN(c2ncc(CO)cc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
A mixture of {5-chloro-6-[(3R)-3-methyl-piperazin-1-yl]-pyridin-3-yl}-methanol from step (g) above (825 mg, 3.0 mmol) and 2-chloro-6-trifluoromethyl-4-(3,4,5-trifluoro-phenyl)-1H-benzoimidazole (1.05 g, 3.0 mmol, Example 51b) in EtOH (5 mL) reacted under the conditions of Example 3c to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 590 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:14][CH2:15][CH3:16])[C:11]=1[S:12][CH3:13])[CH:7]=[O:8])[CH3:2].[OH:17]O.O>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:14][CH2:15][CH3:16])[C:11]=1[S:12]([CH3:13])=[O:17])[CH:7]=[O:8])[CH3:2]
Reactant: OO
Reactant: CCOc1cc(C=O)cc(OCC)c1SC
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(C=O)cc(OCC)c1S(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 3,5-diethoxy-4-methylsulfanyl-benzaldehyde (0.28 g, 1.16 mmol, 1.0 equiv) in conc. acetic acid (5 mL) was added a solution of 35% hydrogen peroxide in water (0.13 mL, 0.15 g, 1.50 mmol, 1.3 equiv). After stirring the solution for 2 h at rt the reaction mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phases dried over MgSO4. The organic solvent was removed by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with ethyl acetate (1% methanol) providing 0.25 g (84%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.50 (t, J=7.0 Hz, 6H), 3.11 (s, 3H), 4.15-4.26 (m, 4H), 7.07 (s, 2H), 9.93 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.50, 37.62, 65.34, 106.10, 125.13, 139.95, 159.53, 191.07. MS (ISP): 257.1 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[N:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[N:28][C:23]=2[NH:22][CH:21]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:18][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:29]([C:27]3[N:28]=[C:23]4[NH:22][CH:21]=[N:20][C:24]4=[CH:25][CH:26]=3)=[O:30])[CH3:19])[N:5]=2)[CH:16]=[C:15]([F:17])[C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1ccc2nc[nH]c2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1ccc2nc[nH]c2n1
Yield: 54.9 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.060 g, 0.215 mmol), 3H-imidazo[4,5]pyridine-5-carboxylic acid (0.035 g, 0.215 mmol), DIPEA (0.112 ml, 0.646 mmol), HOBt hydrate (0.050 g, 0.323 mmol) and EDCI (0.062 g, 0.323 mmol) using the method of Example 274 affording 0.050 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.22 (d, 3H), 4.46 (m, 3H), 6.99 (d, 1H), 7.81 (d, 1H), 7.89 (m, 3H), 8.09 (d, 1H), 8.63 (s, 1H), 8.80 (d, 1H), 13.00 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[CH2:12][C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>>[C:13]([CH2:12][NH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([OH:15])=[O:14]
Reactant: O=C(O)CCl
Reactant: Nc1ncccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CNc1ncccc1C(=O)O

Procedure:
2-(Carboxymethyl-amino)-nicotinic acid 501 is prepared by reacting commercially available 2-Amino-nicotinic acid 500 with 2-chloroacetic acid in the presence of base (e.g. sodium carbonate) typically at room temperature for 1-4 hours followed by purification and isolation by conventional means (e.g. acid base extraction and recrystallization).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[F:12][C@@H:13]1[C@H:17]([OH:18])[C@@H:16]([CH2:19][OH:20])[O:15][C@H:14]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:14]2[O:15][C@H:16]([CH2:19][OH:20])[C@@H:17]([OH:18])[C@H:13]2[F:12])=[C:4]([Cl:11])[N:3]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Nc1nc(Cl)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3F)c2n1
Temperature: 37 °C

Procedure:
