Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1([CH3:24])[CH2:22][NH:21][C:20](=[O:23])[CH2:19]1>>[CH3:17][C:18]1([CH3:24])[CH2:22][N:21]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][N:13]=2)[C:20](=[O:23])[CH2:19]1
Reactant: CC1(C)CNC(=O)C1
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Product: CC1(C)CC(=O)N(Cc2ccc(C#Cc3ccccc3)cn2)C1

Procedure:
The title compound, light brown oil, MS: m/e=305.2 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and 4,4-dimethyl-pyrrolidin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH2:11].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](N1C=CN=C1)=[S:20].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:19]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)=[S:20]
Reactant: NCCc1c(F)cccc1F
Reactant: S=C(Nc1ccccn1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cccc(F)c1CCNC(=S)Nc1ccccn1
Temperature: 25 °C
Yield: 10.1 %

Procedure:
A solution of 2-(2,6-difluorophenyl)ethylamine (0.43 g, 2.7 mmol) and 1-[(2-pyridyl)thiocarbamoyl]imidazole (0.55 g, 2.7 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 27 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant oil was purified by chromatography on silica gel to provide 0.08 g (10%) of the titled product as a pale yellow solid:
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[C@:15]2([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:16](=[O:17])[C@@H:11]([C@:12]([CH3:42])([CH2:28][CH2:29][CH2:30][C:31]([CH3:41])([O:33][Si:34]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:35][CH3:36])[CH3:32])[C@@H:13]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:14]2)[C:10](=[O:43])[CH:9]=1.Cl[Si:45]([CH3:48])([CH3:47])[CH3:46].[Li]N1C(C)(C)CCCC1(C)C>CCOC(C)=O.CCCCCC>[CH3:6][O:7][C:8]1[C@:15]2([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:16](=[O:17])[C@@H:11]([C@:12]([CH3:42])([CH2:28][CH2:29][CH2:30][C:31]([CH3:41])([O:33][Si:34]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:39][CH3:40])[CH3:32])[C@@H:13]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:14]2)[C:10](=[O:43])[C:9]=1[Si:45]([CH3:48])([CH3:47])[CH3:46]
Reactant: C[Si](C)(C)Cl
Reactant: CC[Si](CC)(CC)OC(C)(C)CCC[C@]1(C)[C@@H](CC=C(C)C)C[C@@]2(CC=C(C)C)C(=O)[C@@H]1C(=O)C=C2OC
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)CCC[C@]1(C)[C@@H](CC=C(C)C)C[C@@]2(CC=C(C)C)C(=O)[C@@H]1C(=O)C([Si](C)(C)C)=C2OC
Temperature: 0 °C
Yield: 90.2 %

Procedure:
A THF (1 mL) solution of 44 (22.9 mg, 42.0 μmol, 1 equiv.) was cooled to −78° C. in a 10-mL test tube, and chlorotrimethylsilane (53 μL, 0.42 mmol, 10 equiv.) and a freshly prepared THF solution of lithium tetramethylpiperidide (0.50 M, 420 μL, 0.21 mmol, 5 equiv.) were sequentially added. The golden yellow solution was slowly warmed to 0° C. over 1 h and quenched at 0° C. with saturated aqueous NaHCO3. The mixture was warmed to room temperature and extracted thrice with EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to a yellow oil. Flash column chromatography (20 mL SiO2, 98:2 hexane:EtOAc) afforded 23.4 mg (37.9 μmol, 90% yield) of 45 as a colorless oil. TLC Rf 0.40 (95:5 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 5.02-4.97 (m, 2H), 3.83 (s, 3H), 3.11 (s, 1H), 2.51 (dd, J=14.4, 6.3 Hz, 1H), 2.37 (dd, J=14.5, 7.5 Hz, 1H), 2.15-2.11 (m, 1H), 1.99 (dd, J=14.0, 3.7 Hz, 1H), 1.69 (s, 3H), 1.68-1.63 (m, 9H), 1.57 (s, 3H), 1.48 (td, J=12.7, 3.9 Hz, 1H), 1.46-1.37 (m, 2H), 1.30 (td, J=12.2, 4.1 Hz, 1H), 1.26-1.24 (m, 1H), 1.21 (s, 3H), 1.21 (s, 3H), 1.14 (td, J=12.6, 4.2 Hz, 1H), 0.94 (t, J=7.9 Hz, 9H), 0.80 (s, 3H), 0.57 (q, J=8.1 Hz, 6H), 0.23 (s, 9H). 13C NMR (126 MHz; CDCl3): δ 207.9, 198.6, 185.7, 133.70, 133.59, 127.7, 122.8, 120.0, 73.7, 72.6, 64.1, 59.7, 46.7, 45.7, 41.8, 39.29, 39.27, 30.6, 30.0, 29.7, 27.6, 26.02, 25.97, 18.21, 18.14, 17.88, 17.83, 7.4, 7.0, 0.8. HRMS-ESI (m/z): [M+H]+ calculated for C36H64O4Si2, 617.4416. found, 617.4395.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([C:25]2[CH:26]=[C:27]([CH2:31]O)[N:28]([CH3:30])[N:29]=2)[CH:21]=[CH:22][C:23]=1[Cl:24].CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:31][C:27]3[N:28]([CH3:30])[N:29]=[C:25]([C:20]4[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=4)[CH:26]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cn1nc(-c2ccc(Cl)c(Cl)c2)cc1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(Cl)c(Cl)c4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with [5-(3,4-dichloro-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[5-(3,4-dichloro-phenyl)-2-methyl-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>O>[NH2:11][C:4]1[N:3]=[C:2]([NH:16][CH2:12][CH2:13][CH2:14][CH3:15])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][NH:8]2
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: CCCCN
Solvent: O
Product: CCCCNc1nc(N)c2nc[nH]c2n1
Yield: 85.4 %

