Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:47]=[CH:46][C:5]([C:6]([NH:8][C@:9]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([O:42][CH:43]([CH3:45])[CH3:44])[CH:36]=2)([C:21]2[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=2)[CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:48]([F:51])([F:50])[F:49].C([BH-](CC)CC)C.[Li+]>C1COCC1>[F:1][C:2]1[CH:47]=[CH:46][C:5]([C:6]([NH:8][C@:9]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([O:42][CH:43]([CH3:45])[CH3:44])[CH:36]=2)([C:21]2[CH:26]=[C:25]([O:27][C:28]([F:32])([F:33])[CH:29]([F:30])[F:31])[CH:24]=[C:23]([F:34])[CH:22]=2)[CH2:10][C:11]2[CH:20]=[CH:19][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:48]([F:51])([F:50])[F:49]
Reactant: COC(=O)c1ccc(C[C@](NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(OC(C)C)c2)cc1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Oc1cc([C@@](Cc2ccc(CO)cc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 68.4 %

Procedure:
To a solution of (R)-methyl 4-(2-(4-fluoro-3-(trifluoromethyl)benzamido)-2-(4-fluoro-3-isopropoxyphenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)benzoate (20 mg, 0.027 mmol) in THF (2 mL) at −78° C. was added a solution of lithium triethylborohydride (1.0 M in THF, 0.5 mL, 0.5 mmol). The reaction mixture was stirred at −78° C. for 1.5 h. The reaction was quenched by the addition of 1 N NaOH (1 mL) and diluted with EtOAc (15 mL). The organic portion was washed with sat. NaCl (2×10 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC Sunfire 5μ C18 30×100 mm column, eluting with 20-90% MeOH/H2O containing 0.1% TFA, 10 min gradient, flow rate 40 mL/min, wavelength 220 nm) to yield (R)-4-fluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-(4-(hydroxymethyl)phenyl)ethyl)-3-(trifluoromethyl)benzamide (Example 348, 13 mg, 78% yield) as a colorless film. LCMS: RT=2.17 min [M+H] 704.1 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm); HPLC: RT=4.0 min (Phenomenex Luna C18 4.6×50 mm column, eluting with 10-90% MeOH/H2O containing 0.2% PPA, flow rate 4 mL/min, wavelength 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 7.91 (1H, d, J=6.59 Hz), 7.85-7.87 (1H, m) 7.26-7.31 (1H, m), 7.16 (2H, d, J=7.91 Hz), 6.93-7.05 (4H, m), 6.68-6.73 (3H, m), 6.60-6.66 (2H, m), 5.75-6.01 (1H, m), 4.64 (3H, s), 4.35 (1H, m), 4.06 (1H, d, J=13.2 Hz), 3.74 (1H, d, J=13.2 Hz), 1.29 (3H, d, J=6.15 Hz), 1.26 (1H, s), 1.23 (3H, d, J=6.15 Hz).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>>[NH2:15][C:14]1[CH:16]=[CH:17][C:11]([Br:10])=[CH:12][C:13]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccc(Br)cc1
Product: Nc1ccc(Br)cc1C(=O)c1ccccc1
Yield: 19.8 %

Procedure:
The procedure was in the same manner as described in example 15, except that the starting material was benzoic acid instead of p-chlorobenzoic acid and 4-bromoaniline instead of 4-chloroaniline. The title compound was obtained as yellow needle crystal, and yield 19.8%, m.p.109-110° C.
Reaction SMILES: C([O:4][C:5]1[C:10]([CH2:11][CH3:12])=[CH:9][C:8]([OH:13])=[C:7]([C:14](=[O:16])[CH3:15])[C:6]=1[CH3:17])(=O)C.[C:18]1(=O)[CH2:21][CH2:20][CH2:19]1.N1CCCC1.O>C1(C)C=CC=CC=1>[CH2:11]([C:10]1[CH:9]=[C:8]2[C:7]([C:14](=[O:16])[CH2:15][C:18]3([O:13]2)[CH2:21][CH2:20][CH2:19]3)=[C:6]([CH3:17])[C:5]=1[OH:4])[CH3:12]
Reactant: O=C1CCC1
Reactant: CCc1cc(O)c(C(C)=O)c(C)c1OC(C)=O
Solvent: O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CCc1cc2c(c(C)c1O)C(=O)CC1(CCC1)O2
Yield: 15.2 %

