Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([CH3:12])[CH:11]=2)=[N:3]1.[I:13]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>>[I:13][C:5]1[C:4]([C:7]2[S:8][CH:9]=[C:10]([CH3:12])[CH:11]=2)=[N:3][N:2]([CH3:1])[CH:6]=1
Reactant: Cc1csc(-c2ccn(C)n2)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: Cc1csc(-c2nn(C)cc2I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a solution of 1-methyl-3-(4-methyl-2-thienyl)-1H-pyrazole (4.7 mmol) in 14 mL dry 1V, N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (5.0 mmol) in small portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane:dichloromethane 100:0 to 0:100) to afford 1.26 g 4-iodo-1-methyl-3-(4-methyl-2-thienyl)-1H-pyrazole (84% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14](F)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:25]C1C=C2C(N3C(=C2)C(=O)NCC3C)=NC=1)[CH3:24].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C:10](=[CH:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14]([O:25][CH2:23][CH3:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(F)cnc3N21
Reactant: CCOc1cnc2c(c1)cc1n2C(C)CNC1=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: [Al+3]
Product: CCOc1cnc2c(c1)cc1n2[C@H](C)CN(C(=O)OC(C)(C)C)C1

Procedure:
This compound was prepared in analogy to Example 1, intermediate h) from 7-ethoxy-4-methyl-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one and lithium aluminium hydride and protection of the free amine with di-tert-butyl-dicarbonate and 4-(dimethylamino)pyridine.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:26]([O:28][C:29](=[O:40])[CH:30]([CH2:36][CH2:37][CH2:38]Cl)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:27].C(N(CC)CC)C>CN1C(=O)CCC1>[CH2:26]([O:28][C:29](=[O:40])[CH:30]([CH2:36][CH2:37][CH2:38][N:22]1[CH2:21][CH2:20][N:19]([C:16]2[S:17][CH:18]=[C:14]([C:6]3[CH:5]=[CH:4][C:3]4[C:2]([CH3:25])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=4[CH:7]=3)[N:15]=2)[CH2:24][CH2:23]1)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:27]
Reactant: CCOC(=O)C(CCCCl)C(=O)OCC
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCNCC4)n3)ccc21
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(CCCN1CCN(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1)C(=O)OCC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
200 mg (0.53 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazine were dissolved in 5 ml of NMP, 235 μl (1.06 mmol) of 2-(3-chloropropyl)malonic acid diethyl ester and 220 μl (1.59 mmol) of triethylamine were added, and the mixture was stirred at 100° C. overnight. The reaction mixture was evaporated to dryness and purified by means of preparative HPLC. The product is in the form of the TFA salt.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>C(O)C>[ClH:27].[NH2:8][C@H:12]([CH2:11][OH:10])[CH2:13][N:14]1[CH2:15][CH2:16][CH:17]([C:20]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[O:28])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CN2CCC(C(=O)c3ccc(Cl)cc3)CC2)COC1(C)C
Agent: Cl
Solvent: CCO
Product: N[C@H](CO)CN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-4-[4-(4-chloro-benzoyl)-piperidin-1-ylmethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.68 g, 1.55 mmol) is added to a solution of hydrogen chloride in ethanol (5 ml, 5.5M). The reaction mixture is stirred at ambient temperature for 1 hour, then evaporated to dryness to afford [1-((S)-2-amino-3-hydroxy-propyl)-piperidin-4-yl]-(4-chloro-phenyl)-methanone hydrochloride. [MH] 297.0.
Reaction SMILES: [CH2:1]([N:4]([CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[C:5](=[O:8])[CH2:6][Cl:7])[C:2]#[CH:3].C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([N:4]([CH2:9][CH:10]1[O:11][CH2:12][CH2:13][CH2:16][CH2:15][O:14]1)[C:5](=[O:8])[CH2:6][Cl:7])[C:2]#[CH:3]
Reactant: C#CCN(CC(OCC)OCC)C(=O)CCl
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C#CCN(CC1OCCCCO1)C(=O)CCl

