Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:24]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([CH3:26])[CH3:25].C(=O)([O-])O.[Na+]>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:32][C:31]1[CH:34]=[CH:35][C:28]([O:27][CH:24]([CH3:26])[CH3:25])=[CH:29][CH:30]=1
Reactant: CC(C)Oc1ccc(C=O)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COC=Cc1ccc(OC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
A suspension of 140 g of methoxymethyl-triphenylphosphonium chloride in 400 ml of tert.-butyl methyl ether is treated with 45 g of potassium tert.-butylate within 5 minutes at 0° C. while gassing with nitrogen and the mixture is stirred for a further 10 minutes. Then, a solution of 41 g of 4-(isopropyloxy)-benzaldehyde in 100 ml of tert.-butyl methyl ether is added dropwise at 0° C. within 30 minutes. The reaction mixture is stirred at room temperature for a further 16 hours and then poured into 750 ml of 0.8N sodium hydrogen carbonate solution. The aqueous phase is separated and back-extracted with diethyl ether. The organic phase is washed neutral with water, dried over magnesium sulphate and concentrated. The residue is suspended in 800 ml of hexane. After cooling to 0° C. the triphenylphosphine oxide is filtered off and the filtrate is concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 9:1) gives 45 g of pure 1-methoxy-2-(4-[isopropoxy]phenyl)ethene.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].[CH2:17]([O:19][C:20]([C:22]1[N:26]2[N:27]=[C:28](Cl)[CH:29]=[CH:30][C:25]2=[N:24][N:23]=1)=[O:21])[CH3:18]>CN(C=O)C>[CH2:17]([O:19][C:20]([C:22]1[N:26]2[N:27]=[C:28]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[CH:29]=[CH:30][C:25]2=[N:24][N:23]=1)=[O:21])[CH3:18]
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: CCOC(=O)c1nnc2ccc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnc2ccc(OCc3c(-c4ccccc4)noc3C)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (60 mg, 0.32 mmol) in DMF (2 mL) was added sodium hydride (55% dispersion in mineral oil, 15 mg, 0.35 mmol). The mixture was stirred at room temperature overnight. After addition of a solution of 6-chloro-1,2,4-triazolo[4,3-b]pyridazine-3-carboxylic acid ethyl ester (79 mg, 0.35 mmol) in DMF (2 mL) the mixture was stirred at room temperature overnight. Then the mixture was evaporated, extracted (ethyl acetate/water) and the organic phase was dried with sodium sulfate and concentrated. Purification by preparative HPLC on reversed phase eluting with acetonitrile/water [0.1% aq NH3 (25%)] afforded the title compound (20 mg, 14%) as a white solid. MS: m/e=380.0 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]=[CH:13]3)[CH2:5][CH2:4]1.N1C=CN=C1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C>[Si:31]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]=[CH:13]3)[CH2:5][CH2:4]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(CN3CCC(CO)CC3)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2cc(CN3CCC(CO[Si](C)(C)C(C)(C)C)CC3)ccc21
Yield: 76.4 %

Procedure:
In a similar manner to Step 1 of Reference Example 18, 5-(4-hydroxymethylpiperidinomethyl)-1-(tert-butoxycarbonyl)indole (2.85 g, 8.27 mmol) was dissolved in DMF (50 mL), and the solution was treated with imidazole (619 mg, 9.09 mmol and tert-butyldimethylsilyl chloride (1.37 g, 9.09 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain 5-[4-(tert-butyldimethylsilyloxy)methylpiperidinomethyl]-1-(tert-butoxycarbonyl)indole (2.90 g, yield 76%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]1[CH2:18][O:17][S:14](=[O:16])(=[O:15])[CH2:13][CH2:12]1>>[S:14]([CH2:13][CH2:12][CH2:11][CH2:18][C:7]1[C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1)([OH:17])(=[O:16])=[O:15]
Reactant: O=S1(=O)CCCCO1
Reactant: Cc1nc2ccccc2s1
Product: Cc1nc2c(CCCCS(=O)(=O)O)cccc2s1
Temperature: 135 °C
Yield: 98.1 %

