Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=2[C:17]([F:20])([F:19])[F:18])=[CH:4][S:5][CH:6]=1.[OH-].[Na+]>CCO.O>[CH3:1][C:2]1[C:3]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[C:17]([F:20])([F:18])[F:19])=[CH:4][S:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2cscc2C)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cscc1-c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A solution of methyl 4-(4-methyl-3-thienyl)-3-(trifluoromethyl)benzoate (3 g; 9.99 mmol; 1 eq.) in EtOH (90 mL) at RT was treated with sodium hydroxide (5.99 mL; 5 M; 29.97 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated to give a brown solid which was taken up in water (300 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with HCl cc to pH 2 and extracted with EtOAc (250 mL). The organic layer was dried over MgSO4 and concentrated affording the title compound as a brown oil (2.60 g, 90%). 1H NMR (DMSO-d6, 300 MHz) δ 13.07 (br s, 1H), 8.34-8.24 (m, 2H), 7.57-7.54 (m, 1H), 7.47-7.46 (m, 1H), 7.34-7.33 (m, 1H), 1.98 (s, 3H). LC/MS (Method A): 284.9 (M−H)−. HPLC (Method A) Rt 4.53 min (Purity: 95.5%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:56][C:57]1[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][C:65]([O:67][CH3:68])=[O:66])=[CH:59][CH:58]=1>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:56][C:57]2[CH:58]=[CH:59][C:60]([CH2:63][CH2:64][C:65]([O:67][CH3:68])=[O:66])=[CH:61][CH:62]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)CCc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80.6 mg, 0.172 mmol) in dichloromethane (3 ml) were added DIPEA (89.0 mg, 0.685 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (106 mg, 0.437 mmol). The mixture was stirred for 20 mins under argon before methyl 3-(4-aminophenyl)propanoate (33.4 mg, 0.186 mmol) was added. After 2 hrs, the reaction mixture was diluted with dichloromethane, washed with sat. NaHCO3, water and brine. After drying over Na2SO4 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes to give chiral methyl 3-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)propanoate (104.2 mg, 96%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 628.19. found: 628.1.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]>[Pd].C(O)C>[CH2:1]([N:3]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: CCCCCCCN(CC)CCCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCN(CC)CCCCc1ccc(N)cc1

Procedure:
A solution of 2.03 g. (6.3mM) of N-ethyl-N-n-heptyl-4(4-nitrophenyl)butylamine in 100 ml of 2B ethanol containing 1 g of 5% palladium on carbon was stirred under hydrogen at 50 p.s.i. for sixteen hours at 25° C. The reaction mixture was filtered and the solvent was removed by evaporation under reduced pressure to give 1.49 g of N-ethyl-N-n-heptyl-4-(4-aminophenyl)butylamine as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([Cl:33])(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C(O)(=O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[N:19])=[CH:15][C:16]=2[Cl:33])[CH2:11][CH:10]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2Cc1ccccc1
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CC(=O)O
Product: N#Cc1cc(Cl)c2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a solution of compound 165A (121 mg, 0.3 mmol) in acetic acid (2 mL) at RT was added benzyltrimethylammonium tetrachloroiodate (125.7 mg, 0.3 mmol). The reaction mixture was stirred at RT for 30 min, and then concentrated under reduced pressure. The resultant residue was partitioned between saturated aqueous NaHCO3 solution and CH2Cl2. The separated aqueous layer was extracted with CH2Cl2 (15 mL×2). The combined CH2Cl2 extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified using preparative HPLC (YMC S5 ODS 20×100 mm) eluting with MeOH (50-80%) in H2O for 8 min, and then 80% MeOH in H2O for 7 min to give the title compound (108 mg, 82%) as a white solid. HPLC: 99% at 7.65 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 438 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19]>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:21]([O:20][CH2:18][CH3:19])=[O:22])[CH:24]=2)=[CH:3][CH:4]=1)([CH3:17])[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Product: CCOC(=O)c1cccc(-c2ccc(C(C)(C)C(=O)NCC(C)C)cc2)c1
Yield: 65 %

Procedure:
Prepared in a similar manner to Example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and 3-(ethoxycarbonyl)phenylboronic acid. Yield: 65%. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.4 (t, 3H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (t, 2H), 4.4 (t, 2H), 7.48 (d, 2H), 7.54 (d, 1H), 7.64 (d, 2H), 7.8 (d, 1H), 8.04 (d, 1H), 8.3 (t, 1H). MS (M+H, 368).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)=[O:5])C.[C:12]1([CH2:18][O:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(#N)C>C(Cl)Cl>[C:12]1([CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[O:25])=[CH:27][CH:28]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: O=C(Nc1nc(C(=O)O)cs1)c1ccc(OCc2ccccc2)cc1
Reaction time: 18 h
Yield: 70 %

