Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].[CH3:23]N(C=O)C>>[CH3:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[N:15]([CH3:23])[C:16](=[O:21])[C:17]([F:19])([F:18])[F:20]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)C(F)(F)F
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cccc([N+](=O)[O-])c1N(C)C(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
To a stirred suspension of NaH (112 mg, 2.80 mmol, 60% dispersion in mineral oil) in DMF (5 mL) at 0° C. was added 3-nitro-2-(2,2,2-trifluoro-acetylamino)-benzoic acid methyl ester (750 mg, 2.55 mmol) portion wise. The resulting mixture was stirred for 1 h, then Mel (175 mL, 2.80 mmol) was added and the progress of the reaction was followed by LCMS. Upon consumption of 3-nitro-2-(2,2,2-trifluoro-acetylamino)-benzoic acid methyl ester, the reaction mixture was quenched with aqueous NH4Cl, and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate-hexane to provide 2-[methyl-(2,2,2-trifluoro-acetyl)-amino]-3-nitro-benzoic acid methyl ester. MS m/z: 275.0 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.Br.[CH3:23][N:24]1[CH2:31][C:30]2[CH2:29][NH:28][CH2:27][C:26]=2[CH2:25]1.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][C:30]5[CH2:31][N:24]([CH3:23])[CH2:25][C:26]=5[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CN1CC2=C(CNC2)C1
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CN1CC2=C(C1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Reaction time: 8 h
Yield: 62.7 %

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.42 g), 3-methyl-3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide (0.47 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.63 g) were dissolved in acetonitrile (20 ml) and refluxed for 7 hours. The reaction mixture was kept at room temperature overnight and then the produced precipitate was filtered, washed with acetonitrile and methanol to give the title compound 0.36 g (yield 62%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH3:17][CH2:18][O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21]>>[C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:4]2[N:3]=[C:2]([NH2:1])[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=2)[CH2:24][CH2:23]1)([O:19][CH2:18][CH3:17])=[O:21]
Reactant: CCOC(=O)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Product: CCOC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
In a reaction vessel equipped with stirrer, thermometer and drying tube was charged 60 ml. of isoamyl alcohol, 10 g. (0.042 mole) of 4-amino-2-chloro-6,7-dimethoxyquinazoline (prepared as described in U.S. Pat. No. 3,511,836) and 7.3 g. (0.047 mole) ethyl-N-piperazinocarboxylate (Aldrich Chemical Co.). The mixture was heated at 100° C. for 3 hours and allowed to stand overnight at room temperature. The mixture was diluted with 120 ml. of isoamyl alcohol and filtered to obtain 14.3 g. (94%) of the hydrochloride salt of the title compound, which melted sharply at 295° C.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=[O:4].C([Li])CCC.CCCCCC.CB(C)C.[OH:29]O>O1CCCC1.O.C(O)(=O)C>[OH:29][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1]
Reactant: OO
Reactant: CC(C)(C)C(=O)Nc1ccncc1
Agent: CB(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1ccncc1O
Reaction time: 2.5 h
Yield: 67 %

Procedure:
2,2-dimethyl-N-pyridin-4-yl-propionamide (1.6 g, 8.977 mol) was dissolved in anhydrous tetrahydrofuran (20 ml) under nitrogen atmosphere and then cooled to −780, and then 2.5M solution of n-butyl lithium (n-BuLi) in n-hexane (9 ml, 22.443 mmol) was added thereto dropwise and then stirred at 0□ for 2.5 hours until yellow crystals were formed. After cooling the reaction mixture to −78□, trimethylboron (2.5 ml, 22.443 mmol) was added thereto dropwise for 10 minutes, and the temperature was raised slowly up to □0. After stirring for 2 hours, acetic acid (1.9 ml) and 30% w/w aqueous solution of hydrogen peroxide were added dropwise to the reaction solution at 0□, and then after stirring for 30 minutes, water (1 ml) was added thereto dropwise and then stirred at room temperature for 18 hours. Water was added and the mixture was evaporated under reduced pressure, and the residue was extracted by using water and 10% isopropanol/chloroform. The combined organic layer was treated with active carbon and the filtrate was washed with saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=20:1. The fractions containing the product were collected and evaporated to obtain white solid (1.16 g, 67%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH2:17]([C:24]1[CH:28]=[C:27]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[N:26]([CH2:35][CH3:36])[N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH:37]([C@@H:39]1[C@@H:43]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[CH:45]=2)[CH2:42][N:41]([C@@H:51]2[C:55]([CH3:57])([CH3:56])[CH2:54][O:53][C:52]2=[O:58])[CH2:40]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:17]([C:24]1[CH:28]=[C:27]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:37][C@@H:39]3[C@@H:43]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[CH:45]=4)[CH2:42][N:41]([C@@H:51]4[C:55]([CH3:57])([CH3:56])[CH2:54][O:53][C:52]4=[O:58])[CH2:40]3)[CH2:31][CH2:30]2)[N:26]([CH2:35][CH3:36])[N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)COC(=O)[C@@H]1N1C[C@H](c2cccc(F)c2)[C@@H](C=O)C1
Reactant: CCn1nc(Cc2ccccc2)cc1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nc(Cc2ccccc2)cc1C1CCN(C[C@H]2CN([C@H]3C(=O)OCC3(C)C)C[C@@H]2c2cccc(F)c2)CC1
Reaction time: 2 h
Yield: 37.5 %

