Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[NH2:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.O>CC(C)=O>[NH:11]1[C:10]([NH:9][C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[S:8])=[CH:14][CH:13]=[N:12]1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1cc[nH]n1
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)NC(=S)Nc1ccn[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Ethoxycarbonyl isothiocyanate (3.16 g, 24.07 mmol) was added to 3-aminopyrazole (Aldrich) (2.0 g, 24.07 mmol) in acetone (20 mL). The reaction mixture was stirred at room temperature for 1 hour. Then cold water (100 mL) was added to the reaction mixture. The solid precipitate was collected through filtration, washed with water (50 mL), and then air dried to give 4.64 g (90%) of ethyl 1H-pyrazol-5-ylcarbamothioylcarbamate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]1=[O:16])[O:6][CH2:7][CH3:8])[CH3:2].[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:6][CH2:7][CH3:8])[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=2)[C:10]1=[O:16])[CH3:2]
Reactant: CCOC(=O)C(OCC)n1cccc(N)c1=O
Reactant: COc1cccc(B(O)O)c1
Product: CCOC(=O)C(OCC)n1cccc(Nc2cccc(OC)c2)c1=O

Procedure:
Using an analogous procedure as described in example 21.1, (RS)-(3-amino-2-oxo-2H-pyridin-1-yl)-ethoxy-acetic acid ethyl ester (example 19.2) was reacted with 3-methoxy phenylboronic acid to give (RS)-ethoxy-[3-(3-methoxy-phenylamino)-2-oxo-2H-pyridin-1-yl]-acetic acid ethyl ester. Light green gum. MS 347.4 ([M+H]+)
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C@@H:41]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:42]Br)=[C:34]2[C:39]=1[NH:38][C:37](=[O:40])[CH:36]=[CH:35]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+].[I-].[Na+]>CS(C)=O.O>[C:1]12([CH2:11][O:12][C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][CH2:42][C@@H:41]([C:33]4[CH:32]=[CH:31][C:30]([O:29][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[C:39]5[C:34]=4[CH:35]=[CH:36][C:37](=[O:40])[NH:38]5)[O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:16]=[CH:17][CH:18]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCCc1cccc(OCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1cccc(OCC23CC4CC(CC(C4)C2)C3)c1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a solution of Intermediate 41 (0.117 g, 0.41 mmol) in dimethyl sulfoxide (0.8 mL) and a solution of (R)-8-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)-ethyl)quinolin-2(1H)-one (0.2 g, 0.41 mmol) in dimethyl sulfoxide (0.8 mL) was added sodium hydrogen carbonate (0.103 g, 1.23 mmol) and sodium iodide (0.092 g, 0.61 mmol). The resulting reaction mixture was stirred at 150° C. for 1 hour. The mixture was poured into water and the precipitate was collected by filtration and washed with ether and ethyl acetate. The title compound was obtained as a brown solid (0.231 g, 57%) and was used in the next step without further purification. MS (M+): 694.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](C(Cl)(Cl)Cl)[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.[F:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:25][CH2:24][CH2:23][F:22])[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1
Reactant: OCCF
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nccc(-n2c(OCCF)nc3ccc(Br)cc32)n1
Yield: 78.5 %

Procedure:
A solution of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 1.23 mmol), 2-fluoroethan-1-ol (236 mg, 3.68 mmol) and cesium carbonate (1.2 g, 3.68 mmol) in N,N-dimethylformamide (3 mL) was stirred in a 20-mL sealed tube under nitrogen overnight at room temperature. The reaction mixture was diluted with 30 mL of water and the precipitate was collected by filtration to give 340 mg (79%) of 4-[6-bromo-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as a yellow solid; LC-MS: m/z=+352 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[C:3]=1[NH2:11].[C:12](=S)=[S:13]>O1CCCC1>[F:10][C:4]1[C:3]2[NH:11][C:12](=[S:13])[NH:1][C:2]=2[CH:7]=[C:6]([F:8])[C:5]=1[F:9]
Reactant: Nc1cc(F)c(F)c(F)c1N
Reactant: S=C=S
Solvent: C1CCOC1
Product: Fc1cc2[nH]c(=S)[nH]c2c(F)c1F
Temperature: 25 °C
Yield: 22.9 %

