Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(O)C.[BH4-].[Na+]>C(Cl)(Cl)Cl>[OH:3][CH:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)OCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(O)c1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
60.98 g (0.24 mol) of benzyl 4-acetylbenzoate (II-19), 100 ml of ethanol and 300 ml of chloroform were supplied into a four-necked flask equipped with a stirrer and a thermometer. Then 4.6 g (0.12 mol) of sodium borohydride was added at 15°-25° C., over a period of 10 minutes. The mixture was kept at the same temperature for 2 hours and the resulting reaction mixture was poured into ice-water and extracted twice with 200 ml of ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure to obtain 58.37 g (95% yield) of benzyl 4-(1-hydroxyethyl)phenylcarboxylate (III-19). nD25 =1.5682.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH2:24])[CH3:23])[C:19]([N:25]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH:24][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:23])[C:19]([N:25]2[CH2:26][CH2:27][C:28]([F:32])([F:31])[CH2:29][CH2:30]2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(F)(F)CC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC(F)(F)CC1

Procedure:
A mixture of 6-bromo-9H-purine (0.0244 g, 0.123 mmol), 1-[5-chloro-8-(4,4-difluoropiperidin-1-yl)quinolin-7-yl]ethanamine (0.020 g, 0.061 mmol), and N,N-diisopropylethylamine (0.021 mL, 0.12 mmol) in ethanol (0.2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H21ClF2N7 (M+H)+: m/z=444.1; Found: 444.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(O)(C)C>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1cnc2ncc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1cccc(Br)c1
Solvent: CC(C)O
Product: N#Cc1cnc2ncc([N+](=O)[O-])cc2c1Nc1cccc(Br)c1

Procedure:
A mixture of 7.5 g (32 mmol) of 4-chloro-6-nitro-[1.8]naphthyridine-3-carbonitrile and 5.5 g (32 mmol) of 3-bromo-aniline in 175 ml of isopropanol was stirred at reflux for 2 hr. and 45 min. The mixture was cooled, solid was collected, and washed with ether giving 12.9 g of the title compound as the yellow hydrochloride salt: mass spectrum (electrospray, m/e): M+H 370, 373.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[N+:14]([O-])[C:13]=2[C:19]([O:21][CH3:22])=[O:20])[N:4]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+].[CH3:34][N:35]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)C(Cl)=O>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:19]([O:21][CH3:22])=[O:20])=[N:14][C:15]([N:35]([CH3:34])[CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:16][CH:17]=2)[N:4]=1
Reactant: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc[n+]1[O-]
Reactant: CN(Cc1ccccc1)C(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1nc(N(C)Cc2ccccc2)ccc1Oc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
20 g (77.1 mmol) of methyl 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate N-oxide, 15 g (116 mmol) of diisopropylethylamine and 46.2 g (308.2 mmol) of sodium iodide were suspended in 200 ml of acetonitrile and stirred at room temperature for 15 minutes. To this mixture, 21.2 g (115.4 mmol) of N-methyl-N-benzylcarbamoyl chloride dissolved in 20 ml of acetonitrile was added at room temperature. The mixture was refluxed. Foaming started at a temperature slightly lower than the boiling point, and such foaming terminated in about 30 minutes. The reaction was continued for further 10 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried, concentrated and then purified by silica gel column chromatography to obtain the desired product.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH:7][N:8]=[C:9]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=1)[C:10]([NH:12][CH:13]1[C:31](=[O:32])[N:15]2[C:16]([C:28]([O-:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]3[N:26]([CH3:27])[N:25]=[N:24][N:23]=3)[CH2:18][S:19][C@H:14]12)=[O:11].[Na+]>O.N1C=CC=CC=1>[CH2:5]([O:4][C:2]([O:7][N:8]=[C:9]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=1)[C:10]([NH:12][CH:13]1[C:31](=[O:32])[N:15]2[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]3[N:26]([CH3:27])[N:25]=[N:24][N:23]=3)[CH2:18][S:19][C@H:14]12)=[O:11])=[O:3])[CH3:6]
Reactant: Cn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3cccc(O)c3)[C@H]2SC1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1cccc(O)c1
Yield: 52.5 %