Procedure:
A mixture of 3-acetyl-6-ethyl4-hydroxy-2-methylphenyl acetate (5.18 g), cyclobutanone (4.5 g) and pyrrolidine (1.5 mL) in toluene (50 mL) was stirred at refluxing temperature with a Dean Stark. After 8 hours it was poured into water and the toluene was separated, dried, and evaporated. The residue was dissolved in MeOH (50 mL) with LiOH (2 g), stirred at room temperature for 3 hours, poured into water, and extracted with ethyl acetate. The ethyl acetate was washed, dried, and evaporated. The residue was purified by silica gel column eluting with 15% ethyl acetate in hexane, giving 7-ethyl-6-hydroxy-5-methylspiro[chroman-2,1′-cyclobutan]-4-one as a light brown oil (0.82 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([C:33]([O:35]CC2C=CC=CC=2)=[O:34])[CH:22]=[CH:21][C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.O1CCOCC1.[Li+].[OH-]>O>[CH2:1]([O:8][C:9]1[C:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([C:33]([OH:35])=[O:34])[CH:22]=[CH:21][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)c1ccc(C(=O)O)c(OCc2ccccc2)c1OCc1ccccc1
Temperature: 60 °C

Procedure:
2 (56.970 g, 0.102 mol) was dissolved in 200 mL 1:1:EtOH:dioxane in a 1-L round-bottom flask, resulting in a dark orange, clear solution, to which a suspension of LiOH (7.315 g, 0.305 mol) in 75 mL water was added. The flask was fitted with a reflux condenser and magnetically stirred. The emulsion (containing undissolved LiOH) was heated to 60° C. for 12 h, and became a translucent, orange solution. The reaction mixture was filtered through a M glass frit, dissolved in 500 mL basic water, and washed with DCM (3×250 mL). The aqueous layer was acidifed with ˜80 mL conc. HCl, and the resulting white precipitate was filtered and washed with water. The solid was dried using house vacuum overnight, ground into a white powder, and dried on the vacuum line for 12 h (100%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([C:25]([O:27]C)=[O:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:10][C:9]=2[CH3:31])=[O:6])[CH2:3][CH2:2]1>CO.[OH-].[Na+]>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([C:25]([OH:27])=[O:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:10][C:9]=2[CH3:31])=[O:6])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc2c(Oc3ccc(NC(=O)NC4CC4)c(C)c3)ccnc2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(C)c3)c2cc1C(=O)O
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 58.7 %

