Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([NH2:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=1>>[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([NH:41][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])([CH3:39])[CH3:40])=[CH:34][CH:33]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: Cc1ccc(C(C)(C)N)cc1
Product: Cc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Yield: 88 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-(4-methylphenyl)-1-methylethylamine (prepared as described in Preparation 10h) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 88%.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.NCCC[CH2:35][NH:36][C:37](=[O:39])[CH3:38]>>[C:37]([NH:36][CH2:35][CH2:12][CH2:11][CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])(=[O:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: CC(=O)NCCCCN
Product: CC(=O)NCCCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using N-(4-aminobutyl)acetamide instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 372 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.36 (1H, s) 8.11 (1H, t, J=5.56 Hz) 8.02 (1H, d, J=5.47 Hz) 7.77 (2H, d, J=5.47 Hz) 7.48 (1H, d, J=5.47 Hz) 7.31 (1H, dd, J=3.51, 2.54 Hz) 6.82 (1H, d, J=5.47 Hz) 6.43 (1H, dd, J=3.51, 1.95 Hz) 3.19-3.27 (2H, m) 2.96-3.07 (2H, m) 1.77 (3H, s) 1.44-1.59 (2H, m) 1.39 (2H, dd, J=8.40, 6.83 Hz)
Reaction SMILES: [CH:1]([Si:4]([O:11][CH2:12][CH:13]([OH:23])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH3:24]I>>[CH:8]([Si:4]([O:11][CH2:12][CH:13]([O:23][CH3:24])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])([CH3:9])[CH3:10]
Reactant: CC(C)[Si](OCC(O)CNC(=O)OC(C)(C)C)(C(C)C)C(C)C
Reactant: CI
Product: COC(CNC(=O)OC(C)(C)C)CO[Si](C(C)C)(C(C)C)C(C)C
Yield: 62 %

Procedure:
Using a procedure analogous to Example 57-B, 3-(t-butoxycarbonylamino)-2-hydroxypropyl triisopropylsilyl ether and methyl iodide gave the title compound (13 g, 62%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([OH:30])=O)=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:33])[CH:8]=1)[CH3:2].Cl.[CH3:35][NH:36][O:37][CH3:38].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:33])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]([N:36]([O:37][CH3:38])[CH3:35])=[O:30])=[CH:31][CH:32]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CNOC
Reactant: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(OCC(=O)O)cc3)c2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(OCC(=O)N(C)OC)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
To a solution of [4-({[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)phenoxy]acetic acid (0.22 g, 0.49 mmol), N,O-dimethylhydroxylamine hydrochloride (72 mg, 0.74 mmol), triethylamine (0.12 mL, 0.86 mmol) and 1-hydroxybenzotriazole (98 mg, 0.64 mmol) in N,N-dimethylformamide (15 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (122 mg, 0.64 mmol) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5-2:1) to give the title compound (160 mg, yield 66%) as a colorless oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](/[C:16](/[CH3:36])=[CH:17]/[CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C@H:27]([O:33][CH2:34][CH3:35])[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13](/[C:16](/[CH3:36])=[CH:17]/[CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C@H:27]([O:33][CH2:34][CH3:35])[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(Cl)cc3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(Cl)cc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydroxide (1M, 2.3 ml, 2.3 mmol) was added to a solution of (E)-(S)-ethyl 3-{4-[3-(4′-chloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate (example 52) (0.600 g, 1.25 mmol) in ethanol (10 ml) and the mixture stirred at room temperature for 18 h, then heated to 80° C. for 2 h. The resulting mixture was partitioned between water (50 ml) and ethyl acetate (50 ml) and the aqueous layer acidified to pH1 by addition of 1N HCl. The aqueous layer was separated and further extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine, dried (MgSO4), evaporated, and the product and vacuum dried at 40° C. for 72 h, to give (E)-(S)-3-{4-[3-(4′-chloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid as a colourless solid; 0.53 g (94%).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CC(C)=O.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Clc1nc(Cl)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of cyanuric chloride (18.4 g, 10 mmol) in acetone (100 ml) and crushed ice (500 g), a mixture of triethylamine (30.0 g, excess) and morpholine (8.7 g, 10 mmol) was added at −10° C. After the addition, reaction mixture was stirred at room temperature and for 1 hour and diluted with 50 ml water. Separated white solid was filtered and washed with water. The white solid was dried and filtered. The crude product was found to be pure and taken to next step with out purification. Yield: 18 g, 76%; (M+H) 236.4
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]#[N:13].Cl[C:15]([O:17][CH3:18])=[O:16]>CN(C)C=O>[CH3:18][O:17][C:15](=[O:16])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]#[N:13]
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Reactant: COC(=O)Cl
Solvent: CN(C)C=O
Product: COC(=O)Nc1ccc2[nH]cc(CC#N)c2c1