Procedure:
To a solution of 1,2-diamino-3,4,5-trifluoro-benzene (2.5 g, 15.4 mmol) in 20 mL of tetrahydrofuran under argon, are added 2.3 mL (38.6 mmol) of carbon disulfide. The reaction mixture is heated at reflux temperature for 3 h, upon which 2.3 mL (38.6 mmol) of carbon disulfide are added and reflux is maintained for 16 h. Carbon disulfide 2.3 mL (38.6 mmol) is added and reflux is maintained for 8 h, upon which 2.3 mL (38.6 mmol) of carbon disulfide are added and reflux is maintained for 16 h. The reaction mixture is then cooled to room temperature and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a prepacked 90 g 15-40 μm silica gel cartridge (eluting solvent: cyclohexane/ethyl acetate 90/10 v/v; rate: 35 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a prepacked 90 g 15-40 μm silica gel cartridge (eluting solvent: dichloromethane/methanol 100/0, then 98/2 v/v; rate: 40 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. 0.72 g of 4,5,6-trifluoro-1,3-dihydro-benzimidazole-2-thione is obtained as an off-white solid. LCMS-DAD-ELSD: 203(−): [M−H]−; 205(+): [M+H]+.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1.O>CN(C)C=O>[NH2:1]/[C:2](/[CH3:9])=[C:3](/[C:18](=[O:19])[NH:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C(C(=O)Nc1ccc(Cl)cc1)=C(/C)N
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a stirred solution of 12.9 g (0.10 mole) of ethyl 3-aminocrotonate in 50 ml of anhydrous dimethylformamide is added during 10 min. 15.36 g (0.10 mole) of p-chlorophenyl isocyanate in 50 ml of the same solvent. A mild exotherm (5° C.) results. After stirring for 3 hours, the reaction solution is slowly added with stirring to 1.5 l of deionized water. The white solid product is collected by vacuum filtration, washed with water and air dried at 45°-55° to give 23 g of ethyl 3-amino-2-(4-chlorophenylcarbamoyl)crotonate. Recrystallization of a 2.0 g. portion of this material from 15 ml of ethanol gives 1.5 g of pure ethyl 3-amino-2-(4-chlorophenylcarbamoyl)crotonate.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([I:12])=[CH:8][N:7]3[CH:13]=2)[CH2:3][CH2:2]1.[C:14]([O-])(=[O:16])C.[Na+].C=O>CC(O)=O>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([I:12])=[CH:8][N:7]3[C:13]=2[CH2:14][OH:16])[CH2:3][CH2:2]1
Reactant: Ic1ccc2nc(C3CC3)cn2c1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1c(C2CC2)nc2ccc(I)cn12
Temperature: 50 °C

Procedure:
To a solution of 2-cyclopropyl-6-iodoimidazo[1,2-a]pyridine (1.5 g) in AcOH (20 ml) were added sodium acetate (2.39 g) and 40% aqueous formaldehyde solution (4 ml), and the mixture was heated at 50° C. for 6 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:16][C:17]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:18]=1[C:19]([O:21]C)=[O:20].Cl>O1CCCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:17]([CH2:16][O:14][CH2:13][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:18]([CH:23]=1)[C:19]([OH:21])=[O:20]
Reactant: OCC1CCCCC1
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)ccc1COCC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.4 %

Procedure:
To a solution of potassium tert-butoxide (533 mg, 4.75 mmol) in tetrahydrofuran (10 ml) was added cyclohexylmethanol (594 mg, 5.20 mmol) in tetrahydrofuran (2.5 ml), methyl 2-(bromomethyl)-5-chlorobenzoate (250 mg, 0.95 mmol) in tetarahydrofuran (2.5 ml) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The resulting solution was acidified with 2 N hydrochloric acid solution (pH ca. 2) at 0° C. It was extracted with dichloromethane, the organic extracts were dried over sodium sulfate and concentrated to afford 302 mg of crude 5-chloro-2-[(cyclohexylmethoxy)methyl]benzoic acid. This carboxylic acid was converted into 132 mg (31%) of the title compound according to the procedure described in step 6 of Example 1:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.Br[CH:10]([C:20]1[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=1)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O>CN1CCCC1=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=3)=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[N:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccnc1Cl
Reactant: CSc1nccc(C(Br)C(=O)c2ccc(F)cc2)n1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3c(Cl)nccn23)n1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 5.1 %

