Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[C:12]([O:18][CH3:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.[Li+].[OH-]>C1COCC1>[Cl:17][C:13]1[CH:14]=[C:15]([Cl:16])[C:8]2[O:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[C:9]=2[C:12]=1[O:18][CH3:19]
Reactant: CCOC(=O)c1oc2c(Cl)cc(Cl)c(OC)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(Cl)cc(Cl)c2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To 110 mg of 5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 1 mL of THF and 3 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried under vacuum to give 96 mg (96% yield) of 5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid, obtained as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6]1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>ClCCl>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]([OH:11])=[O:12])=[CH:16][CH:15]=1
Reactant: O=C1CCCC(=O)O1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCCC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 57.5 %

Procedure:
A suspension of 22.32 g (0.167 mol) of aluminum chloride in 35 ml of dichloromethane is prepared. It is cooled to 0° C. and a mixture of 8.3 g (0.0728 mol) of glutaric anhydride (dihydro-2H-pyran-2,6(3H)-dione) and 8.4 ml (0.0895 mol) of fluorobenzene in 20 ml of dichloromethane is added slowly. The mixture is stirred for 15 hours at room temperature and then hydrolyzed in acidified iced water. The precipitated product is filtered off, washed with water and then dried under reduced pressure. The crude product is then recrystallized from 90 ml of ethyl acetate to give 8.8 g of the expected product in the form of beige crystals (yield=57.5%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([CH2:13][CH3:14])[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Mg].Cl[CH:17]1[CH2:21][CH2:20][CH:19]=[CH:18]1>O1CCCC1>[CH:21]1([CH2:2][CH2:3][CH:4]([CH2:13][CH3:14])[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH2:20][CH2:19][CH:18]=[CH:17]1
Reactant: CCC(CCCl)O[Si](C)(C)C(C)(C)C
Reactant: ClC1C=CCC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(CCC1C=CCC1)O[Si](C)(C)C(C)(C)C

Procedure:
Further following the procedure described in Example 6B, substituting 3-chloro-1-ethylpropoxy(1,1-dimethylethyl)dimethylsilane (78 g, 0.33 moles) diluted in tetrahydrofuran (100 ml), granular magnesium (24 g, 1.00 moles), tetrahydrofuran (100 ml), 0.1M solution of Li2CuCl4 (1.0 mmole), and 3-chlorocyclopentene (33 g, 0.33 moles) dissolved in tetrahydrofuran (50 ml), one obtains [3-(2-cyclopenten-1-yl)-1-ethylpropoxy](1,1-dimethylethyl)dimethylsilane. The crude product is distilled under reduced pressure leaving a clear yellow oil (21 g, 0.078 moles), BP 69° C./0.1 mm.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.Cl.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:15]([C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1)[CH2:12]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1c2ccc(Br)cc2CN1[C@H]1CC[C@H](O)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (0.500 g, 1.62 mmol), trans-4-aminocyclohexanol hydrochloride (0.295 g, 1.95 mmol), and potassium carbonate (0.44 g, 3.2 mmol) in ethanol (5.0 mL) was stirred in a sealed vial at 50° C. for 4 h. After cooling, the mixture was diluted with ethyl acetate (10 mL), and was filtered. The filtrate was concentrated under reduced pressure. The residue was triturated with ethyl ether (3 mL). The precipitates were collected by filtration and washed with ethyl ether to afford the desired product. LCMS (M+H)+=309.9/312.0.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH:8]1[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]1>>[NH:8]1[CH:12]=[C:11]([NH:13][C:5](=[O:7])[CH3:6])[CH:10]=[N:9]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cn[nH]c1
Product: CC(=O)Nc1cn[nH]c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
Acetic anhydride (0.7 ml, 8.433 mmol) was added dropwise at 0° C. to 1H-pyrazol-4-amine (0.7 g, 8.433 mmol). The mixture was stirred for 30 min at RT and quenched by the addition of crushed ice. The mixture was extracted with ethyl acetate The combined organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the product in 54% yield. (0.6 g). LC-MS (ESI): Calculated mass: 125.0; Observed mass 126.0 [M+H]+ (rt: 0.115 min).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:44])[CH:15]([C:20]1[CH:21]=[C:22]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[CH:23]=[C:24]([O:26]CC2C=CC=CC=2)[CH:25]=1)[CH2:16][C:17]([CH3:19])=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:44])[CH:15]([C:20]1[CH:21]=[C:22]([C:34]2[CH:35]=[CH:36][C:37]([C:40]([F:42])([F:41])[F:43])=[CH:38][CH:39]=2)[CH:23]=[C:24]([OH:26])[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 93 %