Procedure:
Diisopropylethylamine (0.018 mL, 0.1 mmol) was added to a solution of 4-(3-benzyl-1-ethyl-(1H-pyrazol-5-yl))piperidine trifluoroacetate (37 mg, 0.1 mmol, from Example 1, Step C) in 0.5 mL of 1,2-dichloroethane (DCE). A solution of dihydro-3-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)-pyrrolidin-1-yl)-4,4-dimethyl-2(3H)furanone (25 mg, 0.082 mmol, from Step D) in 0.5 mL of DCE was then added, followed by a slurry of sodium triacetoxyborohydride (30 mg, 0.144 mmol) in 0.5 mL of DCE. The reaction mixture was mixed well, then allowed to stand at room temperature for 2 h. The mixture was concentrated and purified by preparative HPLC (column: YMC combiprep ODS-A 20×50 mm, gradient: 10% acetonitrile/water w/0.1% TFA to 100% acetonitrile/water w/0.1% TFA over 8 min, then ramp to 10% acetonitrile/water w/0.1% TFA over 2 min, flow: 20 mL/min), followed by conversion to the free base by solid phase extraction (column: Varian SCX, loading: methanol, elution: 2.0M ammonia in methanol) to afford 17.2 mg (37% yield) of the title compound. ESI-MS. M/z; (M+H)=559.7; HPLC A: 2.34 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[C:38]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)(=[O:40])[CH3:39].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:38]([C:41]1[CH:42]=[CH:43][C:44]([C:2]2[N:3]=[C:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7]4[N:15]=[CH:16][CH:17]=[CH:18][C:6]=4[N:5]3[C:19]=2[C:20]2[CH:21]=[CH:22][C:23]([C:26]3([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[CH:45][CH:46]=1)(=[O:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Yield: 77.9 %

