Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][CH:12]([C:14]([O:16]C)=[O:15])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl>C1COCC1.O>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1CC(c2cccc(C(F)(F)F)c2)=NO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CC(c2cccc(C(F)(F)F)c2)=NO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of methyl 3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxylate (2.3 g, 8.4 mmol) in THF (10 mL) was added 2 M of sodium hydroxide in water (10 mL) at 0° C. The reaction mixture was slowly warmed to ambient temperature, stirred for 2 h, neutralized with 2 N HCl to pH 7, and extracted with ethyl acetate (2×50 mL). The organic extracts were combined, washed with saline solution (50 mL), dried over sodium sulfate, concentrated in vacuo. The residue was chromatographed on silica gel, eluting with methylene chloride/methanol (95/5 to 80/20). The appropriate fractions were combined and concentrated in vacuo to give 3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxylic acid (2.18 g, 100%) as a white crystalline solid. LCMS: 258.2 (M−H−, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:23])[C:17]=1[F:24].[CH2:25]([N:27]1[CH:32]=[C:31]([C:33](O)=[O:34])[C:30](=[O:36])[N:29]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:28]1=[O:44])[CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:33]([C:31]2[C:30](=[O:36])[N:29]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:28](=[O:44])[N:27]([CH2:25][CH3:26])[CH:32]=2)=[O:34])=[C:18]([F:23])[C:17]=1[F:24]
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3F)c2cc1OC
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2F)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxyquinolin-4-yloxy)-2,3-difluoro-phenylamine and 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=270-272° C.; LCMS m/z=593 (M+1); 1H NMR (CDCl3) δ: 11.08 (s, 1H), 8.63 (s, 1H), 5.51 (d, 1H, J=6 Hz), 8.28-8.22 (m, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.25-7.23 (m, 4H), 7.09-7.03 (m, 1H), 6.46 (d, 1H, J=5 Hz), 4.05 (d, 6H), 4.04-3.99 (m, 2H), 1.47 (t, 3H, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[N:7]([CH2:15][CH:16](OC)[O:17]C)[N:6]=[CH:5]2.C1COCC1.C([O-])(O)=O.[Na+]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[N:7]([CH2:15][CH:16]=[O:17])[N:6]=[CH:5]2
Reactant: COC(=O)c1cc(Cl)cc2cnn(CC(OC)OC)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cc2cnn(CC=O)c12
Temperature: 25 °C
Yield: 74.7 %

Procedure:
Methyl 5-chloro-1-(2,2-dimethoxyethyl)-1H-indazole-7-carboxylate (733 mg, 2.5 mmol) from Step B above was refluxed in 2 N HCl (8 mL) and THF (8 mL) until the reaction was complete by TLC (3-5 h). After cooling to room temperature, the pH of the reaction mixture was adjusted to 8 with NaHCO3, then extracted with ethyl acetate. The organic layers were combined, dried (Na2SO4), filtered, concentrated and purified by column chromatography (silica gel, 1:1 ethyl acetate/hexanes) to afford methyl 5-chloro-1-(2-oxoethyl)-1H-indazole-7-carboxylate as an off-white solid (472 mg, 76%): 1H NMR (300 MHz, CDCl3) δ 9.77 (s, 1H), 8.10 (s, 1H), 8.05 (s, 1H), 7.94 (s, 1H), 5.60 (s, 2H), 4.03 (d, J=8.4 Hz, 1H), 3.93 (s, 3H); MS (ESI+) m/z 253 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@:8]([O:12][Si](C)(C)C)([CH3:11])[C:9]#[N:10])[C:5]([F:17])=[C:4]([Si:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:3]=1.[ClH:25]>C1COCC1>[ClH:25].[NH2:10][CH2:9][C@:8]([C:6]1[C:5]([F:17])=[C:4]([Si:18]([CH2:21][CH3:22])([CH2:23][CH3:24])[CH2:19][CH3:20])[CH:3]=[C:2]([Br:1])[N:7]=1)([OH:12])[CH3:11]
Reactant: CC[Si](CC)(CC)c1cc(Br)nc([C@@](C)(C#N)O[Si](C)(C)C)c1F
Agent: Cl
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)nc([C@](C)(O)CN)c1F
Yield: 102.1 %

