Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21]>ClCCl>[Si:24]([O:6][CH2:5][CH2:4][C@H:3]([NH2:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26]
Reactant: N[C@@H](CCO)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC[C@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
1.50 g of (S)-3-amino-3-phenylpropan-1-ol hydrochloride were initially charged in 20 ml of dichloromethane and then 2.77 ml of triethylamine and 1.30 g of tert-butyldimethylchlorosilane were added. After stirring at room temperature for 3 hours, the reaction solution was extracted three times with 30 ml of water, dried by means of a phase separator cartridge (Isolute®), concentrated by rotary evaporation and dried under high vacuum. This gave the product (2.06 g) with a molecular weight of 265.5 g/mol (C15H27NOSi); MS (ESI): m/e=266 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>N1C=CC=CC=1>[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])=[O:14]
Reactant: NC(=O)c1ccsc1N
Reactant: O=C(Cl)c1ccccc1F
Solvent: c1ccncc1
Product: NC(=O)c1ccsc1NC(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
2-Amino-thiophene-3-carboxylic acid amide (8.73 g, 61.4 mmole) was dissolved in pyridine (100 ml), cooled to 0° C., and 2-fluorobenzoyl chloride was added dropwise over 20 min, then the reaction was allowed to warm to room temperature with stirring overnight. The pyridine was removed under vacuum, dichloromethane and water were added. The product was precipitated as a grey solid and was washed with diluted hydrochloric acid, water and air dried. The dichloromethane layer was separated, washed with diluted hydrochloric acid, and water, dried over sodium sulfate (anh.) and the solvent was removed to give a total of 12.45 g product (77% yield).
Reaction SMILES: C[N:2](CCO)C.CCO.[C:10]([C:12]1[CH:13]=[C:14]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])C=1)[C:20]1[CH2:19][CH2:18][C@@H:17]([NH:33][C:34]([CH:36]3[CH2:38][CH2:37]3)=[O:35])[CH2:16][C:15]2=1)#[N:11]>>[C:10]([C:12]1[CH:13]=[C:14]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[N:2]=1)[C:20]1[CH2:19][CH2:18][CH:17]([NH:33][C:34]([CH:36]3[CH2:38][CH2:37]3)=[O:35])[CH2:16][C:15]2=1)#[N:11]
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C2CC2)C1
Reactant: CN(C)CCO
Solvent: CCO
Product: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)n2)CCC(NC(=O)C2CC2)C1

Procedure:
Prepare the title compound from cyclopropanecarboxylic acid(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)amide (Preparation 69) (10.0 g, 35.8 mmol) and 2-bromomethyl-6-fluoro-pyridine (Preparation 44) (7.49 g, 39.4 mmol) by essentially following procedures as described in Preparation 45 to obtain 4.30 g (31%) of a salmon colored solid. Resolve the enantiomers using chiral chromatography essentially as described for Example 194, but using 0.2% DMEA/EtOH eluent. (R)-Isomer is first to elute. Slurry the solid in EtOAc and filter to give the title compound. m.p.=243-245° C.; MS (ES): m/z 389 (M+1).
Reaction SMILES: [CH:1]([NH:3][CH:4](P(OCC)(OCC)=O)[C:5]([O:7][CH2:8][C:9]([Cl:12])([Cl:11])[Cl:10])=[O:6])=[S:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29](=O)[CH2:30][O:31][CH2:32][O:33][CH3:34]>CC(C)=O.C(Cl)Cl>[CH3:34][O:33][CH2:32][O:31][CH2:30][C:29]1[CH2:28][S:2][CH:1]=[N:3][C:4]=1[C:5]([O:7][CH2:8][C:9]([Cl:10])([Cl:11])[Cl:12])=[O:6]
Reactant: COCOCC(=O)CCl
Reactant: CCOP(=O)(OCC)C(NC=S)C(=O)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COCOCC1=C(C(=O)OCC(Cl)(Cl)Cl)N=CSC1
Reaction time: 4 h

Procedure:
A solution of 2,2,2-trichloroethyl α-thioformamidodiethylphosphonoacetate (3.87 g.) in acetone (50 ml.) is treated with powdered potassium carbonate (4.15 g) and 1-chloro-3-methoxymethyloxy-propan-2-one (1.60 g.). The mixture is stirred for 4 hrs. at room temperature under a nitrogen atmosphere, then filtered. Evaporation of the filtrate leaves a residue which is dissolved in methylene chloride. The solution is washed with dilute aqueous dipotassium hydrogen phosphate and water, dried over magnesium sulfate, filtered and evaporated in vacuo affording 2,2,2-trichloroethyl 5-methoxymethyloxymethyl-6H-1,3-thiazine-4-carboxylate.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](=[O:21])[NH:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.N1C=CC=CC=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>ClCCl>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([O:21][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCC[C@H]3C)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@H]3C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-methyl 3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.70 mmol) in dichloromethane (30 mL) was added pyridine (221 mg, 2.79 mmol) and then Tf2O (395 mg, 1.40 mmol) dropwise with stifling at 0° C. The resulting solution was stirred overnight at room temperature, then quenched by the addition of ice-water (50 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford (R)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (250 mg, crude).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C(O)(C(F)(F)F)=O.C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](/[N:15]=[CH:18]\[N:19]([CH3:21])[CH3:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(OCc2ccccc2)ccn1
Reactant: COC(OC)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CN(C)/C=N\c1cc(OCc2ccccc2)ccn1
Temperature: 50 °C