Procedure:
A mixture of tert-butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (30 mg, 0.058 mmol), m-acetylphenyl boronic acid (19 mg, 0.12 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4 mg, 0.006 mmol), and 2M Na2CO3 aq. (0.058 mL, 0.12 mmol) in DMF (1 mL) was treated with microwave (160° C. for 1 hour). The mixture was diluted with AcOEt, washed with water (×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (n-hexane/AcOEt=1:1×2) to afford the desired product (27 mg, 77%) as a yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.17 (dd, J=7.7, 1.4 Hz, 1H), 8.02 (d, J=4.6 Hz, 1H), 7.86 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.32 (td, J=8.0, 1.7 Hz, 1H), 7.18-7.15 (m, 2H), 6.96 (d, J=8.0 Hz, 1H), 6.80 (d, J=7.4 Hz, 1H), 6.60 (dd, J=8.0, 5.2 Hz, 1H), 6.25 (s, 1H), 5.13 (br s, 2H), 2.59-2.53 (m, 5H), 2.50-2.42 (m, 2H), 2.21-2.12 (m, 1H), 1.95-1.87 (m, 1H), 1.40 (br s, 9H). LCMS: 598 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].[CH:13]([N-]C(C)C)(C)C.[Li+].IC.C([O-])(O)=O.[Na+]>O1CCCC1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[C:6]2=[O:12]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1CCc2c(F)cc(F)cc21
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1Cc2c(F)cc(F)cc2C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
According to Scheme 3, step 1: to a solution of 4,6-difluoro-indan-1-one (5.0 g, 29.8 mmol) in dry tetrahydrofuran (100 ml) at −78° C. a 2M solution of lithiumdiisopropylamide (16.4 ml, 32.7 mmol) in tetrahydrofuran was added dropwise and the mixture was stirred for 1 h at −78° C. Then iodomethane (4.64 g, 32.7 mmol) was added and the mixture was slowly warmed to 25° C. After addition of aqueous saturated NaHCO3 the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SO4 and filtered, solvents were evaporated in vacuo. The crude product was purified by silica gel chromatography (eluting with 0% to 100% ethyl acetate in heptane to give 1.15 g of 4,6-Difluoro-2-methyl-indan-1-one (7a).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:10]=3[N:9]=2)[CH2:4][C@H:3]1[O:21][CH3:22].[Cl:23][C:24]1[N:25]=[C:26]([C:31](O)=[O:32])[NH:27][C:28]=1[CH2:29][CH3:30].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:23][C:24]1[N:25]=[C:26]([C:31]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:10]=4[N:9]=3)[CH2:4][C@H:3]2[O:21][CH3:22])=[O:32])[NH:27][C:28]=1[CH2:29][CH3:30]
Reactant: COC(=O)c1cccc2[nH]c(N3CC[C@H](N)[C@H](OC)C3)nc12
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc4c(C(=O)OC)cccc4[nH]3)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-1H-benzimidazole-4-carboxylate obtained in Example (187c) (220 mg, 0.75 mmol) and 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (130 mg, 0.75 mmol) were dissolved in DMA (5 ml). WSC hydrochloride (580 mg, 3 mmol) and HOBt (100 mg, 0.75 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was recrystallized from an ethyl acetate/hexane solvent to obtain the title compound as crystals.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:36])[CH2:15][NH:16][CH2:17][CH:18]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:36])[CH2:15][N:16]([C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:17][CH:18]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22]
Reactant: COC(=O)CNCC(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: COC(=O)CN(CC(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Benzylchloroformate (1.4 mL, 9.81 mmol) is added dropwise to a solution of N,N-dimethylaminopyridine (1.09 g, 8.93 mmol) and [2-tert-butoxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-propylamino]-acetic acid methyl ester (3.06 g, 8.12 mmol) in CH2Cl2 at RT. The resulting mixture is stirred overnight then concentrated to dryness. The crude product is purifed by flash chromatography eluting with 1% MeOH/CH2Cl2 to yield the title compound (3.52 g, 6.89 mmol) as a colorless oil. Ion spray MS, [M+H]+=511.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH2:8]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12](Cl)=[O:13])[CH2:9][CH3:10]>N1C=CC=CC=1>[CH2:8]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12]([O:7][CH2:1][CH:2]([O:6][C:12](=[O:13])[CH:11]([CH2:15][CH2:16][CH3:17])[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][O:5][C:12](=[O:13])[CH:11]([CH2:15][CH2:16][CH3:17])[CH2:8][CH2:9][CH3:10])=[O:13])[CH2:9][CH3:10]
Reactant: CCCC(CCC)C(=O)Cl
Reactant: OCCC(O)CO
Solvent: c1ccncc1
Product: CCCC(CCC)C(=O)OCCC(COC(=O)C(CCC)CCC)OC(=O)C(CCC)CCC

