Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:11]([O:9][C:5]1[CH:4]=[C:3]([CH3:10])[C:2]([Br:1])=[C:7]([CH3:8])[CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)cc(C)c1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (8.00 g, 39.8 mmol) and benzyl bromide (5.80 mL, 47.7 mmol) in N,N-dimethylformamide (130 mL) was added potassium carbonate (8.25 g, 59.7 mmol), and the mixture was stirred at 80° C. for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=97/3) to give the title compound (9.97 g, yield 86%) as a colorless oil.
Reaction SMILES: [C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.COO[CH:34](OOC)[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1.[Na+].[Cl-]>C(Cl)Cl>[CH3:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([CH:34]2[O:7][CH:6]([C:5]([NH:4][CH2:3][CH2:2][C:1]([OH:15])=[O:14])=[O:13])[C:8]([CH3:10])([CH3:9])[CH2:11][O:12]2)=[CH:36][CH:37]=1
Reactant: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)O
Reactant: COOC(OOC)c1ccc(OC)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2OCC(C)(C)C(C(=O)NCCC(=O)O)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Pantothenic acid (7) (4.6 g, 2.24×10−2 mols) was dissolved in dry DCM (30 mL). Camphor sulfonic acid (0.52 g, 2.24×10−3 mols) and p-anisaldehyde-dimethoxy-acetal (3.82 mL, 2.24×10−2 mols) were added to the reaction mixture. The reaction was stirred overnight at room temperature with a drying tube. The crude reaction product was concentrated and purified silica gel chromatography (6:1 hexane:EtOAC-EtOAc) to yield a white solid (8A1) (3.8 g, 51% yield). mp=135-136° C. 1HNMR (400 MHz, DMSO) 0.93 (s, 3H), 0.99 (s, 3H), 2.38 (t, 2H, J=6.8 Hz), 3.25 (m, 1H), 3.34 (m, 1H), 3.5.9 (d, 1H, J=10.8 Hz), 3.62 (d, H, J=10.8 Hz), 3.74 (s, 3H), 4.07 (s, 1H), 5.50 (s, 1H), 6.91 (d, 2H, J=8.8 Hz), 7.41 (d, 2H, J=8.8 Hz). 13C-NMR (400 Mz, DMSO) 19.7, 22.2, 33.2, 34.4, 34.9, 55.8, 78.0, 83.8, 101.1, 114.0, 128.4, 131.1, 160.3, 168.9, 173.8. IR (NaCl, thin film), 3420, 2959, 1729, 1654, 1617, 1540, 1520, 1251, 1105 cm−1. MS (ESI) [M+Na]+360.1. HRMS (FAB) (m/z): [M+H]+ calcd for C17H23O6N, 338.1598, found 338.1594.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:15][S-:16].[Na+].[ClH:18]>CN(C)C=O>[ClH:18].[CH3:15][S:16][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1cc(OC(F)(F)F)ccc1F
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(OC(F)(F)F)cc1CN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Step 1) A mixture of 2-fluoro-5-(trifluoromethoxy)benzonitrile (6.55 g) and sodium methanethiolate (2.46 g) was stirred in N,N-dimethylformamide (50 ml) at room temperature for 3 hr. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. A solution of the obtained residue in tetrahydrofuran (20 ml) was added at 0° C. to a suspension of lithium aluminum hydride (1.45 g) in tetrahydrofuran (250 ml). The mixture was stirred at room temperature for 2 hr, and treated with sodium sulfate 10 hydrate. The mixture was further stirred at room temperature for 30 min, and the inorganic substance was filtered off through celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (10 ml) was added. The mixture was crystallized from methanol-ethyl acetate to give 1-[2-(methylsulfanyl)-5-(trifluoromethoxy)phenyl]methanamine hydrochloride (4.3 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH:9]([C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1)[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)(=O)=O.[CH2:29]1[CH:33]2[CH2:34][NH:35][CH2:36][CH:32]2[CH2:31][N:30]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([CH:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:8][CH2:7][CH2:6][N:35]2[CH2:34][CH:33]3[CH2:29][N:30]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:31][CH:32]3[CH2:36]2)=[CH:26][CH:25]=1)#[N:28]
