Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[H-].[Na+].Br[CH:14]([C:16]1[N:21]2[N:22]=[CH:23][N:24]=[C:20]2[N:19]=[CH:18][CH:17]=1)[CH3:15]>COCCOC>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:14]([C:16]2[N:21]3[N:22]=[CH:23][N:24]=[C:20]3[N:19]=[CH:18][CH:17]=2)[CH3:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(Br)c1ccnc2ncnn12
Reactant: CC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)c1ccc(OC(C)c2ccnc3ncnn23)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-hydroxyacetophenone (1.36 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g, prepared in a similar manner to that described in Example 6 above) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The reaction mixture was stirred at room temperature for 24 hours. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the mixture and the residue was dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide followed by water. Evaporation of the solvent afforded a crude product which was recrystallised from ethyl acetate, to give 7-[1-(4-acetylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 0.87 g, (m.p. 136°-138° C.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[N:6][C:5](Br)=[CH:4][CH:3]=1.[CH3:9][CH2:10]N(C(C)C)C(C)C.[OH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH2:1]([C:2]1[N:7]=[N:6][C:5]([N:22]2[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]2)=[CH:4][CH:3]=1)[CH2:9][CH3:10]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(Br)nn1
Reactant: OC1CCNCC1
Product: CCCc1ccc(N2CCC(O)CC2)nn1

Procedure:
Following a procedure similar to that of Example 3, 81 millimoles of 6-methyl-3-bromopyridazine was combined with 16 mL DIPEA and 163 mmoles of 4-hydroxypiperidine and heated to 120° for 16 hours to obtain 6-methyl-3-(4-hydroxy-1-piperdinyl)pyridazine (Formula IV: Y=bond, R=CH3) in 24% yield. 6.8 Mmols of the latter and 7.4 mmoles of 2-methyl-5-(4-hydroxy-3,5-dimethyl phenyl)-2H-tetrazole (Formula III: R2 =R3 =R4 =CH3) were reacted with equimolar amounts of DEAD and TPP essentially as described above in Example 1c. Recrystallization from methanol gave a 74% yield of the compound of Formula I (R1 =R2 =R3 =R4 =CH3, Y=bond), m.p. 188°-189° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[S:19][CH:20]=[C:21]([Br:23])[CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[SH:38]>CO>[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38][CH:17]([C:18]1[S:19][CH:20]=[C:21]([Br:23])[CH:22]=1)[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)/C(=C/c1cc(Br)cs1)NC(=O)OCc1ccccc1
Reactant: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Sc1ccccc1N)c1cc(Br)cs1
Yield: 45.8 %

Procedure:
The title compound was prepared according to the method of Example 94b, employing methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-(4-bromo-2-thienyl)acrylate (96a) (8.13 g, 20.5 mmol), triethylamine (1.43 g, 14.1 mmol), and 2-aminothiophenol (14.0 g, 112 mmol) in anhydrous methanol (80 mL). Purification by flash chromatography an silica gel eluting with 4:1 (v/v) hexane/ethyl acetate yielded a solid, which was recrystallized from 6:1 (v/v) hexane/ethyl acetate to afford the title compound (4.90 g, 46%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.44 (s, 3H), 4.63 (t, 1H, J=8.1 Hz), 4.92 (d, 1H, J=7.4 Hz), 5.09 (m, 2H), 5.46 (bs, 2H), 6.38 (t, 1H, J=7.5 Hz), 6.66 (d, 1H, J=8.3 Hz), 6.80 (s, 1H), 6.99-7.03 (m, 2H), 7.32-7.39 (m, 5H), 7.52 (s, 1H), 8.28 (d, 1H, J=9.2 Hz). MS APCI, m/z=521, 523. LC/MS: 2.71 min.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:15]([NH2:17])=[O:16])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:18][C:19]([CH:22]=O)([CH3:21])[CH3:20].[NH:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[N:25]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:24]1([CH:22]([NH:17][C:15]([C:10]2[C:9]3[C:8]4[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:2](=[O:1])[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:16])[C:19]([CH3:20])([CH3:21])[CH3:18])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[N:25]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: NC(=O)c1cccc2c1-c1ccccc1C2=O
Reactant: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)c1cccc2c1-c1ccccc1C2=O)n1nnc2ccccc21

Procedure:
A suspension of the product from Example 68A, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as in Example 1C to provide the title compound.