Procedure:
After dissolving N-cyclopropyl-N′-[2-methyl-4-(6-methoxycarbonyl-7-methoxy-4-quinolyl)oxyphenyl]urea (173 mg, 0.3972 mmol) in methanol (3 ml), 2N aqueous sodium hydroxide (1 ml) was added and the mixture was heated and stirred at 60° C. for 45 minutes. The solvent was distilled off under reduced pressure, the precipitated crystals were redissolved in methanol, and then 1N hydrochloric acid was added to pH 4 and saturated brine was further added. After extraction with ethyl acetate/tetrahydrofuran, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained crystals were suspended in acetone/diethyl ether and then filtered out and dried by aspiration to obtain the title compound (95 mg, 0.2332 mmol, 56.80%) as brown crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C@H:8]1[CH2:12][N:11]([S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C@H:10]([CH2:26][OH:27])[CH2:9]1)([CH3:6])([CH3:5])[CH3:4].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CS(C)=O>[CH2:28]([O:27][CH2:26][C@@H:10]1[CH2:9][C@@H:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])[CH2:12][N:11]1[S:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)(=[O:15])=[O:14])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](CO)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)O[C@@H]1C[C@@H](COCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
R2—ether formation: To a slurry of sodium hydride (60% in mineral oil, 2.75 g) in DMSO (100 ml) were added (2S,4R)-[4-tert-butoxy-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-methanol (11.2 g) in portions within 0.5 h and benzyl bromide (7.2 ml) dropwise within 0.5 h at 20° C. The reaction mixture was stirred at room temperature for 1.5 h, poured onto ice/water and extracted with EtOAc. The organic phases were washed with water and brine, dried over magnesium sulphate and concentrated. The residue was crystallized from acetone/Et2O/hexane to obtain (2S,4R)-2-benzyloxymethyl-4-tert -butoxy-1-(naphthalene-2-sulfonyl)-pyrrolidine (10.05 g) as a colorless solid, mp 101–103° C., MS: 454 (MH+).
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:26])[CH:6]([S:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.[CH3:29][S:30]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][CH:35]=1)(=[O:32])=[O:31]>>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][S:16][CH:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:41](=[O:42])[CH2:40][C:37]3[CH:36]=[CH:35][C:34]([O:33][S:30]([CH3:29])(=[O:31])=[O:32])=[CH:39][CH:38]=3)=[CH:12][CH:13]=2)[C:5]([OH:4])=[O:26])=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)Oc1ccc(CC(=O)O)cc1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CO)cc1)SCCc1ccc(F)cc1
Product: CS(=O)(=O)Oc1ccc(CC(=O)OCc2ccc(CC(SCCc3ccc(F)cc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-(4-hydroxymethyl-phenyl)-propionic acid 2,2,2 trichloro-ethyl ester (33 mg, 0.072 mmol) and (4-methanesulfonyloxy-phenyl)-acetic acid (15 mg, 0.065 mmol) in the same manner as described for example 1. The crude product was purified by flash chromatography (yield: 2.0 mg, 5.6%). Mass Spectrum: M+H+ 547.10.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=1[CH2:9][OH:10].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].C1(C)C=CC=CC=1>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[O:1][CH2:2][C:3]3[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=3[CH2:9][O:10]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: OCc1ccc(CO)c(CO)c1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(C2OCc3ccc(CO)cc3CO2)cc1
Yield: 62.6 %

Procedure:
10 g of (3,4-bis-hydroxymethylphenyl)methanol (59.4 mmol) (prepared according to Nakazaki, M.; Yamamoto, K. And Miura, Y.; J. Org. Chem., 43(6), (1978), 1041-1044), 100 ml of toluene, 8.98 g of 4-nitrobenzaldehyde (59.4 mmol) and 0.6 g of Montmorillonite KSF (10 mg/mmol) are introduced into a flask equipped with a Dean-Stark. The mixture is heated under reflux for 2 hours 30 minutes. The montmorillonite is filtered off and the reaction medium is allowed to return to room temperature, with stirring. The reaction product crystallizes. After filtration and drying under vacuum at 50° C., 11.2 g of [7-(4-nitrophenyl)-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl]methanol are obtained.
Reaction SMILES: [CH2:1]([NH:16][C:17]1[CH:34]=[CH:33][C:20]([C:21]([N:23]2[CH:27]([C:28]([O:30]CC)=[O:29])[CH2:26][S:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].S1CC(C(O)=O)NC1>C(=O)(O)[O-].[Na+].CC(C)=O>[CH2:1]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([N:23]2[CH:27]([C:28]([OH:30])=[O:29])[CH2:26][S:25][CH2:24]2)=[O:22])=[CH:33][CH:34]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCC=CCCCNc1ccc(C(=O)N2CSCC2C(=O)OCC)cc1
Agent: O=C(O)C1CSCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCCCC=CCCCNc1ccc(C(=O)N2CSCC2C(=O)O)cc1