Procedure:
A mixture of 2-methylbenzothiazole (1.49 g, 10 mmol) and 1,4-butane sultone (4.0 g, 30 mmol) was heated in a pressure tube at 130-140° C. for 3 hours. The mixture was allowed to cool to room temperature, and the resulting mass was triturated with ethyl acetate (50 ml) until a gray solid separated. The solid was collected by centrifugation, washed with ethyl acetate and dried under vacuum to yield 2.8 g (96%) of Compound 1.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH:19]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1.[BH4-].[Na+]>CO>[CH:19]1([N:24]2[CH2:25][CH2:26][N:27]([CH2:1][C:3]3[CH:18]=[CH:17][C:6]([O:7][C:8]4[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=4)=[CH:5][CH:4]=3)[CH2:28][CH2:29]2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: C1CCC(N2CCNCC2)C1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN3CCN(C4CCCC4)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 36.2 %

Procedure:
Combine 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.303 g, 1.25 mmol) and 1-cyclopentyl piperazine (0.198 g, 1.28 mmol) in methanol (11 mL) and stir. After 15.5 h, add sodium borohydride (0.109 g, 2.88 mmol), and stir at ambient temperature. After 1 h, concentrate the reaction mixture and purify by silica gel chromatography (ethyl acetate→4:1 ethyl acetate:methanol) to provide 0.172 g (36%) of the title compound as an off white solid: high resolution mass spectrum (electrospray): m/z calc for C22H29N4O2 381.2291, found 381.2306; 1H NMR (DMSO-d6): 8.66 (d, 1H, J=2.4 Hz), 8.30 (dd, 1H, J=2.9, 8.8 Hz), 7.48-7.43 (m, 2H), 7.18-7.13 (m, 2H), 7.04 (d, 1H, J=7.8 Hz), 3.61 (s, 2H), 3.00-2.25 (m, 9H), 2.01-1.88 (m, 2H), 1.82-1.69 (m, 2H), 1.69-1.56 (m, 2H), 1.53-1.38 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:10][CH:9]1[CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1C[O:38]CC1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:16])[CH3:15])[CH:10]([OH:38])[CH:9]1[CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)=CC1CCNC(=O)OCc1ccccc1
Agent: B
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C(O)C1CCNC(=O)OCc1ccccc1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
A solution containing 7 (440 mg, 0.92 mmol) in anhydrous THF (15 mL) was cooled to −30° C. Borane (1M/THF, 3.68 mL) was added dropwise. After 10 min, the reaction mixture was allowed to slowly warm to 0° C. at which point TLC analysis revealed complete consumption of 7. The reaction mixture was recooled to −10° C. and 1M NaOH (2.6 mL) was added followed by the addition of 35% hydrogen peroxide (0.73 mL). The reaction mixture was then warmed to 0° C. After 1 h, the reaction mixture was quenched by the addition of saturated aqueous Na2S2O3 and the product was extracted with EtOAc. The combined organic extracts were washed successively with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (4:1 hexanes/EtOAc) to afford 250 mg (55%) of 8. 1H NMR (CDCl3, 300 MHz), mixture of rotomers: δ7.25 (m, 5H), 6.07 (m, 0.6H), 5.93 (m, 0.2H), 5.67 (m, 0.2H), 5.00 (m, 2H), 4.03 (m, 1.5H), 3.84 (m, 0.75H), 3.75-3.63 (m, 1.5H), 3.54 (m, 1.25H), 3.37 (m, 0.6H), 3.26 (m, 0.4H), 3.13 (m, 1.5H), 2.95 (m, 0.75H), 1.90 (m, 1H), 1.67 (m, 1H), 1.36 (s, 9H), 0.80 (s, 9H), 0.00 (s, 6H) ppm. Mass spectrum, m/z [495.2] (M+H)+.
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:27][C:28]1[N:32]=[C:31](Cl)[S:30][N:29]=1>C1COCC1>[C:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:31]3[S:30][N:29]=[C:28]([Cl:27])[N:32]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: Clc1nsc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3nc(Cl)ns3)CC2)CC1