Reaction SMILES: [CH3:1]I.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[O:22][CH3:23])=[CH:16][CH:15]=1.[H-].[Na+].O>CN(C)C=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:1])[C:21](=[O:24])[O:22][CH3:23])=[CH:16][CH:15]=1
Reactant: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N(C)c1ccc(OCc2nc3ccccc3s2)cc1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
0.27 ml of methyl iodide were added to a solution of 138.6 mg of methyl N-[4-(benzothiazol-2-ylmethoxy)phenyl]carbamate (prepared as described in Example 11) in 5 ml of dimethylformamide cooled in an ice-water bath and then 19.4 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to the resulting mixture. The reaction mixture was stirred at the same temperature for 10 minutes, the temperature of the mixture was then elevated to room temperature and the mixture was stirred for a further 30 minutes. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude crystalline solid which was purified by column chromatography through silica gel using a 2:1 by volume mixture of hexane and ethyl acetate to give 126.7 mg (yield 87%) of the title compound as a solid having a melting point of 85°-87° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:17])[N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]([CH3:10])[C:8]=1[CH3:9].C(N(CC)CC)C.[CH3:25][S:26]([Cl:29])(=[O:28])=[O:27].[Cl-].[NH4+]>ClCCl>[CH3:10][N:7]1[C:8]([CH3:9])=[C:4]([CH2:3][CH2:2][O:1][S:26]([CH3:25])(=[O:28])=[O:27])[C:5](=[O:17])[N:6]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:29][CH2:2][CH2:3][C:4]1[C:5](=[O:17])[N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]([CH3:10])[C:8]=1[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(CCO)c(=O)n(-c2ccccc2)n1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CCCl)c(=O)n(-c2ccccc2)n1C
Product: Cc1c(CCOS(C)(=O)=O)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (700 mg, 3.01 mmol), triethylamine (0.84 mL, 6.0 mmol), and methyl sulfonyl chloride (0.28 mL, 3.6 mmol) in dichloromethane (5.0 mL) was stirred at room temperature for 4 h. The reaction mixture was treated with saturated ammonium chloride and extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification via silica gel column chromatography provided methanesulfonic acid 2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-ethyl ester (384 mg) and 4-(2-chloro-ethyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (310 mg) in 41% combined yield. LCMS 311.3 (M+1) and LCMS 251.3 (M+1), respectively.
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH:19][C:20](OC1C=CC(Cl)=CC=1)=[O:21].[CH3:31][S:32]([NH:35][NH2:36])(=[O:34])=[O:33].CCN(C(C)C)C(C)C>O1CCOCC1>[O:21]=[C:20]1[N:36]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])[C:3](=[O:30])[C:4]2[C:5](=[CH:6][C:7]([C:15]([F:18])([F:17])[F:16])=[C:8]([CH:10]3[CH2:14][CH2:13][O:12][CH2:11]3)[CH:9]=2)[NH:19]1
Reactant: CS(=O)(=O)NN
Reactant: COC(=O)c1cc(C2CCOC2)c(C(F)(F)F)cc1NC(=O)Oc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(C3CCOC3)cc2c1=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
2-(4-Chloro-phenoxycarbonylamino)-5-(tetrahydro-furan-3-yl)-4-trifluoromethyl-benzoic acid methyl ester (80 mg, 0.18 mmol) was dissolved in dioxane (1 mL) and, after addition of CH3SO2NHNH2 (21.8 mg, 1.1 equiv) and i-Pr2NEt (61.7 μL, 2 equiv), the mixture was stirred for 18 h (TLC control) at 80° C. The crude product was purified by flash chromatography with DCM to DCM/MeOH 85:15 as eluent. The obtained product was dried, dissolved in a small quantity of DCM and precipitated with hexanes. The white solid was filtered off and dried to provide the title compound (50 mg, 70% yield) (394 [M+H]+, rt 4.58 min.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O.S(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C(N(C(C)C)CC)(C)C>C1COCC1>[OH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: Nc1ccccc1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COc1cc(C(=O)Nc2ccccc2O)ccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Methoxy-4-methyl benzoic acid (1.2 g, 7.2 mmol) and thionyl chloride (10 mL) was heated to reflux conditions under argon until no starting material was observed by TLC. After cooling mixture to rt and concentration in vacuo, the resulting brown oil was dissolved in THF (15 mL) and slowly added to a cooled mixture of 2-aminophenol (780 mg, 7.1 mmol), diisopropylethyl amine (1.5 mL, 8.6 mmol) and THF (20 mL) at 0° C. Reaction mixture was allowed to warm to rt. After one hour, no starting material acid was observed by TLC. After concentrating reaction mixture in vacuo, the resulting brown oil was purified by flash chromatography on silica gel, using 1:4 EtOAc:hexanes. This afforded the desired intermediate, N-(2-hydroxyphenyl)-3-methoxy-4-methylbenzamide, as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:3]=1.