Procedure:
N-Propargyl-N-(2,2-diethoxyethyl)-α-chloroacetamide (10 grams), butandiol-1,4 (3 ml) and trace amounts of toluenesulfonic acid are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated until no more ethanol is given off. After this time sodium carbonate (1 gram) is added to the mixture with stirring and the resulting mixture is distilled to yield the desired product N-propargyl-N-(1,3-dioxepan-2-ylmethyl)-α-chloroacetamide.
Reaction SMILES: [Na].[F:2][C:3]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:4][CH2:5][OH:6].Cl[C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[N:14]=1.Cl>>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([NH:20][C:15]2[N:16]=[C:17]([CH3:19])[CH:18]=[C:13]([O:6][CH2:5][CH2:4][C:3]([F:11])([F:2])[C:7]([F:10])([F:9])[F:8])[N:14]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1
Reactant: OCCC(F)(F)C(F)(F)F
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Agent: Cl
Agent: [Na]
Product: COc1cc(Nc2nc(C)cc(OCCC(F)(F)C(F)(F)F)n2)ccc1-n1cnc(C)c1
Temperature: 100 °C
Yield: 64.5 %

Procedure:
Sodium (6.9 mg, 0.3 mmol) was dissolved under stirring and heating under an atmosphere of argon in 3,3,4,4,4-pentafluorobutan-1-ol (676 mg, 4.0 mmol). To this solution (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (66 mg, 0.20 mmol) was added and the reaction mixture was stirred for 16 h at 20° C. and then heated to 100° C. for 4 h. The reaction mixture was poured onto water and was acidified with 1N aqueous hydrochloric acid solution. It was extracted twice with diethyl ether. The aqueous layer was set to basic pH with 1N aqueous sodium hydroxide solution and extracted three times with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (59 mg, 64%) as a pale-yellow solid.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[C:20]([Cl:36])[N:21]3[C@H:24]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)=[C:17]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:16]=2)=[CH:11][N:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH3:64][S:65](Cl)(=[O:67])=[O:66]>C(Cl)Cl>[Cl:36][C:20]1[N:21]([C@H:24]2[CH2:28][CH2:27][N:26]([S:65]([CH3:64])(=[O:67])=[O:66])[CH2:25]2)[C:22]2[C:18]([N:19]=1)=[C:17]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[N:16]=[C:15]([C:12]1[CH:13]=[N:14][C:9]([NH2:8])=[N:10][CH:11]=1)[N:23]=2
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2c(Cl)nc3c(N4CCOCC4)nc(-c4cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc4)nc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC[C@H](n2c(Cl)nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc32)C1
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
tert-Butyl (3S)-3-(2-{2-[bis(tert-butoxycarbonyl)amino]pyrimidin-5-yl}-8-chloro-6-morpholin-4-yl-9H-purin-9-yl)pyrrolidine-1-carboxylate (1.32 g, 1.88 mmol) was dissolved in methylene chloride (5 ml) followed by the addition of trifluoroacetic acid (5 ml) and the resulting mixture was stirred for 0.5 hours. The solvent was removed azeotropically with toluene and evaporated under reduced pressure. The residue was dissolved in methylene chloride followed by the addition of triethylamine (1 ml) and methanesulfonyl chloride (170 μl, 2.26 mmol) with ice cooling and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was partitioned with ethyl acetate and water, and the solid that was not dissolved in either layer was collected by filtration, washed with ethyl acetate and water, and dried. This solid was suspended in methylene chloride, and then the insoluble matter was collected by filtration and dried to give the title compound (0.38 g, 42%) as a pale grey solid.
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].S(OC)(O[CH3:24])(=O)=O.[H-].[Na+]>CN(C)P(N(C)C)(N(C)C)=O>[CH3:24][O:9][C:3]1[CH2:4][CH:5]2[N:1]([C:7](=[O:8])[CH2:6]2)[C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: COS(=O)(=O)OC
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Yield: 20.5 %

