Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][CH2:18][N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: OCCCCl
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CCCO

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 3-chloro-1-propanol: 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=8.5 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 6.56 (s, 1H), 4.30 (t, J=6.9 Hz, 2H), 3.62 (br, 2H), 2.51 (s, 3H), 1.99 (m, 2H), 1.61 (s, 1H); MS (ES) m/z 283 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]([C:10](OC)=[O:11])=[N:8][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:6]1.O.[NH2:25][NH2:26]>CO>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]([C:10]([NH:25][NH2:26])=[O:11])=[N:8][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:6]1
Reactant: COC(=O)c1nc(-c2ccccn2)nn1Cc1ccccc1F
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1nc(-c2ccccn2)nn1Cc1ccccc1F
Temperature: 70 °C

Procedure:
To a solution of methyl 1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carboxylate I-35 (115 mg, 0.368 mmol) in methanol (2 mL) was added hydrazine hydrate (72 μL, 1.5 mmol). The solution was heated to 70° C. for 3.5 h, at which point the solvent was removed in vacuo to give 1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbohydrazide C as a white solid. To the crude solid (17 mg, 0.054 mmol) suspended in ethyl acetate (600 μL) was added acetic formic anhydride (0.03 mL, taken from a 2:1 (molar ratio) of formic acid to acetic anhydride, allowed to age 2 h prior to addition). After stirring for 1.25 h, the solution was diluted with ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organics were dried over MgSO4, filtered, and the solvent was removed in vacuo to give the crude intermediate D that was carried on without further purification. To the crude solid was added phosphoryl chloride (237 μl, 2.54 mmol) and the solution was heated to 60° C. for 6.5 h. The solution was diluted with ethyl acetate (75 mL) and saturated aqueous sodium bicarbonate (75 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organics were washed with brine (50 mL), dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. Purification by silica gel chromatography (20-95% ethyl acetate in hexanes) gave 2-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)-1,3,4-oxadiazole I-42 (7.5 mg, 0.023 mmol, 42% yield for three steps) as a white solid.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH:23]=[O:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:26].[K+].Cl.S(=O)(O)[O-].[Na+]>CC(C)=O.O>[C:1]([O:20][CH2:21][CH2:22][C:23]([OH:26])=[O:24])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1.5 h
Yield: 82.2 %

