Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])=[O:17])[CH2:12][CH2:11]2)=[CH:2]1.[OH-].[Na+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=1>C1COCC1>[F:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])=[O:17])[CH2:12][CH2:11]3)=[CH:2]2)=[CH:49][CH:48]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: N#Cc1cccc(C(=O)N2CCC(c3c[nH]c4ccccc34)CC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1cccc(C(=O)N2CCC(c3cn(Cc4ccc(F)cc4)c4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-[4-(1H-Indol-3-yl)-piperidine-1-carbonyl]-benzonitrile (0.08 g, 0.24 mmol) is dissolved in 2 ml THF, then 2 ml of 50% NaOH, 0.2 ml tetrabutyl ammonium hydroxide (1.0M in MeOH), 4-fluoro-benzyl bromide (0.055 g, 0.29 mmol) are added and the reaction mixture is stirred at RT for 1.5 hours. The layers are separated and the organic solvent is removed under the reduced pressure, purified by a silica gel flash column using heptane and ethyl acetate as the elutes.
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:10]3[N:11]=[C:12]([CH2:14][C:15]([NH:17][NH2:18])=[O:16])[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[K+].[N:26]#[C:27]Br>CO>[C:1]1([C:7]2[CH:20]=[CH:19][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:16][C:27]([NH2:26])=[N:18][N:17]=4)[S:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CBr
Reactant: NNC(=O)Cc1nc2ccc(-c3ccccc3)cc2s1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: Nc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Reaction time: 3 h
Yield: 39.3 %

Procedure:
To a suspension of 2-(6-phenylbenzo[d]thiazol-2-yl)acetohydrazide (105 mg, 0.33 mmol) (described in WO 2011/074560) in MeOH (4 mL) was added potassium bicarbonate (42 mg, 0.42 mmol) followed by cyanogen bromide (0.036 mL, 0.37 mmol) and the reaction mixture stirred for 3 h. The solvent was removed under reduced pressure and the residue purified on silica gel chromatography eluting with 0.5 to 8.5% MeOH/DCM to give Compound 89a (40 mg, 37% yield) as an orange solid. LCMS=1.75 min using analytical method (M), 309.0 (M+H). 1H NMR (400 MHz, CDCl3 containing CD3OD) δ 8.09 (d, J=1.5 Hz, 1H), 8.03 (d, J=8.5 Hz, 1H), 7.74 (dd, J=8.5, 1.8 Hz, 1H), 7.68-7.61 (m, 2H), 7.50-7.44 (m, 2H), 7.41-7.36 (m, 1H), 4.59 (s, 2H).
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[C:2]([C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Yield: 59.2 %

Procedure:
To a solution of 3-[3-(1-hydroxyethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (3.99 g, 0.0107 mol) in dry methylene chloride under a nitrogen atmosphere is added powdered 4 Å molecular sieves followed by pyridinium dichromate (4.85 g, 0.0129 mol). The resultant mixture is stirred 22 hours at room temperature, diluted with ether, filtered through silica gel and diatomaceous earth, and concentrated in vacuo to a solid. The solid is recrystallized from ethyl acetate:hexanes to afford he title compound as a white crystalline solid (2.34 g, 59.2%, mp 149° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:12][C:13](=[O:15])[CH3:14])[S:5][C:6]=1[C:7]1[CH:11]=[CH:10][S:9][CH:8]=1.[Br:16]N1C(=O)CCC1=O>C(#N)C>[Br:16][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[C:6]1[S:5][C:4]([NH:12][C:13](=[O:15])[CH3:14])=[N:3][C:2]=1[CH3:1]
Reactant: CC(=O)Nc1nc(C)c(-c2ccsc2)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(=O)Nc1nc(C)c(-c2ccsc2Br)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
N-[4-methyl-5-(3-thienyl)-1,3-thiazol-2-yl]acetamide obtained in Step I as described above (3880 mg; 16.3 mmol; 1 eq) is dissolved in ACN (375 ml). N-bromosuccinimide (2898 mg; 16.3 mmol; 1 eq) is added and the resulting solution is stirred at room temperature for 30 minutes. Solvents are concentrated. Water is added and the desired product is extracted with EtOAc (3 times). Organic phases are washed with water (3 times) and dried over MgSO4, affording the title compound (5000 mg; 97%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[O:18][N:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].[O-]CC.[Na+].O>C(O)C>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[C:14](=[O:18])[CH2:15][C:16]#[N:17])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-c1ccno1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
A solution of 5-(2-nitro-4-trifluoromethylphenyl)-isoxazole (4.91 g) in ethanol (35 ml) was added dropwise to a solution of sodium ethoxide in ethanol (prepared from 0.6 g sodium in 25 ml ethanol). The mixture was stirred at room temperature for 3 hours, poured into water (150 ml) and acidified to pH 1. It was extracted with ether (2×75 ml) and the combined extracts were washed with water, dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was triturated with petroleum spirit (bp 60°-80° C.) and filtered to give 3-(2-nitro-4-trifluoromethylphenyl)-3-oxopropionitrile (4.9 g) as an off-white solid mp 79.5°-80.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@@H:13]([CH3:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[Cl:25][CH2:26][C:27](=N)OCC>ClCCCl>[Cl:25][CH2:26][C:27]1[N:12]([C@@H:13]([CH3:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=N)CCl
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)Nc1c(N)cnc2ccccc12
Agent: Cl
Solvent: ClCCCl
Product: C[C@@H](CNC(=O)OC(C)(C)C)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 60 °C
Yield: 46.6 %