Procedure:
2-Chloroadenine (10.0 g, 59 mmol), butylamine (43 mL, 589 mmol) and water (40 mL) were placed in an autoclave (250 mL), and the content of the autoclave was allowed to react at 180° C. for 18 h. The reaction solution was concentrated under reduced pressure, and water was poured into the residue to precipitate a solid. The precipitated solid was sequentially washed with water, EtOH and acetone. Thus, 10.39 g of the title compound was obtained as a yellowish orange powdery solid (yield: 86%). Intermediate 1 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 300 MHz): 11.92 (br. S, 1H), 7.63 (s, 1H), 6.51 (br. s, 2H), 6.04 (s, 1H), 3.19 (q, 2H), 1.51 (m, 2H), 1.33 (m, 2H), 0.92 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[OH:12])[NH:8][C:5]2=[CH:6][N:7]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1
Reactant: OC(c1ccccc1)c1cc2cc(Cl)ncc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc2cc(Cl)ncc2[nH]1
Reaction time: 60 h
Yield: 69.4 %

Procedure:
(5-Chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methanol (Example 140) (105 mg, 0.41 mmol) was dissolved in methylene chloride (10 mL). Manganese dioxide (358 mg, 4.1 mmol) was added and the reaction mixture was stirred for 60 h. The reaction mixture was filtered through diatomaceous earth and the filter cake was washed several times with methylene chloride. The filtered was concentrated to give a pink solid. Recrystallization from methylene chloride gave (5-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methanone (73 mg, 70%) as a white solid: mp 194-197° C.; 1H NMR (300 MHz, CDCl3) δ7.10 (1H, s), 7.51-7.75 (4H, m), 8.01 (2H, m), 8.79 (1H, s), 9.57 (1H, br s); ESI MS m/z 257 [C14H9ClN2O+H]+; HPLC (Method A) >99% (AUC), tR=21.5 min.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.Cl[C:50]([O:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:51]>C(OCC)(=O)C>[C:33]([C:31]1[CH:30]=[CH:29][C:28]2[N:24]([CH2:23][CH2:22][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH:9]([NH:8][C:50]([O:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:51])[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:19]=3)[C:25](=[O:41])[S:26][C:27]=2[CH:32]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)C(N)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)NC(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Reaction time: 8 h