Procedure:
Ethyl chloroformate (10.9 g.) was dropwise added by small portions with stirring and ice-cooling to a solution of sodium 7-[2-hydroxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (16.3 g.) in a mixture of water (80 ml.) and pyridine (80 ml.), and the mixture was stirred for 1 hour at the same temperature. Water (200 ml.) was added thereto and the mixture was washed with ether. The aqueous layer was adjusted to pH 2 with hydrochloric acid and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and with a sodium chloride aqueous solution and dried over magnesium sulfate. After treating with activated charcoal, the solvent was distilled off and the residual oil was pulverized with a mixture of diisopropyl ether and ether. The powder was collected by filtration, dried and suspended in water (150 ml.). To the suspension was added sodium bicarbonate (1.7 g.). The solution was adjusted to pH 6 with dilute hydrochloric acid and treated with activated charcoal. Dilute hydrochloric acid was added thereto with cooling and stirring and precipitates were collected by filtration, washed with water and dried to give 7-[2-ethoxycarbonyloxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (9.4 g.).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.Cl.[CH3:22][N:23]1[CH:28]2[CH2:29][CH2:30][CH:24]1[CH2:25][NH:26][CH2:27]2>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([CH:25]3[NH:26][CH2:27][CH:28]4[N:23]([CH3:22])[CH:24]3[CH2:30][CH2:29]4)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CN1C2CCC1CNC2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Cl
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(C3NCC4CCC3N4C)c(F)c21
Temperature: 25 °C
Reaction time: 22 h
Yield: 44.5 %

Procedure:
A mixture of 1.40 g (5.0 mmole) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 2.0 g (8 mmole) of 8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride [P. A. Sturm et al., J. Med. Chem., 17, 481 (1974)], 2.0 ml (13.3 mmole) of 1,8-diazobicyclo[5.4.0]undec-7-ene, and 75 ml of acetonitrile was heated under reflux for 1.5 hr and then stirred at room temperature for 22 hours. The reaction mixture was evaporated to dryness and the residue was recrystallized from 2-propanol to give 0.84 g of the title compound, mp 184°-187° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1.Br[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1>[Pd]>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH:19][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: COCCn1ccc(NC(=O)c2nc(C)ccc2N)n1
Agent: [Pd]
Product: COCCn1ccc(NC(=O)c2nc(C)ccc2Nc2cc(F)cc(F)c2)n1

Procedure:
The title compound was prepared from 3-tert-Butoxy-carbonylamino-6-methyl-pyridine-2-carboxylic acid methyl ester in accordance with the general method of example 4; step 2 using 1-(2-Methoxy-ethyl)-1H-pyrazol-3-yl amine instead of 2-chloro-4-aminopyridine to yield {2-[1-(2-Methoxy-ethyl)-1H-pyrazol-3-ylcarbamoyl]-6-methyl-pyridin-3-yl}-carbamic acid tert-butyl ester as a yellow oil, MS (ISP): m/e=376.5 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid [1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-amide as a yellow oil, MS (ISP): m/e=276.3 (M+H+). Palladium catalysed arylation in accordance with the general method described in example 20 using 1-Bromo-3,5-difluorobenzene instead of 3-bromopyridine yielded the final compound as a light brown solid, MS (ISP): m/e=388.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:23](=[O:25])[CH3:24])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br)=[CH:11][CH:12]=2)[CH:7]=1.[OH:27][C:28]1[C:33]([CH2:34][CH2:35][CH3:36])=[C:32]([OH:37])[CH:31]=[CH:30][C:29]=1[C:38](=[O:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:23](=[O:25])[CH3:24])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:37][C:32]3[CH:31]=[CH:30][C:29]([C:38](=[O:40])[CH3:39])=[C:28]([OH:27])[C:33]=3[CH2:34][CH2:35][CH3:36])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)COc1ccc2ccc(OCCOCCBr)c(C(C)=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCOCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 75.7 %