Procedure:
By means of the alkaline hydrolysis method of Example 2 the ethyl ester of Example 385 is converted to the subject carboxylic acid. This acid is also prepared using the procedure of Example 385 except that the acylation of the thiazolidine-4-carboxylic acid is carried out in aqueous acetone sodium bicarbonate solution.
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:12]([O:14]C)=O)=[CH:5][N:6]2[C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7]2)=O.[OH-].[NH3+:17][NH2:18]>>[CH:1]1[C:3]2=[C:11]3[N:6]([CH:5]=[C:4]2[C:12](=[O:14])[NH:18][N:17]=1)[CH2:7][CH2:8][CH2:9][CH2:10]3
Reactant: N[NH3+]
Reactant: COC(=O)c1cn2c(c1C=O)CCCC2
Agent: [OH-]
Product: O=c1[nH]ncc2c3n(cc12)CCCC3
Temperature: 100 °C
Yield: 83 %

Procedure:
A 100 mL single-neck round-bottomed flask was charged with hydrazinium hydroxide (20 mL), methyl 1-formyl-5,6,7,8-tetrahydroindolizine-2-carboxylate 192a (2.5 g, 12.0 mmol). The reaction mixture was heated at 100° C. for 4 hours. After this time the reaction was cooled to room temperature and filtered to afford 192b as a yellow solid (1.9 g, 83%). MS: (M+H)+ 190.3. 1H NMR (500 MHz, DMSO) δ 11.44 (s, 1H), 8.03 (s, 1H), 7.42 (s, 1H), 4.18 (t, J=6.0 Hz, 2H), 2.96 (t, J=6.5 Hz, 2H), 1.98-1.93 (m, 2H), 1.87-1.82 (m, 2H).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)\[C:5]#[N:6].C(O)(=[O:15])C.OO>O>[CH3:1][O:2]/[N:3]=[C:4](/[C:7]1[CH:12]=[N+:11]([O-:15])[CH:10]=[CH:9][N:8]=1)\[C:5]#[N:6]
Reactant: CC(=O)O
Reactant: CO/N=C(\C#N)c1cnccn1
Agent: OO
Solvent: O
Product: CO/N=C(\C#N)c1c[n+]([O-])ccn1
Temperature: 70 °C

Procedure:
A mixture of Z-α-methoxyiminopyrazineacetonitrile (4 g), acetic acid (15 ml) and 30% hydrogen peroxide in water (15 ml) was heated at a temperature of 70° C. over one night. The reaction mixture was concentrated and treated with water and chloroform. The chloroform layer was separated and dried over magnesium sulphate. Evaporation of the solvent and successive crystallization of the residue from alcohol afforded Z-α-methoxyimino-2-pyrazineacetonitrile-4-oxide, m.p. 144°-145° C.
Reaction SMILES: [CH2:1]([CH:3]1[C:9]2[CH:10]=[C:11]([O:17][CH3:18])[C:12]([N+:14]([O-])=O)=[CH:13][C:8]=2[CH2:7][CH2:6][N:5]([CH2:19][CH3:20])[C:4]1=[O:21])[CH3:2].[H][H]>[Pd].CCO>[NH2:14][C:12]1[C:11]([O:17][CH3:18])=[CH:10][C:9]2[CH:3]([CH2:1][CH3:2])[C:4](=[O:21])[N:5]([CH2:19][CH3:20])[CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: CCC1C(=O)N(CC)CCc2cc([N+](=O)[O-])c(OC)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC1C(=O)N(CC)CCc2cc(N)c(OC)cc21
Yield: 92.6 %