Procedure:
Borane dimethyl sulfide complex (16.55 g, 218 mmol) was added to a solution of crude (S)-2-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2-trimethylsilanyloxy-propionitrile (47 g, 109 mmol) in 470 ml THF. The mixture was refluxed for 2 h. The heating bath was removed and the reaction mixture was quenched by careful and dropwise addition of MeOH. After the evolution of gas had ceased, aq. 6M HCl (23.6 ml, 142 mmol) was added slowly. The resulting solution was evaporated and the residue was dissolved in MeOH and evaporated (twice) to yield 44.5 g of a yellow foam, pure enough for further reactions. HPLC: RtH1=2.617 min; ESIMS: 363, 365 [(M+H)+, 1Br]; 1H-NMR (400 MHz, CDCl3): 7.93 (s, br, 3H), 7.53 (d, 1H), 6.11 (s, br, 1H), 3.36-3.27 (m, 1H), 3.18-3.09 (m, 1H), 1.53 (s, 3H), 0.99-0.81 (m, 15H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C@@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]([CH2:7]O)[N:6]=1.S(Cl)([Cl:17])=O>C(Cl)Cl>[Cl:17][CH2:7][CH:5]1[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:3][C:2]([CH3:1])=[N:6]1
Reactant: O=S(Cl)Cl
Reactant: CC1=NC(CO)[C@H](c2ccccc2)O1
Solvent: ClCCl
Product: CC1=NC(CCl)[C@H](c2ccccc2)O1
Reaction time: 8 h

Procedure:
To a stirred mixture of ((5S)-2-methyl-5-phenyl-1,3-oxazolin-4-yl)methan-1-ol (1.0 mg, 5.23 mmol) in methylene chloride (15 mL) was added thionyl chloride (570 μL, 7.81 mmol) dropwise at 0° C. The resulting mixture was stirred under an atmosphere of nitrogen for 8 hours, then concentrated under a reduced pressure to afford (5S)-4-chloromethyl-2-methyl-5-phenyl-4,5-dihydro-1,3-oxazole as a white solid (960 mg, M+1=210.1). B. To a stirred mixture of (2R)-3-((2S)-2-methylpiperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol (51 mg, 0.13 mmol) in tert-amylalcohol (5 mL) was added triethylamine (90 μL, 0.65 mmol), followed by (5S)-4-chloromethyl-2-methyl-5-phenyl-1,3-oxazole (29 mg, 0.14 mmol). The resulting mixture was stirred at 95° C. for 12 hours, concentrated, and purified by preparative chromatograph (1:19 MeOH:CH2Cl2) to afford (2R)-3-{(2S)-4-[((4S,5S)-2-methyl-5-phenyl(1,3-oxazolin-4-yl))methyl]-2-methylpiperazinyl}-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol; (5 mg, M+1=495.2). B. Preparation of a Compound of Formula I
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:21])=[C:4]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[N:17]1[CH:16]=[CH:15][C:14]([C:13]2[O:21][C:3]3[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][C:4]=3[N:12]=2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(Cl)c1O)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Cl)c2oc(-c3ccncc3)nc2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 0.42 g of N-[3-chloro-5-(trifluoromethyl)-2-hydroxyphenyl]isonicotinamide, 5 ml of tetrahydrofuran and 0.38 g of triphenylphosphine, 0.64 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred while heating at room temperature for one hour and then at 50° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(pyridin-4-yl)-7-chloro-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 64”).
Reaction SMILES: [Na+].[Na+].[Na+].[NH2:4][C:5]1[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:10]2.O.O.O.C([O-])(=O)C.[Na+].[N+](C1C(S(O)(=O)=O)=C(C=CC=1)C([O:43][C:44](=O)[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([N+:51]([O-:53])=[O:52])[C:46]=1[S:54]([OH:57])(=[O:56])=[O:55])=O)([O-])=O>O>[N+:51]([C:47]1[C:46]([S:54]([OH:57])(=[O:55])=[O:56])=[C:45]([CH:50]=[CH:49][CH:48]=1)[C:44]([NH:4][C:5]1[CH:6]=[C:7]([S:23]([OH:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:10]2)=[O:43])([O-:53])=[O:52]
Reactant: Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Reactant: O=C(OC(=O)c1cccc([N+](=O)[O-])c1S(=O)(=O)O)c1cccc([N+](=O)[O-])c1S(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12)c1cccc([N+](=O)[O-])c1S(=O)(=O)O

