Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[C:48]([CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])[CH3:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH:50]([C:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)=[O:49])[CH2:51][CH2:52]2)([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Product: CCOCCn1c(C(=O)C2CCN(CCC3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-[1-(2-ethoxy-ethyl)-1H-benzoimidazole-2-carbonyl]-piperidine to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([NH2:27])=[N:24][O:25][N:26]=2)=[CH:18][CH:17]=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:23]1[C:22]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[N:26][O:25][N:24]=1)=[O:6]
Reactant: Nc1nonc1-c1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(=O)Nc2nonc2-c2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
200 mg (0.85 mmol) of 2-chloro-4-(methylsulfonyl)benzoic acid and 167 mg (0.85 mmol) of 4-(4-chlorophenyl)-1,2,5-oxadiazol-3-ylamine are dissolved in 24 ml of CH2Cl2 at RT and treated with 0.12 ml (0.85 mmol) of triethylamine, 21 mg (0.17 mmol) of DMAP and 1814 mg (1.28 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF). The reaction mixture is stirred for 30 h at RT and subsequently washed twice with in each case 5 ml of water. The organic phase is dried over Na2SO4 and evaporated. The residue is purified by column chromatography (silica gel, heptane/ethyl acetate). Yield 140 mg (36%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH2:38]C)=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[CH2:26]O)=[CH:22][N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1.C(P(CCCC)CCCC)CCC.[NH:53]1[CH:57]=[N:56][CH:55]=[N:54]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]([N:53]4[CH:57]=[N:56][CH:55]=[N:54]4)[CH:25]=[CH2:26])=[CH:22][N:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1
Reactant: c1nc[nH]n1
Reactant: CCc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2/C=C/CO)cc1OC
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: C=CC(c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)n1cncn1
Reaction time: 15 h
Yield: 44.9 %

Procedure:
To a mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-ethyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propen-1-ol (1.00 g), tributylphosphine (0.77 g), 1H-1,2,4-triazole (0.26 g) and tetrahydrofuran (30 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.95 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 1-(1-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenyl)-1H-1,2,4-triazole as crystals (0.48 g, yield 45%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:9]=1)[CH:5]=[O:6].[CH2:15](O)[CH2:16][OH:17]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:17][CH2:16][CH2:15][O:6]2)[CH:7]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[CH:9]=1
Reactant: OCCO
Reactant: O=Cc1cc(Br)cc(OC(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1cc(Br)cc(C2OCCO2)c1
Yield: 53.7 %

