Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:10]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:11]=3[N:12]=[CH:13][C:14]=2[C:15]2[CH2:19][C:18]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[O:17][N:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:36]Cl.[CH2:38]1[CH2:40][CH2:39]1.O>CN(C)C=O>[CH:2]1([NH:8][C:9]2[C:10]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:11]=3[N:12]=[CH:13][C:14]=2[C:15]2[CH2:19][C:18]3([CH2:24][CH2:23][N:22]([CH2:36][CH:38]4[CH2:40][CH2:39]4)[CH2:21][CH2:20]3)[O:17][N:16]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCl
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCNCC4)C3)cnc21
Reactant: C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCN(CC5CC5)CC4)C3)cnc21
Temperature: 75 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
N-cyclohexyl-1-ethyl-5-(1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride salt (70 mg, 0.00016 mole) (example 22) was taken in dimethylformamide (5 ml). Potassium carbonate (69 mg, 0.00050 mole) and cyclopropane methyl chloride (0.20 ml, 0.000021 mole) were added. The reaction mixture was stirred at 70-80° C. overnight. Water was added and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuum. The crude product obtained was purified by preparative thin layer chromatography.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6]Br.[NH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:15].[CH2:16]([OH:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1>[CH2:16]([O:24][CH2:4][CH2:5][CH2:6][N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:15])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: BrCCCBr
Reactant: CCCCCCCCO
Reactant: O=C1CCCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCOCCCN1CCCCCC1=O
Yield: 69.4 %

Procedure:
A mixture of 0.93 g of 60% sodium hydride and 100 ml of dry toluene was incorporated dropwise with 3.00 g of n-octyl alcohol, heated under reflux for one hour, thereafter incorporated with 14.1 g of 1,3-dibromopropane, further refluxed for 12 hours and then filtered to remove insoluble materials to obtain a filtrate. The thus obtained filtrate was washed with water, dried, freed from the solvent by distillation off and then finally distilled to obtain a colorless transparent substance. 4.59 g of the thus obtained substance was added to a mixture of 2.07 g of azacycloheptane-2-one, 0.80 g of 60% sodium hydride and 150 ml of dry toluene, after which the whole was refluxed for 12 hours and then filtered to remove insoluble materials to obtain a filtrate. The thus obtained filtrate was washed with water, dried, freed from the solvent by distillation off at reduced pressure and then finally distilled to obtain 3.60 g of colorless 1-[3-(n-octyloxy) propyl] azacycloheptane-2-one having the following appearance, column temperature and analysis:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:25][C:20]4(OCC[O:21]4)[CH2:19][CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.C1COCC1.Cl.C(=O)([O-])O.[Na+]>O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:25][CH:20]([OH:21])[CH2:19][CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: Clc1cc(-c2nc3c(o2)CC2(CC3)OCCO2)ccc1OCC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: OC1CCc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To 2-(3-chloro-4-(cyclopropylmethoxy)phenyl)-4,7-dihydro-5H-spiro[1,3-benzoxazole-6,2′-[1,3]dioxolane] (10.0 g) in a mixed solvent of THF (50 mL)-methanol (25 mL)-water (25 mL) was added 6 M hydrochloric acid (27.6 mL), and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. To the organic layer was added sodium tetrahydroborate (1.05 g), and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.61 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([NH:12][CH3:13])=[CH:10][N:11]=1)[C:5]([O:7]C)=O.[C:14]([O:18][C:19]([C:21]1[C:26](C(OC)=O)=CC(Cl)=NC=1)=[O:20])(C)(C)C.C(O)(C(F)(F)F)=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:12]([CH3:13])[C:26](=[O:33])[C:21]([C:19]([O:18][CH3:14])=[O:20])=[C:5]2[OH:7]
Reactant: CNc1cnc(Cl)cc1C(=O)OC
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1cc(Cl)ncc1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)c1c(O)c2cc(Cl)ncc2n(C)c1=O