Procedure:
A mixture of 2.4 g of [[8-acetyl-7-[2-[2-bromoethoxy)ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester, 1.32 g of 1-(2,4-dihydroxy-3-propylphenyl)-ethanone and 1.17 g of anhydrous potassium carbonate in 48 ml of anhydrous acetone and 16 ml of anhydrous dimethylformamide was stirred at reflux for 18 hours. The mixture was filtered and filtrate was concentrated to an oil. The oil was purified by flash column chromatography (10% ethyl acetate-toluene) to yield 2.3 g, mp. 89°-90° C. (76%) of [[8-acetyl-7-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:24]1[C:25]([F:35])=[CH:26][C:27]([F:34])=[C:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:24]4[C:25]([F:35])=[CH:26][C:27]([F:34])=[C:28]([S:30]([NH2:33])(=[O:31])=[O:32])[CH:29]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)c(Cl)c4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(3,4-dichloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.8) (82 mg, 0.25 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (68 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (39 mg, 30%). MS (ISP) 519.0 [(M+H)+]; mp 280–281° C.
Reaction SMILES: [C:1]([C:5]1[C:9]([Cl:10])=[CH:8][NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:11]=[O:12].C(N(CC)CC)C>CC(C)=O>[C:1]([C:5]1[C:9]([Cl:10])=[CH:8][N:7]([CH2:11][OH:12])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1n[nH]cc1Cl
Reactant: C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)c1nn(CO)cc1Cl
Temperature: 130 °C
Reaction time: 7 h
Yield: 111.2 %

Procedure:
The mixture of 0.62 g of 3-t-butyl-4-chloro-1H-pyrazole, 0.24 g of paraformaldehyde and 0.10 g of triethylamine was stirred at 130° C. for 7 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. Hexane was added to the residue obtained by concentration of the filtrate under reduced pressure, as a result, a crystal was formed. The crystal was collected to obtain 0.82 g of 3-t-butyl-4-chloro-1H-pyrazole-1-ylmethanol.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[C:10]([NH2:22])=[CH:11][C:12]2[CH2:13][C:14]3[C:19]([C:20]=2[CH:21]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[Br:8][C:9]1[C:10]([N:22]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:11][C:12]2[CH2:13][C:14]3[C:19]([C:20]=2[CH:21]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Nc1cc2c(cc1Br)-c1ccccc1C2
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Brc1cc2c(cc1N(c1ccccc1)c1ccccc1)Cc1ccccc1-2

Procedure:
8.0 g (42.2 mmol) of copper(I) iodide and 11.7 ml (97.5 mmol) of trans-cyclohexanediamine are added to a vigorously stirred suspension of 47.7 g (234 mmol) of iodobenzene, 26 g (100 mmol) of 3-bromo-9H-fluoren-2-ylamine and 416.4 g (1961 mmol) of potassium phosphate in 1170 ml of dioxane, and the mixture is heated under reflux for 16 h. After cooling, the precipitated solid is filtered off with suction, washed three times with 50 ml of toluene, three times with 50 ml of ethanol:water (1:1, v:v) and three times with 100 ml of ethanol. Yield: 33 g (80 mmol), 80%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:15])[C:12](O)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[NH2:17][NH2:18]>CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:15])[C:12]([NH:17][NH2:18])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: CC(C(=O)O)c1ccc2ncccc2c1
Solvent: CO
Solvent: O
Product: CC(C(=O)NN)c1ccc2ncccc2c1
Yield: 82 %

