Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][CH2:13][F:14])=[O:10])[CH:5]=[CH:4][C:3]=1[C:15]1[N:16]=[C:17]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2C)[C:18]2[CH2:23][N:22](C(OCC)=O)[CH2:21][C:19]=2[N:20]=1.ClC1N=[C:39](N2CCOCC2)[C:40]2CN(C(C)C)C[C:41]=2N=1>>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][CH2:13][F:14])=[O:10])[CH:5]=[CH:4][C:3]=1[C:15]1[N:16]=[C:17]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[C:18]2[CH2:23][N:22]([CH:40]([CH3:41])[CH3:39])[CH2:21][C:19]=2[N:20]=1
Reactant: CC(C)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Reactant: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCF)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Product: CC(C)N1Cc2nc(-c3ccc(NC(=O)NCCF)cc3F)nc(N3CCOCC3)c2C1

Procedure:
Method as (S)-ethyl 2-(2-fluoro-4-(3-(2-fluoroethyl)ureido)phenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (Example 168) using 4-(2-chloro-6-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine (intermediate 34).
Reaction SMILES: O[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(S(F)(F)[F:16])CC)C>C(Cl)Cl>[F:16][C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)C(C)(C)O
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)F
Temperature: -70 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Ethyl 2-hydroxyisobutyrate (12.43 g) was stirred in dry methylene chloride (65 ml) at -70° C. under nitrogen. Diethylaminosulphur trifluoride (30.32 g) in dry methylene chloride (5 ml) was added slowly, maintaining the temperature at -70° C. After completion of the addition, the mixture was stirred at -70° C. for 1 hour and was then allowed to warm to room temperature, stood for 3 hours and then overnight. The reaction was then carefully added to ice with vigorous stirring, and the resultant methylene chloride layer combined with a further methylene chloride extract of the aqueous layer. The total organic fraction was washed with brine, dried over magnesium sulphate and the solvent carefully distilled, to leave ethyl 2-fluoro-isobutyrate as a bronze liquid (12.8 g); 1H NMR analysis indicated that this material was >95% pure, and contained 2-3% of ethyl methacrylate. NMR (CDCl3, 270 MHz) δ 1.31(3H,t), 1.58(6H,d), 4.25(2H,q) ppm; 1H NMR (CDCl3, 254 MHz, 19F) δ -148.0 (1F, septet) ppm.
Reaction SMILES: C(OC([O:6][C:7]1[CH:22]=[CH:21][C:10]([CH:11]=[CH:12][C:13]([O:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[O:14])=[CH:9][C:8]=1[O:23][CH3:24])=O)C.O.C(=O)([O-])[O-].[Na+].[Na+].Cl>CO>[OH:6][C:7]1[CH:22]=[CH:21][C:10]([CH:11]=[CH:12][C:13]([O:15][CH2:16][CH:17]=[C:18]([CH3:19])[CH3:20])=[O:14])=[CH:9][C:8]=1[O:23][CH3:24]
Reactant: CCOC(=O)Oc1ccc(C=CC(=O)OCC=C(C)C)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C=CC(=O)OCC=C(C)C)ccc1O
Reaction time: 4 h
Yield: 73 %

Procedure:
In 60 ml of methanol is dissolved 1.78 g of prenyl 4-ethoxycarbonyloxy-3-methoxycinnamate. To the solution is added 15 ml of water followed by addition of 0.56 g of sodium carbonate. The mixture is stirred for 4 hours followed by addition of 100 ml of water and then 1N hydrochloric acid to acidify the mixture. The resulting mixture is extracted with chloroform, and the organic layer is washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is subjected to column chromatography on silica gel. From the fraction eluted with chloroform is obtained 1.02 g of prenyl 4-hydroxy-3-methoxycinnamate (5). Spectroscopic data of the product support the structure of the formula (5) below.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[C:21](=O)[CH3:22])=[CH:15][CH:14]=1.C1(C)C=CC(S([NH:39][NH2:40])(=O)=O)=CC=1>C(O)(=O)C>[CH3:22][C:21]1[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:14][CH:15]=2)[NH:40][N:39]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: CC(=O)C(=Cc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccncc1
Solvent: CC(=O)O
Product: Cc1n[nH]c(-c2ccc(OCc3ccc4ccccc4n3)cc2)c1-c1ccncc1