[C:23]([NH2:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24]>C(O)(C)C>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[C:6](=[O:9])[N:7]([CH3:8])[C:2]([NH:32][C:23]([CH3:25])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:24])=[N:3][C:4]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][CH:12]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reactant: CC(C)(N)c1ccccc1
Solvent: CC(C)O
Product: Cn1c(NC(C)(C)c2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Temperature: 25 °C

Procedure:
2-Chloro-3-methyl-6-(4-pyridyl)-5-(4-fluorophenyl)-4(3H)-pyrimidinone (5.43 g, 17.2 mmol) and cumyl amine (4.65 g, 34.4 mmol) were combined in dry isopropyl alcohol (ca. 40 mL) and the mixture was heated at reflux for 48 h. The reaction was cooled to RT, the solvent was evaporated in vacuo and the residue was partitioned between sat. aq. NaHCO3 and CHCl3. The organic layer was dried over Na2SO4 and then concentrated. The residue was purified by flash chromatography (1% MeOH/NH3:CHCl3) to provide the product as a tan solid; MS: m/z (M+H)+ 415; C25H23FN4O requir. 414.5.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:10]([Mg]Br)[CH3:11].C(OCC)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[CH2:10][CH3:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1cccc(Cl)n1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1cccc(Cl)n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 6-chloropicolinaldehyde (1.00 g, 7.06 mmol) in 20 mL of THF at −78° C. was added ethylmagnesium bromide, 3.0 M solution in diethyl ether (3.53 mL, 10.60 mmol) slowly. The reaction mixture was stirred at −78° C. for 2 h. The reaction mixture was quenched with sat'd NH4Cl aqueous solution, and extracted with ether (3×100 mL). The combined organic layers were dried over Na2SO4 and evaporated to provide the crude product. The crude product was purified by chromatography on silica gel, eluting with 10 to 60% EtOAc/hexane to provide the title compound. Mass Spectrum (ESI) m/z=172 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:5][C:6]1[C:7]([NH:19][CH2:20][CH:21]2[CH2:23][CH2:22]2)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[CH:21]1([CH2:20][N:19]2[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:10]=[CH:11][C:6]=3[CH2:5][CH:4]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[C:3]2=[O:2])[CH2:23][CH2:22]1
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1NCC1CC1)c1ccc(OC)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(C2Cc3cnc(Nc4ccccc4)nc3N(CC3CC3)C2=O)cc1
Temperature: 85 °C

Procedure:
To a solution of crude 3-(2-phenylamino-4-cyclopropylmethylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester (51.3 mg) (from Example 14a supra) in glacial acetic acid (1 mL) was added concentrated sulfuric acid (0.1 mL) in one portion. The reaction mixture was heated at 85° C. for 3 hours. The reaction mixture was cooled, diluted with ethyl acetate (50 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography to give 8-cyclopropylmethyl-6-(4-methoxy-phenyl)-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidine-7-one as a light yellow amorphous solid. (Yield 6.7 mg, 14.8%, 2 steps).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:24])[N:5]([CH3:23])[C:6]1[N:7]2[CH:12]=[N:13][C:14]=1[C:15]1[N:19]=[C:18]([CH:20]2[CH2:22][CH2:21]2)[O:17][N:16]=1.[C-:25]#[N:26].[Na+]>CN(C)C=O.O>[C:25]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:24])[N:5]([CH3:23])[C:6]1[N:7]2[CH:12]=[N:13][C:14]=1[C:15]1[N:19]=[C:18]([CH:20]2[CH2:22][CH2:21]2)[O:17][N:16]=1)#[N:26]
Reactant: Cn1c(=O)c2c(Br)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(C#N)cccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