Procedure:
2-Amino-4-thiazolecarboxylic acid ethyl ester (6.85 g, 39.8 mmol) was allowed to react with 4-phenylmethoxybenzoyl chloride (10.72 g, 43.8 mmol) according to the procedure in Example 1. The reaction was completed in 18 hours. After workup and flash chromatography on silica gel eluting with 1-7% acetonitrile in methylene chloride, the ethyl ester of 2-[[4-phenylmethoxybenzoyl]amino]-4-thiazolecarboxylic acid was obtained (70% yield) and was hydrolyzed to the corresponding acid with 1.0N NaOH as described in Example 1.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[C:9]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:9]12([O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=3[O:2]1)[CH2:13][CH2:12][CH2:11][CH2:10]2
Reactant: Oc1ccccc1O
Reactant: O=C1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)OC1(CCCC1)O2
Reaction time: 18 h

Procedure:
Catechol (11 g) and cyclopentanone (9 ml) were heated under reflux in toluene (150 ml) with p-toluenesulfonic acid (0.18 g) with a water trap. After 18 hours, the mixture was concentrated and purified by chromatography (silica gel, heptane/ethyl acetate 4:1). This resulted in the product with the molecular weight of 176.22 (C11H12O2); MS (ESI): 177 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.COCCOCCOC>[Cu]I.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Ic1ccncc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: COCCOCCOC
Product: c1ccc(COc2ccc(Oc3ccncc3)cc2)cc1
Yield: 86.5 %

Procedure:
The same procedure from Example 143, step 1 was followed using p-benzyloxyphenol (500 mg, 2.5 mmol), Cs2CO3 (1.58 g, 4.85 mmol), 4-iodo pyridine (780 mg, 3.805 mmol), anhydrous dioxane (15 ml), diglyme (34 mg, 0.24 mmol), CuI (17 mg, 0.089 mmol) to give the title compound (600 mg, 57%).
Reaction SMILES: [CH2:1]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][CH2:14]CS([O-])(=O)=O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[I-:22].[Na+]>O1CCCC1>[I:22][CH2:14][CH2:13][C:12]1[CH:20]=[CH:21][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1
Reactant: CCCCCCCCc1ccc(CCCS(=O)(=O)[O-])cc1
Reactant: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(CCI)cc1
Reaction time: 0.17 h

Procedure:
4-Octylphenethylmethane sulfonate (70 g) and dry tetrahydrofuran (500 mL) are charged into a 1 liter single-neck round bottom flask, equipped with a calcium chloride guard tube and shielded with light protecting black cover. The mixture is stirred for 10 minutes, then sodium iodide (133 g) is added and the mixture is stirred overnight at room temperature. The solvent is evaporated under vacuum and the residue is dissolved in water (300 mL) and extracted with ethyl acetate (2×250 mL). Ethyl acetate extracts are combined, washed with aqueous sodium thiosulphate, dried with sodium sulphate, and concentrated under vacuum to give the title compound. Yield: 70 g.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]O)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:29]1[CH:33]=[N:32][CH:31]=[N:30]1>>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:29]4[CH:33]=[N:32][CH:31]=[N:30]4)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: c1nc[nH]n1
Product: C(=C/c1nc(COc2ccc(CCCCCCn3cncn3)cc2)co1)\c1ccccc1
Yield: 65 %

Procedure:
In substantially the same manner as in Working Example 1, 6-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]hexanol was allowed to react with 1,2,4-triazole to give 1-[6-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]hexyl]-1,2,4-triazole. The yield was 65%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 90-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(F)ccc1Cl)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(F)ccc1Cl)C2

Procedure:
A solution of 7-(2-chloro-5-fluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one in ethanol (10 ml) was combined with aminoguanidine hydrochloride (0.041 g), concentrated hydrochloric acid (0.078 ml) and water (0.078 ml), and the mixture was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, and the residue was combined with water and the aqueous layer was washed with ethyl acetate. The aqueous layer was made alkaline with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 1N hydrochloric acid (1 ml) and concentrated. The resultant crystal was recrystallized from ethanol-ethyl acetate to obtain 7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound G) (0.05 g) as a colorless crystal.
Reaction SMILES: O=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.CN.[BH3-][C:23]#[N:24].[Na+]>CCO>[CH3:23][NH:24][CH:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CCO
Product: CNC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 1.5 h
Yield: 46.2 %