Procedure:
To a stirred solution of 41.1 g of 3-trityloxy-propionaldehyde in 330 ml of acetone and 120 ml of water were added portionwise, within 90 minutes, 20.65 g of potassium permanganate, the temperature of the mixture being maintained at 20° to 25° C. Stirring was continued for 90 minutes, and then the pH of the mixture was set to 5 by addition of 13 ml of 3N hydrochloric acid. Within 40 minutes, there were added dropwise 200 ml of 38% sodium bisulfite solution at a temperature of 20° to 25° C. The pH was lowered to 2 by the addition of 60 ml of 3N hydrochloric acid, and subsequently the mixture was extracted with 11 of ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was crystallized from ethyl acetate/hexane to yield 35.5 g of 3-trityloxy-propionic acid as white solid of m.p. 159°-161° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[O:11]([CH2:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>[OH-].[Na+]>[O:11]([CH2:18][C:19]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)COc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(COc1ccccc1)Nc1ccccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a solution of anthranilic acid (5 g, 0.036 mol) in NaOH (3 g, 30 mL) was added phenoxyacetyl chloride (6.2 g, 5.2 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 min, acidified with dilute hydrochloric acid and filtered. The filtered solid was dissolved in EtOAc and filtered. The filtrate was dried, filtered, concentrated and dried for 4 h under vacuum, affording 8 g (81%) of the title compound, mp 201-203° C. A small amount (100 mg) of the title compound was recrystallized from EtOH, affording 75 mg of the title compound, mp 202-203° C.; 1H NMR (DMSO-d6) δ 13.70 (s, 1H, COOH), 12.20 (s, 1H, NH), 8.71 (d, 1H, J=8.4), 8.02 (dd, 1H, J=7.6), 7.65-7.60 (m, 1H), 7.35-6.89 (m, 6H), 4.73 (s, 2H); 13C NMR (DMSO-d6) δ 169.44, 167.23, 157.11, 140.22, 134.34, 131.32, 129.65, 129.45, 123.06, 121.65, 120.96, 119.45, 116.14, 114.81, 114.38, 67.22; MS (EI, m/z) 271 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CCN(C(C)C)C(C)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[C:32]([C:35](O)=[O:36])[S:33][CH:34]=2)=[CH:26][CH:25]=1.O=P(Cl)(Cl)Cl.NCCNCCN.CCN(C(C1C=CC=C(C)C=1)=O)CC.[OH-]>ClCCCl.CC(N(C)C)=O>[Cl:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:35]([C:32]2[S:33][CH:34]=[C:30]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH:31]=2)=[O:36])[CH:11]=1
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: COc1ccc(-c2csc(C(=O)O)c2)cc1
Agent: CCN(CC)C(=O)c1cccc(C)c1
Agent: NCCNCCN
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(-c2csc(C(=O)Nc3cc(Cl)ccc3C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 2 mL vial, methyl 2-amino-4-chlorobenzoate (7.4 mg, 40 μmol) was dissolved into a mixture of 655 μL DCE and 120 μL DMA, followed by addition of DIPEA (600 μmol, 15 eq.). 4-(4-Methoxyphenyl)thiophene-2-carboxylic acid (13.7 mg, 120 μmol, 3 eq.) and POCl3 (28.1 mg, 120 μmol, 3 eq.) were added. The reaction mixture was capped and stirred at room temperature overnight. Another 700 μL of DCE was added to the reaction mixture along with the following resin bound reagents: a resin bound diethylene triamine (PL-DETA, Polymer Labs, 297 μmol, 7.4 eq.) and a hydroxide ion exchange resin (PL-MP Hydroxide, Polymer Labs, 800 μmol, 20 eq.). The vial was recapped and shaken at room temperature overnight. The resin in the reaction mixture was filtered off, rinsed with 300 μL of MeOH and discarded. The combined filtrates were concentrated down in vacuo. The residue was re-dissolved into 1 mL of DMA and 280 μL of 1M aqueous NaOH. The solution was stirred at room temperature overnight. The desired product was isolated directly from this solution via reverse phase C18 preparative HPLC (water/acetonitrile w/0.1% formic acid, 30%-100% eluant gradient) to yield the final product (4.7 mg, 92% purity). MS (EI) for C19H14ClNO4S: 388 (M+H).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([NH:9][C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[N:13]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:12](=[O:26])[N:11]=1)[CH2:2]2.C(N(CC)CC)C.Cl[CH2:35][C:36]1[CH:44]=[CH:43][C:39]2[O:40][CH2:41][O:42][C:38]=2[CH:37]=1>CN(C=O)C>[O:40]1[C:39]2[CH:43]=[CH:44][C:36]([CH2:35][N:8]3[CH:5]4[CH2:6][CH2:7][CH:1]3[CH2:2][CH:3]([NH:9][C:10]3[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=5)[N:13]([CH2:21][C:22]([F:24])([F:25])[F:23])[C:12](=[O:26])[N:11]=3)[CH2:4]4)=[CH:37][C:38]=2[O:42][CH2:41]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: O=c1nc(NC2CC3CCC(C2)N3)c2cc(Cl)ccc2n1CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1nc(NC2CC3CCC(C2)N3Cc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1CC(F)(F)F
Temperature: 50 °C
Reaction time: 6 h
Yield: 59.4 %

Procedure:
To a solution of 4-(8-aza-bicyclo[3.2.1]oct-3-ylamino)-6-chloro-1-(2,2,2-trifluoro-ethyl)-1H-quinazolin-2-one (149 mg, 0.320 mmol) in DMF (10 mL) was added triethylamine (0.3 mL) and 5-Chloromethyl-benzo[1,3]dioxole (0.061 mL, 0.480 mmol). The solution was heated to 50° C. and stirred for 6 hrs. The reaction was partitioned between ethyl acetate and water and the organic phase was washed an additional 2× with water and brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash chromatography (gradient elution: 0→20% MeOH/dichloromethane) to provide 99 mg white solid (60%). 1H NMR (300 MHz, CDCl3) δ ppm 2.10 (m, 4H), 2.32 (m, 2H), 3.56 (m, 3H), 3.77 (s, 2H), 4.87 (m, 2H), 5.96 (s, 2H), 6.77 (d, J=8.0 Hz, 1H), 6.83 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 7.17 (m, 2H), 7.56 (dd, J=2.3, 8.9 Hz, 1H), 7.91 (s, 1H); MS (ESI+Q1MS) m/z 522 [M+2H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][CH:11]([CH:15]=[CH2:16])[CH:12](O)[CH3:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:15]([CH:11]([CH3:10])[CH:12]=[CH2:13])[CH3:16]
Reactant: C=CC(C)C(C)O
Reactant: Cc1ccc(O)c(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C=CC(C)C(C)Oc1ccc(C)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.6 %

