Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:5](=[O:14])[NH:6]2.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29](B(O)O)[CH:30]=2)[CH:25]=[CH:24]1>CN(C=O)C.C(N(CC)CC)C>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:2]3[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]4[C:3]=3/[C:4](=[CH:15]/[C:16]3[NH:17][CH:18]=[CH:19][C:20]=3[O:21][CH3:22])/[C:5](=[O:14])[NH:6]4)[CH:30]=2)[CH:25]=[CH:24]1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Reactant: OB(O)c1ccc2cc[nH]c2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccc4cc[nH]c4c3)c21
Temperature: 90 °C
Yield: 57.1 %

Procedure:
A solution of (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl) methylene]-5-nitro-2H-indol-2-one (100 mg, 0.28 mmol) (Starting Material 6) and 6-indoleboronic acid (48 mg, 0.30 mmol) (from Example 48, Step A) were dissolved in 2 mL DMF and 2 mL triethylamine. The solution was degassed for 30 minutes by bubbling argon through the solution. At this time dichlorobis(triphenylphosphine) palladium(II) (20 mg, 0.029) (Aldrich) was added, and the reaction was heated, under argon, at 90° C. for 2 days. Water (20 mL) was then added and the precipitate was filtered off and dried. The product was purified via flash column chromatography (SiO2, 230-400 mesh) with 5% MeOH/CHCl3 to yield 64 mg (57%) (Z)-1,3-dihydro-4-(6-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one as a red powder.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([O:15][CH3:16])[CH:6]=1)=O.[NH2:17][C:18]([NH2:20])=[S:19].C([O-])(=O)C.[Na+]>C(O)C>[NH2:20][C:18]1[S:19][CH:2]=[C:3]([C:5]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([O:15][CH3:16])[CH:6]=2)[N:17]=1
Reactant: NC(N)=S
Reactant: COc1cc(C(=O)CBr)cc([N+](=O)[O-])c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(-c2csc(N)n2)cc([N+](=O)[O-])c1O
Reaction time: 6 h

Procedure:
aaa) A suspension of 2.9 g of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and 761.2 mg of thiourea in 170 ml of ethanol is treated at 60° with 820.3 mg of sodium acetate and stirred for 6 hours. The reaction mixture is then evaporated, the residue is treated with 170 ml of water and heated to 60° for 30 minutes. After cooling the product is filtered under suction and washed with water. There is obtained 4-(2-amino-4-thiazolyl)-2-methoxy-6-nitrophenol of m.p. 248°-250° (from ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>C(O)(=O)C>[N:15]1[CH:16]=[CH:17][C:12]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])=[CH:13][CH:14]=1
Reactant: Clc1ccncc1
Reactant: Nc1cccc(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1cccc(Nc2ccncc2)c1

Procedure:
3-(4-Pyridinylamino)benzoic acid was prepared from 41.1 g of m-aminobenzoic acid and 34.0 g of 4-chloropyridine in 110 ml of acetic acid, heated at reflux for 6 hours. With a work-up procedure similar to that of Example 33, there was obtained 48.5 g of product, m.p. 172°-180° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[O:11][CH2:13][CH:14]1[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: COc1cc(O)c(Br)cc1F
Product: COc1cc(OCC2CC2)c(Br)cc1F

Procedure:
Starting from commercially available 2-bromo-4-fluoro-5-methoxy-phenol (example A4) and bromomethyl-cyclopropane the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[O:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26].[OH-].[NH4+:34]>>[NH2:34][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:22])([CH3:23])[CH3:21])=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:24][S:25]([C:28]3[O:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:27])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: [NH4+]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2Cl)c(-c2ccnc(Cl)n2)s1
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2Cl)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide (75 mg, 0.147 mmol) and ammonium hydroxide (3 mL), the title compound was obtained as an off-white solid (49 mg, 68% yield). MS (ESI): 490 [M+H]+.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][NH2:5].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.N1C=CC=CC=1>[C:18]([NH:5][CH2:4][CH2:3][C:2]([OH:1])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCC(O)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCC(O)(c1ccccc1)c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To the solution of 58.0 g of 3-hydroxy-3,3-diphenylpropylamine in 700 ml of methylene chloride and 30.5 g of pyridine, that of 37.5 g of benzoyl chloride in 300 ml of methylene chloride is added dropwise during 2 hours while stirring and cooling with an ice-bath. Stirring is continued for 1 hour at 0°-5°, the mixture washed twice with 200 ml of N hydrochloric acid, 150 ml of 5% aqueous sodium hydroxide and 25 ml of water each, dried, evaporated and the residue triturated with diethyl ether, to yield the N-benzoyl-3-hydroxy-3,3-diphenylpropylamine melting at 140°-141°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:24][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(F)ccc3o2)c1
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(F)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-5-fluorobenzoxazole (221 mg, 0.8 mmol) and propylamine (328 μL, 4.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl>[N:11]1([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: N#Cc1ccc(CN2CCOCC2)cc1
Yield: 79.2 %