Procedure:
Following the method of Example 4(i), 5-amino-1H-indole-3-acetonitrile (0.8 g) in dimethylformamide (10 ml) was reacted with methyl chloroformate (0.5 ml) to give the title compound (0.44 g) as a white solid m.p. 146°-8° after column chromatography (Kieselgel 60, 100 g) eluted with ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([C:30]2[N:35]=[C:34]([C:36]#[N:37])[C:33]3[N:38]=[CH:39][N:40]([CH3:41])[C:32]=3[CH:31]=2)[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[C:24]=1[OH:25].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:25][C:24]2[C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][C:21]([C:30]3[N:35]=[C:34]([C:36]#[N:37])[C:33]4[N:38]=[CH:39][N:40]([CH3:41])[C:32]=4[CH:31]=3)=[CH:20][C:19]=2[Cl:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCBr)CC1
Reactant: Cn1cnc2c(C#N)nc(-c3cc(Cl)c(O)c(C(F)(F)F)c3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Cn1cnc2c(C#N)nc(-c3cc(Cl)c(OCCCN4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)cc21

Procedure:
4-(3-Bromo-propyl)-piperazine-1-carboxylic acid tert-butyl ester (172 mg) was added to a mixture of 6-(3-chloro-4-hydroxy-5-trifluoromethyl-phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (165 mg) and potassium carbonate (130 mg) in acetonitrile (15 ml). The mixture was refluxed for 4 hours, then ethyl acetate (50 ml) and water (30 ml) were added and the organic layer was washed with brine, then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a crude product, 4-{3-[2-chloro-4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-6-trifluoromethyl-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[N:4]=1.[C:17]([C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26]2)=[N:23][CH:24]=1)#[N:18]>>[C:17]([C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([C:30]([NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:8]([C:5]4[N:4]=[C:3]([C:2]([F:15])([F:1])[F:16])[O:7][N:6]=4)[CH:9]=3)=[O:31])[CH2:26]2)=[N:23][CH:24]=1)#[N:18]
Reactant: Nc1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)C2)nc1
Product: N#Cc1ccc(N2CCC(C(=O)Nc3cccc(-c4noc(C(F)(F)F)n4)c3)C2)nc1
Yield: 58 %

Procedure:
This compound was synthesized from 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)aniline and 1-(5-cyanopyridin-2-yl)pyrrolidine-3-carboxylic acid as described for example 37 step 3 (65 mg, yield 58%). 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.48-8.47 (m, 2H), 7.85-7.81 (m, 2H), 7.75 (d, J=7.8 Hz, 1H), 7.58-7.54 (m, 1H), 6.59 (d, J=8.9 Hz, 1H), 3.77-3.66 (m, 3H), 3.52 (m, 1H), 3.33 (m, 1H), 2.35-2.29 (m, 1H), 2.23 (m, 1H). MS (ESI) m/z: Calculated for C20H15F3N6O2: 428.12. found: 429.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30](Cl)=[N:29][CH:28]=1.C(N(CC)CC)C.N12CCN(CC1)CC2>CN(C=O)C.O>[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:23])[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=3)([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:4]=2)=[N:29][CH:28]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)nc1
Reaction time: 0.17 h
Yield: 25 %