To 140 mg 6-bromo-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)4,5--dihydro-4-methyl-5-oxo-imidazo(1,5-a)quinazoline in 5 ml dimethyl formamide (DMF) 40 mg cuprous cyanide was added. Thereafter further 5 ml DMF was added and the resulting mixture was heated to 130°-150° C. for 60 minutes with stirring. To this mixture 110 mg sodium cyanide in 5 ml water was added and thereafter further 30 ml water. The resulting mixture was extracted with 30 ml ethyl acetate and thereafter four times with 20 ml ethyl acetate. The combined organic phase was washed with water and dried with calcium chloride. Evaporation in vacuo gave 24 mg of the title compound. M.p. 115°-125° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=O)=[CH:4][CH:3]=1.[NH2:12][C@H:13](CO)[CH:14]([CH3:16])[CH3:15]>ClC1C=CC=CC=1>[CH:14]([C@H:13]1[CH2:9][O:8][C:6]([C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:12]1)([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)[C@H](N)CO
Solvent: Clc1ccccc1
Product: CC(C)[C@H]1COC(c2ccc(O)cc2)=N1
Yield: 58 %

Procedure:
Under an argon atmosphere, a mixture of methyl 4-hydroxybenzoate (1.5 mmol), (L)-valinol (1.8 mmol), Zn4(OCOCF3)6O (0.15 mmol) and chlorobenzene (2.5 mL) was heated under reflux for 12 hours. From the resulting solution, the solvent was removed using an evaporator, and the residues were purified by silica gel column chromatography to give (S)-4-isopropyl-2-(4-hydroxyphenyl)-1,3-oxazoline in 58% yield. The compound was identified by comparison with physical property data of the known compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:5]1[C:13]2[C:8](=[C:9]([C:16]([F:19])([F:18])[F:17])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:20])[CH3:4].CCN(CC)CC.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:1][CH2:2][CH:3]([N:5]1[C:13]2[C:8](=[C:9]([C:16]([F:19])([F:17])[F:18])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:20])[CH3:4])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
To a solution of 1-(1-hydroxypropan-2-yl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 7) (0.110 g, 0.390 mmol) and Et3N (0.068 mL, 0.487 mmol) in CH2Cl2 (4 mL) was added methanesulfonyl chloride (0.038 mL, 0.487 mmol) dropwise. After stirring at rt for 2 h, the reaction mixture was concentrated to dryness. The residue was partitioned between EtOAc (30 mL) and 0.2N HCl (15 mL). The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using a 25-60% EtOAc-hexane gradient to give 2-(5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl)propyl methanesulfonate (0.145 g, 97% yield) as a colorless oil: MS (ESI): m/z 361 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:6][C:7]=1[Cl:8].C([Mg]Cl)(C)C.C([Li])(C)(C)C.CN(C)[CH:30]=[O:31]>O1CCCC1.O>[Cl:8][C:7]1[C:2]([CH:30]=[O:31])=[CH:3][CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:6]=1
Reactant: Clc1ccc(CNc2ccc(Br)c(Cl)n2)cc1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(NCc2ccc(Cl)cc2)nc1Cl
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To (5-bromo-6-chloro-pyridin-2-yl)-(4-chloro-benzyl)-amine (539, 2.60 g, 7.83 mmol) in tetrahydrofuran (60.0 mL) under an atmosphere of nitrogen at −78° C., isopropylmagnesium chloride (2.00 M in tetrahydrofuran, 4.20 mL) was added over 10 minutes. The reaction was stirred at −78° C. for 20 minutes, then allowed to warm to room temperature for 10 minutes. The reaction was cooled to −78° C. tert-Butyllithium (1.70 M in hexane, 10.2 mL) was added to the reaction over 10 minutes. After 40 minutes, N,N-dimethylformamide (1.80 mL, 0.0232 mol) was added to the reaction. The reaction was stirred at −78° C. for 40 minutes, then allowed to warm to room temperature for another 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 35% to 100% ethyl acetate in hexane to give a light yellow solid (540, 1.0 g, 45.4%). MS (ESI) [M−H+]−=279.0.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]([C:8]3ON=C(N)[N:9]=3)C[N:3]([CH2:4]2)[CH2:2]1.[C:14]([Cu])#[N:15].CN(C=[O:21])C>O>[N:15]1[O:21][N:9]=[C:8]2[CH:6]=[C:5]([C:4]#[N:3])[CH:1]=[CH:2][C:14]=12
Reactant: N#C[Cu]
Reactant: CN(C)C=O
Reactant: Nc1noc(C2CN3CCC2C3)n1
Solvent: O
Product: N#Cc1ccc2nonc2c1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To a stirred solution of 5-bromobenzo[c][1, 2, and 5]oxadiazole (2.0 g, 10.050 mmol) in DMF (50 mL) was added CuCN (1.79 g, 230.10 mmol) at RT under an inert atmosphere. The reaction mixture was then heated at 140° C. for 24 h., cooled to RT, diluted with water (10 mL) and stirred for 10 min. The precipitated solid was filtered off and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford benzo[c][1,2,5]oxadiazole-5-carbonitrile (0.7 g, 48%) as a yellow solid.