Procedure:
Dissolve 4-cyanobenzaldehyde (5 g, 38.1 mmol), morpholine (4.15 g, 47.7 mmol) and acetic acid (2.2 mL, 38.1 mmol) in DCE (100 mL). Add sodium cyanoborohydride (3.59 g, 57.2 mmol), and stir the mixture overnight. Add water (100 mL), separate the layers and extract the aqueous layer with DCM (3×50 mL). Wash the combined organic extracts with brine, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:2 over 1.25 h, 80 mL/min) to obtain the desired intermediate as a colorless oil (6.1 g, 79%). MS (APCI+) m/z: 203 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]1[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:24][C:25]3[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=3)[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: Cn1ccc(CCl)n1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc(CN2C(=O)C3COCCN3c3nc(Cl)ncc32)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a mixture of 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (100 mg, 0.416 mmol), K2CO3 (115 mg, 0.831 mmol) in DMF (2 mL) at 0° C., was added 3-(chloromethyl)-1-methyl-1H-pyrazole (54.3 mg, 0.416 mmol). The mixture was stirred at 0° C. for 30 minutes and then at room temperature for overnight. Water was added and the mixture was extracted with EtOAc (2×). The aqueous layer was basified and then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo to give 2-chloro-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (104 mg) which was used in the next step without further purification. MS [M+H] Found 335
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:22])[CH2:3][CH2:2]1.[ClH:23]>C(O)C.O1CCOCC1>[ClH:23].[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)[O:7][CH2:6][C:5]2=[O:22])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=C1COC2(CCNCC2)CN1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
1,1-Dimethylethyl 4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate was dissolved in ethanol (300 mL) and cooled over an ice bath. A 4M solution of hydrogen chloride in dioxane (300 mL) was added, such that the temperature remained low. The ice bath was removed and the mixture was stirred at ambient temperature overnight. The solid was collected, washed with a little ethanol and diethyl ether to give the title product (47.1 g, 58%). The mother liquors were treated with diethyl ether (1.2 L), stirred for 30 min, and the solid was collected and dried to give a total combined yield of 78% of the title product (63.69 g) over the three steps. MS(ES)+ m/e 211.0[M+H+]; 1H NMR (400 MHz, DMSO-d6) δ 9.17-8.64 (m, 2 H), 4.04 (s, 2 H), 3.14 (d, J=13.1 Hz, 2 H), 3.01-2.85 (m, 2 H), 2.83-2.71 (m, 1 H), 1.96-1.83 (m, 2 H), 1.83-1.68 (m, 2 H), 0.76-0.67 (m, 2 H), 0.64-0.55 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.Cl.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)CC>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][N:28]([C:4]3[N:3]=[C:2]([NH2:1])[C:7]([NH2:8])=[CH:6][CH:5]=3)[CH2:29][CH2:30]2)=[CH:17][CH:16]=1
Reactant: O=C(CCCN1CCNCC1)c1ccc(F)cc1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCO
Product: Nc1ccc(N2CCN(CCCC(=O)c3ccc(F)cc3)CC2)nc1N
Reaction time: 0.17 h