Procedure:
To a solution of 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pent-4-enoyl]-oxazolidin-2-one from the previous step (6.7 g, 1 1.2 mmol) in MeOH (150 mL) was added 10% Pd/C (670 mg, 10 w %). The black suspension was hydrogenated at 5-50 psi overnight. The mixture was filtered through a celite pad and the solvent was removed in vacuo to obtain relatively pure 4-benzyl-3-[2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoyl]-oxazolidin-2-one (5.4 g, 93%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)=[NH:21])[CH:17]=3)[CH:12]=[CH:11]2)[CH2:6][CH2:5]O[CH2:3][CH2:2]1.I.[ClH:28]>CCOCC.CO>[ClH:28].[ClH:28].[CH2:6]([N:1]([CH2:2][CH3:3])[CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[NH:21])[CH:17]=2)[CH:12]=[CH:11]1)[CH3:5]
Reactant: N=C(Nc1ccc2ccn(CCCN3CCOCC3)c2c1)c1cccs1
Agent: Cl
Agent: I
Solvent: CO
Solvent: CCOCC
Product: CCN(CC)CCCn1ccc2ccc(NC(=N)c3cccs3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Reaction performed as described in Example 40, compound 150. Following isolation of the HI salt by precipitation, the salt was dissolved in ethanol. Amberlite resin (3.00 g) was added to the solution, and the mixture stirred at room temperature for 30 minutes. The reaction was diluted with ethyl acetate (30 mL) and filtered. The filtrate was concentrated to afford a yellow oil. The material was absorbed onto silica gel and purified by silica gel column chromatography (5% 2M ammonia in methanol, 95% dichloromethane). The resulting yellow oil was found to be the desired product, compound 152, by 1H-NMR analysis. The oil was dissolved in anhydrous dichloromethane (5 mL) and transferred to an argon purged reaction vial. The solution was treated with 1M hydrochloric acid in ether (3 mL) and the salt oiled out immediately. The reaction was stirred for 10 minutes and filtered. The vial and the filter were washed with ethyl acetate and the filtrate discarded. The yellow-brown oil which remained in the reaction vial was dissolved in methanol and the solution poured through the filter. The filter was washed with methanol and all organics combined and concentrated to afford a yellow oil. Additional drying under high vacuum afforded a yellow oil, compound 153. Yield: 80.1 mg of yellow oil. 1H-NMR (DMSO-d6) δ 7.74-7.73 (d, J=3.3 Hz, 1H), 7.61-7.60 (d, J=4.5, 1H), 7.47-7.44 (d, J=8.1 Hz, 1H), 7.27 (s, NH), 7.22-7.21 (d, J=3 Hz, 1H), 7.11-7.08 (t, J=4.8 Hz, 1H), 6.92 (s, 1H), 6.60-6.57 (dd, J=1.2, 8.4 Hz, 1H), 6.34-6.33 (d, J=3 Hz, 2H), 4.16-4.12 (t, J=6.9 Hz, 2H), 2.46 (s, 4H), 2.36-2.31 (t, J=6.6 Hz, 2H), 1.93-1.83 (quintet, J=6.7 Hz, 2H), 1.67 (s, 4H) MW 353.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8][O:9][CH:10]=1)=[O:5])C.O.[OH-].[Li+].CO>C1COCC1.O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=1
Reactant: CCOC(=O)c1conc1-c1ccccn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1conc1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a suspension of 3-pyridin-2-yl-isoxazole-4-carboxylic acid ethyl ester (9.52 g, 44 mmol) in THF (530 mL) was added a solution of lithium hydroxide monohydrate (11.0 g, 263 mmol) in water (265 mL) followed by methanol (265 mL) at 0° C. and the resulting mixture stirred at room temperature for 1 h. The mixture was then evaporated to half volume and then acidified to pH 4 with HCl (1N) and cooled to 0° C. for 30 min. A solid precipitated and was filtered off and dried to afford the title compound (6.55 g, 79%) which was obtained as an off white solid. MS: m/e=189.3 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[N:4][C:3]=1Cl.O.O.O.O.O.O.O.O.O.[S-2:20].[Na+].[Na+]>CC(O)C>[NH2:1][C:2]1[C:3]([SH:20])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1
Reactant: [S-2]
Reactant: Nc1nc(Cl)c(Cl)nc1Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Nc1nc(Cl)c(Cl)nc1S
Yield: 58 %