Reaction SMILES: CC([N:5]([C@:9]([C:13]([NH:15][C:16]1[CH:17]=[N:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]3[O:29][CH2:30][CH2:31][C:32]4([CH2:34][CH2:33]4)[C:24]=23)=[N:20][CH:21]=1)=[O:14])([CH3:12])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:32]12([C:24]3[C:25](=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:19]3[N:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C@:9]([CH3:12])([CH2:10][CH3:11])[NH2:5])=[CH:17][N:18]=3)[O:29][CH2:30][CH2:31]1)[CH2:33][CH2:34]2
Reactant: CC[C@](C)(C(=O)Nc1cnc(Oc2cccc3c2C2(CCO3)CC2)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@](C)(N)C(=O)Nc1cnc(Oc2cccc3c2C2(CCO3)CC2)nc1
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To a solution of 1,1-dimethylethyl[(1R)-1-({[2-(2,3-dihydrospiro[chromene-4,1′-cyclopropan]-5-yloxy)-5-pyrimidinyl]amino}carbonyl)-1-methylpropyl]carbamate (Intermediate 224, 5 mg, 10.67 μmol) in dry Dichloromethane (1 mL) cooled to 0° C. TFA (0.822 μL, 10.67 μmol) was added dropwise. The reaction mixture was stirred for 2 hours at the same temperature. The reaction was allowed to reach room temperature then the volatiles were evaporated. The residue was diluted with DCM (2 mL), and washed with NaHCO3 sat. sol. (7 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford the title compound (4 mg) as a yellow oil that was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].CC1(C)C(C)(C)OB([C:19]2[C:28]3[C:23](=CC=C[CH:27]=3)[CH:22]=[N:21][CH:20]=2)O1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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.O>[F:10][C:3]1[C:2]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:28]=2[CH3:27])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: CC1(C)OB(c2cncc3ccccc23)OC1(C)C
Reactant: N#Cc1cccc(Br)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: Cc1ccncc1-c1cccc(C#N)c1F
Temperature: 90 °C
Yield: 86.9 %

Procedure:
To a solution of 3-bromo-2-fluorobenzonitrile (2.0 g, 10.00 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (2.81 g, 11.00 mmol) in a mixture of DME (30 mL), ethanol (15 mL), and water (15 mL) was added Na2CO3 (4.24 g, 40.0 mmol). This suspension was degassed with a stream of N2 for 10 minutes and then tetrakis(triphenylphosphine)palladium(0) (0.578 g, 0.500 mmol) was added followed by degassing with nitrogen for 10 minutes. The tube was then sealed and heated to 90° C. for 14 hours. The vessel was cooled to room temperature and diluted with EtOAc and water. The mixture was further diluted with brine and extracted three times with EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated to give the crude product as a brown oil. The crude material was purified by flash chromatography on silica using an ISCO machine (80 g SiO2 column, 60 mL/min, 0-20% acetone in CH2Cl2 over 20 minutes, tr=8 minutes) to give the title compound (2.18 g, 8.69 mmol, 87% yield) as a pale yellow solid. ESI MS (M+H)+=249.1.