Procedure:
700 mg of the compound obtained in Step A are dissolved in 10 ml of ethyl acetate; 0.494 ml of triethylamine is then added and the temperature is lowered to 0° C. 0.229 ml of butyl chloroformate is added and the mixture is allowed to return to ambient temperature and is stirred overnight.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([O:15][C:16]2[N:17]=[N:18][CH:19]=[CH:20][C:21]=2[N:22]2[CH2:27][CH2:26][CH:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]2)[CH2:12]1.[BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[Cl-].[NH4+]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH:13]([O:15][C:16]2[N:17]=[N:18][CH:19]=[CH:20][C:21]=2[N:22]2[CH2:23][CH2:24][CH:25]([CH:28]([OH:30])[CH3:29])[CH2:26][CH2:27]2)[CH2:14]1
Reactant: CC(=O)C1CCN(c2ccnnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(O)C1CCN(c2ccnnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
1-(1-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyridazin-4-yl)piperidin-4-yl)ethanone (100 mg, 0.25 mmol) was dissolved in 10 ml of methanol. This solution was cooled down to 0° C. using an ice bath and sodium tetraborohydride (19 mg, 0.50 mmol) was added by portions. The reaction mixture was stirred for 4 hours at ambient temperature, and then saturated aqueous solution of ammonium chloride (5 mL) was added. The methanol was evaporated off under reduced pressure then the reaction mixture was taken up in ethyl acetate. The organic layer was separated from the aqueous layer. The aqueous layer was back extracted one more time with ethyl acetate. The organic layers were combined and dried over magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by column chromatography on silica gel to give (racemic mixture) 1-(1-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyridazin-4-yl)piperidin-4-yl)ethanol (76 mg, 0.19 mmol, 75% yield). ESI-MS (M+1): 406 calc. for C23H27N5O2 405. PDE10 IC50 (uM): 0.0767. 1H NMR (CD3OD, 400 MHz) δ (ppm): δ (ppm) 8.40 (m, 1H); 8.14-8.10 (d, J=8.8 Hz, 1H); 7.97 (d, J=8.8 Hz, 1H); 7.64-7.58 (m, 2H); 7.51-7.46 (m, 1H); 7.20-7.16 (m, 1H); 6.80-6.79 (m, 1H); 6.62 (d, J=9.2 Hz, 1H); 5.62-5.59 (m, 1H); 4.61-4.57 (m, 2H); 4.18-4.15 (m, 2H); 3.96-3.93 (m, 2H); 3.48-3.43 (m, 1H); 2.73-2.67 (m, 2H); 1.91-1.88 (m, 1H); 1.66-1.64 (m, 1H); 1.42-1.34 (m, 3H); 1.11-1.10 (d, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:7]=1)=[O:5])C.[ClH:17]>>[ClH:17].[CH2:13]([C:8]1[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:11]=[C:10]([CH3:12])[CH:9]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1cc(C)cc(CC(C)C)n1
Agent: Cl
Product: Cc1cc(CC(C)C)nc(C(=O)O)c1

Procedure:
A solution of 6-isobutyl-4-methyl-pyridine-2-carboxylic acid ethyl ester (174 mg, 0.78 mmol) in 6 N aq. HCl (20 mL) is stirred at 65° C. for 18 h. The solvent is evaporated and the remaining residue is dried under HV to give 6-isobutyl-4-methyl-pyridine-2-carboxylic acid hydrochloride as green oil; LC-MS: tR=0.58 min, [M+1]+=194.09.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[NH:28][C:29]1[S:30][C:31]2[CH:37]=[C:36]([NH2:38])[CH:35]=[CH:34][C:32]=2[N:33]=1>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[NH:28][C:29]1[S:30][C:31]2[CH:37]=[C:36]([NH:38][C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[CH:35]=[CH:34][C:32]=2[N:33]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)c5ccc(C(F)(F)F)cc5)cc4s3)c2cc1OC

Procedure:
N-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]-4-trifluoromethylbenzamide was prepared from p-trifluoromethylbenzoyl chloride (17 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 44 mg, 83 μmol, 73%). LC/ESI-MS: m/z=526 [M+H]+; m/z=524 [M−H]−; Rt=3.67 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:17]CC2C=CC=CC=2)=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:7]=1>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:7]=1
Reactant: CC1(C)OB(c2cc(F)ccc2OCc2ccccc2)OC1(C)C
Solvent: CCO
Product: CC1(C)OB(c2cc(F)ccc2O)OC1(C)C