Procedure:
A 6.6 g portion of 8-amino-1,3,6-naphthalenetrisulfonic acid trisodium salt and 2.92 g of sodium acetate trihydrate are dissolved in 180 ml of water at 2° C. A 4.0 g portion of 3-nitrosulfobenzoic anhydride is added with stirring. A 400 ml portion of water is added and the mixture is allowed to stand 21/2 hours, filtered and the filtrate is cooled, acidified with 2-3 ml of hydrochloric acid and diluted with ethanol. The pink solid is collected by filtration, washed with 85% ethanol, ether and dried giving 2.5 g of 8-(3-nitro-2-sulfobenzamido)-1,3,6-naphthalene trisulfonic acid, tetrasodium salt.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.C1([O:20][C:21]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=O)C=CC=CC=1>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:21]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:20])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)nn1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Product: CCOC(=O)COC(=O)N1CCN(c2ccc(Cl)nn2)CC1

Procedure:
The process is performed as described in Example 1 (step 1.2.). Starting with 1.60 g (8.05 mmol) of 3-chloro-6-(1-piperazinyl)pyridazine (J. Med. Chem., 18, 2002, 4011-4017) and 1.99 g (8.86 mmol) of ethyl [(phenyloxy-carbonyl)oxy]acetate, prepared in step 1.1. of Example 1, and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, 1.70 g of product are obtained in the form of a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[O:13][CH2:14][CH3:15])#[N:2].Br[CH2:17][CH2:18][CH2:19]CC>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][CH2:17][CH2:18][CH3:19])#[N:2]
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Reactant: CCCCCBr
Product: CCCCCOc1cc(S(=O)(=O)Cl)ccc1C#N

Procedure:
The titled compound was prepared analogously to 4-cyano-3-ethoxy-benzenesulfonyl chloride (Intermediate 127c) by replacing bromoethane with 1-bromopentane.
Reaction SMILES: C(O[C:4](=[O:34])[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:18]([CH2:19][C:20]3[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([CH3:27])[N:21]=3)[C:17]3[CH:28]=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[C:16]=3[N:15]=2)[CH2:9][CH2:8]1)C.CO.[NH3:37]>>[OH:26][C:25]1[C:20]([CH2:19][N:18]2[C:17]3[CH:28]=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[C:16]=3[N:15]=[C:14]2[NH:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][C:4]([NH2:37])=[O:34])[CH2:12][CH2:11]2)=[N:21][C:22]([CH3:27])=[CH:23][CH:24]=1
Reactant: CCOC(=O)CCN1CCC(Nc2nc3c(C)cc(C)cc3n2Cc2nc(C)ccc2O)CC1
Reactant: N
Solvent: CO
Product: Cc1cc(C)c2nc(NC3CCN(CCC(N)=O)CC3)n(Cc3nc(C)ccc3O)c2c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
A mixture of 3-{4-[1-(3-Hydroxy-6-methyl-pyridin-2-ylmethyl)-4,6-dimethyl-1H-benzoimidazol-2-ylamino]-piperidin-1-yl}-propionic acid ethyl ester (0.0065 mol) in methanol/NH3 7N (15 ml) was stirred in a sealed vessel at 70° C. for 12 hours. The solvent was evaporated until dryness. The residue (0.3 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 85/14/1; 5 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.09 g, 32%) was crystallized from diisopropylether. The precipitate was filtered off and dried, yielding 0.086 g of 3-{4-[1-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-4,6-dimethyl-1H-benzoimidazol-2-ylamino]-piperidin-1-yl}-propionamide (compound 5, 30%, melting point: 212° C.).
Reaction SMILES: [CH3:1][CH:2]([NH2:26])[CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[N:9]=[CH:8]2.CCN(C(C)C)C(C)C.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>C(#N)C>[CH3:36][O:37][CH2:38][C:39]([NH:26][CH:2]([CH3:1])[CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[N:9]=[CH:8]2)=[O:40]
Reactant: CC(N)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccccc1
Reactant: COCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCC(=O)NC(C)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
1-Methyl-2-phenyl-2-(1-pyridin-2-yl-1H-indazol-5-yloxy)-ethylamine (118a, 14 mg, 0.041 mmol), DIPEA (12 ul, 0.070 mmol) and acetonitrile (2 ml) were charged in a 7 ml vial. Methoxyacetyl chloride (12 ul, 0.13 mmol) was added, the vial was sealed and the solution stirred (magnetic bar) at r.t. for 1 h. Concentration and purification on C18 (Kromasil) with acetonitrile:water:TFA, 45:55:0.1 to 90:10:0.1 over 30 min, afforded 5 mg (29%) of 2-methoxy-N-[1-methyl-2-phenyl-2-(1-pyridin-2-yl-1H-indazol-5-yloxy)-ethyl]acetamide.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Li].[F:13][C:14]1([C:17](=[O:29])[CH2:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([CH3:21])[CH3:20])[CH2:16][CH2:15]1>C1COCC1>[F:13][C:14]1([C:17]([OH:29])([CH2:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)([CH3:21])[CH3:20])[CH2:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(CC(=O)C1(F)CC1)c1ccc(F)cc1
Reactant: Cc1ccnc2ccccc12
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(CC(O)(Cc1ccnc2ccccc12)C1(F)CC1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 24.2 %