Procedure:
4-Chloro-3-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 130, step 7) was added to a solution of methyl-6-chloro-nicotinate (41 mg, [CAS Reg. No. 73781-91-6]) in DMF (0.6 mL) followed by the addition of triethylamine (0.021 mL). Stirring was continued for 10 minutes at r.t. Then 1,4-diazabicyclo[2.2.2]octane (1.9 mg) was added and the mixture was stirred over night at r.t. The reaction mixture was poured into water, extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate:heptane=3:7) to give the desired compound as a colorless gum (14 mg, 25%). MS (neg. ion, m/e)=499.1 [(M−H)−].
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[C:16]([O:18][CH:19]([F:21])[F:20])[N:15]([CH3:22])[N:14]=2)=[CH:9][CH:8]=1>C(Cl)(Cl)(Cl)Cl>[Cl:4][C:17]1[C:13]([C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=2)=[N:14][N:15]([CH3:22])[C:16]=1[O:18][CH:19]([F:21])[F:20]
Reactant: Cn1nc(-c2ccc(Cl)cc2)cc1OC(F)F
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(-c2ccc(Cl)cc2)c(Cl)c1OC(F)F
Temperature: 20 °C
Reaction time: 2 h

Procedure:
74.0 g (0.549 mol) of sulfuryl chloride dissolved in 200 ml of carbon tetrachloride were added slowly dropwise to a solution of 128.9 g (0.5 mol) of 3-(4-chlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 500 ml of carbon tetrachloride, the ensuing reaction being exothermic with evolution of gas. After the end of the reaction the mixture was stirred at about 20° C. for a further 2 h. The reaction solution was then washed with about 300 ml each of water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, and then dried and concentrated. Yield: 139.3 g; 1H-NMR (270 MHz, in CDCl3): δ [ppm]=7.79 (d, 2H), 7.43 (d, 2H), 6.70 (t, 1H), 3.85 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[NH:20][CH2:19][C:17]2=[C:18]3[C:13](=[C:14]([CH2:21][C:22](=[O:24])[NH2:23])[CH:15]=[CH:16]2)[CH:12]=[CH:11][N:10]3[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O:26][C:27](=O)[C:28](=O)[C:29]1[C:37]2[C:32](=[C:33]([CH2:38][O:39][Si:40]([CH:47]([CH3:49])[CH3:48])([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42])[CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1>>[C:1]([O:5][C:6]([CH:8]1[NH:20][CH2:19][C:17]2=[C:18]3[C:13](=[C:14]([C:21]4[C:22](=[O:24])[NH:23][C:27](=[O:26])[C:28]=4[C:29]4[C:37]5[C:32](=[C:33]([CH2:38][O:39][Si:40]([CH:41]([CH3:43])[CH3:42])([CH:47]([CH3:49])[CH3:48])[CH:44]([CH3:46])[CH3:45])[CH:34]=[CH:35][CH:36]=5)[NH:31][CH:30]=4)[CH:15]=[CH:16]2)[CH:12]=[CH:11][N:10]3[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1Cn2ccc3c(CC(N)=O)ccc(c32)CN1
Reactant: COC(=O)C(=O)c1c[nH]c2c(CO[Si](C(C)C)(C(C)C)C(C)C)cccc12
Product: CC(C)[Si](OCc1cccc2c(C3=C(c4ccc5c6c4ccn6CC(C(=O)OC(C)(C)C)NC5)C(=O)NC3=O)c[nH]c12)(C(C)C)C(C)C

Procedure:
Beginning with 7-Carbamoylmethyl-3,4-dihydro-1H-[1,4]diaze-pino[6,7,1-hi]indole-2-carboxylic acid tert-butyl ester and oxo-(7-triisopropylsilanyloxymethyl-1H-indol-3-yl)-acetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Fc1ccc(Br)nc1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(F)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 2-bromo-5-fluoropyridine. ESI-MS (m/z): 419 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][S:8][C:7]=1[NH:19]C(OC(C)(C)C)=O)=[O:5])[CH3:2].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=Cc2ccccc2)csc1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(C=Cc2ccccc2)csc1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 56 %