Procedure:
To a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (2.15 g, 8.05 mmol) in EtOH (20 mL) was added 33% methanamine in EtOH (3.7 g, 40.3 mmol), and the mixture was stirred at r.t for 1.5 h. Then NaBH3CN (1.5 g, 24.2 mmol) was added to the mixture. After that the resulting mixture was stirred at r.t overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as brown oil (1.05 g, 46.2%).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]=[C:16]([O:26][CH3:27])[N:15]=2)[CH2:10][CH:9]1[C:28](=[O:40])[NH:29][C:30]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32][CH:31]1[CH:33]=[CH2:34])=[O:7])(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:38]([O:37][C:35]([C:30]1([NH:29][C:28]([CH:9]2[CH2:10][CH:11]([O:13][C:14]3[CH:19]=[C:18]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:17]=[C:16]([O:26][CH3:27])[N:15]=3)[CH2:12][CH:8]2[C:6]([OH:7])=[O:5])=[O:40])[CH2:32][CH:31]1[CH:33]=[CH2:34])=[O:36])[CH3:39]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc(OC)n2)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc(OC)n2)CC1C(=O)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 133.8 %

Procedure:
To a solution of compound 13a (1.0 g, 1.81 mmol) in DCM (30 ml) was added triethylsilane (0.53 g, 4.53 mmol) and TFA (20 ml) and the mixture was stirred at room temperature for 1 hour. The solution was evaporated under reduced pressure and co-evaporated two times with toluene which gave the title compound (1.2 g), (M+H)+496.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:9][CH:8]([CH2:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH2:7]1)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)O>C(Cl)Cl>[CH2:14]([CH:11]([CH2:12][CH3:13])[CH2:10][CH:8]1[CH2:9][CH:6]([CH:4]=[O:5])[CH2:7]1)[CH3:15]
Reactant: CCC(CC)CC1CC(C(=O)N(C)OC)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: ClCCl
Product: CCC(CC)CC1CC(C=O)C1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-methoxy-N-methyl-3-(2-ethylbutyl)cyclobutanecarboxamide (13.2 g) in methylene chloride (35 mL) was added dropwise diisobutylaluminum hydride (1.0 M in methylene chloride)(76.0 mL) at −78° C. After stirring at −78° C. for 2.5 hr, 1 M sulfuric acid was added dropwise to the mixture. The mixture was stirred at ice temperature for 20 min. The organic layer was removed, and the aqueous layer was extracted with methylene chloride (15 mL×2). The combined organic layer was washed with 0.5 N sulfuric acid (50 mL×2), water (50 mL) and brine, then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate comprising the title compound was used in the next step.
Reaction SMILES: Br[C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:35]=[CH:34][C:10]([CH2:11][N:12]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])[C:13]3[C:14]([CH3:24])=[C:15]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Br-].[CH2:39]([O:41][C:42](=[O:47])[CH2:43][CH2:44][CH2:45][Zn+])[CH3:40]>>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[CH2:25][N:12]([CH2:11][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:36]=[CH:37][C:2]([CH2:45][CH2:44][CH2:43][C:42]([O:41][CH2:39][CH3:40])=[O:47])=[CH:3][CH:4]=2)=[CH:35][CH:34]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][S:20]([CH3:23])(=[O:21])=[O:22])[C:14]=1[CH3:24]
Reactant: CCOC(=O)CCC[Zn+]
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2ccc(Br)cc2)cc1)Cc1ccc(F)cc1F
Agent: [Br-]
Product: CCOC(=O)CCCc1ccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc(NS(C)(=O)=O)c3C)cc2)cc1