Procedure:
To a solution of 4-methylquinoline (69 mg, 0.482 mmol) in THF cooled on dry ice/acetone was added 0.4 mL of lithium dilsopropylamide (1.5 M in hexanes). The mixture was placed in a cold bath at −20° C. to −30° C. for 15 minutes and then cooled to −78° C. 1-(1-Fluorocyclopropyl)-3-(4-fluorophenyl)-3-methylbutan-1-one (49 mg, 0.206 mmol) was added dropwise as a solution in 0.5 mL of THF. The cold bath was then removed and the mixture stirred for 1 hour. The reaction was quenched by addition of 0.5 mL of water and diluted with ethyl acetate. The organic phase was separated, washed with water, dried, filtered, and the solvent evaporated in vacuo. Fractionation of the residue by preparative layer chromatography (developer: ethyl acetate-hexanes (2:1)) gave the title compound (0.019 g, 24% yield) (slightly less polar than lepidine) as an oil that crystallized on standing in hexanes, m.p. 152° C.-155° C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH2:4][C:5]#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:42].Cl>C(Cl)Cl.O>[F:1][C:2]([F:29])([F:30])[CH:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH2:4][CH:5]=[O:42]
Reactant: CO
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C(F)(F)F)c3)ncnc21
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=O)C(F)(F)F)c3)ncnc21
Temperature: -47.5 °C
Reaction time: 3 h
Yield: 46.8 %

Procedure:
To a −70° C. solution of 4,4,4-trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (1.06 g, 0.00243 mol) (see, Example 93, Step 1) in DCM (10 mL, 0.2 mol) was added 1.0 M diisobutylaluminum hydride in DCM (4.8 mL). The resulting mixture was stirred for 3 h and allowed to warm during this time interval from −70 to −25° C., after which the reaction was cooled back at −70° C. Methanol (1.5 mL, 0.037 mol) was added, followed by 2.0 M HCl in water (15 mL). Insoluble material was then filtered from the reaction mixture. The organic filtrate was washed sequentially with: 2.0 M HCl in water, water and saturated aqueous NaCl. The washed organic phase was dried over sodium sulfate and was concentrated using a rotory evaporator to give 0.58 g of the crude product as a pale yellow foam/solid. The crude product was chromatographed with 0-80% ethyl acetate/hexanes to give the purified product (0.5 g) as a pale orange oil (47% yield).
Reaction SMILES: [CH2:1]([CH:4]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH2:10]2)[C:7](=[O:25])[NH:6][C:5]1=O)[CH:2]=C.I([O-])(=O)(=O)=O.[Na+].[NH2:33][NH2:34]>C1COCC1.O.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+].C(O)(=O)C.[Os](=O)(=O)(=O)=O>[O:25]=[C:7]1[NH:6][C:5]2[N:33]=[N:34][CH:2]=[CH:1][C:4]=2[N:8]1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: C=CCC1C(=O)NC(=O)N1C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NN
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCC(n2c(=O)[nH]c3nnccc32)CC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 6.8 %