Procedure:
tert-Butyl (2S)-2-[(3-aminoquinolin-4-yl)amino]propylcarbamate (4.60 g, 14.55 mmol) was dissolved in 150 mL of anhydrous 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (3.45 g, 21.8 mmol) was added and the reaction was heated to 60° C. for 24 hours. The reaction mixture was cooled and washed with saturated sodium bicarbonate solution (2×100 mL) followed by brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give an orange solid. Chromatography (SiO2, 60-80% EtOAc/hexanes) gave tert-butyl (2S)-2-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate (2.54 g) as a tan solid.
Reaction SMILES: [Mg].Br[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[B:13](OCC)([O:17]CC)[O:14]CC>O1CCCC1>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[B:13]([OH:17])[OH:14]
Reactant: Brc1ccc2ccccc2c1
Reactant: CCOB(OCC)OCC
Agent: [Mg]
Solvent: C1CCOC1
Product: OB(O)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
Magnesium (60.27 mmol) and tetrahydrofuran (30 mL) were put in a three-necked round bottom flask and stirred. To the solution, 2-bromonaphthalene (13.07 mmol) was added, and the reaction mixture was heated. After that, 2-bromonaphthalene (32.02 mmol) dissolved in tetrahydrofuran (30 mL) was added dropwise to the solution. The reaction mixture was heated and refluxed for 4.5 hours. After that, the mixture was cooled to −78° C. (EtO)3B (111.66 mmol) was added dropwise over 15 minutes. Then, the mixture was warmed to room temperature and stirred for additional 5 hours. Then, the mixture was cooled to 0° C. The reaction was quenched by the addition of 1 M hydrochloric acid stirring for 2 hours. The reaction mixture was extracted with diethyl ether three times. The combined extracts was washed with brine and dried over anhydrous sodium sulfate. After the drying, the extract was filtered. Then the filtrate was concentrated. The obtained solid was recrystallized in benzene to give GA40 (9 mmol, yield: 77%).
Reaction SMILES: [Cl:1]Cl.CS[CH2:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:7]=1[NH2:8].[ClH:17].O>C(Cl)CCl>[ClH:1].[Cl:17][CH2:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[C:7]=1[NH3+:8]
Reactant: ClCl
Reactant: CSCc1cccc(C(F)(F)F)c1N
Agent: Cl
Solvent: O
Solvent: ClCCCl
Product: [NH3+]c1c(CCl)cccc1C(F)(F)F
Temperature: 60 °C
Yield: 92.7 %