Procedure:
The product from Example 48B and 4-ethoxy-4-oxobutylzinc bromide (purchased from Aldrich) were processed as described in Example 49 to provide the title compound. MS (ESI+) m/z 623 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([O:10][CH3:11])[C:7](=[O:9])[CH:8]=1.[C:12](Cl)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([O:10][CH3:11])[C:7](=[O:9])[CH:8]=1)(=[O:14])[CH3:13]
Reactant: COc1c[nH]c(CO)cc1=O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: COc1c[nH]c(COC(C)=O)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 8.3 g of 2-(hydroxymethyl)-5-methoxypyridin-4(1H)-one in 30 mL of pyridine, 5.7 mL of acetyl chloride was dropped under cooling with ice. After warming to room temperature, the mixture was stirred at 55 to 60° C. for 2 hours 30 minutes. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=95:1 to 80:20 to obtain 6.7 g of (5-methoxy-4-oxo-1,4-dihydropyridin-2-yl)methyl acetate as a brown foam.
Reaction SMILES: Cl.[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1)[C:9](=[O:12])[CH2:10]Cl)([CH3:4])[CH3:3].[NH2:36][CH:37]([C:41]([OH:43])=[O:42])[CH2:38][CH2:39][SH:40]>>[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([N:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[CH2:23][CH2:24]2)=[O:18])=[CH:34][CH:35]=1)[C:9](=[O:12])[CH2:10][S:40][CH2:39][CH2:38][CH:37]([C:41]([OH:43])=[O:42])[NH2:36])([CH3:3])[CH3:4]
Reactant: NC(CCS)C(=O)O
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: Cl
Product: CC(C)OCCN(C(=O)CSCCC(N)C(=O)O)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
Analogously to Example 1, 1-{4-[N-(2-isopropoxyethyl)-N-chloroacetylamino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine hydrochloride is reacted with DL-homocysteine (=2-amino-4-mercaptobutyric acid), yielding (±)-1-{4-[N-(2-isopropoxyethyl)-N-(3carboxy-3-amino-propylmercapto-acetyl)-amino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine.
Reaction SMILES: F[C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[F:19][C:20]([F:31])([F:30])C1C=CC=CC=1B(O)O>>[F:19][C:20]([F:31])([F:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: O=C(O)c1csc(-c2ccccc2C(F)(F)F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (2-(trifluoromethyl)phenyl)boronic acid gave the title compound.
Reaction SMILES: Cl.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na+]>O.CC(C)=O>[OH2:9].[OH2:9].[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:12])=[CH:3][CH:4]=1)([OH:11])(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
VD 1827 hydrochloride (6.3 g, 10 mmole) was dissolved in a mixture of water (40 ml) and acetone (10 ml). A solution of sodium 4-toluenesulfonate (1.94 g, 10 mmole in water (10 ml) was added dropwise with stirring. After stirring for 1 hour at room temperature and 2 hours at 5° C., the crystalline precipitate was collected, washed with water (2×10 ml) and dried in vacuo to yield the title compound as colourless crystals with melting point 141°-148° C. dec.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]4[CH2:23][CH2:22]4)[CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:28])[N:11]3[C:24]([O:26][CH3:27])=[O:25])[CH2:2]1.[CH3:29][C:30]([CH3:32])=O>>[CH:21]1([N:19]2[CH:20]=[C:16]([C:15]3[C:6]([O:5][CH:3]4[CH2:2][N:1]([CH:30]([CH3:32])[CH3:29])[CH2:4]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:24]([O:26][CH3:27])=[O:25])[C@@H:10]([CH3:28])[CH2:9][CH2:8]4)[CH:17]=[N:18]2)[CH2:22][CH2:23]1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CNC3)c2CC[C@@H]1C
Reactant: CC(C)=O
Product: COC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CN(C(C)C)C3)c2CC[C@@H]1C

Procedure:
(S)-Methyl 6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(1-isopropylazetidin-3-yloxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate was synthesized from (S)-methyl 5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate and acetone according to the procedure outlined above for Example 40. 1H NMR (400 MHz, CD3OD) δ ppm 0.85-0.95 (m, 6H), 1.05-1.15 (m, 7H), 1.45-1.55 (m, 1H), 2.15-2.52 (m, 3H), 2.80-2.90 (m, 1H), 3.01-3.11 (m, 2H), 3.40-3.50 (m, 2H), 3.67-3.71 (m, 1H), 3.78 (s, 3H), 4.15-4.25 (m, 1H), 4.51-4.62 (m, 1H), 7.20-7.35 (m, 2H), 7.76 (s, 1H), 7.97 (s, 1H). MS (ESI, pos. ion) m/z 425 [M+H]+.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][NH2+:8][CH2:9][CH2:10]Cl)=[CH:5][CH:4]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[S:24])=[C:18]([CH2:25][CH3:26])[CH:17]=1)#[N:15]>>[C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]2[N:8]([CH2:7][C:6]3[CH:12]=[CH:13][C:3]([Cl:2])=[CH:4][CH:5]=3)[CH2:9][CH2:10][S:24]2)=[C:18]([CH2:25][CH3:26])[CH:17]=1)#[N:15]
Reactant: ClCC[NH2+]Cc1ccc(Cl)cc1
Reactant: CCc1cc(C#N)ccc1N=C=S
Agent: [Cl-]
Product: CCc1cc(C#N)ccc1N=C1SCCN1Cc1ccc(Cl)cc1

Procedure:
2-Hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give N-(4-chlorobenzyl)-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-(4-chlorobenzyl)-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2-(4-cyano-2-ethylphenylimino)-3-(4-chlorobenzyl)-1,3-thiazolidine.