Reactant: COc1ccc(OC(CCCOS(C)(=O)=O)c2ccc(C#N)cc2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(OC(CCCN2CC3CN(C(=O)OC(C)(C)C)CC3C2)c2ccc(C#N)cc2)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 60 %

Procedure:
4-(4-Cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl methanesulfonate (1.12 g, 2.8 mmol; see step (c) above), tert-butyl hexahydropyrrolo[3,4-c]-pyrrole-2(1H)-carboxylate (0.59 g, 2.8 mmol; see Preparation A above) and Cs2CO3 were mixed in CH3CN (30 mL) and stirred at rt for 3 days. The mixture was then filtered and evaporated. Purification on silica (ethyl acetate:MeOH (9:1) eluant) gave 0.9 g (60%) of the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH:9][O:10]C)[C:3]=1[Cl:12].Cl(O)(=O)(=O)=O>C1COCC1.O>[Cl:12][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:8][CH:9]=[O:10]
Reactant: COC=Cc1cccc(Cl)c1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: O
Product: O=CCc1cccc(Cl)c1Cl
Temperature: 0 °C
Yield: 99.4 %

Procedure:
To a solution of 15.0 g (0.074 mole) 1,2-dichloro-3-(2-methoxyethenyl)benzene in 150 ml of THF was added 15 ml of 35% perchloric acid in water. The reaction was refluxed for 3.5 hr then poured into ice/water. The aqueous layer was extracted two times with ether, the organics were washed with water, brine and dried (MgSO4). Evaporation of the solvent gave 13.91 g of crude 2,3-dichlorobenzeneacetaldehyde a yellow oil (99%).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)=[CH:12]/[CH2:13][OH:14])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.O[C:23]1[CH:34]=[CH:33][C:26]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:25]([CH3:35])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH:1]1([S:4][C:5]2[CH:6]=[CH:7][C:8](/[C:11](/[C:15]3[CH:16]=[CH:17][C:18]([I:21])=[CH:19][CH:20]=3)=[CH:12]/[CH2:13][O:14][C:23]3[CH:34]=[CH:33][C:26]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:25]([CH3:35])[CH:24]=3)=[CH:9][CH:10]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)COc1ccc(O)cc1C
Reactant: OC/C=C(\c1ccc(I)cc1)c1ccc(SC2CC2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC3CC3)cc2)cc1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The above allyl alcohol (3.40 g, 8.30 mmol), methyl (4-hydroxy-2-methylphenoxy)-acetate (1.79 g, 9.13 mmol; compound VÚFB-21004) and triphenylphosphine (2.5 g, 9.55 mmol) were dissolved in a mixture of anhydrous toluene (38 mL) and tetrahydrofuran (13 mL). The mixture was cooled to 0° C., kept under nitrogen and a degassed solution of diisopropyl azodicarboxylate (1.88 mL, 9.55 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was allowed to warm up to ambient temperature and then was stirred overnight. The solvents were evaporated in vacuo and the residue was submitted to flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 10:1-8:1) affording methyl (Z)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-(4-iodophenyl)allyloxy]-2-methyl-phenoxy]acetate as yellowish oil.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:16])[CH2:8][CH:9]([CH3:15])[C:10]([O:12]CC)=O.[CH3:23][C:24]1[S:25][CH:26]=[C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[CH:32]=O)[N:28]=1>>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:16]([CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([C:27]3[N:28]=[C:24]([CH3:23])[S:25][CH:26]=3)[CH:30]=2)[C:10](=[O:12])[CH:9]([CH3:15])[CH2:8]1
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Reactant: CCOC(=O)C(C)CC(N)c1ccccc1-c1ccccc1
Product: Cc1nc(-c2cccc(CN3C(=O)C(C)CC3c3ccccc3-c3ccccc3)c2)cs1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-([1,1′-biphenyl]-2-yl)-4-amino-2-methylbutanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.97 min.; [M+H]+: 439.03 g/mol.