Procedure:
A mixture of 4-(4-((quinolin-2-yl)methoxy)phenyl)-3-(pyridin-4-yl)but-3-en-2-one (1.00 g, 2.60 mmol) and p-toluensulfonylhydrazine (484 mg, 2.6 mmol) in acetic acid (14 mL) was heated at reflux for 10 h. Additional p-toluenesulfonylhydrazine (242 mg, 0.5 mmol) was added and the mixture heated at reflux 2 h. The mixture was concentrated, the residue dissolved in dichloromethane and the resulting solution washed with water (2×25 mL), dried and concentrated. The residue was chromatographed on silica eluted with 1%, 2%, and 3% methanol in dichloromethane containing 0.5% concentrated ammonium hydroxide giving a solid which was triturated with ether and dried. Yield 293 mg, 29%. 1H NMR (CDCl3, 400 mHz) δ 8.51 (m, 2H), 8.18 (d, 1H, J=8.7 Hz), 8.06 (d, 1H, J=7.9 Hz), 7.81 (d, 1H, J=8.3 Hz), 7.72 (m, 1H), 7.64 (d, 1H, J=8.3 Hz), 7.54 (m, 1H), 7.24 (m, 2H), 7.13 (m, 2H), 6.96 (m, 2H), 5.36 (s, 2H), 2.33 (s, 3H). HPLC-MS (system 1) 4.65 min, m/e 393 (MH+).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[CH3:13][C:14]1([CH3:22])[S:18][CH2:17][NH:16][CH:15]1C(O)=O>C1(C)C=CC=CC=1>[CH3:13][C:14]1([CH3:22])[S:18][CH2:17][N:16]2[CH:15]1[CH2:3][CH:2]1[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]1
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: CC1(C)SCNC1C(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC3N(CSC3(C)C)C2C1

Procedure:
8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl)-carbamate are heated under reflux overnight with 8.1 g (50 mmol) of 5,5-dimethylthiazolidine-4-carboxylic acid in 200 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:17]=[C:18]=S.[NH2:20][C:21]1[C:22]([NH:37][CH3:38])=[CH:23][C:24]([O:32][CH2:33][CH:34]([F:36])[F:35])=[C:25]([CH:31]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27].CC(C)N=C=NC(C)C>CN(C=O)C>[CH2:29]([O:28][C:26]([C:25]1[C:24]([O:32][CH2:33][CH:34]([F:35])[F:36])=[CH:23][C:22]2[N:37]([CH3:38])[C:18]([NH:17][C:3]3[CH:4]=[C:5]([CH2:6][NH:7][C:8]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:14])[CH:15]=[CH:16][C:2]=3[Cl:1])=[N:20][C:21]=2[CH:31]=1)=[O:27])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Reactant: CCOC(=O)c1cc(N)c(NC)cc1OCC(F)F
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nc(Nc3cc(CNC(=O)OC(C)(C)C)ccc3Cl)n(C)c2cc1OCC(F)F
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 4-chloro-3-isothiocyanatobenzylcarbamate ((see Example 2, step (c)) 974 mg; 3.26 mmol) and ethyl 5-amino-2-(2,2-difluoroethoxy)-4-(methylamino)benzoate ((see Example 59, step (g)) 894 mg; 3.26 mmol) in DMF (10 mL) was stirred over night at rt. DIC (411 mg; 3.26 mmol) was added and the mixture was heated at 90° C. for 1.5 h. The mixture was concentrated and the residue was recrystallized from EtOAc/petroleum ether and washed with Et2O to give the sub-title compound. Yield: 1.75 g (99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[OH:18])=[C:4]([F:20])[CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:21])=[C:4]([F:20])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)cc2F)c(O)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C(=O)Nc2ccc(Cl)cc2F)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of compound 2a (0.59 g, 2 mmole) in anhydrous acetone (10 mL) were added potassium carbonate (0.69 g, 5 mmole) and iodomethane (0.28 mL, 4.4 mmole) and refluxed 8 hr. After cooled to room temperature, the reaction mixture was filtered through Celite and concentrated. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: C([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)(=O)C.[C:17]([O:20]O)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([O:20][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:15][CH:16]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OO
Reactant: COC(=O)C(C)Oc1ccc(C(C)=O)cc1
Solvent: CC(=O)O
Product: COC(=O)C(C)Oc1ccc(OC(C)=O)cc1
Temperature: 58 °C
Yield: 83.8 %