Procedure:
A solution of tert-butyl 4,4′-bipiperidine-1-carboxylate (537 mg; 2.00 mmol) in dry THF (10 mL) was treated with triethylamine (307 μL; 2.20 mmol). A solution of 3,5-dichloro-1,2,4-thiadiazole (341 mg; 2.20 mmol) in THF (5 mL) was added dropwise at ambient temperature. An immediate precipitate was accompanied by a mild exotherm. The mixture was stirred until it returned to ambient temperature. The mixture was filtered and the filtrate evaporated to afford the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[N:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1)=[O:4].[CH:15]([Mg]Br)([CH3:17])[CH3:16].[NH4+].[Cl-]>C1COCC1.C(Cl)Cl>[CH3:16][CH:15]([C:11]1[CH:10]=[C:9]([CH3:12])[N:8]=[N:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:14])([CH3:13])[CH3:1])[CH3:17]
Reactant: Cc1ccc(NC(=O)C(C)(C)C)nn1
Reactant: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(C(C)C)c(NC(=O)C(C)(C)C)nn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
A solution of 2,2-dimethyl-N-(6-methyl-pyridazin-3-yl)-propionamide (4.00 g, 20.73 mmol) in THF (50 mL) is stirred at 0° C. 2.0 M iPrMgBr (46.6 mL, 93.26 mmol) is then added dropwise. The reaction is stirred at 0° C. for 30 min, then it is refluxed for 2 h. It is cooled to rt, poured into ice-H2O; sat. NH4Cl is added and extracted with EtOAc; dried with Na2SO4, filtered and concentrated. The crude material is dissolved in CH2Cl2 (100 mL), treated with 12 (5.8 g, 22.80 mmol) and stirred at rt for 2 h. The reaction is diluted with CH2Cl2 (100 mL), washed with 5% Na2SO3 (3×100 mL); dried with Na2SO4, filtered and concentrated. Purification of the crude material gives the title compound (1.38 g, 5.87 mmol, 28%). ES-MS (m/z): calcd for C13H21N3O (M+H)+: 236.3. found: 236.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[O:9][C:8](/[C:10](=[N:13]/[S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])/[CH2:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[CH3:1][S:2]([C:5]1[O:9][C:8]([C@@H:10]([NH:13][S@@:14]([C:16]([CH3:17])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH3:12])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC/C(=N\[S@](=O)C(C)(C)C)c1ccc(S(C)(=O)=O)o1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](N[S@](=O)C(C)(C)C)c1ccc(S(C)(=O)=O)o1
Reaction time: 2 h

Procedure:
To a chilled (−78° C.) solution of (R)-2-methyl-propane-2-sulfinic acid[1-(5-methanesulfonyl-furan-2-yl)-prop-(E)-ylidene]-amide (0.360 g, 1.18 mmol) in THF (15 mL) was added a 1 M solution of L-Selectride (2.4 mL, 2.4 mmol) in THF in several portions. After stifling for 2 hours, the mixture was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes to afford (R)-2-methyl-propane-2-sulfinic acid[(S)-1-(5-methanesulfonyl-furan-2-yl)-propyl]-amide.
Reaction SMILES: CNN(NC)[C:4]([S:6][C:7]1[C:8]([C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1)=O.CO.C[O-].[Na+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29](CS)=[CH:28][CH:27]=1>CO>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:4][S:6][C:7]2[C:8]([C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:28][CH:27]=1
Reactant: CNN(NC)C(=O)Sc1cccnc1C(=O)OC
Reactant: COc1ccc(CS)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncccc1SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
A solution of 1.20 g (5 mmol) of methyl 3-(N,N-dimethylaminocarbamoylthio)pyridine-2-carboxylate in 5 mL of methanol and 1.5 mL (6 mmol) of 4.1M sodium methoxide methanol was stirred at room temperature for 10 minutes. Then the solvent was concentrated and the residue was dissolved in 5 mL of N,N-dimethylformamide and 5 mL of tetrahydrofuran. 0.936 g (6 mmol) of p-methoxybenzylmercaptan was added and the solution was stirred at room temperature for 18 hours. The solution was partitioned between ether and water and the aqueous layer was extracted with two portions of ether. The combined extracts were washed with brine, dried and concentrated. Recrystallization from methanol afforded 0.90 g (62%) of pale tan needles, m.p. 99°-100° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.[CH:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)([CH3:35])[CH3:34]>>[CH:15]1([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([C:39]3[CH:40]=[CH:41][C:36]([CH:33]([CH3:35])[CH3:34])=[CH:37][CH:38]=3)=[C:24]([CH3:30])[CH:23]=2)[C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:9][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Oc2cc(C)c(Br)c(C)c2)C2CCCCC2)cc1
Reactant: CC(C)c1ccc(B(O)O)cc1
Product: Cc1cc(OC(c2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)cc(C)c1-c1ccc(C(C)C)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[(4-bromo-3,5-dimethyl-phenoxy)-cyclohexyl-methyl]-benzoylamino}-propionic acid methyl ester and 4-isopropyl phenyl boronic acid. MS: 526.2 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[OH:20].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:31][CH3:32])(=O)=O>CS(C)=O>[CH2:31]([O:20][C:3]1[C:4]2=[C:13]3[N:8]([CH:7]([CH3:19])[CH2:6][CH2:5]2)[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11](=[O:15])[C:12]3=[CH:14][C:2]=1[F:1])[CH3:32]
Reactant: CCOS(=O)(=O)OCC
Reactant: CC1CCc2c(O)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1c(F)cc2c(=O)c(C(=O)O)cn3c2c1CCC3C