Reaction SMILES: I[C:2]1[CH:56]=[CH:55][C:5]([O:6][CH:7]2[CH2:18][N:17]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20])[CH2:16][CH2:15][CH2:14][N:13]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[CH2:12][CH2:11][CH2:10][N:9]([S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[N+:52]([O-:54])=[O:53])(=[O:45])=[O:44])[CH2:8]2)=[CH:4][CH:3]=1.[CH2:57]([OH:63])[CH2:58][CH2:59][CH2:60][C:61]#[CH:62]>C1COCC1.C(N(CC)CC)C.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>[OH:63][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][C:2]1[CH:56]=[CH:55][C:5]([O:6][CH:7]2[CH2:8][N:9]([S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[N+:52]([O-:54])=[O:53])(=[O:44])=[O:45])[CH2:10][CH2:11][CH2:12][N:13]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N+:40]([O-:42])=[O:41])(=[O:32])=[O:33])[CH2:14][CH2:15][CH2:16][N:17]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-:30])=[O:29])(=[O:20])=[O:21])[CH2:18]2)=[CH:4][CH:3]=1
Reactant: C#CCCCCO
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC(Oc2ccc(I)cc2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC(Oc2ccc(CCCCCCO)cc2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 5b (250 mg, 0.26 mmol) and 5-hexyn-1-ol (43 μL, 0.39 mmol) were dissolved in the mixture of dry THF (6 mL) and triethylamine (2 mL) and the mixture was deaerated with argon. Pd(Ph3P)2Cl2 (3.6 mg, 0.005 mmol) and CuI (1.9 mg, 0.01 mmol) were added, and the mixture was stirred overnight at RT in dark. All volatiles were removed in vacuo. The residue was suspended in dichlormethane, washed twice with water and dried over Na2SO4. Purification on silica gel (eluent: MeOH: CH2Cl2, 1:9, v/v) yielded the title compound. 1H NMR (CDCl3): 7.99 (1H, m); 7.87 (2H, m); 7.78-7.57 (tot 9H); 7.29 (2H, d, J 8.8); 6.97 (2H, d, J 8.8); 5.12 (1H, m); 4.08 (2H, dd, J 4.6 and 15); 3.81-3.69 (tot 10H); 3.13 (2H, dd, J 5.1 and 15); 2.42 (2H, t, J 6.6); 1.78-1.63 (tot 4H); 1.32 (1H, t, J 4.7). ESI-TOF MS: required for C39H43N6O14S3+ (M+H)+ 915.19; found 915.24.
Reaction SMILES: [P:1]([O-:42])([O:32][CH:33]=[C:34]1[CH2:39][CH2:38][CH2:37][CH2:36][N+:35]1([CH3:41])[CH3:40])([O:3][CH2:4][CH:5]([O:24]CC1C=CC=CC=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2]>[Pd].C(O)C>[P:1]([O-:42])([O:32][CH:33]=[C:34]1[CH2:39][CH2:38][CH2:37][CH2:36][N+:35]1([CH3:41])[CH3:40])([O:3][CH2:4][CH:5]([OH:24])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2]
Reactant: CCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OC=C1CCCC[N+]1(C)C)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOCC(O)COP(=O)([O-])OC=C1CCCC[N+]1(C)C
Yield: 86.1 %

Procedure:
The procedures of Example 8-(1) were repeated using 300 mg of 2-benzyloxy-3-hexadecyloxypropyl 1,1-dimethylpiperidinio-2-ylmethyl phosphate prepared in Example 9, 50 mg of palladium(5%)-carbon and 30 ml of ethanol, to give 220 mg of 3-hexadecyloxy-2-hydroxypropyl 1,1-dimethylpiperidinio-2-ylmethyl phosphate.