Procedure:
6 g 2-amino-6-chloro-3-nitropyridine, 12.6 g 1-(4-fluorophenyl)-4-(1-piperazinyl)-1-butanone dihydrochloride and 20 g potassium carbonate in 120 ml n-propanol are stirred under reflux for 21/2 hours. The mixture is then treated with 400 ml water, stirred for further 10 minutes and cooled in an ice bath. The resulting precipitate is filtered off, washed with water, dissolved in methylene chloride, dried over sodium sulphate and evaporated. The resulting 1-(4-fluorophenyl)-4-[4-(2-amino-3-nitro-pyridin-6-yl)-1-piperazinyl]-1-butanone, m.p. 128°-130°, is without further purification dissolved in 400 ml methanol. 3 g palladium on charcoal (5%) are added to the solution and the mixture is hydrogenated under normal conditions. The catalyst is filtered off and the solvent distilled off to give 1-(4-fluorophenyl)-4-[4-(2,3-diaminopyridin-6-yl)-1-piperazinyl]-1-butanone which is used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:24]=[N+:25]=[N-:26])=[CH:12][C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)c1nnc(Cl)cc1Nc1ccc(Br)cc1F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1nnc(N=[N+]=[N-])cc1Nc1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
To a solution of 4-(4-bromo-2-fluoro-phenylamino)-6-chloro-pyridazine-3-carboxylic acid tert-butyl ester (300 mg, 034 mmol) in DMF (5 ml) under argon at room temperature is added sodium azide (96 mg, 1.48 mmol) with stirring. The reaction mixture is stirred at 50° C. for 6 hours. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and washed with water, saturated NaHCO3 (20 ml×3) and saturated NaCl (30 ml×3). The organic layer is dried over Na2SO4 and concentrated. The residue is purified by flash column chromatography to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8]2)=[C:4]([CH3:14])[C:3]=1[CH:15]=O.O.[OH-].[Na+].Cl.[CH3:21][C:22]([CH3:24])=[O:23]>>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:12])([CH3:13])[CH2:8]2)=[C:4]([CH3:14])[C:3]=1[CH:15]=[CH:21][C:22](=[O:23])[CH3:24]
Reactant: CC(C)=O
Reactant: Cc1c(Cl)c(C=O)c(C)c2c1CC(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(C)c2c(c(C)c1Cl)CC(C)(C)C2
Yield: 65 %

Procedure:
To a solution of 21.8 g of the 6-chloro-2,2,4,7-tetramethylindan-5-carboxaldehyde in 67 ml of absolute acetone was added 33 ml of water and 36.5 g of 2% NaOH. After refluxing for 20 hours, the solution was acidified with 2N HCl and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 16.6 g of the title compound as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11].C1C(=O)N([Br:27])C(=O)C1>C(#N)C>[Br:27][C:17]1[CH:18]=[C:13]([O:12][CH:10]([C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[C:14]([NH2:19])=[N:15][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: CC#N
Product: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 0.25 h
Yield: 76 %

Procedure:
3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-aminopyridine (24.0 g, 79.9 mmol) was dissolved in acetonitrile (250 mL), and to which was added NBS (14.2 g, 79.9 mmol) under the cooling of ice bath. After 15 min, the solvent in the resultant mixture was evaporated under reduced pressure, and then purified via silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to yield the target product as solid powder of soil colour (23.2 g, 61.1 mmol; yield=76%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:5]([N+:17]([O-:19])=[O:18])=[C:4](F)[CH:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.O>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:5]([N+:17]([O-:19])=[O:18])=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:3]=1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)c(Cl)cc1F
Reactant: NC1CCOCC1
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)c(Cl)cc1NC1CCOCC1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
To a suspension of 2-(4-chloro-2-fluoronitrobenzen-5-yl)benzoxazole (see Working Example 112-1) (0.38 g, 1.3 mmol) in acetonitrile (8 mL) was added 4-aminotetrahydropyran (0.30 g, 2.9 mmol), and this was heated to reflux for 2 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered. The crystals obtained were purified by silica gel column chromatography to yield the title compound (0.10 g, 21% yield) as brown crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C.[Pt](=O)=O>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][NH2:10])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: NCCc1ccc(O)cc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: NCCC1CCC(O)CC1
Yield: 125.7 %

Procedure:
2-(4-Hydroxyphenyl)ethylamine (1.37 g, 10.0 mmol, 1.0 eq ) was dissolved in acetic acid (10 ml), and platinum dioxide catalyst (137 mg) was added. The mixture was stirred at 3 kgf/cm2 in a stream of hydrogen at 70° C. for 5 hours. The reaction mixture was filtered through Celite and the catalyst was washed with toluene. The filtrate was concentrated under reduced pressure to give 2-(4-hydroxycylohexyl)ethylamine (1.8 g).
Reaction SMILES: [F:1]F.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1>C(#N)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([F:1])[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=1
Reactant: FF
Reactant: COC(=O)C(=O)Cc1ccc(Cl)cc1
Solvent: CC#N
Product: COC(=O)C(=O)C(F)c1ccc(Cl)cc1