Procedure:
A solution of 3-bromo-5-trifluoromethoxybenzaldehyde (20, 2.00 g, 7.43 mmol), ethylene glycol (2.31 g, 37.2 mmol), para-toluenesulfonic acid (50 mg, 0.26 mmol) in anhydrous toluene (50 mL) was refluxed using a Dean-Stark apparatus for 3 h. The solution was concentrated and the product purified by silica gel chromatography eluting with 0-10% EtOAc in hexanes to afford the title compound (1.25 g, 54%) as a clear, colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.57 (t, J=1.5 Hz, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 5.79 (s, 1H), 4.12-4.01 (m, 4H).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]([NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[N:14][CH:13]=1)([CH3:9])([CH3:8])[CH3:7].CO.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[C:6]([NH:10][C:11](=[O:19])[C:12]1[C:17]([CH:1]([CH3:3])[CH3:2])=[CH:16][C:15]([Cl:18])=[N:14][CH:13]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)[Mg]Cl
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)nc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc(Cl)ncc1C(=O)NC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
7.0 ml (14.1 mMol) iso-Propylmagnesium chloride solution (2M in THF) were added over 5 minutes to a solution of 1.0 g (4.7 mMol) N-tert.-butyl-6-chloro-nicotinamide in 5.0 ml THF cooled to 0° C. and the reaction mixture was stirred 18 hours at room temperature. After cooling to 0° C., 1.14 ml (28.2 mMol) methanol were added over 10 minutes, followed, after 15 minutes, by 1.17 g (5.2 mMol) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. After stirring 30 minutes at room temperature, the red-brown solution was concentrated under reduced pressure to about 10 g, heated to 50° C. and 20 ml tert.-butyl-methylether were added. The resulting suspension was stirred 1 hour at 55° C., then 1 hour at room temperature and filtered. The filtrate was concentrated under reduced pressure and digested in 9 ml n-hexane/ethyl acetate 4:1 to yield 0.67 g (56%) N-tert.-butyl-6-chloro-4-(prop-2-yl)-nicotinamide as a beige powder of m.p.=130-140° C. (dec.)
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([NH2:19])=[C:13]([O:20][CH3:21])[N:12]=1.N1C=CC=CC=1.[C:28]([CH2:32][C:33](Cl)=[O:34])([CH3:31])([CH3:30])[CH3:29]>ClCCl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([NH:19][C:33](=[O:34])[CH2:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:13]([O:20][CH3:21])[N:12]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: COc1nc(N2CCc3ccccc3C2)nc(OC)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1nc(N2CCc3ccccc3C2)nc(OC)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a mixture of 4c (0.219 g, 0.76 mmol) and pyridine (0.06 g, 0.76 mmol) in dichloromethane (5 ml) was added tert-butylacetyl chloride (0.102 g, 0.76 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield the title compound (0.262 g, 0.73 mmol, 96%). 1H NMR (CDCl3, 400 MHz) δ 1.10 (s, 9H), 2.20 (s, 2H), 2.90 (t, J=5.8 Hz, 2H), 3.92 (s, 6H), 4.01 (t, J=5.8 Hz, 2H), 4.87 (s, 2H), 6.14 (s, 1H), 7.15-7.19 (m, 4H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1.O>ClCCl>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[C:15]([C:5](=[O:8])[CH2:6][CH3:7])[CH:16]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCC(=O)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 91.1 %

Procedure:
Aluminium chloride (3.747 kg) was added to dichloromethane (7.0 l) at room temperature and propionyl chloride (1.297 kg) was then added over a 10 minute period. The mixture was stirred for 45 minutes and then a solution of 4-bromoanisole (1.312 kg) in dichloromethane (0.87 l) was added over a 15 minute period. The mixture was heated under reflux for 6.5 hours and then kept overnight at room temperature. The ice-cooled reaction mixture was quenched by the slow addition of ice (15 kg) over 1.5 hours. The mixture obtained was stirred for 15 minutes, the layers were separated and the aqueous layer extracted with dichloromethane (2×1.0 l). The organic layers were combined and washed with water (2×2.0 l), then two-thirds of the solvent removed by distillation at atmospheric pressure. Methanol (5.63 l) was then added slowly and the distillation continued until a pot temperature of 64° C. and a head temperature of 62° C. was achieved. Water (0.4 l) was added slowly and the mixture was cooled resulting in the precipitation of an off-white solid. Further water (0.4 l) was then added slowly and the precipitated solid granulated at about 10° C. for 2 hours. The solid was then filtered off, washed sparingly with a 6:1 methanol/water mixture and dried under reduced pressure at 50° C. to provide the title compound (1.464 kg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[CH:25])[CH3:21]>CCCCCCC.CCOC(C)=O>[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[C:25][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C#N)cc2)cc1
Reactant: C#CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCN(CC)CC#Cc1ccc(C#N)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-cyano-phenyl ester and diethyl-prop-2-ynyl-amine following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 6:4; yield (95.4 mg, 90%); 1H NMR δ (CDCl3): 7.58 (d, J=8.65 Hz, 2H), 7.49 (d, J=8.63 Hz, 2H), 3.64 (s, 2H), 2.61 (q, J=7.16 Hz, 4H), 1.11 (t, J=7.15 Hz, 6H); LCMS m/z: 212.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:9])[C:3]=1[CH3:10].[OH:11]O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:11])=[C:4]([CH3:9])[C:3]=1[CH3:10]
Reactant: Cc1cnc(C)c(C)c1Cl
Reactant: OO
Solvent: CC(=O)O
Product: Cc1c[n+]([O-])c(C)c(C)c1Cl
Temperature: 60 °C
Yield: 83 %