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13]Cl)[N:8]=[C:7](C(Cl)(Cl)Cl)[N:6]=1>CO>[CH:11]1([C:9]2[N:10]=[C:5]([NH2:4])[N:6]=[C:7]([O:2][CH3:1])[N:8]=2)[CH2:13][CH2:12]1
Reactant: Nc1nc(CCCCl)nc(C(Cl)(Cl)Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc(C2CC2)n1
Temperature: 60 °C
Reaction time: 1.33 h
Yield: 12.7 %

Procedure:
To a solution of 10.8 g of sodium methylate in 50 ml of methanol are added 28.9 g of 2-amino-4-(3-chloropropyl)-6-trichloromethyl-1,3,5-triazine, and the mixture is stirred at 60° C. for 80 minutes. The formed suspension is filtered under suction, diluted with 250 ml of water, and extracted 3 times with 200 ml of ethylene chloride each time. The organic phases are dried, filtered, and concentrated by evaporation. The oil which remains is purified through a silica gel column, the eluant used being methylene chloride/ether (3:1). The eluant is evaporated off to leave 2.1 g of the title product, which is recrystallised from ether/chloroform, m.p. 158°-159° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:15]([CH3:24])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[C:9]2=3)=[C:4]([Cl:25])[CH:3]=1.[CH3:26][C:27]([CH3:29])=[O:28].CO>C1COCC1>[Cl:25][C:4]1[CH:3]=[C:2]([C:27]([OH:28])([CH3:29])[CH3:26])[CH:7]=[CH:6][C:5]=1[CH:8]1[S:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]([CH3:24])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:9]1=2
Reactant: Cn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(Br)cc1Cl
Reactant: CC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(C(C)(C)O)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
To a degassed solution of 4-(4-bromo-2-chloro-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.255 g, 0.59 mmol, see Ex.#3 step D) in anhydrous THF (2.5 mL) was added dropwise isopropylmagnesium chloride lithium chloride complex solution (2.25 mL, 1.3 M in THF, 2.93 mmol) at about 0° C. After complete addition, the mixture was stirred at rt for about 4 h, then cooled to about −40° C. and acetone (0.3 mL, 4.1 mmol) was added dropwise. Subsequently, the mixture was warmed to rt, treated with methanol (2 mL) and concentrated in vacuo. The residue was dissolved in ethyl acetate (40 mL), washed with saturated aqueous ammonium chloride (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, diethyl ether) to give 2-[3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]phenyl]propan-2-ol (0.095 g, 0.23 mmol, 39%) as a white foam: LC-MS (Table 1, Method e) Rt=6.53 min; m/z 415 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 1.52 (3 H, s) 1.53 (3 H, s) 1.69 (1 H, s) 2.71 (1 H, ddd, J=15.0, 5.2, 2.0 Hz) 2.88 (1 H, ddd, J=15.0, 9.3, 2.6 Hz) 3.21-3.29 (1 H, m) 3.57-3.66 (1 H, m) 3.79 (1 H, dd, J=3.8, 5.4 Hz) 3.83 (3 H, s) 6.84 (1 H, s) 7.08 (1 H, ddd, J=7.5, 4.8, 1.1 Hz) 7.20 (1 H, dd, J=8.1, 1.8 Hz) 7.27 (1 H, d, J=8.1 Hz) 7.52 (1 H, d, J=1.8 Hz) 7.59 (1 H, td, J=7.9, 1.8 Hz) 7.73 (1 H, dt, J=7.9, 1.1 Hz) 8.53 (1 H, ddd, J=4.8, 1.8, 1.0 Hz); and 4-(2-chlorophenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.035 mg, 0.10 mmol, 17%) as a white foam: LC-MS (Table 1, Method e) Rt=7.62 min; m/z 357 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.72 (1 H, ddd, J=15.1, 6.1, 2.2 Hz) 2.87 (1 H, ddd, J=15.1, 9.1, 2.5 Hz) 3.23-3.32 (1 H, m) 3.57-3.66 (1 H, m) 3.81 (1 H, br s) 3.84 (3 H, s) 6.82 (1 H, s) 7.05-7.13 (3 H, m) 7.25-7.31 (1 H, m) 7.36-7.42 (1 H, m) 7.59 (1 H, td, J=7.7, 1.5 Hz) 7.72 (1 H, dt, J=8.0, 1.1 Hz) 8.52 (1 H, ddd, J=4.8, 1.5, 0.8 Hz).