Procedure:
To a solution of 3-chloropyrazin-2-ylamine (1.3 g, 10 mmol) in 1-methyl-2-pyrrolidinone (1 mL) heated to about 150° C. was added dropwise over about 15 min a solution of 2-bromo-1-(4-fluorophenyl)-2-(2-methylsulfanylpyrimidin-4-yl)ethanone (prepared according to WO2003000682; 0.34 g, 1 mmol) in 1-methyl-2-pyrrolidinone (1 mL). After about 30 min of stirring at about 150° C., the mixture was cooled to ambient temperature, diluted with DCM, extracted three times with 1N HCl and six times with 2N NaOH. The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by silica gel chromatography with heptane/EtOAc (stepwise gradient, 5:1, 3:1) to give 0.019 g (5%) of the title compound: LC/MS (Table 1, Method b) Rt=2.28 min; MS m/z: 372.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O)([CH3:4])([CH3:3])[CH3:2].[CH3:14][NH:15][NH2:16].S(=O)(=O)(O)O>C(O)C>[CH3:14][NH:15][N:16]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: CNN
Reactant: CC(C)(C)C(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CNN=C(c1ccc(Cl)cc1)C(C)(C)C

Procedure:
29.5 g ofg 4-chlorophenyl tert.-butyl ketone (0.15 mol) in 750 ml ethanol was heated under reflux with an excess (118 ml) of methl hydrazine and 3 ml of concentrated sulphuric acid for 4.5 hours. It was concentrated almost to dryness and the added to water. After extraction with methylene chloride and then drying and concentrating the extract in vacuo, there was obtained an oil which eventually crystallised. The resulting crude product used immediately.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][C:4]=1[CH3:13])=[O:2].[CH3:14]N(C=O)C.[H-].[Na+].CI>O>[CH:1]([C:3]1[N:7]([CH3:14])[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][C:4]=1[CH3:13])=[O:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(C)c(C=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cc(C)c(C=O)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 5-formyl-4-methyl-1H-pyrrole-2-carboxylate (0.97 g) and DMF (10 ml) was added sodium hydride (0.23 g) under ice-cooling, followed by stirring at room temperature for 0.5 hour. To a reaction mixture was added methyl iodide under ice-cooling, followed by stirring at room temperature for 15 hours. To the reaction mixture was added water under ice-cooling, followed by stirring at room temperature. The solid precipitated was collected by filtration and washed with water to obtain ethyl 5-formyl-1,4-dimethyl-1H-pyrrole-2-carboxylate (1.0 g).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][NH2:12])=[CH:4][C:3]=2[O:2]1.[CH2:13]1[O:21][C:20]2[CH:19]=[CH:18][C:17]([N:22]=[C:23]=[O:24])=[CH:16][C:15]=2[O:14]1>C1C=CC=CC=1>[CH2:13]1[O:21][C:20]2[CH:19]=[CH:18][C:17]([NH:22][C:23]([NH:12][CH2:11][CH2:10][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:1][O:2][C:3]=4[CH:4]=3)=[O:24])=[CH:16][C:15]=2[O:14]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: O=C=Nc1ccc2c(c1)OCO2
Solvent: c1ccccc1
Product: O=C(NCCc1ccc2c(c1)OCO2)Nc1ccc2c(c1)OCO2

Procedure:
A solution of 3,4-methylenedioxyphenylethylamine (0.25 g, 1.5 mmol) and 3,4-methylenedioxyphenyl isocyanate (0.25 g, 1.5 mmol) in benzene (25 ml) was refluxed for 1 hour. The precipitate formed was filtered, washed with benzene then dried to give pure DC-0078B (0.43 g, 85%) as a pale brown solid.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:11]=[C:12]([C:16](=[O:18])[CH:17]=2)[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].O>C(OCC)(=O)C>[C:27]([O:25][C:22]1[CH:21]=[CH:20][C:19]([N:10]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([N:2]([CH3:26])[CH3:1])=[CH:4][CH:5]=3)=[CH:17][C:16](=[O:18])[C:12]([C:13]([OH:15])=[O:14])=[CH:11]2)=[CH:24][CH:23]=1)(=[O:29])[CH3:28]
Reactant: CN(C)c1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(O)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc(-n2cc(C(=O)O)c(=O)cc2-c2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
With 1 g of 6-(4-dimethylaminophenyl)-1-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinic acid was mixed 10 ml of acetic anhydride and the resulting mixture was subjected to reaction at 130° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and introduced into 150 ml of water. After stirring the mixture for 1 hour, 150 ml of ethyl acetate was added to the mixture, and the organic layer was separated, washed with 100 ml of water and then with 50 ml of a saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the residue was added 20 ml of diethyl ether, and the resulting mixture was filtered to obtain 0.75 g of 1-(4-acetyloxyphenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 128°-131° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][O:9][CH:10](OC)[CH2:11][CH:12](OC)OC.[F:19][C:20]([F:26])([F:25])[S:21][CH2:22][C:23]#[N:24]>[Cl-].[Cl-].[Zn+2]>[C:23]([C:22]([S:21][C:20]([F:26])([F:25])[F:19])=[CH:12][CH:11]=[CH:10][O:9][CH3:8])#[N:24]
Reactant: N#CCSC(F)(F)F
Reactant: COC(CC(OC)OC)OC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Product: COC=CC=C(C#N)SC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.3 %