Procedure:
2-Quinolin-6-yl-propionic acid (5.6 g, 26.1 mmol), hydrazine hydrate (1.6 mL) and methanol (150 mL) were combined and heated to reflux for 72 hours. After such time the mixture was concentrated in vacuo and portioned between NaHCO3 (200 mL) and dichloromethane (150 mL). The aqueous phase was extracted with dichloromethane (2×150 mL) and the combined organic extracts dried (Na2SO4) and concentrated in vacuo to return the title compound as a white solid (4.6 g, 21.4 mmol, 82%). 1H-NMR (DMSO-d6, 500 MHz): 9.30 (1H, bs), 8.85 (1H, dd), 8.33 (1H, dd), 7.95 (1H, d), 7.86 (1H, d), 7.74 (1H, dd), 7.51 (1H, dd), 4.22 (3H, s), 3.74 (1H, q), 1.44 (3H; MS: m/z 216 [M+H+]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].Br[C:25]1[C:26]([F:36])=[CH:27][C:28]([F:35])=[C:29]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[C:26]([F:36])=[CH:27][C:28]([F:35])=[C:29]([S:31]([NH2:34])(=[O:32])=[O:33])[CH:30]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cc(S(N)(=O)=O)c(F)cc4F)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (178 mg, 0.5 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (136 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (125 mg, 47%). MS (ISN) 525.2 [(M−H)−]; mp 294° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][C:6]#[N:7].[H-].[Na+].[C:13](=O)([O:17]CC)[O:14][CH2:15][CH3:16]>C1COCC1>[CH2:15]([O:14][C:13](=[O:17])[CH:5]([C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=1)[C:6]#[N:7])[CH3:16]
Reactant: N#CCc1cccc(Cl)c1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
step 1—A solution 3-chlorobenzyl cyanide (10 g, 66 mmol) dissolved in diethyl carbonate (80 mL) was added over 15 min to a suspension of NaH (8.7 g, 0.218 mol, 60% dispersion in oil) in THF (70 mL) cooled to 0° C. The resulting mixture was stirred at RT for 12 h, heated at reflux for 14 h then cooled to RT and quenched with H2O. The reaction mixture was partitioned between Et2O and H2O and the aqueous layer was adjusted to pH 3 with 2M aqueous HCl and thrice back-extracted with Et2O. The combined organic layers were washed with water, brine, dried (Na2SO4), filtered and evaporated to afford 10.1 g (68% yield) of (3-chloro-phenyl)-cyano-acetic acid ethyl ester which was used in the next step without purification.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:5](=[O:17])[NH:6][C:7]([S:11][CH:12]([CH3:16])[C:13](=O)[CH3:14])=[N:8][C:9]=1[CH3:10].[BrH:18]>C(O)(=O)C>[BrH:18].[Br:18][CH2:2][CH2:3][C:4]1[C:5](=[O:17])[N:6]2[C:13]([CH3:14])=[C:12]([CH3:16])[S:11][C:7]2=[N:8][C:9]=1[CH3:10]
Reactant: CC(=O)C(C)Sc1nc(C)c(CCO)c(=O)[nH]1
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc2sc(C)c(C)n2c(=O)c1CCBr
Temperature: 90 °C

Procedure:
A mixture of 36 parts of 5-(2-hydroxyethyl)-6-methyl-2-[(1-methyl-2-oxopropyl)thio]-4(3H)-pyrimidinone and 240 parts of a hydrobromic acid solution 60% in acetic acid was stirred and heated for 4 hours at 90° C. The reaction mixture was evaporated and the residue was suspended in 400 parts of 2-propanone. The solid product was filtered off, washed with 2-propanone and dried, yielding 44 parts of 6-(2-bromoethyl)-2,3,7-trimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one monohydrobromide; mp. 172° C. (intermediate 12).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:10][C:11]1[CH:12]=[C:13]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][C:15]1([CH2:17][CH2:16]1)[C:14]2=[N:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25]>CCOCC.C1COCC1.[Zn]>[Br:10][C:11]1[CH:12]=[C:13]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][C:15]1([CH2:17][CH2:16]1)[C:14]2([C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[NH:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2OCC12CC2
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(F)(F)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2OCC12CC2
Reaction time: 4 h
Yield: 96.6 %