Procedure:
11.3 g (72.8 mmol) 4-chloro-2,3,5-trimethylpyridine was dissolved in 50 ml acetic acid and heated to 60° C. and 6.2 ml (50% H2O2) was added slowly and the temperature maintained for several hours and finally increased to 90° for two hours. The solvent was evaporated and extracted from alkaline water with diethyl ether to remove unreacted starting material. The water phase was saturated with sodium chloride and extracted several times with methylene chloride. The methylene chloride was dried and evaporated to give 10.1 g of product. Yield 83%. M.p. 147°-148° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1.[C:10]1([S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:8][C:6]1[N:7]=[C:2]([NH:1][C:20]([NH:19][S:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:18])=[O:17])=[O:21])[N:3]=[N:4][C:5]=1[CH3:9]
Reactant: Cc1nnc(N)nc1C
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Product: Cc1nnc(NC(=O)NS(=O)(=O)c2ccccc2)nc1C
Reaction time: 4 h

Procedure:
To a dry, well stirred mixture of 6 g of 3-amino-5,6-dimethyl-1,2,4-triazine in 100 ml of methylene chloride at ambient temperature and pressure was added 9 g of benzenesulfonyl isocyanate. The mixture was stirred for 4 hours and the precipitated product removed by filtration. After washing with 1-chlorobutane, the product melted at 155°-158°.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][Br:13].C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][Br:13]
Reactant: BrC(Br)(Br)Br
Reactant: O=C(CCCCBr)NCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(CCCCBr)NCCCCCBr
Reaction time: 12 h
Yield: 33.6 %

Procedure:
Part A. A solution of N-(5-hydroxypentyl)-5-bromopentanamide (4.07 g, 15.3 mmol) and carbon tetrabromide (7.61 g, 22.9 mmol) in methylene chloride (75 mL) was cooled to 0° C., and treated with a solution of triphenylphosphine (6.02 g, 22.9 mmol) in methylene chloride (30 mL) dropwise. After stirring for 12 hours, the reaction mixture was evaporated, and the residual oil was separated by flash chromatography (1:1 ethyl acetate-hexane) to afford the oily product, N-(5-bromopentyl)-5-bromopentanamide (1.69 g, 5.14 mmol, 34%). 1H NMR (CDCl3): 5.96 (1H, br s); 3.40 (4H, t, J=6.6 Hz); 3.24 (2H, q, J=6.2 Hz); 2.20 (2H, t, J=7.0 Hz); 1.94-1.74 (6H, m); 1.58-1.42 (4H, m).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[C:10]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1.Cl.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28](Cl)=[O:29]>C(Cl)Cl>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28]([N:21]1[CH2:20][CH2:19][N:18]([C:10]2[C:9]([CH3:8])=[CH:14][C:13]([N+:15]([O-:17])=[O:16])=[CH:12][N:11]=2)[CH2:23][CH2:22]1)=[O:29]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1cc([N+](=O)[O-])cnc1N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])cnc1N1CCN(C(=O)c2c(F)cccc2F)CC1
Reaction time: 8 h
Yield: 93 %

Procedure:
Add triethylamine drop wise (3 equiv) to a suspension of 1-(3-methyl-5-nitro-pyridin-2-yl)-piperazine; hydrochloride (6.91 g, 24.13 mmol) in DCM (120 mL). Add 2,6-difluorobenzoylchloride (1 equiv.) Stir the mixture at room temperature overnight. Add additional 2,6-difluorobenzoylchloride (1.6 mL) and triethylamine (1.5 equiv.) to run reaction to completion. Allow the reaction to stand overnight. Dilute with DCM and extract several times with water. Dry the organic layer over Na2S2O4, filter, and remove solvent under reduced pressure. Wash solid several times with hexane to obtain. 8.08 g of (2,6-difluoro-phenyl)-[4-(3-methyl-5-nitro-pyridin-2-yl)-piperazin-1-yl]-methanone (93% yield). ES+(m/z): 363 [M+1]
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1C.N([O-])=[O:12].[Na+]>>[CH3:9][C:7]1[CH:8]=[C:3]([OH:2])[C:4](=[CH:5][CH:6]=1)[OH:12]
Reactant: COc1cc(C)ccc1C
Reactant: O=N[O-]
Agent: [Na+]
Product: Cc1ccc(O)c(O)c1
Temperature: 2.5 °C
Reaction time: 5 h
Yield: 65.7 %