Procedure:
A solution of acetic anhydride (52 mL), 1,1,3,3-tetramethoxypropane (26.4 g, 0.16 mL), trifluoromethylthioacetonitrile (14.5 g, 0.1 mol) and ZnCl2 (1 g) was heated at reflux. After 18 hours, the mixture was distilled up to 100° at atmospheric pressure. The residue was then cooled to 25° C. and filtered. The clear solution was distilled to yield 3.5 g of 4-cyano-4-trifluoromethylthio-3-butenealdehydedimethylacetal (bp 65°-93° C. at 18 mm) and 5.3 g of 1-cyano-1-trifluoromethylthio-4-methoxy-1,3-butadiene (bp 83°-105° C. at 0.5 mm). This material was combined and used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][NH:11][CH2:12][CH2:13][OH:14])[CH:3]=[CH:2]1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCCl>[CH2:26]([O:25][C:23](=[O:24])[N:11]([CH2:12][CH2:13][OH:14])[CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCCNCc1cccc2cc[nH]c12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)N(CCO)Cc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
To a solution of 2-[(1H-indol-7-ylmethyl)-amino]-ethanol (4.4 g) in 1,2-dichloroethane (40 mL) was added triethylamine (4.85 mL, 34.6 mmol) followed by benzyl chloroformate (3.57 mL, 25.34 mmol). The mixture was allowed to stir at room temperature for 2 hours. The mixture was quenched by addition of water (20 mL), and 1.0 M sodium hydroxide (10 mL). The organic layer was separated and the aqueous layer extracted with 1,2-dichloroethane (20 mL). The combined organic extracts were washed with 1.0 M hydrochloric acid (20 mL), water (20 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography, eluting with 20% ethyl acetate in hexanes to 40% ethyl acetate in hexanes to afford (2-hydroxy-ethyl)-(1H-indol-7-ylmethyl)-carbamic acid benzyl ester (2.79 g, 52% combined yield for two steps) as a colorless oil. 1H NMR (CDCl3) 400 MHz δ: 9.97 (br s, 1H), 7.75-6.9 (m, 8H), 6.54 (br s, 1H), 5.21 (s, 2H), 4.9-4.6 (m, 3H), 3.85-3.57 (m, 2H), 3.55-3.23 (m, 3H); LCMS M+H=325.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[Br:16]Br.O>C(Cl)(Cl)Cl>[Br:16][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccccc1-c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccccc1-c1ccccc1
Reaction time: 0.25 h
Yield: 114.4 %

Procedure:
To a solution of 1.86 g of 2-acetyl-biphenyl in 10 ml of anhydrous chloroform, a solution of 1.29 g of bromine in 1.5 ml of anhydrous chloroform was added at 15°-20° C. When the addition was complete, the solution was stirred for 15 minutes, then poured into water. The chloroformic solution was washed with sodium bicarbonate and water, dried over calcium chloride and evaporated to dryness. 2.54 g of 2-bromoacetyl-biphenyl were obtained; the product could be used for reaction with imidazole without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[C:5]2[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:15]=1.Br[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1>>[NH2:26][CH2:25][C:3]1[C:2]([NH:1][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[N:15][C:6]2[N:7]([CH3:14])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[C:4]=1[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: BrCc1ccc2ccccc2c1
Reactant: COc1ccc(F)cc1-c1c(C#N)c(N)nc2c1c(=O)n(C)c(=O)n2C
Product: COc1ccc(F)cc1-c1c(CN)c(NCc2ccc3ccccc3c2)nc2c1c(=O)n(C)c(=O)n2C