Procedure:
A 250 mL, single-neck, round-bottomed flask was charged with 4-(benzyloxy)pyridin-2-amine (6.012 g, 30.02 mmol), dimethoxy-N,N-dimethylmethanamine (5.535 ml, 39.03 mmol) and ethanol (100.1 ml). A few drops of TFA were added and the reaction was heated to 50° C. for 4 hours. The reaction was cooled to ambient temperature and concentrated. The crude product was used in the next step without purification.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH:10]([O:23][C:24]([CH:26]1[N:31]2[C:32](=[O:43])[CH:33]([NH:34][C:35](=[O:42])[CH2:36][C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)[C@H:30]2[S:29][CH:28]=[C:27]1[CH2:44]O)=[O:25])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(Cl)Cl>[F:7][CH2:44][C:27]1[CH:26]([C:24]([O:23][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:25])[N:31]2[C:32](=[O:43])[CH:33]([NH:34][C:35](=[O:42])[CH2:36][C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)[C@H:30]2[S:29][CH:28]=1
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CO)=CS[C@H]12
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CF)=CS[C@H]12
Reaction time: 0.5 h

Procedure:
To a solution of 0.322 g of diethylaminosulfur trifluoride in 10 ml of CH2Cl2 at -78° under N2 is added a solution of 1.04 g of benzhydryl-3-hydroxymethyl-7-(2-thienylacetamido)-2-cephem-4-carboxylate in 50 ml of CH2Cl2. The mixture is stirred for 0.5 hour then poured into 100 ml of H2O and the CH2Cl2 layer dried (MgSO4) and evaporated in vacuo. The residue is chromatographed on silica with CHCl3 to give benzhydryl 3-fluoromethyl-7-(2-thienylacetamido)-2-cephem-4-carboxylate, which can be purified by recrystallization from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[NH:17][C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:31])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[N:17]([CH3:31])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3-methyl-4-trifluoromethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.84 ppm (d, 1H), 7.37 ppm (d, 1H), 6.38 ppm (s, 1H), 5.25 ppm (m, 1H), 3.57 ppm (d, 3H), 1,36 ppm (d, 6H),
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:42]I>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][CH3:42])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:27][CH:28]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2OC)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.296 mmol, 0.16 g; Example 43) in DMF (2 mL) at 0° C. was added sodium hydride (80 mg) followed by methyl iodide (0.2 mL) and continued stirring at 0° C. for 30 min. The reaction mixture was diluted with ethyl acetate (10 mL) and quenched excess NaH by drop-wise addition of methanol. This was washed with brine (10 mL), organic layer was dried, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluating with 20% ethyl acetate in hexanes to afford (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester (0.145 g) as an oil.
Reaction SMILES: C(OP([C:9]([O:25][CH3:26])([O:23][CH3:24])[CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1)(OCC)=O)C.[Li]CCCC.CCCCCC.[C:38]1([CH3:58])[CH:43]=[CH:42][C:41]([C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[C:51]([CH:54]=O)[CH:52]=3)[C:47]([CH3:57])([CH3:56])[CH2:46][CH:45]=2)=[CH:40][CH:39]=1>C1COCC1>[CH3:26][O:25][CH:9]([O:23][CH3:24])[CH2:10]/[C:11](/[C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=1)=[CH:54]\[C:51]1[CH:52]=[C:53]2[C:48]([C:47]([CH3:57])([CH3:56])[CH2:46][CH:45]=[C:44]2[C:41]2[CH:40]=[CH:39][C:38]([CH3:58])=[CH:43][CH:42]=2)=[CH:49][CH:50]=1
Reactant: CCOC(=O)c1ccc(CCC(OC)(OC)P(=O)(OCC)OCC)cc1
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(C=O)cc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(/C(=C/c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)CC(OC)OC)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cold (-78° C.) solution of ethyl 4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 350 mg, 0.9 mmol, available in accordance with EPO Application No. 0 210 929 published on Feb. 4, 1987), in THF (9 mL), was added n-BuLi in hexane (1.6M solution, 0.7 mL, 1.1 mmol). The mixture was stirred for 1.5 hours. To this solution 1-(tol-4-yl)3,4-dihydro-4,4-dimethyl-7-naphthaldehyde (Compound C, 200 mg, 0.72 mmol), in THF (1 mL) was added and the mixture was gradually warmed to ambient temperature (4 h). The reaction was quenched by adding water (5 mL), and extracted with ethyl acetate (3×25 mL). The organic layer was washed with brine (10 mL), dried with MgSO4 and the solvent was removed by distillation. The crude material was purified by silicagel chromatography to afford the title compound as a colorless off.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[C:4]=1[N:13]1[CH2:17][CH:16]([CH2:18][N:19]=[N+]=[N-])[O:15][C:14]1=[O:22])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[C:4]=1[N:13]1[CH2:17][CH:16]([CH2:18][NH2:19])[O:15][C:14]1=[O:22])[CH3:2]
Reactant: [H][H]
Reactant: CCc1ccc2nc(C)[nH]c2c1N1CC(CN=[N+]=[N-])OC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc2nc(C)[nH]c2c1N1CC(CN)OC1=O