Procedure:
A solution of 1.0 g of 6,7-dihydro-9-fluoro-8-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 1.4 g of potassium carbonate and 2.0 ml of diethyl sulfate in 15 ml of dimethyl sulfoxide was heated at its reflux temperature for sixteen hours. The solution was then evaporated to dryness by heating on a steam bath under a stream of nitrogen. Fifty ml of 1% aqueous sodium hydroxide solution was added to the resulting residue. The mixture was heated on a steam bath for one hour, acidified with concentrated hydrochloric acid and cooled. The solid was separated by filtration and recrystallized from aqueous ethanol to provide 6,7-dihydro-8-ethoxy-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 208°-210° C. (dec.). Analysis: Calculated for C16H16FNO4 : %C,63.0;%H,5.3;%N, 4.6; Found: %C,62.9;%H,5.3;%N,4.6.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11]I)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>CN(C)C=O.O>[CH3:1][O:2][C:3]([C:5]1([CH2:11][S:15][C:13](=[O:16])[CH3:14])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CI)CCOCC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(CSC(C)=O)CCOCC1
Reaction time: 18 h
Yield: 97 %

Procedure:
4-Iodomethyltetrahydropyran-4-carboxylic acid methyl ester (3.05 g) was dissolved in N,N-dimethylformamide (20 ml) at room temperature and potassium thioacetate (1.47 g) added. The mixture was stirred for 18 hours then diluted with water (50 ml) and extracted with diethyl ether (4×25 ml). The combined organics were washed with saturated sodium bicarbonate solution (3×20 ml) and brine (20 ml), then dried (MgSO4), filtered and evaporated under reduced pressure to give the title compound as a yellow solid (2.42 g, 97%).
Reaction SMILES: [C:1]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[C:7]([OH:33])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CI.[C:36](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[C:7]([O:33][CH3:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2cccc3cc[nH]c23)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1cc(C(C)(C)C)ccc1CN(CCc1ccc(F)cc1)C(=O)c1cccc2cc[nH]c12
Temperature: 60 °C
Yield: 39.3 %