Procedure:
1,3-Diethyl-8-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (205 mg, 0.70 mmol) was charged to 10 ml EtOH in a Parr bottle and then 50 mg of 10% Pd/C was also charged. The resulting suspension was shaken under 40 psi hydrogen (g) for 2 h. The resulting suspension was filtered through celite and evaporated to yield 7-amino-1,3-diethyl-8-methoxy-1,3,4,5-tetrahydro-3-benzazepin-2-one (170 mg, 93%) which was used crude in the next reaction. 1H-NMR (CDCl3) δ 6.58 (s, 1H), 6.44 (s, 1H), 3.92-3.77 (m, 5H), 3.70-3.40 (br s, 1H), 3.58-3.38 (m, 3H), 3.09 (p, J=7 Hz, 1H), 2.95 (p, J=7 Hz, 1H), 2.20 (p, J=7 Hz, 1H), 1.90 (p, J=7 Hz, 1H), 1.10 (t, J=7 Hz, 3H), 1.04 (t, J=7 Hz, 3H); LC/Ms (ESI+): 263 (M+H).
Reaction SMILES: [CH:1]1[C:14]2[C:5]([S:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.C(N(CC)CC)C.[CH2:23]([SH:27])[CH2:24][CH2:25][CH3:26].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[CH2:23]([S:27][C:4]1[C:3](=[O:15])[CH:2]=[CH:1][C:14]2[C:5]=1[S:6][C:7]1[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=1)[N:13]=2)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCS
Reactant: O=c1ccc2nc3ccccc3sc-2c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCSc1c2sc3ccccc3nc-2ccc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of phenothiazin-3-one (0.21 g) in 20 ml THF was added triethylamine (0.28 ml) and n-butanethiol (0.2 ml). The mixture was refluxed for 15 hours and then cooled to room temperature. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.22 g) was added and the reaction was stirred for 2 hours at 25°. The solvent was removed in vacuo. The residue was chromatographed on neutral alumina (Act III) and eluted with 15% EtOAc/hexane to afford the title compound, m.p. 72° C.
Reaction SMILES: [N:1]([C@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)=[N+]=[N-]>CO.[Pd]>[F:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][C@H:4]2[NH2:1])=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=N[C@@H]1CCCc2ccc(F)cc21
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1CCCc2ccc(F)cc21
Reaction time: 8 h
Yield: 91.2 %

Procedure:
(R)-1-azido-7-fluoro-1,2,3,4-tetrahydronaphthalene (4.85 g) was dissolved in methanol (70 mL) and mixed with Pd/C (10%, wet, 485 mg), applied to Parr apparatus under H2 (35 psi) overnight. The catalyst was removed by filtration and washed twice with MeOH. The filtrate and washings were combined and evaporated under reduced pressure to give a yellow oil product (3.82 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ 7.28 (dd, 1H), 7.06 (t, 1H), 6.91 (m, 1H), 3.74-3.76 (m, 1H), 2.60-2.72 (m, 2H), 2.10 (broad, 2H), 1.80-1.90 (m, 2H), 1.45-1.67 (m, 2H). 19F NMR (400 MHz, DMSO-d6) δ −117.6.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([C:13]#N)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1>O1CCCC1.C1([Mg]Cl)C=CC=CC=1>[CH3:1][N:2]([CH3:15])[C:3]1([C:13]2[CH:11]=[CH:12][CH:3]=[CH:4][CH:5]=2)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 193.1 %

Procedure:
50.0 g 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile were dissolved in 400 ml analytical grade tetrahydrofuran, 216 ml of a commercially obtainable two molar solution of phenylmagnesium chloride in tetrahydrofuran were added dropwise under a nitrogen atmosphere, while cooling on an ice-bath, and the mixture was stirred overnight, while warming to room temperature. For working up, 200 ml ice-cold ammonium chloride solution (20 wt. %) were added, while stirring and cooling on an ice-bath, and after 30 minutes the phases were separated. The aqueous phase was extracted twice with 250 ml ether each time, the extracts were combined with the organic phase, the mixture was washed with 200 ml water followed by 200 ml saturated sodium chloride solution, dried over sodium sulfate and filtered and the filtrate was concentrated. 60.0 g dimethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH:10]2[CH2:16][O:15][C:14]3[CH:17]=[CH:18][C:19]([CH2:21][C:22]([O:24]C)=[O:23])=[CH:20][C:13]=3[O:12][CH2:11]2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].C(C1C=CC(OCC2OC3C=CC(CC(OC)=O)=CC=3C2)=C(CCC)C=1O)(=O)C>>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH:10]2[CH2:16][O:15][C:14]3[CH:17]=[CH:18][C:19]([CH2:21][C:22]([OH:24])=[O:23])=[CH:20][C:13]=3[O:12][CH2:11]2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC2COc3ccc(CC(=O)OC)cc3OC2)ccc(C(C)=O)c1O
Agent: CCCc1c(OCC2Cc3cc(CC(=O)OC)ccc3O2)ccc(C(C)=O)c1O
Product: CCCc1c(OCC2COc3ccc(CC(=O)O)cc3OC2)ccc(C(C)=O)c1O