Procedure:
Chlorine (7.60 grams, 1.07 mol) was bubbled into a mechanically stirred solution of 221.0 grams (1.00 mol) of 2-methylthiomethyl-6-trifluoromethyl aniline in 2 liters of ethylene dichloride over 60 minutes while maintaining the reaction temperature below 20° C. A white suspension formed initially, became very thick halfway through the addition, and dissolved to give way to a cloudy solution at the end of the addition. The mixture was then heated to 60° C. while maintaining a steady stream of HCl bubbling through. Water (25 ml, 1.4 mol) was added and the HCl treatment was maintained at 60° C. for 15 minutes at which point a clear solution was obtained. Excess water was removed by azeotropic distillation (780 ml of solvent were removed) and the resulting solution was cooled to 0° C. with a steady stream of HCl bubbling through. Filtration, washing of the solids with 150 ml of cold ethylene dichloride and air-drying gave 228.0 grams (92.7%) of off-white 2-chloromethyl-6-trifluromethyl anilinium hydrochloride. This compound properties and analysis are described above.
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH2+:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:22]=2[N:23]=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:21]2[O:20][C:19]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]3[C:10]([O:9][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:11])=[N:23][C:22]=2[CH:24]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCC[NH2+]1
Reactant: Clc1ccc2oc(Cl)nc2c1
Agent: [Cl-]
Product: O=C(OCc1ccccc1)[C@@H]1CCCCN1c1nc2cc(Cl)ccc2o1

Procedure:
The title compound was prepared by a similar method to Preparation 2 from (2S)-2-((benzyloxy)carbonyl]piperidinium chloride (see EP 530167 A1 9303031 and 2,5-dichloro-1,3-benzoxazole [see J.O.C. (1996), 61(10), 3289-3297]. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 95:5, by volume, hexane:ethyl acetate to afford benzyl (2S)-1-(5-chloro-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH:14]=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:4]=1[NH:5][CH2:13][CH:14]=[O:15])[CH3:2]
Reactant: CCc1cccc(OC)c1N
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCc1cccc(OC)c1NCC=O
Temperature: 150 °C

Procedure:
2-Ethyl-6-methoxyaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at about 150° C. for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-ethyl-6-methoxyanilino)acetaldehyde.
Reaction SMILES: [CH2:1]([NH:7][C:8]([NH2:10])=[O:9])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14](O)=[O:15])#[N:12].C(OC(=O)C)(=O)C>O>[NH2:12][C:11]1[N:7]([CH2:1][C:2]2[O:6][CH:5]=[CH:4][CH:3]=2)[C:8](=[O:9])[NH:10][C:14](=[O:15])[CH:13]=1
Reactant: NC(=O)NCc1ccco1
Reactant: N#CCC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Nc1cc(=O)[nH]c(=O)n1Cc1ccco1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A solution of furfurylurea (7.0 g, 50.0 mmol), cyanoacetic acid (4.7 g, 55.0 mmol), and acetic anhydride (50 ml) was heated to 95° C. for 3 hours. After cooling to ambient temperature the solution was concentrated under reduced pressure to give a crude intermediate that was stirred with water (30 ml). After concentrating, the residue was dissolved in water (100 ml) and treated with a 50% aqueous sodium hydroxide solution (10 ml) to give a pH of 13. This solution was heated at 70° C. for 30 minutes, cooled and filtered. The wet solids were stirred in boiling ethanol for 15 minutes, cooled to ambient temperature and filtered. The filtrate was evaporated under reduced pressure to give 6-amino-1-furfuryluracil (5.5 g, 53% yield) as an orange solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[N:27][C:28]=3[NH2:30])[N:23]([CH:31]3[CH2:36][CH2:35][N:34]([CH:37]4CCN(C)CC4)[CH2:33][CH2:32]3)[N:22]=2)=[CH:17][C:16]=1[O:44][CH3:45]>N1C=CC=CC=1>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[N:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:9](=[O:10])[C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=4)=[C:16]([O:44][CH3:45])[CH:17]=3)[C:29]=12
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 5 h
Yield: 68.4 %