Procedure:
To a suspension of activated zinc (3.44 g, 52.5 mmol) in Et2O-THF (50% v/v, 80 ml) under reflux was slowly added a solution of ethyl bromodifluoroacetate (8.00 g, 39.4 mmol) and N-(6-bromo-4H-spiro[chromene-3,1′-cyclopropan]-4-ylidene)-2-methylpropane-2-sulfinamide (4.68 g, 13.1 mmol) in Et2O-THF (50% v/v, 80 ml) over 40 minutes, and the mixture was stirred for 4 hours at the same temperature. After cooling, the mixture was filtrated through celite pad and washed with EtOAc. To the filtrate were added saturated aqueous NH4Cl and EtOAc. After separation, the water layer was extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (EtOAc:hexane=20:80-100:0) to give ethyl {6-bromo-4-[(tert-butylsulfinyl)amino]-4H-spiro[chromene-3,1′-cyclopropan]-4-yl}(difluoro)acetate (6.08 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[CH:5]2.ClS([N:32]=[C:33]=[O:34])(=O)=O.[OH-].[Na+]>[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[C:5]2[C:33]([NH2:32])=[O:34]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(F)ccc21
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C(N)=O)c2cc(F)ccc21
Temperature: 25 °C
Yield: 82.3 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (300 mg, 0.82 mmol) in 2-Me-THF (7 mL) is treated with chlorosulfonyl isocyanate (CSI) (85 uL, 2.0 mmol) at 0° C., and the mixture is warmed to rt for 2 h. The mixture is then cooled to 0° C., treated with 1 M NaOH (1 mL), diluted with brine (20 mL), and extracted with EtOAc (3×20 mL). The combined organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo to afford 5-fluoro-1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1H-indole-3-carboxylic acid amide (275 mg, 83%). MS: 408 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.27 (s, 1H), 8.35 (d, 1H), 8.26 (s, 1H), 8.20 (d, 1H), 7.95 (d, 1H), 7.59 (m, 3H), 7.15 (m, 1H), 2.78 (s, 3H). IC50=8 nM.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[NH:20][C:21]2[C:26]([C:27]=1[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[CH:25][CH:24]=[C:23]([C:34]([O:36][CH3:37])=[O:35])[CH:22]=2)[CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47].Cl>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[NH:20][C:21]2[C:26]([C:27]=1[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[CH:25][CH:24]=[C:23]([C:34]([O:36][CH3:37])=[O:35])[CH:22]=2)[CH2:9][CH2:10][O:11][S:46]([CH3:45])(=[O:48])=[O:47])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CN(CCO)C(=O)OC(C)(C)C)[nH]c2c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CN(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(2-{[N-tert-butoxycarbonyl-N-(2-hydroxyethyl)amino]methyl}phenyl)-3-cyclohexyl-1H-indole-6-carboxylate (424 mg, 0.830 mmol) and triethylamine (0.14 ml, 1.0 mmol) in chloroform (5.0 ml) was added dropwise methanesulfonyl chloride (0.07 ml, 0.90 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 2-(2-{[N-tert-butoxycarbonyl-N-(2-methanesulfonyloxyethyl)amino]methyl}phenyl)-3-cyclohexyl-1H-indole-6-carboxylate as a crude product. The obtained crude product was used for Step 5 without purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[CH2:5]([C@@H:7]1[O:9][CH2:8]1)[Cl:6]>C1COCC1.B(F)(F)F.CCOCC>[Cl:1][CH2:2][C@H:3]([OH:4])[CH2:8][O:9][CH2:7][CH2:5][Cl:6]
Reactant: ClC[C@H]1CO1
Reactant: OCCCl
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: O[C@@H](CCl)COCCCl
Temperature: 45 °C
Yield: 866.9 %

Procedure:
2-chloroethanol (34.8 g, 43.2 mmol) and boron trifluoride diethyl etherate (0.136 mL, 1.08 mmol) were dissolved in 20 mL of THF and cooled in an ice bath. (R)-(−)-epichlorohydrin (10.0 g, 10.8 mmol) in 10 mL of THF was added slowly through a syringe. After the addition, the ice bath was removed and the mixture was heated in a 45° C. oil bath for 90 min at which time the reaction was complete. The reaction was concentrated in vacuo to give an oily crude product (R)-1-chloro-3-(2-chloroethoxy)propan-2-ol (2I, 16.2 g, 86.6% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.56-3.71 (m, 6H) 3.85-3.92 (m, 3H).