Procedure:
Compound 70 was prepared from 70a and 2-(bromomethyl)naphthalene, according to procedures described in the synthesis of Compound 56. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.21 (s, 3H) 3.54 (s, 3H) 3.67 (s, 3H) 4.69 (d, J=14.7 Hz 1H) 4.92 (d, J=14.7 Hz, 1H) 6.64 (dd, J=8.2, 2.9 Hz, 1H) 6.98 dd, J=4.3, 9.1 Hz, 1H) 7.03-7.11 (m, 1H) 7.37-7.42 (m, 1H) 7.44-7.50 (m, 1H) 7.69-7.86 (m, 5H). MS [m+H] calc'd C28H27FN5O3 450; found 450.
Reaction SMILES: [F-].[K+].C1OCCOCCOCCOCCOCCOC1.[Br:21][C:22]1[C:23]([O:37]C(=O)C2C=CC=CC=2)=[CH:24][C:25]([O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:26][CH:27]=1>C(#N)C>[C:29]([O:28][C:25]1[CH:24]=[C:23]([OH:37])[C:22]([Br:21])=[CH:27][N:26]=1)(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(Oc1cc(OC(=O)c2ccccc2)c(Br)cn1)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: O=C(Oc1cc(O)c(Br)cn1)c1ccccc1
Yield: 62.3 %

Procedure:
There were mixed 0.15 g of potassium fluoride, 0.35 g of 18-crown-6 and 50 ml of acetonitrile. The mixture was refluxed for 30 minutes and 0.50 g of 5-bromo-2,4-dibenzoyloxypyridine was added thereto. The mixture was refluxed overnight, left to stand for cooling and concentrated. The concentrate was extracted with ethyl acetate and washed with water. The ethyl acetate layer was concentrated and the concentrate was treated with ether, giving 0.23 g of the title compound in a yield of 62%.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:37][CH2:36][C:12]2([C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]4[CH2:29][CH2:28][CH:27]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:26][CH2:25]4)=[CH:20][C:19]=3[F:35])[CH2:14][CH2:13]2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[F:35][C:19]1[CH:20]=[C:21]([CH:24]2[CH2:29][CH2:28][CH:27]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:26][CH2:25]2)[CH:22]=[CH:23][C:18]=1[N:15]1[CH2:14][CH2:13][C:12]2([CH2:11][CH2:10][NH:9][CH2:37][CH2:36]2)[C:16]1=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(N4CCCC4)CC3)cc1F)C2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1N(c2ccc(C3CCC(N4CCCC4)CC3)cc2F)CCC12CCNCC2

Procedure:
The title compound was prepared in the same manner as Example 17 by using hydrochloric acid in dioxane to hydrolyze 2-[2-fluoro-4-(4-pyrrolidin-1-yl-cyclohexyl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[N:10][C:5]2=[CH:4][CH:3]=1.O.[NH2:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[NH2:16][C:17]1[CH:22]=[C:21]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[N:10][C:5]3=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CC(=O)Nc1nc2ccc(Br)nc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cccc(N)c3)nc2s1
Temperature: 94.5 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
N-(5-bromothiazolo[5,4-b]pyridin-2-yl)acetamide (1.504 g, 5.527 mmol), 3-aminophenylboronic acid monohydrate (1.316 g, 8.493 mmol), Pd(dppf)C12-DCM complex (604.4 mg, 0.7401 mmol), and potassium carbonate (2.292 g, 16.58 mmol) were suspended in 1,4-dioxane (45 ml) and water (15 ml) was added. Argon was bubbled through the solution for about 30 seconds, and then the flask was fit with a reflux condensor and placed in a preheated oil bath (90-99° C.) and stirred under argon for 4 hours. The reaction was cooled to room temperature, filtered, and the solid was washed with DCM and MeOH. The filtrate was concentrated, treated with DCM and MeOH, and filtered. The solid was collected and set aside, and the filtrate was concentrated, treated with Et2O, and filtered. Solid washed with Et2O. This solid was combined with the first batch and dried under high vacuum first at room temperature, and then at ˜50° C. This solid was treated with deionized water and filtered, and the solid was washed with water, collected, and dried under high vacuum in water bath (˜50° C.) to afford N-(5-(3-aminophenyl)thiazolo[5,4-b]pyridin-2-yl)acetamide (1.22 g, 78% yield). MS (ESI pos. ion) m/z: 285. Calculated exact mass for C14H12N4OS 284.