Procedure:
4-(Trifluoromethyl)-1-benzenecarbonyl chloride (48 mg, 0.231 mmol) was added to a solution of 3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (101 mg, 0.231 mmol) in pyridine (1.0 mL). After 5 hours, the solvent was evaporated and the residue was purified by flash column chromatography to give N1-{4-[4-amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-4-(trifluoromethyl)benzamide (83 mg, 59%). 1H NMR (CDCl3-d) δ 1.68 (m, 2H), 1.82 (m, 4H), 2.01 (m, 4H), 2.29 (s, 3H), 2.44 (m, 3H), 2.93 (m, 2H), 3.30 (m, 2H), 4.03 (s, 3H), 4.77 (m, 1H), 5.60 s, 2H), 7.33 (m, 2H), 1.79 d, J=8.19 Hz, 2H), 8.04 (d, J=8.04 Hz, 2H), 8.37 (s, 1H), 8.66 (m, 2H). LCMS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 3.5 mL/min.): MH+ =609.4, Rt=2.50 min.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([OH:13])[C:10]([OH:12])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[C:14]1(C)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[O:11]=[C:10]1[O:12][C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O:13][CH:9]1[P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8]
Reactant: Cc1ccccc1
Reactant: CCOP(=O)(OCC)C(O)C(=O)O
Solvent: CO
Product: CCOP(=O)(OCC)C1OC2(CCCCC2)OC1=O
Temperature: 110 °C

Procedure:
In a reaction vessel with a descending condenser, 50 g (0.236 Mol) (diethoxy-phosphinyl)-hydroxyacetic acid (A) and 240 mL toluene are mixed at ambient temperature and then heated to 110° C. When the boiling temperature of toluene is reached, a mixture of 71.7 mL (0.471 Mol) cyclohexane-dimethylketal (B) and 10 mL toluene are slowly added dropwise, while the azeotrope of toluene and methanol is distilled off. After the addition has ended the reaction mixture is refluxed for 90 minutes. Any solvent distilled off is replaced by the addition of 50 mL toluene. In order to achieve total conversion, a further 10 mL (0.066 Mol) of cyclohexane-dimethylketal (B) are added dropwise. The mixture is heated to a 110° C. for another hour and the solvent distilled off is replaced by the addition of another 100 mL toluene. After the addition of another 120 mL toluene the solvent is distilled off in vacuo. The residue is taken up in 200 mL tert.butyl-methylether and successively extracted twice with 200 mL of 10% potassium carbonate solution, once with 250 mL of 30% sodium bisulphite solution and once with 150 mL of 30% sodium bisulphite solution. After subsequent extraction with 40 mL saturated saline solution the organic phase is dried and evaporated down.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[CH3:4][C:5]1([CH2:10][CH2:11][C:12](OC)=[O:13])[O:9][CH2:8][CH2:7][O:6]1.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:4][C:5]1([CH2:10][CH2:11][C:12](=[O:13])[CH2:2][C:1]#[N:3])[O:9][CH2:8][CH2:7][O:6]1
Reactant: CC#N
Reactant: COC(=O)CCC1(C)OCCO1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(CCC(=O)CC#N)OCCO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
An acetonitrile solution (10 ml) containing 5.0 g of methyl 2-methyl-l,3-dioxolane-2-propionate was added dropwise to 10 ml of a DMF suspension containing 2.3 g of 60% sodium hydride, and stirred at room temperature for 4 hours. The reaction mixture was poured into ice water, acidified with a saturated citric acid solution and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=3:2) to provide 3.0 g of 2-methyl-β-oxo-1,3-dioxolane-2-pentanenitrile as oil.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[C:6]([CH3:13])[C:3]=1[C:4]#[N:5]>C(O)C.Cl.O>[Cl:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([CH3:13])[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)c1C#N
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)c(Cl)c1C#N
Yield: 31.8 %

Procedure:
A solution of 2-chloro-6-methyl-3-nitrobenzonitrile (6.3 g) in ethanol (23 ml) was added to a solution of stannous chloride dihydrate (21.7 g) in concentrated hydrochloric acid (19 ml). The mixture was then heated at reflux for 15 minutes, cooled and diluted with water (200 ml). The fine white powder which precipitated was separated, dried and crystallized from ethanol (10 ml) to give 2-chloro-3-cyano-4-methylaniline (1.7 g), m.p. 117°-119° C., in the form of colourless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:13]=[C:14]([CH3:16])[CH3:15].S(=O)(=O)(O)O>ClCCl>[C:14]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:16])([CH3:15])[CH3:13]
Reactant: C=C(C)C
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)c1cccc(OC(C)(C)C)c1
Reaction time: 48 h