Procedure:
A mixture of 19.9 g. (0.1 mol.) of aminotrichloropyrazine, 25.2 g. (0.105 mol.) of sodium sulfide nonahydrate in 500 ml. of 2-propanol was heated to boiling under reflux for 5 hours. After cooling, the reaction mixture was filtered. The filtrate was neutralized with hydrochloric acid and filtered. The solid was washed with water and dried to give 11.4 g. (58% yield) of product.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:14]([CH3:17])(=O)=O)=[N:7]2.O>CN(C=O)C>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:14][CH3:17])=[N:7]2
Reactant: COc1ccc2nc(S(C)(=O)=O)ccc2c1Br
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2nc(SC)ccc2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 5-bromo-2-methanesulfonyl-6-methoxy-quinoline was dissolved in 20 mL DMF and treated with 3 eq NaSCH3. After stirring 1 hour at room temperature the mixture was poured into water and extracted with ether. The crystalline product, 5-bromo-6-methoxy-2-methylsulfanyl-quinoline, was isolated in quantitative yield.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:3].CCN(C(C)C)C(C)C.[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C:52](Cl)=[O:53])[CH2:48][CH2:47]1>ClCCl.ClCCl.CO>[CH2:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:2][CH3:3])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:52]([N:49]5[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]5)=[O:53])[CH2:33][CH2:34]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:11]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCNCC3)nc1-2
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(C(=O)N4CCN(C)CC4)CC3)nc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-1-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride (40 mg, 0.075 mmol) in dichloromethane (1 mL) at 0° C., DIPEA (0.2 mL, 1.1 mmol), and 4-methylpiperazine-1-carbonyl chloride (17 mg, 0.09 mmol) were added. The mixture was then stirred at room temperature for 3 h. Solvent evaporated to dryness and the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol: 9/1) to 38 mg of the title compound (86% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:17]#[C:18][C:19]([C:22]4[N:27]=[CH:26][CH:25]=C[N:23]=4)([OH:21])[CH3:20])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:28][CH2:29][CH2:30][O:31][CH3:32])[CH:5]=[CH:4][N:3]=1.IC1C=CC2N=C([O:42]CCOC)N(C3C=CN=C(N)N=3)C=2C=1.CC1ON=C([C@](O)(C#C)C)N=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:17]#[C:18][C@:19]([C:22]4[N:27]=[C:26]([CH3:25])[O:42][N:23]=4)([OH:21])[CH3:20])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:28][CH2:29][CH2:30][O:31][CH3:32])[CH:5]=[CH:4][N:3]=1
Reactant: COCCOc1nc2ccc(C#CC(C)(O)c3ncccn3)cc2n1-c1ccnc(N)n1
Reactant: COCCOc1nc2ccc(I)cc2n1-c1ccnc(N)n1
Agent: C#C[C@@](C)(O)c1noc(C)n1
Product: COCCOc1nc2ccc(C#C[C@@](C)(O)c3noc(C)n3)cc2n1-c1ccnc(N)n1

Procedure:
The title compound was prepared by the procedure described for the synthesis of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-methoxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol (Example 121-c), by reacting 4-[6-iodo-2-(2-methoxyethoxy)-1,3-benzodiazol-1-yl]pyrimidin-2-amine with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol: 1H NMR (500 MHz, DMSO) delta 1.84 (3H, s), 2.61 (3H, s), 3.31 (3H, s), 3.84-3.69 (2H, m), 4.76-4.63 (2H, m), 6.66 (1H, s), 6.97 (1H, d, J=5.5 Hz), 7.09 (2H, s), 7.28 (1H, dd, J=8.2, 1.5 Hz), 7.46 (1H, d, J=8.2 Hz), 8.18 (1H, d, J=1.0 Hz), 8.39 (1H, d, J=5.5 Hz); LC-MS: m/z=+436.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[NH4+:16]>[Cu]>[NH2:16][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: [Cu]
Agent: [OH-]
Product: CS(=O)(=O)c1ccc(N)c(C(=O)O)c1
Temperature: 127.5 °C
Reaction time: 18 h