Procedure:
133 mg (0.3 mmol) of 1H-indole-7-carboxylic acid (4-tert-butyl-2-hydroxy-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amide, 64 mg (0.45 mmol) of methyl iodide and 83 mg (0.6 mmol) of potassium carbonate were heated in 3 ml acetonitrile for 2 h to 60° C. Additional 32 mg (0.22 mmol) of methyl iodide were added and the reaction mixture was heated to 60° C. over night. The reaction mixture was filtered and the solvent was evaporated. The residue was purified by column chromatography (20 g silica gel; DCM/diethyl ether 10:1) to yield 54 mg (39%) product as a colorless gum. MS (ISP) 459.6 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([OH:25])=O)[CH2:10][C@H:9]1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[F:39][C:40]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:41]=1[CH2:42][C:43]1[CH:44]=[C:45]2[NH:51][CH2:50][C:49]([CH3:53])([CH3:52])[C:46]2=[N:47][CH:48]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([N:51]2[C:45]3[C:46](=[N:47][CH:48]=[C:43]([CH2:42][C:41]4[CH:54]=[CH:55][C:56]([F:58])=[CH:57][C:40]=4[F:39])[CH:44]=3)[C:49]([CH3:53])([CH3:52])[CH2:50]2)=[O:25])[CH2:10][C@H:9]1[CH3:26])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC1(C)CNc2cc(Cc3ccc(F)cc3F)cnc21
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ncc(Cc3ccc(F)cc3F)cc21
Temperature: 20 °C
Reaction time: 24 h
Yield: 51.3 %

Procedure:
A mixture of (2R,5S)-4-carboxymethyl-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.12 g, 0.32 mmol), 1,1′-carbonyldiimidazole (0.057 g, 0.35 mmol) and DCM (5 mL) was stirred at 20° C. for 24 h. 6-(2,4-Difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (0.088 g, 0.32 mmol) was added and the mixture heated at 35° C. for 24 h. Solvent was evaporated and the residue dissolved in 1,2-dichloroethane and the mixture was heated to 60° C. for 24 h. Mixture was partitioned between saturated aqueous NaHCO3 (30 mL) and DCM (3×20 mL) and combined organic extracts were dried and evaporated to give an oil. Chromatography (SiO2, gradient elution, 0-100% EtoAc in petrol 40-60) gave the title compound (0.103 g) as an oil. MS: [M+H]+=628.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:19]([NH:29][S@:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)=[N:4][CH:5]=[C:6](N2C(=O)C3C(=CC=CC=3)C2=O)[CH:7]=1.[Br:36]C1C(/C=N\[S@](C(C)(C)C)=O)=NC(Br)=CC=1>>[Br:1][C:2]1[C:3]([C@@H:19]([NH:29][S@:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)=[N:4][C:5]([Br:36])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[S@](=O)/N=C\c1nc(Br)ccc1Br
Reactant: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Product: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(Br)ccc1Br

Procedure:
The title compound (42D) was prepared according to the method presented for the synthesis of compound 30D of Example 30 utilizing 42C. MS (m/z) 496.99 [M+H]+
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH:7][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=1>[OH-].[Na+]>[F:15][C:14]([F:16])([F:17])[C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=C(O)CCCl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCOc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 16.9 %

Procedure:
3-Chloropropionic acid (25 g) was added dropwise to a 2 N aqueous sodium hydroxide solution (120 mL) of 3-hydroxybenzotrifluoride (25 g). The reaction mixture was refluxed for one hour while the pH was maintained at 10 or more with a 5 N aqueous sodium hydroxide solution. The reaction mixture was cooled to room temperature and was then washed with diethyl ether. Subsequently, 1 N hydrochloric acid was added thereto so that the solution became acidic. The reaction mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and n-hexane was then added to the residue to perform crystallization. The title compound (6.1 g) was obtained as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O:10][CH2:11][C:12]#[CH:13]>C(N(CC)CC)C.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]#[C:12][CH2:11][O:10][CH3:9])=[N:3][CH:4]=1
Reactant: C#CCOC
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCC#Cc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
A solution of 2,5-dibromo-pyridine (41, 4.64 g, 19.6 mmol), 3-methoxy-propyne (30, 1.66 mL, 19.7 mmol), and copper(I) iodide (0.084 g, 0.44 mmol) in 61.6 mL of triethylamine was purged with nitrogen, and bis(triphenylphosphine)palladium(II) chloride (0.31 g, 0.44 mmol) was added at 0° C. The resulting mixture was stirred at 0° C. for 1 hour, then at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, then washed with water and brine. The organic layer was dried with anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was purified by silica gel flash chromatography eluting with ethyl acetate and hexane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (42, 2.64 g).