Procedure:
In the same manner as in Example 1, methyl 3-(4-chlorophenyl)pyruvate is dissolved in acetonitrile (500 ml) and reacted with fluorine at -10° C. After the same work-up as in Example 1, the resulting crude product is rectified to give syrupy methyl 3-(4-chlorophenyl)-3-fluoropyruvate (7.49 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6](O)=[CH:7][CH:8]=2)[CH:3]=1.[NH3:13].O.S([O-])([O-])=O.[NH4+].[NH4+].Cl>C(OCC)(=O)C>[NH2:13][C:6]1[CH:7]=[CH:8][C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: N
Reactant: Oc1ccc2ccc(Br)cc2c1
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc2ccc(Br)cc2c1
Temperature: 150 °C
Reaction time: 27 h

Procedure:
According to the procedure described in the aforementioned reference [L. C. Anderson et al., Journal of the American Chemical Society (J. Am. Chem. Soc.), vol. 65, p.241, 1943], 2-bromo-7-hydroxynaphthalene (2.23 g, MAYB) was added with 30% aqueous ammonia (30 ml) and ammonium sulfite monohydrate (2.69 g, WAKO) and stirred in a shield tube at 150° C. for 27 hours. The reaction mixture was added with ethyl acetate (90 ml) for extraction and then added with 1 N aqueous hydrochloric acid (1.5 l). The aqueous layer was separated, washed with ethyl acetate, then neutralized by adding 5 N aqueous sodium hydroxide (300 ml) under ice cooling and extracted with ethyl acetate again. The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate 26, 1.00 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][N:18]=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH2:17][NH:18][CH2:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3cnccc23)CC1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CCNC3)CC1
Temperature: 25 °C
Yield: 44 %

Procedure:
4-Isoquinoline-5-yl-piperazine-1-carboxylic acid tert-butyl ester (1.5 g) from Step 2 was dissolved in 5 mL of tetrahydrofuran (THF), and excess borane (BH3) in THF was added thereto. The mixture was brought to reflux for 1 hour, and allowed to cool to room temperature. The mixture was then further cooled in an ice bath, and water was carefully added to the reaction mix to consume excess borane. The reaction mix was then diluted with EtOAc, washed with saturated aqueous sodium bicarbonate (NaHCO3), dried over MgSO4, and chromatographed to provide 4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester as a viscous oil (0.668 g).
Reaction SMILES: I[C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:4][CH:3]=1.C(N(CC)CC)C.[C:26]([Si:28]([CH3:31])([CH3:30])[CH3:29])#[CH:27]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][Si:28]([C:26]#[C:27][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:4][CH:3]=1)([CH3:31])[CH3:30]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(I)[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(C#C[Si](C)(C)C)[nH]1
Yield: 81.8 %

Procedure:
A solution of (S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1 g, 2.75 mmol), triethylamine (1.92 mL, 13.8 mmol) and copper(I) iodide (0.105 g, 0.551 mmol) in DMF (30 mL) was degassed under vacuum and backfilled with nitrogen. Ethynyltrimethylsilane (1.35 g, 13.8 mmol) and Pd(Ph3P)4 (0.159 g, 0.138 mmol) were added and then the reaction was sealed and heated at 50° C. for 1d. The reaction was concentrated to remove the volatiles and the residue was purified on a BIOTAGE® (silica gel, eluted with 0 to 40% ethyl acetate/hexanes) to yield (S)-tert-butyl 2-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (751 mg, 2.25 mmol, 82% yield) as brownish foam.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[C:17]([CH:18]=[O:19])=[C:16]([F:20])[CH:15]=[CH:14][C:13]=1[NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:23].[OH-].[K+].Cl>CO>[F:11][C:12]1[C:17]([CH:18]([OH:19])[C:10]2[C:3]3[C:2]([CH3:1])=[N:7][CH:6]=[N:5][C:4]=3[NH:8][CH:9]=2)=[C:16]([F:20])[CH:15]=[CH:14][C:13]=1[NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:23]
Reactant: CC(C)CS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Reactant: Cc1ncnc2[nH]ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncnc2[nH]cc(C(O)c3c(F)ccc(NS(=O)(=O)CC(C)C)c3F)c12
Temperature: 25 °C
Reaction time: 7 h
Yield: 37.8 %

Procedure:
In a round bottom flask, 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (7, 97.0 mg, 0.728 mmol) is combined with 2-methyl-propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (62, 202 mg, 0.728 mmol), potassium hydroxide (204 mg, 3.64 mmol) and 1.4 mL of methanol. The reaction is stirred at room temperature for 7 hours. The reaction is neutralized with 0.1 N aqueous hydrochloric acid and extracted 3× with ethyl acetate. The combined organic layer is washed with brine, dried with sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (77, 113 mg). MS (ESI) [M−H+]−=409.2.