Procedure:
Methyl 2-chloro-5-(methylamino)isonicotinate. To a solution of methyl 5-(tert-butoxycarbonyl)-2-chloroisonicotinate (0.5 g, 1.7 mmol) in dry DCM (10 mL) was added TFA (4.4 mL) with stirring and cooling using an ice-bath. The mixture was stirred at room temperature for 2 hours and then evaporated under reduced pressure. The residue was dissolved in water, and the solution was adjusted to pH=8 by treatment with saturated NaHCO3. The mixture was extracted twice with EtOAc. The combined organic layers were dried over anhydrous MgSO4, and filtered. The filtrate was evaporated under reduced pressure, and the residue was dried in vacuo to give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])C.O.[OH-].[Li+].O.CO>O1CCCC1>[OH:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]([F:20])([F:18])[F:19])[C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1CC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(O)ccc2n1CC(F)(F)F
Yield: 99.7 %

Procedure:
A mixture of 5-hydroxy-1-(2,2,2-trifluoro-ethyl)-1H-indole-2-carboxylic acid ethyl ester (Intermediate 1, step b, 8.5 g, 1.0 eq.), lithium hydroxide monohydrate (1.43 g, 1.15 eq.), water (45 mL), methanol (30 mL) and tetrahydrofuran (90 mL) was heated to reflux for 24 h. The volatiles were removed in vacuo and the resulting solution was acidified (pH ca. 2) with hydrochloric acid (1N). The precipitate was filtered and dried in vacuo to yield 7.65 g (99%) of the desired product as off-white solid. MS (m/e): 258.5 (M−H−, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Br:14])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Br-:14].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:4]2[CH:5]=[CH:6][N+:2]([CH3:1])=[CH:3]2)=[CH:11][CH:10]=1
Reactant: COc1ccc(CBr)cc1
Reactant: Cn1ccnc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cc[n+](C)c2)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 131.4 %

Procedure:
Into a 50 ml one-necked flask surmounted by a condenser, there are successively introduced 1 ml (12.5 mmol) of N-methylimidazole, and then 5 g (18.8 mmol) of 4-methoxybenzyl bromide in solution in 25 ml of toluene. The reaction medium is heated under reflux, with stirring, for 2 h 30 min. After cooling to room temperature, the viscous oil formed is separated by decantation and then dried under vacuum at room temperature, 4.65 g of a pale yellow solid are thus obtained whose characteristics are the following:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:21]3[S:20](=O)[CH2:19][C:18]=2[S:65][CH2:66][S:67][C:68]2[N:69]=[N:70][N:71]([CH3:73])[N:72]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:65][CH2:66][S:67][C:68]2[N:69]=[N:70][N:71]([CH3:73])[N:72]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1nnc(SCSC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)[C@H]3S(=O)C2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: Cn1nnc(SCSC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)[C@H]3SC2)n1
Reaction time: 0.33 h
Yield: 88.2 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(2-methyltetrazol-5-yl thiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (1.38 g: 1.31 mMol.) in dimethylformamide (15 ml) at -20° C. is added phosphorus trichloride (0.33 ml: 3.28 mMol.), and the mixture is stirred at the same temperature for 20 minutes. The reaction mixture is poured into cold two layers of aqueous sodium hydrogen carbonate and ethyl acetate and stirred. The organic layer is taken, washed with water and brine, dried over sodium sulfate and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=5:1) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(2-methyltetrazol-5-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (1.20 g) as yellow foam. Yield: 88%.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1.[C:46](Cl)(=[O:48])[CH3:47].CO>ClCCl>[C:46]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[C:9]5[O:13][CH2:12][O:11][C:10]=5[CH:14]=[CH:15][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:34][CH2:33]1)(=[O:48])[CH3:47]
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[5-(Cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride from example D.f1 (486 mg; 1.0 mmol) and DBU (2.5 mmol) is dissolved in dry dichloromethane (5 mL). Acetyl chloride (1.1 mmol) is syringed into the reaction mixture at ice bath temperature. After addition the mixture is stirred at ambient temperature over night. Methanol (1 mL) is added and stirring is continued for two hours. The volatiles are evaporated. The residue is purified by reversed phase preparative HPLC. The collected product fraction is freeze-dried to yield the title compound as colorless solid.
Reaction SMILES: C(Cl)CCl.CNC[C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH3:17])=[CH:14][CH:13]=[CH:12][CH:11]=2.Cl.[NH2:19][C:20]1[N:25]=[CH:24][C:23](/[CH:26]=[CH:27]/C(O)=O)=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:50][N:51]([CH:53]=[O:54])[CH3:52]>O>[NH2:19][C:20]1[N:25]=[CH:24][C:23]([C:26](=[CH2:27])[C:53]([N:51]([CH3:52])[CH2:50][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH3:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:54])=[CH:22][CH:21]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1[nH]c2ccccc2c1C
Reactant: CN(C)C=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCCl
Product: C=C(C(=O)N(C)Cc1[nH]c2ccccc2c1C)c1ccc(N)nc1
Reaction time: 8 h
Yield: 23 %