Procedure:
Following the procedure of Example 26, but substituting the compound of Example 41 for the compound of Example 25, there was obtained the title compound as a white foam.
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[N:5]=[N:4][CH:3]=1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:14]Cl>CN(C)C=O>[CH3:1][C:2]1[C:6](=[O:7])[N:5]([CH2:14][C:13]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:11]([Cl:10])[CH:12]=2)[NH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CC1=CN=NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c[nH]n(Cc2ccc(Cl)c(Cl)c2)c1=O

Procedure:
19.6 g of 4-methylpyrazol-5-one were added in portions to a suspension of 5.0 g of sodium hydride in 100 ml of absolute dimethylformamide. After the evolution of H2 had ceased, 39 g of 3,4-dichlorobenzyl chloride were added dropwise to the reaction solution.
Reaction SMILES: [N:1]1([CH2:6][C:7]#[C:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Ni].CO>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:21][CH:22]=3)=[O:16])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(C#CCN2CCCC2)nc1
Agent: [Ni]
Solvent: CO
Product: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(CCCN2CCCC2)nc1
Reaction time: 1 h
Yield: 76.9 %

Procedure:
Raney nickel (0.3 g, 0.6 mmol, 10 mol %) was added to the solution of (6-(3-(pyrrolidin-1-yl)prop-1-ynyl)pyridin-3-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (2.2 g, 5.6 mmol) in 20 mL methanol at room temperature, and the reaction mixture was stirred for 1 h under hydrogen atmosphere. Filtered off the nickel and the filtrate was concentrated in vacuo to afford the desired product as a yellow solid (1.7 g, 77.3%).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:9][O:10][CH2:11][C:12]1[S:16][CH:15]=[N:14][C:13]=1[CH3:17]>>[CH3:9][O:10][CH2:11][C:12]1[S:16][C:15]([C:1]([C:4]2[CH:8]=[CH:7][S:6][CH:5]=2)([OH:3])[CH3:2])=[N:14][C:13]=1[CH3:17]
Reactant: COCc1scnc1C
Reactant: CC(=O)c1ccsc1
Product: COCc1sc(C(C)(O)c2ccsc2)nc1C

Procedure:
The title compound was prepared by following the general method of Example 36 but using 3-acetylthiophene and 5-methoxymethyl-4-methylthiazole.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)=[O:4].S(Cl)([Cl:18])=O>CN(C)C=O>[CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:18])=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)c1ccc(C(=O)Cl)cc1
Temperature: 50 °C

Procedure:
A mixture of 150.0 g (0.725 mol) of 4-(2,2-dimethyl-1-oxopropyl)-benzoic acid and 0.3 ml of dimethylformamide are added with stirring at 22° C. to 30° C. to 180 ml (2.47 mol) of thionyl chloride over a period of 60 minutes. The resulting solution is heated to an internal temperature of 85° to 90° C., and maintained at this temperature for 15 minutes. The solution is allowed to cool to 50° C. to remove as much thionyl chloride as possible by vacuum distillation (20-30 torr) at an internal temperature of 45° to 55° C. Distillation is discontinued when the internal temperature reaches 55° C and 95 ml of dry toluene are added. The distillation is continued under vacuum at an internal temperature of 45° to 55° C. and again discontinued when the internal temperature reaches 55° C. at 20-30 torr. After allowing the residue to cool to 25° C. and diluting it with 950 ml of dry toluene, the solution is set aside for use below.