Procedure:
A solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (25.9 mg, 0.1 mMol) in anhydrous hexamethylphosphoramide (1.0 ml) is cooled in an ice-bath and stirred under a nitrogen atmosphere. Dimethyl sulfate (11.4 μl, 0.12 mMol) and 57% sodium hydride in mineral oil (5.0 mg, 0.12 mMol) are added to the solution. The cooling bath is removed and the resulting mixture is stirred at room temperature for 60 minutes. The mixture is diluted with ethyl acetate (10 ml) and water (20 ml), shaken, and the layers separated. The organic layer is washed with water (3×5 ml) and brine, dried with magnesium sulfate, diluted with toluene (10 ml), and evaporated under vacuum to an oil. This material is chromatographed on a 0.25 mm×10×20 cm silica gel GF plate using 3:1 toluene-ethyl acetate as developing solvent. The major UV visible band at Rf 0.1 was removed and eluted with ethyl acetate to provide benzyl 3 -methoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (5.6 mg) as a clear oil: IR (CH2Cl2) 1775 and 1700 cm-1 ; UV (EtOAc) 288 nm; NMR (CDCl3) δ 2.87 (dd, 1, J=2.8 and 16, H6β), 3.03 (m, 2, H4a and H4b), 3.50 (dd, 1, J=5.5 and 16, H6α), 3.80 (m, 1, H5), 3.92 (s, 3, CH3), 5.28 (s, 2, CH2 φ), and 7.40 (m, 5, C6H5); mass spectrum m/e 273 (M+) and 231 (M+-42).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([NH:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1)(=[O:35])[CH3:34]
Reactant: Nc1nc2c(s1)CCN(Cc1ccccc1)CC2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)Nc1nc2c(s1)CCN(Cc1ccccc1)CC2
Yield: 62 %

Procedure:
Prepared from 2-amino-6-benzyl-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine (see Example 4 in GB-A-1321509, melting point of the dihydrochloride 232° C.) and 1.2 equivalents of acetic anhydride by refluxing for 2 hours. Yield: 62% of theory, Melting point: 129°-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O=[As](O[As](=O)=O)=O.O[CH2:21][CH:22]([CH2:24]O)O.S(=O)(=O)(O)O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([CH:21]=[CH:22][CH:24]=[N:12]2)=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N)ccc1[N+](=O)[O-]
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[As](=O)O[As](=O)=O
Solvent: O
Product: COc1cc2ncccc2cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 55.1 %

Procedure:
To a mixture of 3-methoxy-4-nitro-phenylamine (13.4 g, 80.0 mmol), arsenic pentoxide (11.0 g, 48.0 mmol) and glycerol (33 mL, 216.0 mmol) at 100° C., was added, dropwise, concentrated sulfuric acid (4.7 mL, 88.0 mmol). The reaction mixture was then heated at a temperature ranging between 150 and 160° C. for 2 hours and then was cooled. Water (200 mL) was added and the resulting mixture was extracted four times with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc) to give 9.00 g (61% yield) of 7-methoxy-6-nitro-quinoline as an orange solid.
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].[CH3:7][C:8]([CH3:29])([CH3:28])[CH2:9][N:10]1[C:14]2[N:15]=[C:16]([C:19]#[N:20])[N:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C1C=CC2N(O)N=NC=2C=1.Cl.[Cl-].[NH4+]>CN(C=O)C>[C:1]([N:25]1[CH2:26][CH2:27][N:22]([CH2:21][C:11]2[N:10]([CH2:9][C:8]([CH3:29])([CH3:28])[CH3:7])[C:14]3[N:15]=[C:16]([C:19]#[N:20])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH2:23][CH2:24]1)(=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: CC(C)(C)Cn1c(CN2CCNCC2)cc2cnc(C#N)nc21
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCCC(=O)N1CCN(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)CC1
Reaction time: 8 h
Yield: 43.2 %