Procedure:
The subtitle compound was prepared by the method of example 146 step (ii) using the product from step (iii) and ethanol as solvent.
Reaction SMILES: CC([S@]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=1)[CH3:9])=O)(C)C.[ClH:22]>CO>[ClH:22].[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:13]1[N:12]=[CH:11][C:10]([CH:8]([NH2:7])[CH3:9])=[CH:15][CH:14]=1
Reactant: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)(F)F)nc1
Agent: Cl
Solvent: CO
Product: CC(N)c1ccc(OCC(F)(F)F)nc1
Yield: 90 %

Procedure:
A solution of (R)-2-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (6.15 g, 18.9 mmol, Step-4) in 8M hydrochloric acid in methanol (20 mL) is stirred at rt for 2 hours. The reaction mixture is concentrated under reduced pressure. The residue is crystallized from n-hexane/EtOAc to give 4.40 g (90% yield) of the title compound as white solid.
Reaction SMILES: C([Li])CCC.C1([SiH3])C=CC=CC=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[C:22](\[CH3:26])/[CH2:23][O:24][CH3:25])=[CH:17][CH:16]=1.[H][H]>C1COCC1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:26])[CH2:23][O:24][CH3:25])=[CH:17][CH:16]=1
Reactant: COC/C(C)=C/c1ccc(OC)cc1
Reactant: [H][H]
Agent: [Li]CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COCC(C)Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
In a dry sealable Schlenk flask under an argon atmosphere 0.0573 g (0.096 mmol) of (S,S)-ethylene-1,2-bis(η5 -4,5,6,7-tetrahydro-1-indenyl)titanium (S)-1,1'-binaphth-2,2'-diolate was dissolved in THF (10 mL). The vessel was degassed by exposure to vacuum (2 x~10 sec) and put under an atmosphere of hydrogen and subsequently cooled to 0° C. in an ice water bath. After equilibration, a solution of n-butyllithium (0.123 mL, 1.52M in hexanes, 0.187 mmol, 1.95 equiv) was added and the mixture was allowed to stir for 10 min. Phenylsilane (0.030 mL, 0.236 mmol, 2.4 equiv) was then added followed, after 5 minutes, by E-3-(4-methoxyphenyl)-2-methyl-1-methoxy-2-propene (0.345 g, 1.92 mmol, 20 equiv). The flask was sealed and the solution moved into a dry box and transferred to a Parr® high pressure reaction vessel containing a magnetic stir bar. The vessel was sealed and moved to a fume hood where it was charged to ~2000 psig with hydrogen and placed in an oil bath at 65° C. The reaction mixture was allowed to stir for 43.5 h. The vessel was cooled to room temperature, vented and opened to air. The reaction mixture was worked up by partitioning between diethyl ether/hexane (1/4) and water and separating the layers. The aqueous layer was extracted twice with ether/hexane and the combined organic layers were dried over MgSO4. The solvent was removed in vacuo and the residue distilled at reduced pressure to yield 0.225 g (1.42 mmol, 74%) of 3-(4-methoxyphenyl)-2-methyl-1-methoxypropane which had an ee of 92.7%.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)[O:10][CH2:11][C@@H:12]2[C@@H:16]([O:17][CH3:18])[CH2:15][CH2:14][O:13]2)=CC=1.O.CC1C=CC(S(O)(=O)=O)=CC=1.CCN(CC)CC>C(Cl)Cl.CO>[CH3:18][O:17][C@H:16]1[CH2:15][CH2:14][O:13][C@@H:12]1[CH2:11][OH:10]
Reactant: COc1ccc(C(OC[C@H]2OCC[C@@H]2OC)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@H]1CCO[C@@H]1CO
Temperature: 25 °C
Yield: 73.1 %

Procedure:
The product from Example 22D (2.6 g, 6 mmol) in CH2Cl2 (10 mL) and MeOH (10 mL) was treated with 4-methylbenzenesulfonic acid monohydrate (570 mg, 3 mmol). The mixture was stirred at rt for l hr. The mixture was neutralized with excess Et3N. The solvent was removed and the residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-50% MeOH in ethyl acetate) to afford 580 mg (73%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.85 (t, J=6.14 Hz, 1H) 1.95-2.03 (m, 2H) 3.35 (s, 3H) 3.56-3.65 (m, 1H) 3.71-3.78 (m, 1H) 3.82 (dd, J=8.29, 4.30 Hz, 1H) 3.85-3.93 (m, 2H) 3.95-4.02 (m, 1H).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.C(O)(=O)C1C(=CC=CC=1)C(O)=[O:22].C(=O)(O)[O-].[Na+]>CO>[O:22]1[C:2]2([CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH2:4][CH2:3]2)[CH2:1]1
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: C=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 71.9 %