Procedure:
Into a perfectly clean and dry flask were introduced 106.1 g (1 mol) of rectified 1,2,4-butanetriol and 1600 ml of anhydrous pyridine. While stirring, 507.4 g (3.12 mols) of di-n-propylacetyl chloride were added in 60 to 90 minutes care being taken to maintain the temperature below 30° C. The reaction medium was then stirred at room-temperature for 72 hours. The subsequent operations of purification were identical to those carried out in the foregoing Example 13.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H-].[Na+]>C1COCC1>[CH2:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCCCCCCl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: ClCCCCCCOCc1ccccc1
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a stirred solution of 6-chloro-1-hexanol (15.0 g, 0.110 mol) and benzyl bromide (18.8 g, 0.110 mol) in dry THF (200 ml) at room temperature under argon was slowly added (over 30 min.) sodium hydride powder (2.899 g, 0.121 mol). The solution was left overnight and the solids filtered off. The solvent was removed under reduced pressure, the residues taken up into dichloromethane (100 ml) and washed (2×20 ml water). The solution was dried over MgSO4 and the solvent removed to yield an orange oil which was subsequently distilled (160° C., 0.5 mBar) to yield the title compound (17.5 g, 70%) as a colourless oil. C13H19OCl requires 226. Found DCl: MNH4+, 244. δH (CDCl3) 1.49 (4H, m, (CH2)2(CH2)2Cl), 1.70 (2H, p, CH2CH2O), 1.83 (2H, t, CH2CH2Cl), 3.54 3.56 (4H, 2×t, CH2CH2O, CH2Cl), 4.56 (2H, s, CH2Ph), 7.40 (5H, m, Ph). δC (CDCl3) 25.3 (1C, CH2(CH2)2Cl), 26.4 (1C, CH2(CH2)3Cl), 29.3 (1C, CH2(CH2)2O), 32.3 (1C, CH2CH2Cl), 44.8 (1 C, CH2Cl), 69.9, 72.6 (2C, CH2O), 127.2 (1C, CH(CH2)2C), 127.3 (2C, CHC), 128.1 (2C, CHCHC), 138.4 (1C, CCH2O).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17](OC)=O)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5]C=CC=1.C1([C:27]2C3C(=C(CO)C=CC=3)C=C[N:28]=2)C=CC=CC=1>>[CH2:1]([C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:27]#[N:28])[C:11]=2[CH:10]=[CH:9][N:8]=1)[CH2:6][CH3:5]
Reactant: COC(=O)c1cccc2c(-c3ccccc3)nccc12
Reactant: OCc1cccc2c(-c3ccccc3)nccc12
Product: CCCc1nccc2c(CC#N)cccc12

Procedure:
1-Amino-2-(2-hydroxymethylphenyl)ethane and butyryl chloride were successively reacted in the same way as in steps (b) and (c) of Example 12 to afford 1-butyrylamino-2-(2-hydroxymethylphenyl)ethane as an oil. The product was successively reacted in the same way as in steps (d), (e), (f) and (g) of Example 12 to afford 1-n-propylisoquinoline-5-acetonitrile.
Reaction SMILES: C(OC([CH:6]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[O:9][C:8]([CH2:16][O:17][CH3:18])([CH3:15])[C:7]1=[O:19])=O)C.S(=O)(=O)(O)O>O1CCOCC1.[Cl-].[Na+].O>[CH3:18][O:17][CH2:16][C:8]1([CH3:15])[C:7](=[O:19])[CH2:6][C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[O:9]1
Reactant: CCOC(=O)C1C(=O)C(C)(C)OC(C)(COC)C1=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COCC1(C)OC(C)(C)C(=O)CC1=O
Temperature: 110 °C
Yield: 16.2 %

Procedure:
To a solution of 2-methoxymethyl-2,6,6-trimethyl-3,5-dioxotetrahydropyran-4-carboxylic acid ethyl ester (2.11 g, 7.72 mmol) in dioxane (2.5 ml) is added 20% aqueous sulfuric acid (2.5 ml) and the mixture is heated at 110° C. for 2.5 hours. The mixture is cooled to room temperature, diluted with saturated brine and extracted with dichloromethane. The crude material is extracted into aqueous sodium hydroxide, the aqueous phase washed with dichloromethane, then acidified with concentrated hydrochloric acid and extracted into dichloromethane (2×15 ml). The organic phase is concentrated in vacuo to give a crude oil which is purified by flash column chromatography on silica gel (isohexane/diethyl ether 7.5:1.5 ratio) to afford 2-methoxymethyl-2,6,6-trimethylpyran-3,5-dione (0.250 g) as a pink solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].N1C2C(=CC=CC=2)C=C1.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C=O)C>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH3:35]
Reactant: CCOC(=O)CBr
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Agent: c1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2cc(OCc3ccccc3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
5-benzyloxyindole (10.0 g, 44.79 mmol) is dissolved into anhydrous DMF (100 mL) and cooled to 0° C. in an ice water bath. Sodium hydride (2.6 g, 67.18 mmol) is dissolved into anhydrous DMF (100 mL), then slowly added to the indole solution using an addition funnel. The reaction is allowed to stir at 0° C. for 1 h., then the ice bath is removed and the solution is allowed to warm slowly to room temperature. The solution is then cooled back down to 0° C. and ethyl bromoacetate (11.2 g, 67.18 mmol) is then added in one portion. The reaction is allowed to stir at 0° C. for 1 h., then the ice bath is removed and the solution is allowed to warm slowly to room temperature. Upon completion, the reaction is quenched carefully using water, then diluted with EtOAc (300 mL). Brine (100 mL) is added and the two layers are separated in a separatory funnel. The organic layer is rinsed with water (2×75 mL) and then dried over anhydrous magnesium sulfate. The organic layer is then concentrated and purified using flash column chromatography (5% EtOAc/Hexanes) to yield 11.86 g (86%) of (5-Benzyloxy-indol-1-yl)-acetic acid ethyl ester.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1)[CH2:9][C:10]([F:13])([F:12])[F:11])(=O)=O.[Na].[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1>CN(C=O)C>[N:27]1([CH2:6][CH2:7][N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: CS(=O)(=O)OCCN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(CCn2cncn2)CC(F)(F)F)cc1C(F)(F)F
Temperature: 60 °C
Yield: 83 %