Procedure:
Methyl 2-(4-acetylphenoxy)propanoate (22.4 g, 100.0 mL) is dissolved in acetic acid (100 mL). Purified peracetic acid (19%, 58.0 g, 145.0 mmol) is dropwise added to the reaction at 58° C. and 60 mmHgA. The reaction is refluxed for 10 hours at 58° C. and 60 mm HgA whereupon the reaction is analyzed by GLC. The reaction is cooled to room temperature and concentrated under reduced pressure to give pure methyl 2-(4-acetoxyphenoxy)propanoate (20.13 g) (yield 84%):b.p 96-98° C. at 0.15 mm HgA, IR(neat) 1757.8 (vs); 1H NMR (CDC13) delta 1.58 (d, J=6.9 Hz, 3H), 2.23 (s, 3H), 3.72 (s, 3H), 4.70 (q, J=6.9 Hz, 3H), 6.84 and 6.96 (dd, J=9.2 Hz, 4H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH:9]=2)[CH:4]=1.Cl.[NH+]1C=CC=CC=1>>[OH:19][C:15]1[CH:14]=[C:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]3)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(-c2ccc3cc(OC)ccc3c2)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Oc1cccc(-c2ccc3cc(O)ccc3c2)c1

Procedure:
The title compound was prepared by reacting 2-methoxy-6-(3-methoxyphenyl)naphthalene (0.51 g, 1.90 mmol) with pyridinium HCl (6 g) at 190° C. according to method B to yield 0.21 g (47%) of an off white solid: mp 192–194° C.; 1H NMR (DMSO-d6): δ 6.75–6.78 (1H, m), 7.10–7.14 (3H, m), 7.16–7.18 (1H, m), 7.65 (1H, dd, J=1.79 Hz, J=8.57 Hz), 7.75 (1H, d, J=8.77 Hz), 7.84 (1H, d, J=8.77 Hz), 8.01 (1H, d, J=1.59 Hz), 9.51 (1H, s), 9.78, (1H, s); MS (ESI) m/z 235 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[Br:14][CH2:15][CH2:16]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([C:9]([CH3:10])([CH3:12])[CH3:11])[C:3]=1[O:13][CH2:16][CH2:15][Br:14]
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(Br)cc(Br)c1OCCBr

Procedure:
To a solution of 2,4-dibromo-6-tert-butylphenol (5.00 g, 16.2 mmol) in acetone (70 mL) is added 1,2-dibromoethane (2.80 mL, 32.5 mmol) and K2CO3 (6.70 g, 48.7 mmol). The mixture is heated at reflux for 14 h, and then is filtered and evaporated. The residue is purified by chromatography over SiO2 eluting 15 with hexanes. The resulting oil is distilled to give 1,5-dibromo-(2-bromoethoxy)-3-tert-butylbenzene as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5](Cl)=[O:6].[Cl:18][C:19]1[CH:32]=[CH:31][C:22]2[NH:23][C:24]([C@@H:26]([NH2:30])[CH2:27][O:28][CH3:29])=[N:25][C:21]=2[CH:20]=1>C1COCC1>[Cl:18][C:19]1[CH:32]=[CH:31][C:22]2[NH:23][C:24]([C@@H:26]([NH:30][C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([F:1])[CH:3]=3)[CH2:27][O:28][CH3:29])=[N:25][C:21]=2[CH:20]=1
Reactant: COC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(Cl)c1ccc(N2CCOCC2=O)c(F)c1
Solvent: C1CCOC1
Product: COC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c(F)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 41d from 3-fluoro-4-(morpholin-3-on-4-yl)-benzoic acid-chloride and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine with TEA in THF.
Reaction SMILES: [Br:1][CH2:2][CH:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[OH:4].[C:10]1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:10][O:4][CH:3]([CH2:2][Br:1])[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC(CBr)c1cccs1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(CBr)c1cccs1

Procedure:
A solution of the halohydrin, α-(bromomethyl)-2-thiophenemethanol (10.0 g, 0.048 mole), described in Example 4, and p-toluenesulfonic acid (1.0 g) in 100 ml of the lower alkanol methanol, is heated at reflux for 5 hr. The mixture is concentrated and the concentrate extracted with ether. The ether extract is washed with water and brine, dried (MgSO4) and concentrated to yield a brown liquid which is purified by chromatography on silica gel to give α-(bromomethyl)-2-thiophenemethanol methyl ether; nmr (CDCl3) δ 3.36 (s, 3H), 3.58 (m, 2H), 4.68 (t, J = 6.5, 1H), 7.02 (m, 1H), 7.05 (m, 1H), 7.31 (m, 1H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:32])[N:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([Cl:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:32])[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([Cl:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NC1CCCCC1)c1c(O)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Yield: 96.9 %