Procedure:
2-t-Butoxycarbonylamino-4-styryl-thiophene-3-carboxylic acid ethyl ester (0.335 g, 0.848 mmol) was dissolved in anhydrous CH2Cl2 (8 mL). This was treated with trifluoroacetic acid (0.346 mL, 4.49 mmol) and stirred at room temperature for 6 hr. More trifluoroacetic acid (0.346 mL, 4.49 mmol) was added and stirring at room temperature was continued for 30 min. The reaction was neutralized with sat. NaHCO3 (25 mL) and then extracted with CH2Cl2 (2×25 mL). The combined organic layers were washed with H2O (1×25 mL) and brine (1×25 mL). The organic layer was then dried (Na2SO4), filtered and the solvent removed in vacuo. The crude product was purified by flash chromatography (SiO2, 15 EtOAc/85 hexanes) to afford the title compound (0.1298 g, 56%) as an inseparable mixture. MS m/e (CI) 274.0 (M+H)+; 1H NMR (300 MHz, CDCl3): δ ppm 0.85 (d, 1H), 1.32 (m, 4H), 4.26 (m, 1H), 6.75 (s, 1H), 7.18 (m, 4H), 7.35 (d, 1H), 7.52 (d, 1H), 7.66 (d, 1H), 7.78 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[C:9]([CH:21]3[CH2:23][CH2:22]3)[C:10]([N:12]([CH2:17][CH2:18][S:19][CH3:20])[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][C:6]=2[O:5][C:4]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)#[N:2].[OH:31]S([O-])(=O)=O.[K+]>CO.O>[C:1]([C:3]1[C:7]2[CH:8]=[C:9]([CH:21]3[CH2:23][CH2:22]3)[C:10]([N:12]([CH2:17][CH2:18][S:19]([CH3:20])=[O:31])[S:13]([CH3:16])(=[O:14])=[O:15])=[CH:11][C:6]=2[O:5][C:4]=1[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)#[N:2]
Reactant: O=S(=O)([O-])O
Reactant: CSCCN(c1cc2oc(-c3ccc(F)cc3)c(C#N)c2cc1C1CC1)S(C)(=O)=O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)CCN(c1cc2oc(-c3ccc(F)cc3)c(C#N)c2cc1C1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a mixture of Example 12A (0.142 g, 0.320 mmol) in methanol (3 mL) cooled to 0-5° C. was slowly added dropwise a solution of 2 KHSO5.KHSO4.K2SO4 (0.216 g, 0.352 mmol) in water (1 mL). The reaction mixture was stirred for 10 minutes in the ice bath, then at room temperature for 22 hours. The reaction was incomplete by analytical LCMS so additional 2 KHSO5.KHSO4.K2SO4 (111 mg) was added in portions, followed by stirring at room temperature for 2.5 hours. Then more 2KHSO5.KHSO4.K2SO4 (245 mg) was added in portions followed by water (1 mL). The reaction mixture was heated at 50° C. for 4 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and brine. The aqueous phase was further extracted with ethyl acetate (1×). The combined organic extracts were washed with water (2×), dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give a mixture of the title compounds (0.1436 g). MS (ESI+) m/z 494 (M+NH4)+ for sulfone; MS (ESI+) m/z 461 (M+H)+ for sulfoxide.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][N:11]([CH3:13])[CH3:12].[Cl:14][C:15]1[CH:26]=[CH:25][C:18]([CH2:19][N:20]([CH3:24])[CH2:21][CH2:22]O)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]([CH2:21][CH2:22][O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:10][N:11]([CH3:13])[CH3:12])[CH3:24])=[CH:25][CH:26]=1
Reactant: CN(C)Cc1cc(C#N)ccc1O
Reactant: CN(CCO)Cc1ccc(Cl)cc1
Product: CN(C)Cc1cc(C#N)ccc1OCCN(C)Cc1ccc(Cl)cc1