Procedure:
A mixture of 2-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]ethyl methanesulfonate, Example 15C (0.050 g, 0.128 mmol) and 1,2,4-triazole sodium salt (0.023 g, 0.256 mmol) in DMF (2 mL) was heated at 60° C. under N2 for 45 min. Upon cooling, the mixture was partitioned between Et2O and water. The organic phase was washed with water and the combined aqueous phases were extracted twice with Et2O. The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel chromatography (5-80% EtOAc/hexanes gradient followed by 1-10% MeOH/EtOAc gradient) and the product was crystallized from CH2Cl2/hexanes to give the title compound as a white solid (0.038 mg, 83% yield): MS (ES) m/z 364 (M+1).
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:7](Cl)=[C:6]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:5]=1[F:23])=[N+]=[N-]>[Pd].CCO>[NH2:1][C:4]1[C:5]([F:23])=[C:6]([O:17][CH2:18][C:19]([F:21])([F:22])[F:20])[CH:7]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:13])[F:14])[N:9]=1
Reactant: [N-]=[N+]=Nc1nc(OCC(F)(F)F)c(Cl)c(OCC(F)(F)F)c1F
Agent: [Pd]
Solvent: CCO
Product: Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)c1F
Temperature: 100 °C
Yield: 62.3 %

Procedure:
A 350 mL stainless steel pressure reactor equipped with a mechanical stirrer was charged with 6-azido-2,4-bis(2,2,2-trifluoroethoxy)-3-chloro-5-fluoropyridine (14.0 g, 38.0 mmol), EtOH (50 mL), and palladium on carbon (10%, 4.0 g). The reactor was sealed and pressurized with H2 (500 psi). The pressurized reactor was heated to 100° C. After 18 h the pressurized reactor was cooled to ambient temperature. A GC analysis indicated all the starting material was consumed. The reaction was filtered and the volatiles evaporated to afford the crude product as a brown oil. The brown oil was purified by column chromatography (SiO2, hexane/EtOAc) to afford the product as a brown crystalline solid (7.29 g, 62% yield): mp 43-45° C.; 1H NMR (CDCl3) δ 5.84 (d, J=4.1 Hz, 1H), 5.85-4.56 (q, J=8.5, 2H), 4.49-4.37 (m, 4H); GC-MS (EI, 70 eV) m/z (% relative intensity) 308 (100), 289 (26), 239 (74).
Reaction SMILES: [CH2:1]([N:8]=C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:11](=O)(=[O:14])([OH:13])[OH:12]>[N+](C)([O-])=O>[CH2:1]([NH:8][S:11](=[O:13])(=[O:12])[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: O=C=NCc1ccccc1
Solvent: C[N+](=O)[O-]
Product: O=S(=O)(O)NCc1ccccc1
Temperature: 25 °C

Procedure:
Benzylisocyanate (13.3 g) is added dropwise to a stirred mixture of nitromethane (160 ml) and 15% fuming sulfuric acid (5.4 ml) at about 10° C. The reaction mixture is refluxed for about one hour, cooled to RT and the solid filtered and washed with nitromethene. The solid is suspended in ether, filtered, dried and used as a crude solid in the next step.