Procedure:
To an ice-cold concentrated nitric acid (200 mL) was added slowly under stirring over a period of 20 minutes 2-methoxy-1,4-dimethylbenzene (25 g, 184 mmol). To this cold reaction mixture, sodium nitrite (38 g, 552 mmol) was added slowly in lots over a period of 1 h while maintaining the temperature below 2° C. The reaction mixture was stirred at between 0-5° C. for 5 h. The reaction mass was poured into ice-cold water (1000 mL), and the precipitated solid was filtered, washed with cold water (100 mL) and dried. The crude solid was crystallized from ethanol and water (7:1) to yield compound 1 (15 g, 45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[CH3:20]O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH3:20])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: O=C(O)Cc1ccc(-c2ccc(F)cc2F)c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(-c2ccc(F)cc2F)c(F)c1

Procedure:
A solution of 2,2',4'-trifluoro-4-biphenylyl acetic acid (10 g.) in anhydrous methanol (100 ml.) and concentrated sulphuric acid (5 ml.) was refluxed overnight. Excess solvent was distilled and the residue was poured onto ice-water and extracted with ether. The extracts were washed with dilute aqueous sodium bicarbonate and then dried, evaporated and distilled to give a yellow oil, b.p. 142°-146°/0.5 mm., which solidified on cooling. This was crystallized from 62-68 petroleum ether to give methyl 2,2',4'-trifluoro-4-biphenylylacetate, m.p. 74°-77° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][CH:7]([F:21])[O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH2:19][OH:20]>C(Cl)Cl>[CH3:1][S:2]([O:20][CH2:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[O:8][CH:7]([F:21])[F:6])(=[O:4])=[O:3]
Reactant: OCc1c(OC(F)F)ccc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCc1c(OC(F)F)ccc2ccccc12
Yield: 65.4 %

Procedure:
Methanesulfonyl chloride (160 μL, 2.07 mmol) was added to a mixture of (2-(difluoromethoxy)naphthalen-1-yl)methanol (387 mg, 1.73 mmol) in CH2Cl2 (8.63 mL) and TEA (505 μL, 3.62 mmol). After 20 h the mixture was diluted with CH2Cl2, washed with H2O, brine, dried over Na2SO4, filtered and the filtrate was concentrated to provide (2-(difluoromethoxy)naphthalen-1-yl)methyl methanesulfonate (342 mg) as a brown oil that was used without further purification.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][CH:8]=[N:7][CH:6]=[C:5]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19]Br.Cl>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19][N:9]1[C:4](=[O:3])[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][N:7]=[CH:8]1
Reactant: Fc1ccc(CBr)cc1F
Reactant: CCOC(=O)c1cnc[nH]c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cncn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of sodium hydride (0.262 g, 6.54 mmol, 60% dispersion in mineral oil) and ethyl 6-oxo-1,6-dihydropyrimidine-5-carboxylate (1 g, 5.95 mmol) was dissolved in DMF (11.89 ml). After 30 min at room temperature, 3,4-difluorobenzyl bromide (0.761 ml, 5.95 mmol) was added. The reaction mixture was stirred at room temperature overnight and then poured into aqueous hydrochloric acid (10%). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/hexanes, to afford ethyl 1-(3,4-difluorobenzyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate as an off-white solid. LRMS (EST) calc'd for (C14H13F2N2O3) [M+H]+, 295.1; found 295.1.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[N:32][C:33]=2[NH2:35])[N:28]([C@H:36]2[CH2:41][CH2:40][C@@H:39]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[CH2:38][CH2:37]2)[N:27]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:35][C:33]1[N:32]=[CH:31][N:30]=[C:29]2[N:28]([C@H:36]3[CH2:41][CH2:40][C@@H:39]([N:42]4[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]4)[CH2:38][CH2:37]3)[N:27]=[C:26]([C:13]3[CH:12]=[CH:11][C:10]([CH:7]([C:8]#[N:9])[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:15][CH:14]=3)[C:34]=12
Reactant: CC1(C)OB(c2ccc(C(C#N)c3ccccc3)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(C#N)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 26.3 %