Procedure:
Butyric acid (0.35 mmol) and 7-(2,2-dimethyl-propyl)-6-piperazin-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.29 mmol) are dissolved in DMF (10 ml) and cooled with ice. HOBt (0.42 mmol) and WSCD.HCl (0.42 mmol) are added to the cold solution, and the reaction mixture is stirred at 4° C.-25° C. overnight. After saturated ammonium chloride is added to the reaction mixture, the mixture is extracted with AcOEt. The organic layer is washed with saturated ammonium chloride and brine, dried over magnesium sulfate and evaporated down. The crude product is applied to silica gel column chromatography, which is eluted with following solvents: n-hexane:AcOEt=1:1 (v/v), n-hexane:AcOEt=1:4 (v/v) and n-hexane:AcOEt=1:9 (v/v). The solvent of the latter effluent is removed by evaporation and dried in vacuo to afford the title compound. yield 43.2%, Rf=0.19 (n-hexane:AcOEt=1:5).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15]Cl)=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].CO>C1COCC1.C(Cl)(Cl)Cl>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:15][C:14]([CH3:18])([CH3:17])[NH:13][C:11]3=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(CCl)NC(=O)Nc1ccc2ncsc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1(C)CN(c2ccc3ncsc3c2)C(=O)N1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76 %

Procedure:
1-Benzothiazol-6-yl-3-(2-chloro-1,1-dimethyl-ethyl)-urea (I-201a: 620 mg, 2.18 mmol) in dry THF (5 mL) was added dropwise to a stirred mixture of NaH (78 mg, 3.25 mmol) in dry THF (5 mL) under argon atmosphere over a period of 10 minutes at 0° C. The resulting reaction mixture was stirred at room temperature for 45 minutes. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was partitioned between chilled water and ethylacetate. The organic layer was dried over Na2SO4 and concentrated to afford 410 mg of the product (77.35% yield).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:15]2[C:14]([Cl:16])=[N:13][C:12]([S:17][CH3:18])=[N:11][C:10]=2[NH:9][CH:8]=1)(=O)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CO>[Si:19]([O:4][CH2:5][CH2:6][C:7]1[C:15]2[C:14]([Cl:16])=[N:13][C:12]([S:17][CH3:18])=[N:11][C:10]=2[NH:9][CH:8]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CSc1nc(Cl)c2c(CCOC(C)=O)c[nH]c2n1
Solvent: CO
Product: CSc1nc(Cl)c2c(CCO[Si](C)(C)C(C)(C)C)c[nH]c2n1
Reaction time: 8 h

Procedure:
5-(2-Acetoxyethyl)-4-chloro-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine 2.5 (750 mg, 1.66 mmol) was de-acetylated with methanol-aq ammonia (100 ml) and dried by co-evaporation with dry pyridine. The residue was dissolved in dry pyridine (80 ml) and tert-butyldimethylsilyl chloride (598 mg, 3.94 mmol) added. The solution was stirred overnight, evaporated, and residual pyridine removed by co-evaporation with water (2×20 ml). The residue was dissolved in chloroform (500 ml), washed with saturated aq. sodium bicarbonate solution (100 ml), dried (Na2SO4) and evaporated. The crude product was purified by silica gel chomatography (32×400 mm) eluting with chloroform to give a white solid, 826 mg, 88%. Rf (in C) 0.43; δH(d6-DMSO) 12.10 (1 H, br s, NH), 7.28 (1 H, s, 6-H), 3.81 (2 H, t J 7.0, O—CH2), 2.96 (2 H, t J 7.0, O—CH2CH2), 2.53 (3 H, s, CH3), 0.83 (9 H, s, 3×CH3), −0.05 (6 H, s, 2×CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[CH:11][C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:9]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[C:11]([C:28](=[O:29])[CH2:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:9]1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: COC(=O)Cc1cc(O)n(-c2ccccc2Cl)n1
Solvent: C1COCCO1
Product: COC(=O)Cc1nn(-c2ccccc2Cl)c(O)c1C(=O)Cc1ccc(OC)cc1
Yield: 70 %