Procedure:
EDC (438 mg, 1.1 mmol) was added to a solution of N-methyl-(3-methyl-1H-indol-2-yl)methanamine (170 mg, 0.9 mmol), (E)-3-(6-aminopyrid-3-yl)acrylic acid hydrochloride (176 mg, 1.0 mmol), HOBT.H2O (130 mg, 0.9 mmol) and DIPEA (0.58 mL, 2.7 mmol) in dry DMF (5 mL). After stirring overnight, water was added. The precipitate that formed was washed with ethyl acetate and dried to afford the title compound (65 mg, 23%). 1H NMR (300 MHz, DMSO-d6) δ 10.75-0.54 (rotamers, s, 1H), 8.15 (d, J=7.2 Hz, 1H), 7.94 (s, 1H), 7.84 (d, J=7.7 Hz, 1H), 7.40 (d, J=7.0 Hz, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.02-6.97 (m, 2H), 6.47-6.41 (m, 2H), 5.01-4.85 (rotamers, s, 2H), 4.72 (s, 3H), 2.23 (s, 3H); MS (ESI): m/e 321.3 (C19H20N4O+H)+.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)(N1C=CN=C1)=O.[OH:13][C:14]([CH:16]([C:18]1[CH:27]=[CH:26][C:21]([CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:20][CH:19]=1)[CH3:17])=[O:15].[H-].[Na+].[CH2:30]1[CH2:34][O:33][CH2:32][CH2:31]1>>[CH2:22]([C:21]1[CH:20]=[CH:19][C:18]([CH:16]([CH3:17])[C:14]([O:13][C:16]2[CH:17]=[CH:32][CH:31]=[C:30]([C:34]3([OH:33])[CH2:20][CH2:19][CH2:18][CH2:27][CH:11]3[CH2:12][N:8]([CH3:1])[CH3:9])[CH:14]=2)=[O:15])=[CH:27][CH:26]=1)[CH:23]([CH3:24])[CH3:25]
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)Cc1ccc(C(C)C(=O)Oc2cccc(C3(O)CCCCC3CN(C)C)c2)cc1
Reaction time: 2 h

Procedure:
0.76 g (4.8 mmol) of carbonyldiimidazol were added to 1 g (4.8 mmol) of (±)-Ibuprofen in 60 ml of dry THF. The reaction was kept at room temperature for 2 h, after which a 60% solution of 0.59 g (2.4 mmol) of (RR,SS)-3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenol previously treated with 0.1 g (2.5 mmol) of sodium hydride in mineral oil was added.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH:6]([CH:8]=O)[CH2:5][CH2:4][O:3]1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][CH:6](/[CH:8]=[CH:11]/[C:12]([OH:14])=[O:13])[CH2:5][CH2:4][O:3]1
Reactant: O=C(O)CC(=O)O
Reactant: C[C@H]1CC(C=O)CCO1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C[C@H]1CC(/C=C/C(=O)O)CCO1
Temperature: 100 °C