Procedure:
14.7 g of benzyl 4-methylene-1-piperidinecarboxylate was dissolved in 300 ml methanol, 20.4 g of phthalic acid monoperacid magnesium salt and 13.3 g of sodium bicarbonate were added thereto, and the mixture was stirred at room temperature for 7.5 hr. The reaction solution was evaporated. Ethyl acetate was added to the resulting residue which was then washed with water and brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated, and then subjected to silica gel column chromatography to give 11.3 g of benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.C(#N)C.[F:16][C:17]([F:27])([F:26])[C:18]1[N:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][CH:19]=1>C1COCC1.O>[NH2:25][C:24]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([C:17]([F:26])([F:16])[F:27])[N:23]=1)=[CH:2][C:1]#[N:4]
Reactant: CC(C)NC(C)C
Reactant: N#Cc1cccc(C(F)(F)F)n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: N#CC=C(N)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 2.08 ml (13.07 mmol) diisopropylamine in dry THF (12 ml) was cooled to −70° C. under inert gas atmosphere, and 9.26 ml (14.8 mmol) n-butyllithium solution (1.6 M in hexanes) were added dropwise. Then, a solution of 688 μl (13.07 mmol) acetonitrile in dry THF (10 ml) was slowly added over 10 min. The resulting solution was stirred for further 30 min at −70° C. before a solution of 1.50 g (8.72 mmol) 6-(trifluoromethyl)pyridine-2-carbonitrile in dry THF (10 ml) was added. The mixture was allowed to warm to room temperature and stirred for 12 h before water (200 ml) was added slowly. The mixture was extracted several times with dichloromethane (100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield 1.2 g (57% of th.) of the crude title compound (89% purity) which was used in the next step without further purification.
Reaction SMILES: C([O:5][CH2:6][CH:7]([O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH3:16])(C)(C)C.ClCCl.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH2:21]([O:20][CH2:19][CH2:18][O:17][CH:7]([CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6][OH:5])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOCCOCC(COC(C)(C)C)OCCOCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCOCCOCC(CO)OCCOCCCC

Procedure:
Compound 31 was prepared as described for 29. The reagents used were as follows, compound 25 (38.0 g, 0.109 mol.), tetrafluoroboric acid-diethyl ether complex (22 ml of a 54% solution in diethyl ether) dichloromethane (100 ml) and excess potassium carbonate. The final yield was a colorless liquid (17.3 g, 59%), (bpt. 95°-120° C., 0.04 torr): 1H-NMR (CDCl3), d, (ppm). Mass spectroscopy, m/e 293 MH+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[Cl:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([O:14][C:13]([Cl:12])([F:22])[F:23])=[CH:16][CH:17]=1)=[O:7]
Reactant: Nc1ccc(OC(F)(F)Cl)cc1
Reactant: O=C(O)c1ccc(F)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 1.2 using 3-bromo-4-fluorobenzoic acid and 4-(chlorodifluoromethoxy)aniline to afford an off-white solid. UPLC-MS (Condition 3) tR=1.25 min, m/z=394.0 [M+H]+, m/z=391.9 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.37 (d, J=9.17 Hz, 2H) 7.57 (t, J=8.68 Hz, 1H) 7.84-7.91 (m, 2H) 8.03 (ddd, J=8.62, 4.83, 2.32 Hz, 1H) 8.32 (dd, J=6.60, 2.20 Hz, 1H) 10.52 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:15]1COCC1.C[Li].Cl>CCOC(C)=O>[OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH3:15]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]C
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-4-(trifluoromethyl)benzoic acid (10.0 g, 48.5 mmol) and THF (100 mL) was cooled to <5° C. and methyllithium (95 mL, 1.6M solution in diethyl ether, 152 mmol) was slowly added, keeping the internal temperature <20° C. The resulting solution was warmed to ambient temperature and stirred for 1 hour. The solution was then cooled to 10° C. and treated carefully with EtOAc (100 mL) and 2N HCl (100 mL). The reaction mixture was further diluted with EtOAc (100 mL) then washed with water (100 mL) and brine (20 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give the title compound (10.3 g). This material was used without further purification in the next step.