Procedure:
A mixture of 2-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetonitrile (0.120 g, 0.000376 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.083 g, 0.000188 mol), tetrakis-(triphenylphosphine)palladium (0.013 g, 0.000011 mol) and sodium carbonate monohydrate (0.058 g, 0.00047 mol) was heated in a mixture of ethylene glycol dimethyl ether (5 mL) and water (3 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methyl cyanide (0.025 g, 0.0000494 mol) as an off-white solid.
Reaction SMILES: [H][H].[C:3](#[N:12])[C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[CH:5]=1>[Ni]>[C:7]([C:6]1[CH:5]=[C:4]([CH:11]=[CH:10][CH:9]=1)[CH2:3][NH2:12])#[N:8]
Reactant: [H][H]
Reactant: N#Cc1cccc(C#N)c1
Agent: [Ni]
Product: N#Cc1cccc(CN)c1

Procedure:
600 g of m-cyanobenzylamine crude product (m-cyanobenzylamine 90% by weight, m-xylylenediamine 10% by weight) obtained by hydrogen reduction of isophthalonitrile in the presence of sponge metal nickel catalyst was added dropwise in 8 kg of water while stirring at room temperature for dissolution and the solution was left to stand overnight at 5C. The crystals which precipitated were filtered by centrifugation to obtain 783 g of m-cyanobenzylamine hydrate (water content: 48% by weight).
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[CH:12]([SH:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([S:15][CH:12]([CH3:14])[CH3:13])[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: CC(C)S
Reactant: C=CCC1C(=O)C=CC1(C)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCC1=C(C)C(SC(C)C)CC1=O
Reaction time: 5 h
Yield: 96.2 %

Procedure:
Into the same flask as used in Example 1, 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g), isopropylmercaptan (20 g), triethylamine (1 g) and toluene (45 g) were charged, and the mixture was stirred under a nitrogen stream at a temperature of 40° to 70° C. for 5 hours. After completion of the reaction, the mixture was washed with an acid, an alkali and water in order. The organic layer was separated and concentrated to give 2-allyl-3-methyl-4-isopropylthio-2-cyclopentenone (20.2 g). Yield, 96.3%. The product was purified by silica gel chromatography using toluene-ethyl acetate (10:1 by volume). nD20 1.5196.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)[NH2:2].[CH3:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15]>>[NH2:15][C:14]1[N:1]([C:3]2[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=2)[N:2]=[C:12]([C:11]([CH3:18])([CH3:17])[CH3:10])[CH:13]=1
Reactant: NNc1cc[nH]c(=O)c1
Reactant: CC(C)(C)C(=O)CC#N
Product: CC(C)(C)c1cc(N)n(-c2cc[nH]c(=O)c2)n1
Yield: 33 %

Procedure:
Following the procedure for Example 282A Step 1, 4-hydrazinylpyridin-2(1H)-one was heated at 80° C. overnight with 4,4-dimethyl-3-oxopentanenitrile. The reaction mixture was concentrated, triturated with DCM, and purified using silica gel chromatography eluting with a MeOH/DCM gradient (2-10%) to afford 4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)pyridin-2(1H)-one (307 mg, 33% yield). 1H NMR (300 MHz, DMSO d6) δ 1.18 (s, 9H), 5.43 (s, 1H), 5.47 (s, 2H), 6.55 (s, 1H), 6.66 (m, 1H), 7.37 (d, 1H), 11.40 (s, 1H); LC-MS (ESI) m/z 233 (M+H)+