Procedure:
Cyclohexylamine (1.27 mL, 11.17 mmol) was added to a solution of Compound 62 (2.0 g, 5.6 mmol) in toluene (50 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 2.23 g (96%) of white solids. M.P. 158° C. 1H NMR (DMSO-d6): δ 1.22 (m, 2H), 1.35 (m, 3H), 1.56 (m, 1H), 1.67 (m, 2H), 1.88 (m, 2H), 3.87 (m, 1H), 5.51 (s, 2H), 7.16 (m, 2H), 7.24 (m, 1H), 7.32 (m, 2H), 7.42 (d, J=9.0 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.80 (d, J=2.1 Hz, 1H), 10.36 (s, 1H). EIMS m/z 411 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH2:14](Br)[CH:15]=[CH2:16]>CN1CCCC1=O>[CH2:16]([N:4]([CH2:3][CH2:2][OH:1])[C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc(NCCO)cc1
Solvent: CN1CCCC1=O
Product: C=CCN(CCO)c1ccc([N+](=O)[O-])cc1

Procedure:
N-(2-hydroxyethyl)-4-nitrobenzenamine (9.1 g, 0.05 mol) is treated with allyl bromide in N-methylpyrrolidone, also as subsequently discussed in Example 11, to provide N-allyl-N-(2-hydroxyethyl)-4-nitrobenzenamine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:14]([O:18][C:19](=[O:35])[NH:20][C@H:21]([C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30](F)=[CH:29][CH:28]=1)[C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:17])([CH3:16])[CH3:15]>CS(C)=O>[C:14]([O:18][C:19](=[O:35])[NH:20][C@H:21]([C:26](=[O:34])[C:27]1[CH:28]=[CH:29][C:30]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:31][CH:32]=1)[C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:15])([CH3:16])[CH3:17]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(F)cc1)C(C)(C)C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(N2CCOCC2)cc1)C(C)(C)C
Temperature: 120 °C

Procedure:
Morpholine (1.41 mL, 16.2 mmol) and triethylamine (0.25 mL, 1.8 mmol) were added to a solution of [1(S)-(4-fluorobenzoyl)-2,2-dimethylpropyl]-carbamic acid tert-butyl ester (0.5 g, 1.62 mmol) in DMSO (8 mL), and the mixture heated at 120° C. for 15 hours. The solvent was removed in vacuo and the residual solid taken up in ethyl acetate (30 ml), and washed with 10% citric acid (aq.) (1×40 ml). The aqueous layer re-extracted with ethyl acetate (1×30 mL) and the combined organic phases were washed with brine (1×40 mL), dried over MgSO4, filtered and the solvent removed in vacuo to give a pale brown oil which was used without further purification (0.63 g, 100% crude).
Reaction SMILES: [F:1][C:2]([F:23])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][NH:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[F:24][C:25]([F:30])([F:29])[CH:26]1[O:28][CH2:27]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C>[F:1][C:2]([F:23])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:27][CH:26]([OH:28])[C:25]([F:30])([F:29])[F:24])[C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: FC(F)(F)C1CO1
Reactant: N#Cc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: N#Cc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Temperature: 50 °C
Yield: 75.6 %

Procedure:
The benzonitrile (1.58 g, 4.88 mmol) from EX-576A and 1,1,1-trifluoro-2,3-epoxy-propane (546 mL, 6.34 mmol) were dissolved in 4 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (304 mg, 0.49 mmol) was added, and the stirred solution was warmed to 50° C. overnight. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine, dried over MgSO4 and evaporated. The crude product was purified by MPLC on silica gel eluting with dichloromethane to give 1.61 g (76%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]benzonitrile product as a clear oil, greater than 98% by reverse phase HPLC. HRMS calcd. for C19H15F7N2O2: 437.1100 [M+H]+, found: 437.1097. 1H NMR (CDCl3) δ3.60-3.69 (m, 1H), 3.86 (d, 1H), 4.32 (bs, 1H), 4.69 (q, 2H), 5.86 (dt, 1H), 6.85-6.95 (m, 2H), 6.97-7.01 (m, 2H), 7.04-7.12 (m, 2H), 7.23-7.37 (m, 2H).
Reaction SMILES: [C@@H:1]12[CH2:6][C@@H:5]1[CH2:4][C@H:3]([C:7]([NH:9][C:10]1([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH2:12][CH2:11]1)=[O:8])[NH:2]2.CC#N.[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>>[F:26][C:27]([F:36])([F:37])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:2]2[C@@H:3]([C:7]([NH:9][C:10]3([C:13]4[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=4)[CH2:11][CH2:12]3)=[O:8])[CH2:4][C@@H:5]3[C@H:1]2[CH2:6]3)=[CH:30][CH:29]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3C[C@H]4C[C@H]4N3)CC2)cc1
Solvent: CC#N
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3C[C@H]4C[C@H]4N3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
To a solution of methyl 4-(1-((1R,3R,5R)-2-azabicyclo[3.1.0]hexane-3-carboxamido)cyclopropyl)benzoate (D104) (1.7 g, 5.7 mmol) in MeCN (80 ml) Cs2CO3 (2.8 g, 8.5 mmol) and 4-(trifloromethyl)benzylbromide (1.6 g, 6.8 mmol) were added and the resulting mixture was stirred at RT for 4 hrs. Solvent was evaporated and the residue was loaded on a SNAP-Si cartridge (100 g), eluted with a mixture DCM/AcOEt from 10/0 to DCM/AcOEt 9/1. Collected fractions after solvent evaporation afforded the title compound (D147) (2.41 g).
Reaction SMILES: [S:1]1[C:5]([C:6]([C:8]2[CH:13]=[C:12]([Br:14])[C:11]([F:15])=[CH:10][C:9]=2F)=O)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.O.[NH2:22][NH2:23]>>[S:1]1[C:5]([C:6]2[C:8]3[C:9](=[CH:10][C:11]([F:15])=[C:12]([Br:14])[CH:13]=3)[NH:23][N:22]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: O=C(c1cc2ccccc2s1)c1cc(Br)c(F)cc1F
Reactant: NN
Solvent: O
Product: Fc1cc2[nH]nc(-c3cc4ccccc4s3)c2cc1Br