Procedure:
A mixture of (2S)-2-methyltetrahydro-2H-pyran-4-carboxaldehyde (4.0), malonic acid (6.495 g) and piperidine (0.1 ml) in pyridine (10 ml) was heated to 100° C. for 4 hours. The reaction mixture was concentrated and partitioned between ethyl acetate (100 ml) and 1N HCl. The organic layer was dried, evaporated and recrystallised form toluene to give the title compound. Yield 2.48 g. NMR CDCl3 1.2 (m, 4H), 1.5 (m, 1H), 1.7 (m, 2H), 2.45 (m, 1H), 3.5 (m, 2H), 4.05 (m, 1H), 5.8 (d, 1H), 7.0 (dd, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25].Cl>ClCCl>[C:24]([O:17][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(C(=O)c2cc(Br)ccc2O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Br)cc1C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16.75 h

Procedure:
To a yellow solution of 229 mg (0.8 mmol) of 5-bromo-2-hydroxy-4'-methylbenzophenone (Compound K) in 15 mL of dichloromethane (under a blanket of argon) was added 0.07 mL (69 mg, 0.9 mmol) of pyridine followed by 0.07 mL (74 mg, 0.9 mmol) of acetyl chloride. The resultant reaction mixture was stirred at ambient temperature overnight (16.75 hours), poured into 10% HCl (aq.) solution and extracted with ethyl acetate. The layers were separated and the aqueous phase was washed with ethyl acetate. The organic phases were combined and then sequentially washed with sat. NaHCO3 (aq.) solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. Purification by flash chromatography (silica, 20% ethyl acetate in hexane) gave the title compound as a clear, colorless oil.
Reaction SMILES: Br[CH2:2][C@@H:3]([F:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].FC(F)(F)S(O[C:17]1[C:22]([F:23])=[CH:21][C:20]([CH:24]2[CH2:29][CH2:28][Si:27]([CH2:36][CH2:37][CH3:38])(C3C=CC=CC=3)[CH2:26][CH2:25]2)=[CH:19][C:18]=1[F:39])(=O)=O>>[CH2:36]([Si@H:27]1[CH2:26][CH2:25][C@H:24]([C:20]2[CH:19]=[C:18]([F:39])[C:17]([CH2:2][C@@H:3]([F:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[C:22]([F:23])[CH:21]=2)[CH2:29][CH2:28]1)[CH2:37][CH3:38]
Reactant: CCCCCC[C@H](F)CBr
Reactant: CCC[Si]1(c2ccccc2)CCC(c2cc(F)c(OS(=O)(=O)C(F)(F)F)c(F)c2)CC1
Product: CCCCCC[C@H](F)Cc1c(F)cc([C@H]2CC[Si@H](CCC)CC2)cc1F