Procedure:
To a solution of 2-bromo-4-methylphenol (1 g, 5.35 mmol) and 3-methylpent-4-en-2-ol (2.68 g, 26.7 mmol) in THF (20 mL) was added Ph3P (7.01 g, 26.7 mmol) followed by DEAD (4.23 mL, 26.7 mmol) and the resulting mixture was stirred at room temp for 16 h. Water was then added and the mixture was extracted with ether (2×50 mL), dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (0-20% EtOAc/hexane) to afford 2-bromo-4-methyl-1-((3-methylpent-4-en-2-yl)oxy)benzene (860 mg, 3.19 mmol, 59.8% yield) as yellow oil. Product is approx 2:1 mixture of trans/cis isomers. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=2.0 Hz, 1H), 7.08-7.01 (m, 1H), 6.83-6.79 (m, 1H), 6.02-5.89 (m, 1H), 5.16 (q, J=1.8 Hz, 0.5H), 5.14-5.08 (m, 1.5H), 4.31-4.37 (m, 0.3H), 4.28-4.19 (m, 0.7H), 2.64-2.50 (m, 1H), 2.29 (s, 3H), 1.30-1.24 (m, 3H), 1.19-1.14 (m, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:9]=[CH:8][C:7]=1[NH:21][C:22](=[O:30])[C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25].O>N1C=CC=CC=1>[C:1]([NH:5][C:6]1[CH:11]=[C:10]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])[CH:9]=[CH:8][C:7]=1[NH:21][C:22](=[O:30])[C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:25])[F:26])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1N)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cc(S(=O)(=O)c2ccccc2)ccc1NC(=O)C(C)(O)C(F)(F)F
Temperature: 25 °C

Procedure:
Acetyl chloride (0.018 ml) was added to an ice-cooled solution of N-[2-amino-4-(phenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 184) (0.097 g) in pyridine (1 ml) and the solution was allowed to warm up to ambient temperature over 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic extracts were combined, washed with brine and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 10-40% ethyl acetate/hexane to give the title compound (0.89 g) as a solid. Mp 205-207° C.; NMR: 1.5 (s, 3H), 2.1 (s, 3H), 7.57-7.75 (m, 4H), 7.8-7.9 (m, 2H), 7.9-8.05 (m, 3H), 9.8 (brs, 1H), 10.1 (brs, 1H); MS (ESP−): 429.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:13]([NH:18][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CCN
Reactant: CCOC(=O)c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccnc1NCCC(C)C
Temperature: 140 °C
Yield: 75.7 %

Procedure:
A mixture of ethyl 2-chloronicotinate (3.71 g, 20 mmol), isoamylamine (3.03 mL, 26 mmol) and triethylamine (3.62 mL, 26 mmol) was heated in a sealed tube at 140° C. for 8 hours, cooled to 25C, diluted with ethyl acetate and the mixture washed with water. The organic layer was extracted with 1N aqueous hydrochloric acid. The acidic aqueous layer was adjusted to pH 8.0 with saturated sodium bicarbonate solution then extracted with ethyl acetate (2 portions). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3.58 g, 76%). MS (DCI/NH3) m/z 237 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (d, J=6.25 Hz, 6 H) 1.31 (t, J=6.99 Hz, 3 H) 1.47 (q, J=6.99 Hz, 2 H) 1.64 (m, 1 H) 3.47 (m, 2 H) 4.28 (q, J=6.99 Hz, 2 H) 6.59 (dd, J=7.72, 4.78 Hz, 1 H) 7.90 (t, J=5.15 Hz, 1 H) 8.07 (dd, J=7.91, 2.02 Hz, 1 H) 8.28 (dd, J=4.78, 1.84 Hz, 1 H).
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(C)(F)F)CC3)ncc1Cl