Procedure:
A total of 5.7 g of benzo[b]thiophen-2-yl-(5-bromo-2,4-difluorophenyl)methanone obtained in Production Example II-16-a was allowed to react with hydrazine monohydrate by the procedure of Production Example II-10-c and thereby yielded 0.6 g of the title compound as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[N+:18]([C:21]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:26][C:22]=1[C:23](O)=[O:24])([O-:20])=[O:19].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1.O>[N+:18]([C:21]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:26][C:22]=1[C:23]([NH:15][C:12]1[CH:13]=[N:14][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)=[N:10][CH:11]=1)=[O:24])([O-:20])=[O:19]
Reactant: O=C(O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Reactant: Nc1cnc(-c2cccc(C(F)(F)F)c2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cnc(-c2cccc(C(F)(F)F)c2)nc1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
To 2-(3-(trifluoromethyl)phenyl)pyrimidin-5-amine (750 mg, 3.14 mmol, 1.00 equiv) in dichloromethane (50 mL) was added 2-nitro-5-(piperidin-1-yl)benzoic acid (1.18 g, 4.72 mmol, 1.50 equiv), EDC.HCl (1.2 g, 6.28 mmol, 2.00 equiv) and 4-dimethylaminopyridine (770 mg, 6.31 mmol, 2.00 equiv) and the resulting solution was stirred for 48 h at room temperature. The reaction was diluted with 25 mL of water and then extracted with 2×25 mL of dichloromethane. The organic layers were combined, dried over sodium sulfate, concentrated, and the residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:30˜1:5) to give 0.4 g (27%) of product as a yellow solid.
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(O)(=O)C>CC#N>[CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[C:19]([F:29])=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CC(=O)O
Product: Cn1cc(-c2cc3ncc(F)n3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Temperature: 80 °C
Yield: 20 %

Procedure:
3-Cyclopropyl-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 2; 0.200 g, 0.558 mmol), Selectfluor® (0.395 g, 1.12 mmol) and acetic acid (0.320 mL, 5.58 mmol) were suspended in MeCN (20 mL) and heated to 80° C. overnight. The reaction mixture was cooled to ambient temperature and the reaction mixture partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The combined organic extracts were washed with brine, dried, magnesium sulfate and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography, eluting with 1-2% (9:1 MeOH:NH4OH)/dichloromethane to provide the 3-cyclopropyl-3-(4-(3-fluoro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (0.042 g, 0.112 mmol, 20% yield). MS (apci) m/z=377.1 (M+H).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][C:4]2([C:18]3[CH:17]=[N:16][NH:15][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[O:7]2)[CH2:3][CH2:2]1>CO.[Pd]>[NH:1]1[CH2:6][CH2:5][C:4]2([C:18]3[CH:17]=[N:16][NH:15][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[O:7]2)[CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)Oc1ccccc1-c1[nH]ncc12
Agent: [Pd]
Solvent: CO
Product: c1ccc2c(c1)OC1(CCNCC1)c1cn[nH]c1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
A mixture of benzyl spiro[1H-chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (1.11 g, 2.96 mmol) and palladium (10% wt on carbon, 157 mg, 0.15 mmol) in MeOH (15 mL) was set under hydrogen (1 atm) and stirred vigorously at room temperature for 3 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated to afford 1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (570 mg, 80%). ESI-MS m/z calc. 241.1. found 242.5 (M+1)+; Retention time: 0.42 minutes (3 min run).