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.[NH2:21][C:22]([CH:28]1[CH2:30][CH2:29]1)([CH3:27])[CH2:23][C:24]([NH2:26])=[O:25]>>[NH2:26][C:24](=[O:25])[CH2:23][C:22]([NH:21][C:12](=[O:14])[C:9]1[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([C:2]2([F:1])[CH2:3][CH2:4][CH2:5]2)=[CH:11][N:10]=1)([CH:28]1[CH2:30][CH2:29]1)[CH3:27]
Reactant: CC(N)(CC(N)=O)C1CC1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(F)CCC2)cn1
Product: CC(CC(N)=O)(NC(=O)c1cc(OCC(F)(F)F)c(C2(F)CCC2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(1-fluorocyclobutyl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (example 285a) and 3-amino-3-cyclopropyl-butanamide (example 270c) as starting materials and isolated (55 mg, 49%); MS (ESI, m/z): 418.4 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1(O)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[NH:12][C:11]1=[O:21])[CH3:2].N1C=CC=CC=1.O=S(Cl)[Cl:31]>C(Cl)Cl>[Cl:31][C:10]1([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[NH:12][C:11]1=[O:21]
Reactant: CCOc1ccccc1C1(O)C(=O)Nc2ccc(OC)cc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ccccc1C1(Cl)C(=O)Nc2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
5 g (16.7 mmol) of the intermediate from Step A and 2.6 g (33.4 mmol) pyridine were dissolved in 50 mL CH2Cl2 and at 0° C. 3 g (25.1 mmol) SOCl2 were added slowly. Then the reaction mixture was stirred for 30 min. at 0° C. The reaction mixture was poured into an ice/water mixture and the organic phase was separated, washed with H2O, dried over magnesium sulfate and finally the solvent was removed in vacuo. The resulting residue was suspended in ether. The solid residue was separated and dried to give 3.2 g of the intermediate, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][C:25]([F:35])([F:34])[CH2:26][C@@H:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[NH2:28])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[N+:36]([C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)([O-:38])=[O:37]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][C:25]([F:34])([F:35])[CH2:26][C@@H:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[NH:28][S:45]([C:42]1[CH:41]=[CH:40][C:39]([N+:36]([O-:38])=[O:37])=[CH:44][CH:43]=1)(=[O:46])=[O:47])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CCOC(=O)[C@@H](N)CC(F)(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](CC(F)(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
To a solution of the material from Step 8 (210 mg, 0.427 mmol) in pyridine (2 mL) at room temperature were added 4-nitrobenzenesulfonyl chloride (142 mg, 0.641 mmol) and DMAP (10.44 mg, 0.085 mmol). The reaction mixture was stirred at 85° C. overnight, concentrated in vacuo, and the residue was purified by column chromatography on silica gel using ethyl acetate-hexanes (0:100 to 90:10) followed by 10% MeOH/DCM to afford 150 mg of the title compound as a yellow foam. LCMS (M+1)=677.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[CH2:12][N:9]1[CH2:10][CH2:11][C:6]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1

Procedure:
1-(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl)-piperidine-4-carboxylic acid ethyl ester (14.0 g, 26.5 mmol) dissolved in THF:Methanol (100: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 7.87 (60%); off white solid; mp 239 ° C; MS: 501.9 (M+H)+
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH3:23])[C:18](=[O:24])[CH2:17][CH2:16]3)[CH:12]=1)(C)[C:3](O)=O.C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>>[NH2:39][C:2]([C:7]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH3:23])[C:18](=[O:24])[CH2:17][CH2:16]3)[CH:10]=[N:9][CH:8]=1)([CH3:3])[CH3:1]
Reactant: CN1C(=O)CCc2cc(-c3cncc(C(C)(C)C(=O)O)c3)ccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: CN1C(=O)CCc2cc(-c3cncc(C(C)(C)N)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 59 [D], 2-methyl-2-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)propanoic acid (example 72 [C]) was reacted with diphenylphosphoryl azide in presence of TEA and then sodium trimethylsilanoate (1 M in THF) to give the title compound as a light brown amorphous solid. MS: 296.5 (M+H+).
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]>CO>[CH3:1][S:2][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCCCCCCBr
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSCCCCCCCC(=O)O

Procedure:
Sodium thiomethoxide (942 mg, 13.44 mmol) was added to a solution of 8-bromooctanoic acid (500 mg, 2.24 mmol) in methanol (5.6 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, adjusted to pH 1 by adding 1 N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give 8-(methylthio)octanoic acid as a colorless oily substance (426.5 mg, 100%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=1>>[N:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: OCc1ccncc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccncc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and pyridin-4-ylmethanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.29 (2H, d, J=9.2 Hz), 5.72 (1H, d, J=2.0 Hz), 7.38 (2H, d, J=6.4 Hz), 7.44 (1H, dd, J=1.6 Hz, J=5.2 Hz), 7.57 (1H, d, J=2.0 Hz), 8.09 (1H, s), 8.65 (2H, d, J=5.2 Hz), 8.72 (1H, d, J=5.2 Hz). [M+H] Calc'd for C15H11N5O, 278. Found, 278.