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 61e. Product isolated as a pale yellow solid (0.019 g, 21%). MP: 162-165° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 11.00-10.97 (m, 1H), 8.68-8.64 (m, 1H), 8.11 (d, 1H, J=1.8 Hz), 8.09-8.07 (m, 1H), 7.54-7.39 (m, 3H), 7.11-7.06 (m, 1H), 6.64 (s, 1H), 6.18 (br s, 1H), 3.87 (d, 3H, J=1.5 Hz), 3.06-3.02 (m, 3H), 2.90-2.72 (m, 10H), 1.75-1.61 (m, 3H). MS: 531.17 (MH)+.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]([CH3:20])=[N:18][C:17]([CH3:21])=[N:16]2)[N:12]=[C:11]([C:22]([F:25])([F:24])[F:23])[N:10]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:21][C:17]1[N:18]=[C:19]([CH3:20])[N:15]([C:13]2[N:12]=[C:11]([C:22]([F:25])([F:24])[F:23])[N:10]=[C:9]([C@@H:7]3[CH2:8][C@H:6]3[CH2:4][OH:3])[CH:14]=2)[N:16]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cc(-n2nc(C)nc2C)nc(C(F)(F)F)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3CO)nc(C(F)(F)F)n2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of ethyl-trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)cyclopropanecarboxylate (16-4, 430 mg, 1.21 mmol, 1.0 eq.) in anhydrous THF (13.0 mL) at 0° C. was added DIBAL-H (1.0 M in toluene, 3.63 mL, 3.63 mmol, 3.0 eq.) dropwise. The resulting mixture was stirred at 0° C. for 2 hours under an atmosphere of nitrogen gas. The mixture was then quenched with saturated aqueous Rochelle's salt solution (10 mL) at 0° C. and vigorously stirred at room temperature for 1 hour. After dilution with H2O (50 mL), the biphasic mixture was separated. The separated aqueous layer was extracted with EtOAc (3×50 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give trans-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)cyclopropyl)methanol (16-5) as an off-white solid which was carried forward for next step without further purification. 1H NMR (300 MHz, CDCl3) δ 7.87 (s, 1H), 3.86-3.75 (m, 1H), 3.67-3.56 (m, 1H), 2.91 (s, 3H), 2.42 (s, 3H), 2.15 (m, 1H), 2.09-1.97 (m, 1H), 1.63-1.49 (m, 2H). LRMS m/z (M+H) 314 found, 314 required.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:8](=[O:14])[CH2:7][C:6]([CH3:16])([CH3:15])[CH2:5][C:4]=2[N:3]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.O>C(O)C>[CH3:15][C:6]1([CH3:16])[CH2:5][C:4]2[N:3]=[C:2]([N:26]3[CH2:27][CH2:28][N:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:24][CH2:25]3)[C:11]([C:12]#[N:13])=[CH:10][C:9]=2[C:8](=[O:14])[CH2:7]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC1(C)CC(=O)c2cc(C#N)c(Cl)nc2C1
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)c2cc(C#N)c(N3CCN(c4ccccc4)CC3)nc2C1
Yield: 62 %

Procedure:
A solution of 2-chloro-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (0.22 g, 0.94 mmol), 1-phenylpiperazine (0.23 g, 1.4 mmol) and triethylamine (0.14 ml, 0.1 g, 1.0 mmol) in ethyl alcohol (3 ml) was heated at reflux for 4 h. Then water (20 ml) was added and the mixture was extracted by dichloromethane. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (CH2Cl2-hexane, 1:2). The product obtained was recrystallized from ethyl alcohol to give the title compound (0.21 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4](F)[N:3]=1.[CH:14]([O:17][CH2:18][CH2:19][CH2:20][NH2:21])([CH3:16])[CH3:15].C(N(CC)CC)C>O1CCOCC1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4]([NH:21][CH2:20][CH2:19][CH2:18][O:17][CH:14]([CH3:16])[CH3:15])[N:3]=1
Reactant: Nc1nc(F)nc(C(F)(F)F)c1F
Reactant: CC(C)OCCCN
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)OCCCNc1nc(N)c(F)c(C(F)(F)F)n1
Temperature: 0 °C
Yield: 54 %