Procedure:
To a solution of ethyl 3-hydroxybenzoate (20 g, 0.13 mol) in dichloromethane (200 ml) were added isobutene (about 30 g) and conc. sulfuric acid (0.5 ml), and the mixture was left for 2 days. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to give the objective substance (17.3 g, 63%) as an oil.
Reaction SMILES: [OH:1][C@H:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>C1COCC1>[CH3:9][S:10]([O:1][C@H:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@@H](C)O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)OS(C)(=O)=O
Temperature: 12.5 °C
Yield: 60.2 %

Procedure:
(R)-ethyl 2-hydroxypropanoate (15 g, 0.127 mol) and TEA (15.4 g, 0.15 mol) were added to THF and then cooled to 10-15° C. Then MsCl (15 g, 0.13 mol) was added to the solution dropwise with cooling while maintaining the temperature in the range of 10-15° C. at about 2 hours. The mixture was allowed to warm to about 20° C. and the solid was filtered off. The solution was washed with water and dried, concentrated to afford (R)-ethyl 2-(methylsulfonyloxy)propanoate (15 g, 60%). 1H NMR (400 MHz, CDCl3) δ ppm, 5.11-5.14 (q, 1H), 4.24-4.29 (m, 2H), 2.81-3.17 (q, 3H, J=7.2 Hz), 1.61-1.43 (d, 3H, J=7.6 Hz), 1.30-1.32 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C#N)=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3=[N:19][O:21][C:30]([C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)=[C:17]3[CH:18]=2)=[CH:11][CH:10]=[N:9]1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2F)cc1
Reactant: COc1ccc(CC#N)cc1
Product: COc1ccc(-c2onc3ccc(-c4ccnn4-c4ccccc4F)cc23)cc1

Procedure:
The title compound, light yellow solid (27 mg, 20%), MS (ISP) m/z=386.3 [(M+H)+], mp 134° C., was prepared in accordance with the general method of example 1 from 1-(2-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate B) (100 mg, 353 μmol) and commercially available 2-(4-methoxy-phenyl)-acetonitrile.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[C:42]([C:50]([F:53])([F:52])[F:51])=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>>[NH2:32][C:4]1[S:3][C:2]([C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([F:40])[C:42]=2[C:50]([F:51])([F:53])[F:52])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: OB(O)c1cccc(F)c1C(F)(F)F
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(F)c3C(F)(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-fluoro-2-(trifluoromethyl)phenyl)boronic acid gave 267. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.87-7.76 (m, 2H), 7.66-7.50 (m, 2H), 7.44 (s, 2H), 4.90 (dd, J=7.6, 3.8 Hz, 1H), 4.82-4.50 (m, 1H), 3.95-3.75 (m, 2H), 3.70 (s, 3H), 3.13 (dd, J=21.1, 8.4 Hz, 1H), 2.22-2.11 (m, 1H), 1.79-1.51 (m, 5H). LCMS (ES+) m/z 517 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][N:10]=1>>[CH2:15]([C:12]1[CH:11]=[N:10][C:9]([N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)=[N:14][CH:13]=1)[CH3:16]
Reactant: CCc1cnc(Cl)nc1
Reactant: O=C1CCNCC1
Product: CCc1cnc(N2CCC(=O)CC2)nc1

Procedure:
The title compound was synthesized from piperidin-4-one and 2-chloro-5-ethylpyrimidine manner similar to that described in Example 9.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[OH-].[K+].[I:14]I>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([I:14])=[N:5][NH:6]2
Reactant: Fc1cc(F)c2cn[nH]c2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1cc(F)c2c(I)n[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.4 %

Procedure:
To a solution of 4,6-difluoro-1H-indazole (1.16 g, 7.53 mmol) in DMF (60 ml) at room temperature was added potassium hydroxide (1.27 g, 22.6 mmol) and iodine (2.87 g, 11.3 mmol). The maroon reaction mixture was stirred at room temperature for 2 h then quenched with 10% aqueous Na2S2O3 and diluted with water. The mixture was extracted with EtOAc (2×). The combined organics were washed with water, sat LiCl, and sat NaCl, then dried over MgSO4 and concentrated to afford 2.18 g of 4,6-difluoro-3-iodo-1H-indazole as a light brown solid.