Procedure:
The mixture of the above obtained methyl [1-(2-chlorophenyl)-5-hydroxy-1H-pyrazol-3-yl]acetate (Compound of Formula (IV), 1 g, 3.76 mmol, 1 eq.), was suspended in dioxane (10 mL) and Ca(OH)2 (0.557 g, 2 equiv.) and (4-methoxyphenyl)acetyl chloride (0.694 g) under nitrogen, was heated at 120° C. for 45-60 minutes. The resulting red solution was concentrated in vacuo to afford a red syrup that was partitioned between ethylacetate and cold 0.1M HCl. Organic phases were washed with brine and dried over Na2SO4. Evaporation of solvent gave methyl {1-(2-chlorophenyl)-5-hydroxy-4-[(4-methoxyphenyl)acetyl]-1H-pyrazol-3-yl}acetate as a pink solid (1.09 g, 70% yield, 89% HPLC purity). MS (ESI+): 415.9; MS (ESI−): 413.8.
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([O:11][C:12](=[O:18])[C:13](OCC)=[O:14])[CH3:10].CC[O-].[Na+]>>[CH2:9]([O:11][C:12](=[O:18])[C:13](=[O:14])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]1=[O:8])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1CCCCCC1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C1CCCCCC1=O
Temperature: 25 °C
Yield: 52.3 %

Procedure:
Cycloheptanone (1.9998 g, 17.8 mmol) and diethyloxalate (2.42 mL, 17.8 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 5.94 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 13. The crude material was purified with 1:1 Hexanes:CH2Cl2 to obtain 1.9775 g (52.3%) of 13. Note: The product was still not completely pure at this point, but was carried on to the next step. 1H (CDCl3, 400 MHz): δ 4.31 (2H, q, J=7.3 Hz), 2.66-2.58 (2H, m), 2.48-2.43 (2H, m), 1.77-1.59 (6H, m), 1.34 (3H, t, J=7.3H) ppm.
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:32])[N:14]([N:23]=[CH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:33]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:32])[N:14]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: Cc1ccccc1C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1CNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 258A (0.026 g, 0.057 mmol) in tetrahydrofuran (1.2 mL) and methanol (0.005 mL, 0.114 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.045 mL, 0.090 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration, washed with water and dried. The crude product was triturated with dichloromethane/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.29 (s, 3 H) 3.97 (s, 2 H) 6.02 (t, J=6.62 Hz, 1 H) 7.08 (t, J=7.35 Hz, 1 H) 7.23 (s, 3 H) 7.29 (t, J=7.54 Hz, 2 H) 7.47 (m, 1 H) 7.55 (d, J=7.72 Hz, 2 H) 7.67 (m, 2 H) 8.10 (d, J=7.72 Hz, 1 H) 16.31 (s, 1 H). MS (ESI−) m/z 459 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][CH2:31][CH:32]([NH2:34])[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][O:30][CH2:31][CH:32]([NH:34][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:33]
Reactant: COCC(C)N
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCC(C)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 73.2 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (86 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 1-methoxy-2-propylamine (24 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 480.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (bs, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.76 (d, 1H), 7.71 (d, 1H), 7.46 (d, 1H), 7.34 (d, 1H), 4.30-4.15 (m, 1H), 3.62 (bs, 3H), 3.42 (dd, 1H), 3.29 (dd, 1H), 3.27 (s, 3H), 1.14 (d, 3H).
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH3:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[N:12]=[CH:11][C:10]=1[C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:31][CH:32]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][N:15]=2)[N:12]=[CH:11][C:10]=1[C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([CH:33]2[CH2:38][CH2:37][N:36]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1)=[O:25]
Reactant: Cc1c(C(=O)Nc2ccc(C3CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(C3CCN(S(=O)(=O)C(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Isopropylsulfonyl chloride (167 μl) was added at room temperature to a suspension of 5-methyl-N-[6-(piperidin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (215 mg) described in Reference Example 173 and potassium carbonate (237 mg) in N,N-dimethylformamide (1.7 ml), and stirred at room temperature for 4.5 hours. Water was added to the reaction solution, the precipitated solid was washed with ethyl acetate. The resulting solid was purified with a preparative HPLC (water:acetonitrile) to give the titled compound (44 mg) as a white solid.