Procedure:
A mixture of 4.26 mmol 2-chloro-5-methanesulfonyl-benzoic acid, 0.39 mmol Copper powder and 10 ml ammonium hydroxide 25% was heated at 125-130° C. with stirring for 18 hours. Mixture was cooled to room temperature and filtered. The solid was washed with methanol. The filtrate was concentrated in vacuo. The residue was acidified with HCl 1N to pH=2. The obtained solid was washed with water and dried (HV, 50° C., 1 hour) to yield the title compound. MS (m/e): 214.1 (M−H, 100%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:20]([CH3:22])[CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(F)c1
Temperature: 60 °C

Procedure:
To methyl 3-fluoro-4-hydroxy-benzoate (2.00 g, 11.8 mmol) in DMF (12.5 mL) was added K2CO3 (6.50 g, 47.0 mmol) followed by 2-iodopropane (2.35 mL, 23.5 mmol). The mixture was heated at 60° C. for 1.5 h. The mixture was filtered using EtOAc and the filtrate was evaporated under reduced pressure. The residue was dissolved in EtOAc and was washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give methyl 3-fluoro-4-isopropoxybenzoate. ESI-MS m/z calc 212.1. found 213.3 (M+1)+. Retention time: 1.70 minutes (3 min run).
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl.O1CCOCC1>CCOC(C)=O>[CH3:1][S:2]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)C1CCNCC1
Temperature: 0 °C

Procedure:
tert-Butyl 4-(methylsulfonyl)piperidine-1-carboxylate 5-4 (12.270 g, 46.59 mmol) was dissolved in 80 mL EtOAc and the solution was cooled to 0° C. 4.0M HCl in dioxane (58.240 mL, 232.95 mmol) was added and the solution was allowed to warm to room temperature. After 5 hours the reaction was concentrated in vacuo to afford 4-(methylsulfonyl)piperidine 5-5 as a white solid. HCl salt:
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:22])=[C:18]([C:20]#[N:21])[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H][H]>[Ni]>[NH2:21][CH2:20][C:18]1[CH:19]=[C:14]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:15]=[N:16][C:17]=1[Cl:22]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(C#N)c1
Agent: [Ni]
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CN)c1

Procedure:
3-(1-BOC-2-(S)-azetidinylmethoxy)-6-chloro-5-cyanopyridine (0.26 g, 0.80 mmol) from step 92a was stirred in the presence of Raney nickel (0.047 g, 0.80 mmol) under 1 atm of hydrogen at room temperature for 2 hours. The mixture was filtered, and the solvent was removed to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([CH3:22])([CH3:21])[CH2:11][C@:12]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH2:13][C:14]#[CH:15])=[C:6]([CH:9]=1)[CH:7]=[O:8].CC(=CC)C.Cl([O-])=[O:29].[Na+].P([O-])([O-])(O)=O.[Na+].[Na+]>C(O)(C)(C)C.C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([CH3:22])([CH3:21])[CH2:11][C@:12]([OH:20])([C:16]([F:18])([F:19])[F:17])[CH2:13][C:14]#[CH:15])=[C:6]([CH:9]=1)[C:7]([OH:29])=[O:8]
Reactant: C#CC[C@](O)(CC(C)(C)c1ccc(F)cc1C=O)C(F)(F)F
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: C#CC[C@](O)(CC(C)(C)c1ccc(F)cc1C(=O)O)C(F)(F)F
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a solution of 15 g (0.031 mol) of 5-fluoro-2-((S)-3-hydroxy-1,1-dimethyl-3-trifluoromethylhex-5-ynyl)benzaldehyde in 240 mL of tert-BuOH was added a solution of the 62 mL (0.124 mol) of 2-methyl-2-butene in THF (2 M). To this solution was added a solution of the 17.5 g of sodium chlorite (0.150 mol) and 42.8 g of sodium hydrogen phosphate (0.138 mol) in water. The reaction mixture was stirred overnight. The volatiles were removed in vacuo. The aqueous mixture was then acidified to pH=1 with 1 M HCl, extracted with 1200 mL of ethyl acetate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture was chromatographed on silica gel using 10-100% ethyl acetate/hexanes to afford 10.6 g (103%) of 5-fluoro-2-((S)-3-hydroxy-1,1-dimethyl-3-trifluoromethylhex-5-ynyl)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH:18](O)[CH3:19])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:18][CH2:19][Cl:23])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(O)N(Cc1ccc(Cl)cc1)Cc1ccc(Cl)nc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: ClCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)nc1