Procedure:
The general procedure of Example 18 was repeated using (S)-1-bromo-2-fluorooctane and (2,6-difluoro-4-(4-n-propyl-4-phenyl-4-silacyclohexyl)phenyl) trifluoromethanesulfonate, thereby obtaining the intended compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13]([C:20]#[N:21])=[CH:14][NH:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1.C(Cl)Cl>[C:20]([C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[CH:19][C:11]=2[CH:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2][O:1][S:23]([CH3:22])(=[O:25])=[O:24])[NH:15][CH:14]=1)#[N:21]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1c[nH]c2cccc(C(CCO)c3ccccc3)c12
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)OCCC(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 4-(3-hydroxy-1-phenyl-propyl)-1H-indole-3-carbonitrile LX (377 mg, 1.36 mmol) in THF/DCM (1/1, 22 ml) was added MsCl (105 μl, 1.36 mmol) dropwise. The mixture was stirred at 0° C. for 10 minutes, and TEA (226 μl, 1.62 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 2.5 hours, poured into ice/water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated affording methanesulfonic acid 3-(3-cyano-1H-indol-4-yl)-3-phenyl-propyl ester (not shown in above scheme) as a yellow oil. A solution of this crude mesylate in MeNH2 (33% in EtOH, 8.5 ml) was placed in a sealed tube and stirred at 100° C. for 45 minutes. The reaction mixture was concentrated, and the residue was partitioned between a saturated solution of NaHCO3 and EtOAc: The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH) affording 4-(3-methylamino-1-phenyl-propyl)-1H-indole-3-carbonitrile LXI as a white foamy solid (346 mg). MS (M+H)=290.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[C:32]([Cu])#[N:33].O.Cl>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:32]#[N:33])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(Br)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(C#N)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A mixture of 1,3-dibenzyl-8-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (114 mg, 0.24 mmol) and CuCN (43 mg, 0.48 mmol) in 5 mL of DMF was refluxed for 40 min. After the mixture was cooled to r.t., it was poured into a mixture of water and CH2Cl2. 4M HCl was added with vigorous stirring until both layers became homogeneous. The aqueous layer was extracted with additional CH2Cl2, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-50% EtOAc/hexanes+2% AcOH) to give 53 mg of the title compound. MS: (+) m/z 426.14 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]>CN(C)C=O>[CH2:16]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:12])=[CH:6][CH:7]=1)[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CCBr
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCCC(C)C)cc1
Reaction time: 12 h
Yield: 76.2 %

Procedure:
Methyl-4-hydroxyphenylacetate (2.00 g, 12.0 mmol) was added in one portion to a stirred suspension of sodium hydride (60% mineral oil suspension; 528 mg, 13.2 mmol) in dimethylformamide (20 mL) at room temperature under nitrogen. After stirring for 30 min 1-bromo-3-methylbutane (1.99 g, 1.58 mL, 13.2 mmol) was added dropwise over 5 min then stirring was continued for 12 h. The volatiles were evaporated then the residue partitioned between dichloromethane (50 mL) and water (50 mL). The phases were separated and the aqueous phase was washed with dichloromethane (2×50 mL). The organics were combined, dried (magnesium sulfate) and the solvent evaporated. The residue was chromatographed on silica gel (20% diethyl ether: cyclohexane) to give the title compound as a colourless oil (2.16 g, 76%). LC/MS: 3.51 min; z/e 254, calcd (M+18) 254. 1H NMR (400 MHz: CDCl3): 7.15 (2H), 6.85 (2H), 4.00 (2H), 3.70 (3H), 3.55 (2H), 1.85 (1H), 1.70 (2H), 0.95 (6H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[N:16][C:15](C(O)=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[CH3:51][OH:52].C[N:54]([CH:56]=[O:57])C>O>[F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[N:17]=[N:16][C:15]([NH:54][C:56](=[O:57])[O:52][CH3:51])=[CH:14][CH:13]=2)[CH2:10][CH2:11]1
Reactant: CN(C)C=O
Reactant: CO
Reactant: O=C(O)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Nc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine-3-carboxylic acid (150 mg, 0.4 mmol), DPPA (100 μL, 0.46 mmol) and Et3N (65 μL, 0.46 mmol) in DMF (1.5 mL) was stirred at r.t. overnight. MeOH (150 μL, 3.7 mmol) was then added and the mixture was heated at 65-70° C. for 6 h. After cooling, the mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed twice with water, dried (Na2SO4) and concentrated. CombiFlash chromatography (10 g, 40-80% EtOAc in hexanes in 20 min, 20 mL/min, 15 mL/fraction) gave the title compound as a white solid. 1H NMR (500 MHz, acetone-d6): δ 1.89-1.97 (m, 2H), 2.15 (m, 2H), 3.65-3.71 (m, 2H), 3.76 (s, 3H), 3.87-3.93 (m, 2H), 4.94-4.98 (m, 1H), 7.11 (t, 1H), 7.37 (m, 2H), 7.61-7.67 (m, 2H), 8.00 (d, 1H), 9.11 (s, 1H). MS (+ESI) m/z 397 (MH+).