Procedure:
A mixture of (±)-3-(5'-1-ethyl-2-methylbenzimidazolyl)-5-(azidomethyl)oxazolidin-2one (XXXIX, EXAMPLE 70, 0.190 g) and palladium on carbon (10%, 0.065 g) is stirred in ethyl acetate (70 ml) for 15.5 hrs under 1 atm (balloon) hydrogen. The mixture is then filtered and the filtrate concentrated to give the crude product as a solid in an oil. The crude sample is placed on a silica gel column (5 cm×0.5 cm, 40.63 μ) and eluted with ethyl acetate followed by methanol/ethyl acetate mixtures (1/9 10 ml, 1/3 20 ml, 1/1 20 ml. The 1/3 and 1/1 methanol/ethyl acetate fractions are combined and concentrated to give the title compound as a foamy solid. NMR (CDCl3, 300 MHz) 7.64, 7.55, 7.24, 4.70, 4.10, 3.87, 3.12, 3.01, 2.57 and 1.36 δ; CMR (CDCl3, 75.47 MHz) 13.60, 14.77, 38.46, 44.80, 48.61, 73.57, 109.06, 109.17, 114.63, 131.64, 132.86, 142.52, 152.05 and 155.09 δ.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:16][C:17](Cl)=[O:18].Cl>[OH-].[Na+]>[O:18]=[C:17]1[N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][CH2:16]1
Reactant: O=C(Cl)CCl
Reactant: O=C(O)[C@@H](CO)NCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H]1COCC(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared according to the method described by H. H. Otto, Helvetica Chimica Acta, 2004, 87, 90. To an ice cooled solution of N-(phenylmethyl)-D-serine (8.90 g, 45.59 mmol) in 2N NaOH solution (50 mL) was added chloroacetyl chloride (4.36 mL, 54.71 mmol), dropwise over 15 minutes. The reaction was stirred for 30 minutes before adding 30% NaOH solution (4.5 g in 15 mL) and stirring at R.T. for 2 and ½ hours. It was cooled in an ice bath before adding c.HCl solution to pH<1. solid precipitated out. Filtered. Suspended in isopropanol and heated at reflux for 10 minutes. Filtered hot. Solvent evaporated to afford a pale yellow solid. Triturated with Et2O to afford the title compound as a cream solid in 29% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:23][O:24][CH2:25]Cl.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[N:10]([CH2:23][O:24][CH3:25])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCn1nc(-c2cccc(F)c2)c2cc(C(=O)OC)ccc21
Reaction time: 0.5 h

Procedure:
A total of 1.0 g of methyl 3-(3-fluorophenyl)-1H-5-indazolecarboxylate obtained in Production Example I-4-e was dissolved in 15 ml of N,N-dimethylformamide, and 200 mg of sodium hydride (60% oily) was added under ice-cooling, followed by stirring for 30 minutes. To the reaction mixture was added 0.4 ml of chloromethyl methyl ether, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:10), to give 0.95 g of methyl 3-(3-fluorophenyl)-1-(methoxymethyl)-1H-5-indazolecarboxylate as colorless needles. This compound was dissolved in 15 ml of tetrahydrofuran, and 8.0 ml of a solution of diisobutylaluminum hydride in toluene was added dropwise at room temperature. While cooling the reaction mixture, water was added. The mixture was acidified with diluted hydrochloric, and extracted with ethyl acetate for two times. The organic layer was washed with sodium hydrogencarbonate and water, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 0.78 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH3:21])(=[O:10])=[O:9])[CH2:3]1.[N:22]1[N:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:25]2=[C:24]([C:31](O)=[O:32])[CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:12]=2[CH3:21])(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:31]([C:24]1[CH:23]=[N:22][N:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:25]=12)=[O:32]
Reactant: Cc1cc(C(F)(F)F)ccc1S(=O)(=O)N1CCN[C@@H](C)C1
Reactant: O=C(O)c1cnn2cccnc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)ccc1S(=O)(=O)N1CCN(C(=O)c2cnn3cccnc23)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.5 %