Procedure:
This compound was prepared in a manner analogous to that set forth in Step C of Example 1, using 6.0 grams (0.0193 mole) of 2-{[(6-chloro(3-pyridyl)methyl][(4-chlorophenyl)methyl]amino}ethan-1-ol, 2.4 grams (0.0203 mole) of thionyl chloride and four drops (catalyst) of pyridine in 75 mL of chloroform. The crude product was purified with column chromatography on silica gel. Elution was accomplished using 15% ethyl acetate in hexane then 30% ethyl acetate in hexane as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 5.7 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[C:16](=O)[N:15]([CH3:18])[C:13](=O)[CH2:12]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:12][CH2:13][N:15]([CH3:18])[CH2:16]1
Reactant: CN1C(=O)CC(c2c[nH]c3ccc(Br)cc23)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(Br)cc23)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a stirred solution of 3-(5-bromo-1H-indol-3-yl)-N-methylsuccinimide (1.3 g, 4.23 mmol) in anhydrous tetrahydrofuran (12 mL) at 0° C., was added lithium aluminum hydride (1M solution in tetrahydrofuran, 9.3 mL, 9.3 mmol). The resulting mixture was heated to reflux under argon for 2 hours, then cooled to 0° C. and quenched with cold water (2 mL) and ammonium hydroxide (15 mL). The resulting solution was stirred at room temperature for 1 hour and then filtered through celite. The filtrate was evaporated to dryness and the crude product extracted into ethyl acetate (250 mL). The solvent was once again evaporated and the product purified by silica gel chromatography using chloroform/ammonia(2M in methanol) (9:1) as the eluent to provide the title compound as a white solid (0.700 g, 64%). m.p. 152°-154° C.; HRMS (FAB): MH+ for C13H1579BrN2, calculated 279.0496, found 279.0478.
Reaction SMILES: Cl.Br[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]1(/[C:12](=[N:14]/[S:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])/[CH3:13])[CH2:11][CH2:10]1>C1COCC1.[Zn].[Cu]Cl>[C:17]([S:15]([NH:14][C:12]([CH:9]1[CH2:11][CH2:10]1)([CH3:13])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:16])([CH3:18])([CH3:19])[CH3:20]
Reactant: C/C(=N\S(=O)C(C)(C)C)C1CC1
Reactant: CCOC(=O)CBr
Agent: Cl[Cu]
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(NS(=O)C(C)(C)C)C1CC1
Temperature: 0 °C
Yield: 78.9 %

Procedure:
To a flask containing zinc (Note: the zinc powder was activated by stirring 10 gr in 20 mL of 2.0M aqueous solution HCl (caution: strong exotherm occurs)) (3.49 g, 53.4 mmol) and copper (I) chloride (529 mg, 5.34 mmol) under a stream of argon was added dry THF (10.0 ml), the suspension was stirred at reflux for 30 minutes then the heating bath was removed. Slow addition of a solution of ethyl 2-bromoacetate (1.78 g, 10.7 mmol, Eq: 2.0) in dry THF (5.00 ml) (caution: reaction exothermic), when addition completed the suspension was stirred for 30 min at rt then 30 min at 50° C. The reaction was then cooled down to 0° C. and a solution of (E)-N-(1-cyclopropylethylidene)-2-methylpropane-2-sulfinamide (1 g, 5.34 mmol) in dry THF (5.00 ml) was added to the reaction. The reaction was then stirred at 0° C. and let to warm up to room temperature overnight. The reaction mixture was filtered through a pad of Celite and the filter pad was washed twice with ethyl acetate. The filtrate was washed with a 0.25M aqueous solution of citric acid, a 1M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography on silica eluting with a gradient of heptane/ethyl acetate to yield the title compound (1.16 g, 79%) as a yellow oil; MS (ESI, m/z): 276.3 (M+H+).