Procedure:
5 g (0.025 mole) of 4-amino-2,5-difluoro-6-trifluoromethylpyrimidine are dissolved in 150 ml of dioxane. 2.9 g (0.025 mole) of 3-isopropoxypropylamine and 2.5 g (0.025 mole) of triethylamine are added dropwise thereto and the reaction mixture is heated to the boil for five hours. It is cooled and stirred into ice water, and the resulting solid is filtered off, dried and recrystallised from white spirit. 4 g (54% of theory) of the desired pyrimidine, melting point 87° C., are obtained.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([Cl:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)([C:27]3[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=1.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>CN(C=O)C>[Cl:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)([C:27]3[CH:28]=[N:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=[C:2]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: C1COCCN1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Solvent: CN(C)C=O
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(N3CCOCC3)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Temperature: 100 °C

Procedure:
{2,4-Dichloro-3-[4-(1H-pyrazol-1-yl)benzyl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol (100 mg, 0.164 mmol, Intermediate 65), morpholine (144 mg, 1.64 mmol) and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature for 48 hours. The vessel was then cooled to room temperature and the solvent was removed by a stream of nitrogen. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C34H29ClF3N7O2, 659.2. m/z found, 660.3 [M+H]+. 1H NMR (600 MHz, CDCl3) δ ppm 8.80 (d, J=1.9 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.88-7.83 (m, 3H), 7.63 (d, J=1.4 Hz, 1H), 7.60-7.52 (m, 3H), 7.25 (s, 1H), 7.22 (d, J=8.7 Hz, 2H), 7.10 (s, 1H), 6.42 (dd, J=2.4, 1.9 Hz, 1H), 6.21 (d, J=0.9 Hz, 1H), 4.38 (s, 2H), 3.83-3.75 (m, 4H), 3.30 (s, 3H), 3.25-3.16 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:18]([O:20][C:21](=[O:26])[CH2:22][N:23]=[N+:24]=[N-:25])[CH3:19].C1CCN2C(=NCCC2)CC1>C(O)C>[CH2:18]([O:20][C:21](=[O:26])[C:22]([N:23]=[N+:24]=[N-:25])=[CH:14][C:12]1[O:13][C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:17][CH:16]=2)=[CH:10][CH:11]=1)[CH3:19]
Reactant: O=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)o1
Reactant: CCOC(=O)CN=[N+]=[N-]
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)o1)N=[N+]=[N-]
Temperature: 70 °C
Yield: 36.6 %

Procedure:
Absolute ethanol (20 ml) was added to 5-(4-nitro-phenoxy)-furan-2-carbaldehyde (275 mg, 1.18 mmol) and the mixture was heated to 70° C. until a limpid solution was obtained. Azido-acetic acid ethyl ester (1.827 grams, 14.2 mmol) and DBU (286.9 mg, 1.89 mmol) were then added and the mixture was heated at 70° C. for one and a half hours. The solvent was thereafter removed under reduced pressure and a solution of HCl 0.1 M (50 ml) and ethyl acetate (20 ml) were added. After separation of the phases the aqueous phase was extracted with ethyl acetate (2×20 ml), the combined organic phase was dried over Na2SO4 and the organic solvents were evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography to give 148.5 mg of pure 2-azido-3-(5-(4-nitrophenoxy)-furan-2-yl)-acrylic acid ethyl ester (36.5% yield).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[K].[Cl:11][C:12]1[CH:13]=[C:14]([F:19])[C:15](F)=[N:16][CH:17]=1.[C:20]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]#[N:34])[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C1(C)C=CC=CC=1>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][C:30]([C:33]#[N:34])([C:15]2[C:14]([F:19])=[CH:13][C:12]([Cl:11])=[CH:17][N:16]=2)[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: Fc1cc(Cl)cnc1F
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ncc(Cl)cc2F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
Potassium hexamethyldisilazane (1.34 ml, 0.5 M solution in toluene) was slowly added to a solution of 5-Chloro-2,3-difluoro-pyridine (0.1 g) and N-Boc-4-Cyano-Piperidine (0.14 g) in 3 ml toluene at 0° C., under nitrogen. The mixture was stirred at 0° C. for 1 hr. After cooling, the reaction mixture was quenched in 1N HCl. The aqueous phase was extracted twice with ethyl acetate and the combined organic were washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography [SiO2; hexane-ethyl acetate-hexane (4:1)] to give 111 mg (49%) of 5-chloro-4′-cyano-3-fluoro-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert -butyl ester; MS (ES+) 240 (M-Boc+H+).