2-Amino-6-chloropurine (Sigma Chemical Company, 0.8 g, 4.7 mmoles) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.4 g, 1.6 mmoles) were suspended in 25 ml of 10 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. Thymidine phosphorylase (4,000 I.U.) and purine nucleoside phosphorylase (6,500 I.U.) were added and the suspension stirred at 37° C. On day 10, the reaction was diluted to 100 ml with 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. On day 20, the reaction was diluted to 200 ml with 5 mM potassium phosphate buffer, pH 7, which contained 0.04% (w/v) potassium azide, and 2,640 I.U. thymidine phosphorylase and 4,360 I.U. purine nucleoside phosphorylase were added. On day 53, the reaction was filtered. The filtrate was evaporated and the residue stored at 4°. The residues from Reactions 1 and 2 were suspended in water and combined. The suspension was warmed and then filtered. The product which was contained in the filtrate was purified by chromatography on a 7.5×90 cm column of Biogel P-2 (Bio-Rad) with n-propanol/water (3/7) as the solvent, followed by chromatography on a 5×90 cm column of Sephadex G-10 (Pharmacia LKB) with n-propanol/water (3/7) as the solvent. Fractions containing only product were pooled and the solvent removed under vacuum. The residue was suspended in water and lyophilized to obtain the title compound (batch 1). Fractions containing product plus impurities which were eluted off the Sephadex G-10 column were combined and the solvent removed under vacuum. The residue was dissolved in water/MeCN (49/1), and the product was further purified by reversed phase chromatography on C18 silica (Hi-Chrom Prep-40-ODS, Regis Chemical Co.) with water/MeCN (49/1) as the solvent. Product containing fractions were combined and filtered through an 0.2 μm-pore nylon filter to remove residual silica. After the solvent was removed under vacuum, the residue was dissolved in water and filtered through a 0.22 m-pore membrane filter (Millipore GS). Lyophilization of the filtrate yielded the title compound (batch 2) that analyzed as a 0.5 hydrate.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][NH:6][CH2:5][C:4]2[CH:8]=[C:9]([C:11]([NH:13][O:14]C3CCCCO3)=[O:12])[S:10][C:3]1=2.C(N(CC)CC)C.[C:29]1([C@@H:35]([N:37]=[C:38]=[O:39])[CH3:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl.O1CCOCC1>ClCCCl.O1CCCC1>[OH:14][NH:13][C:11]([C:9]1[S:10][C:3]2[C:2]([CH3:1])([CH3:21])[CH2:7][N:6]([C:38]([NH:37][C@H:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH3:36])=[O:39])[CH2:5][C:4]=2[CH:8]=1)=[O:12]
Reactant: C[C@H](N=C=O)c1ccccc1
Reactant: CC1(C)CNCc2cc(C(=O)NOC3CCCCO3)sc21
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H](NC(=O)N1Cc2cc(C(=O)NO)sc2C(C)(C)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A solution of 7,7-dimethyl-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (31 mg, 0.1 mmol) and triethylamine (41.8 μL, 0.3 mmol) in 1,2-dichloroethane (1 mL) was added (S)-1-phenylethyl isocyanate (22.1 mg, 0.15 mmol). The reaction was stirred at room temperature overnight. The solution was evaporated to dryness and the residue obtained was redissolved in tetrahydrofuran (1 mL). 4.0 M of hydrochloric acid in 1,4-dioxane (1 mL, 4 mmol) was added and the reaction solution was stirred at room temperature for 2 hours. The solution was evaporated to dryness, redissolved in DMSO (1 mL) and purified on an Agilent 1100 LC/MSD instrument to afford the title compound (17.8 mg, 46%). LCMS (FA) ES+ 374; 1H NMR (400 MHz, MeOD) δ 7.35-7.24 (m, 5H), 7.20-7.15 (m, 1H), 5.01-4.91 (m, 1H), 4.50 (d, J=4.0 Hz, 2H), 3.50 (d, J=4.6 Hz, 2H), 1.47 (d, J=7.1 Hz, 3H), 1.30 (s, 6H).