Procedure:
The title compound (b.p. 100° C. at 0.1 mbar) was prepared by reacting 4-hydroxy-3-(dimethylaminomethyl)benzonitrile (7.32 g) with N-(4-chlorobenzyl)-N-methylethanolamine (8.29 g) in a similar manner to Example 4.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2=[O:15])#[CH:2].I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>CCN(CC)CC.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.[Cu]I>[CH3:14][C:8]1([CH3:13])[CH2:7][C:6](=[O:15])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[C:2][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:4]=2)[S:9]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(=O)CC(C)(C)S2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CC(C)(C)S3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A solution of 6-ethynyl-2,2-dimethylthiochroman-4-one (82.0 mg. 0.38 mmol) and ethyl 4-iodobenzoate (104.9 mg. 0.38 mmol.) in 5.0 mL Et3N was purged with argon for 10 minutes. To this solution was added bis(triphenylphosphine)palladium(II) chloride (88.0 mg. 0.12 mmol) and copper (I) iodide (22.9 mg. 0.12 mmol). After sparging for an additional 5 minutes with argon, the solution was stirred overnight at room temperature. The reaction mixture was filtered through a pad of Celite using an Et2O wash. Concentration of the filtrate under reduced pressure, followed by column chromatography of the residual solid afforded 100 mg (72%) of ethyl 4-[(2,2-dimethyl-4-oxo-thiochroman-6-yl)ethynyl]-benzoate as a yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.25 (1H, d, J=1.8 Hz), 8.00 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 7.53 (1H, dd, J=1.8, 8.2 Hz), 7.21 (1H, d, J=8.2 Hz), 4.37 (2H, q, J=7.1 Hz), 2.88 (2H, s), 1.47 (6H, s), 1.39 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[C:10]([C:11]([NH:13][C:14]2[C:15]([Cl:25])=[N:16][C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[Cl:25][C:15]1[C:14]([NH:13][C:11]([C:10]2[C:5]([NH:3][CH2:1][CH3:2])=[N:6][CH:7]=[CH:8][CH:9]=2)=[O:12])=[C:19]([C:20]([F:23])([F:22])[F:21])[CH:18]=[C:17]([CH3:24])[N:16]=1
Reactant: CCN
Reactant: Cc1cc(C(F)(F)F)c(NC(=O)c2cccnc2Cl)c(Cl)n1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCNc1ncccc1C(=O)Nc1c(C(F)(F)F)cc(C)nc1Cl
Temperature: 160 °C
Yield: 37.5 %

Procedure:
Ethylamine (0.4 g) was added to a suspension of 1.3 g of 2-chloro-N-(2-chloro-6-methyl-4-trifluoromethyl-3-pyridinyl)-3-pyridinecarboxamide in 5 ml of xylene, and the resulting mixture heated in a pressure tube for 30 min. at 160° C. The cooled mixture was diluted with ethyl acetate, washed, dried, and concentrated. Column chromatography over silica gel (ethyl acetate/hexane, 1:1) gave 0.5 g of the title compound.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]([Si](C)(C)C)[Si](C)(C)C)=[CH:9][CH:8]=1.[C:22]1(=[O:32])[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:24](=[O:31])[O:23]1.S(=O)(=O)(O)O>O1CCCC1>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:24]([C:25]2[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=2[C:22]([OH:32])=[O:23])=[O:31])=[CH:8][CH:9]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: C[Si](C)(C)N(c1ccc(Br)cc1)[Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)C2=C(C(=O)O)CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2.2 g magnesium turnings (83.5 mmol) in 15 ml tetrahydrofuran were added 0.1 mL 1,2-dibromethane to start the Grignard reaction followed by slow addition of 13.0 g 2-(4-bromphenyl)-1,1,1,3,3,3-hexamethyldisilazane (41 mmol) in 70 mL tetrahydrofuran over a period of 20 minutes at room temperature with subsequent stirring for further 30 minutes. The resulting mixture was added dropwise at −78° C. to a solution of 4,5,6,7-tetrahydro-isobenzofuran-1,3-dione (5.6 g) in 70 mL tetrahydrofuran. The reaction mixture was slowly warmed to room temperature. Sulfuric acid (2 mL, 1 M) was added and the solvent was removed under reduced pressure. The residue was added carefully to 20 mL of 0.5 M sulfuric acid solution and the desired product started to precipitate and was extracted with ethyl acetate. Acidification of the water phase and extraction with ethyl acetate was continued until pH˜4-5 (at least three times). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and the solvent was subsequently evaporated under reduced pressure. Purification of the raw material by column chromatography with ethyl acetate/hexane 1:1 and subsequently 100% ethyl acetate resulted in the desired product.