Procedure:
Benzyl 4-(5-allyl-2,4-dioxoimidazolidin-1-yl)piperidine-1-carboxylate (0.480 g, 1.34 mmol) was dissolved in THF (5 mL), and osmium tetroxide (0.05 mL, 2.5% solution in t-butanol) was added followed by a solution of sodium periodate (0.862 g, 4.03 mmol) in water (4 mL). After 24 h, the reaction was diluted with saturated aqueous Na2SO3 and NaHCO3 and extracted with ethyl acetate (4×). The combined organic washes were dried over sodium sulfate, filtered and evaporated to give the crude aldehyde (0.352 g). To a portion of this material (0.250 g, 0.696 mmol) in acetic acid (10 mL) was added hydrazine (0.446 mL, 13.9 mmol). This mixture was heated at 50° C. for 24 h, and then concentrated to dryness. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the product (0.032 g). MS 354.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:51]=[CH:50][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][CH2:35][CH2:36][CH:37]4[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]4)[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:51]=[CH:50][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][CH2:35][CH2:36][CH:37]4[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]4)[C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(OCc2nc3c(OCCCC4CCNCC4)cccc3n2CCCC2CCNCC2)cc1

Procedure:
The title compound is prepared from 2-(4-chlorophenoxymethyl)-4-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole by standard deprotection techniques using trifluoroacetic acid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:15][C@@H:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([CH:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=[CH:21][CH:22]=2)[CH2:17]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl.C(OCC)(=O)C>[CH3:32][N:29]1[CH2:30][CH2:31][CH:26]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][C@H:16]([NH:15][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][CH:13]=2)[CH2:25][CH2:24]3)[CH2:27][CH2:28]1
Reactant: CCCCOc1ccc(C(=O)O)cc1
Reactant: CN1CCC(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C(=O)N[C@@H]2CCc3cccc(C4CCN(C)CC4)c3C2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Butoxybenzoic acid (0.16 g, 0.8 mmol) was dissolved in thionyl chloride (3 mL) and refluxed for 30 minutes. The excess of thionyl chloride was removed in vacuo with toluene. The residue was dissolved in methylene chloride (5 mL) and added dropwise to an ice cold solution of (R)-2-amino-8-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydronaphthalene (0.15 g, 0.6 mmol) and triethylamine (92 mg, 0.9 mmol) in methylene chloride (5 mL). The mixture was stirred for 30 minutes and was then diluted with ethyl acetate, washed with ammonia (2 M) and dried (MgSO4). The solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel using methylene chloride/ethanol 5:1, containing 0.5% of ammonia, as the eluent. The title compound was obtained as white crystals. Yield 170 mg (50%): mp 162-164° C.; [α]21D −2° (c 0.5, CHCl3); EIMS (70 eV) m/z (relative intensity) 420 (40, M+).
Reaction SMILES: [CH:1]([C:16](O)=O)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C(C(O)=O)CC.C1CCN2C(=NCCC2)CC1>>[CH3:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCC(CCCCCCCC=CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCCC
Yield: 45 %

Procedure:
By heating 5 mmol of 1,10-dodecene dicarboxylic acid with 20 mmol of DBU and 10 mmol of cuprous bromide to 340°-360° C. for 30 min. in an argon atmosphere, n-decane was obtained in a yield of 45% of theory.