Procedure:
To a solution of (3S)-3-methyl-1-{[2-methyl-4-(trifluoromethyl)phenyl]sulfonyl}piperazine (100 mg, 0.310 mmol) (may be prepared as described in Description 27), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (55.7 mg, 0.341 mmol), HOBt (52.3 mg, 0.341 mmol) and DIPEA (0.081 ml, 0.465 mmol) in dry DMF (5 ml) at rt was added HBTU (129 mg, 0.341 mmol) and the resulting orange solution stirred at rt for 45 min. Concentration under vacuum left an orange oil. Purification by MDAP and concentration of the desired fractions gave the title compound (108 mg) as a clear film that became a white solid on trituration with ether.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.[CH2:33]([N:36]=[C:37]=[O:38])[CH:34]=[CH2:35]>>[CH2:33]([NH:36][C:37]([NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1)=[O:38])[CH:34]=[CH2:35]
Reactant: C=CCN=C=O
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: C=CCNC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and allyl isocyanate by using the same techniques as in Example 119.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:23][NH2:24]>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])=[N:23][NH:24][C:8]2=[O:9])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccccc2OC)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(-c3ccccc3OC)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 5-methoxy-2-(2-methoxybenzoyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([C:10](N)=[O:11])=[N:8][S:9][C:5]=2[CH:4]=1.[OH-:15].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([C:10]([OH:15])=[O:11])=[N:8][S:9][C:5]=2[CH:4]=1
Reactant: [OH-]
Reactant: COc1ccc2c(C(N)=O)nsc2c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(C(=O)O)nsc2c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of the amide (5.46 mmol) in methanol (100 mL) was added 10 N sodium hydroxide (12 mL). The mixture was heated at reflux for 12 h, cooled to rt, and was acidified to pH <2 by the slow addition of conc. hydrochloric acid. The organic layer was extracted with dichloromethane (2×) and was dried over sodium sulfate. The crude product was purified by chromatography (300/50/1 dichloromethane/methanol/formic acid) to provide 6-methoxy-1,2-benzisothiazole-3-carboxylic acid (89%) as a pink solid. The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according to procedure A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[CH:3]=1.S(Cl)([Cl:12])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][Cl:12])[CH:3]=1
Reactant: OCc1cc(Cl)ccn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: ClCc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.9 %

Procedure:
To a mixture of (4-chloro-pyridine-2-yl)-methanol (146.8 mg, 1.0 mmol) described in Manufacturing Example 51-1-1 and toluene (3 mL) was added thionyl chloride (112 μL, 1.53 mmol) on an ice bath, which was stirred for 1 hour 15 minutes at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (97 mg, 59%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)[CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]2[CH:23]=[CH:22][N:21]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[NH:8][CH:9]=[CH:10][C:3]=34)[N:20]=2)[CH:13]=1
Reactant: Brc1ccnc2[nH]ccc12
Reactant: Oc1ccc(F)cc1-c1cc[nH]n1
Product: Oc1ccc(F)cc1-c1ccn(-c2ccnc3[nH]ccc23)n1
Temperature: 25 °C

Procedure:
4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.00025 mol) and 4-fluoro-2-(1H-pyrazol-3-yl)phenol (0.150 g, 0.000842 mol) were heated neat to 160° C. for 5 h. The reaction was allowed to cool to rt and the residue was purified by prep LC-MS on a C-18 column eluting with a water/ACN gradient containing 0.2% TFA to give the title compound, (0.052 g, 20%, as an amorphous white solid, LC/MS (M+H)+295, 1H NMR (DMSO-d6) δ 12.01 (bs, 1H), 10.25(bs, 1H), 8.81(s,1H), 8.35(d, 1H, J=5.5), 7.77(d, 1H, J=9.5), 7.64(m, 1H), 7.59(d, 1H, J=5.5), 7.32(s, 1H), 7.09(m, 1H), 7.05(m, 1H), 7.01(m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13]C1C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1ccc(Cl)c(OC)c1

Procedure:
4-chloro-3-methoxybenzoic acid (4.5 g) and 0.5 g of PTSA in 100 mL of dry methanol was refluxed for 3 hours. Evaporation and redissoving in ethyl acetate followed by washing with sodium bicarbonate, and concentration, gave methyl 4-chloro-3-methoxybenzoate without purification.