Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18](I)[CH:17]=[C:16]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH3:15])[CH:11]=1.C([Li])CCC.C[Si](C)(C)[N:29]1[CH2:33][CH2:32][CH2:31][C:30]1=O>CCOCC>[Cl:1][C:2]1[CH:19]=[C:18]([C:30]2[CH2:31][CH2:32][CH2:33][N:29]=2)[CH:17]=[C:16]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH3:15])[CH:11]=1
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: Cc1cc(CCCCCOc2c(Cl)cc(I)cc2Cl)on1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc(CCCCCOc2c(Cl)cc(C3=NCCC3)cc2Cl)on1
Yield: 41.6 %

Procedure:
To a solution of 5.0 g 5-[5-(2,6-dichloro-4-iodophenoxy)pentyl]-3-methylisoxazole (Example 12a) in 75 ml dry ether cooled to -78° C. under nitrogen was added 1.4 ml n-butyllithium (9.5 m). A solution of 1.8 g 1-trimethylsilylpyrrolidin-2-one [cf. Feringa et al., Tetrahedron Letters, 507 (1986)] in ether was then added dropwise. The reaction mixture was allowed slowly to come to room temperature, and was washed with water and dried over potassium carbonate. The product was isolated and chromatographed (3:1 hexane:ethyl acetate) and recrystallized from isopropyl acetate/hexane to give 1.8 g 5-{5-[2,6-dichloro-4-(4,5-dihydro-3H-pyrrol-2-yl)phenoxy]pentyl}-3-methylisoxazole, m.p. 57-59° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cu][C:16]#[N:17]>>[C:16]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:17]
Reactant: N#C[Cu]
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Product: N#Cc1ccc(-c2ccc(O)cc2)cc1

Procedure:
4'-Bromo-4-hydroxybiphenyl is reacted with copper (I) cyanide to obtain 4'-cyano-4-hydroxybiphenyl (this substance is known), which is then reacted with a β-alkyloxyethylbromide in the presence of an alkaline material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:15][O:16][C:17](=[O:23])[C@H:18]([CH2:20][CH2:21][CH3:22])[NH2:19]>>[CH3:15][O:16][C:17](=[O:23])[C@@H:18]([NH:19][C:11](=[O:13])[CH2:10][NH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCC[C@H](N)C(=O)OC
Reactant: O=C(O)CNc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CCC[C@H](NC(=O)CNc1ccc(Cl)c(Cl)c1)C(=O)OC

Procedure:
Following General Procedure D and using N-(3,4-dichlorophenyl)glycine (from Example I above) and L-norvaline methyl ester hydrochloride (Sennchem), the title compound was prepared. The reaction was monitored by tlc (Rf=0.32 in 50% ethyl acetate/hexanes) and purification was by silica gel chromatography using ethyl acetate/hexanes as the eluent.
Reaction SMILES: [CH2:1]([C@:8]1([C:24]2[NH:28][C:27]3[CH:29]=[CH:30][C:31](Br)=[CH:32][C:26]=3[N:25]=2)[O:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[N:42]1[CH2:43][N:44](B(O)O)[CH:45]=[CH:46][CH:47]=1>C(O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:1]([C@:8]1([C:24]2[NH:28][C:27]3[CH:29]=[CH:30][C:31]([C:46]4[CH:47]=[N:42][CH:43]=[N:44][CH:45]=4)=[CH:32][C:26]=3[N:25]=2)[O:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)N1C=CC=NC1
Reactant: C[C@H](c1ccc(F)cc1)N1C(=O)O[C@](Cc2ccccc2)(c2nc3cc(Br)ccc3[nH]2)C1=O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@H](c1ccc(F)cc1)N1C(=O)O[C@](Cc2ccccc2)(c2nc3cc(-c4cncnc4)ccc3[nH]2)C1=O
Temperature: 120 °C

Procedure:
To a mixture of (5R)-5-benzyl-5-(5-bromo-1H-benzimidazol-2-yl)-3-[(1R)-1-(4-fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione (25 mg), Pd(OAc)2 (1 mg), dppf (5.5 mg), K3PO4 (31 mg), 3-pyrimidinyl boronic acid (12 mg) in 0.5 mL of ethanol was heated at 120° C. in microwave for 5 min. The reaction mixture was diluted with EtOAc, filtered, concentrated, and then purified via Gilson RP-HPLC (30-100% MeCN/water w/0.1% TFA) to give the title compound. LC/MS 508.1 (M+1). IC50 value=A rating
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]1=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+](=[CH2:26])=[N-]>ClCCl.C(O)C.CCOCC>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH3:26])=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]1=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c(=O)c(C(=O)OCC)c(O)c2ccccc21
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCn1c(=O)c(C(=O)OCC)c(OC)c2ccccc21

Procedure:
A solution of 1.6 g of 1-hexyl-3-ethoxycarbonyl-4-hydroxy-2(1H)-quinolinone in dichloromethane (20 ml) and ethanol (2 ml) was treated with excess diazomethane in ether for 10 mins and is then evaporated. The crude methylation product upon chromatography on silica gel yielded 1-hexyl-3-ethoxycarbonyl-4-methoxy-2(1H)-quinolinone (1.0 g). This product (1 .0 g) in dry toluene (10 ml) was cooled to -78° C. and a 1M solution of diisobutyl aluminum hydride (4.3 ml) was added dropwise in 10min. After 2.5 hours stirring at-78° C. the reaction mixture was worked up by stirring with aqueous ammonium chloride/1N hydrochloric acid followed by extraction with methylene chloride. The crude reduction product was chromatographed on silica gel and crystallized from ethyl acetate/hexane to give 1-hexyl-3-formyl-4-methoxy-2(1H)-quinolinone as a crystalline solid. That the expected product was obtained was confirmed by the spectral data: MS (FAB): m/e 288 (M.+ +1); NMR (CDCl3): δ4.12 (s, 3H, OCH3), 10.5 (s, 1H, CHO).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([CH:39]=O)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:39][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cccc5ccccc45)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and naphthalene-1 carbaldehyde. MS (ESI) m/z 519.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C@H:8]3[CH2:9][CH2:10][C@H:11]([N:14]4[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[NH:16][C:15]4=[O:23])[CH2:12][CH2:13]3)[CH2:5][CH2:6]2)=[O:39])[CH:34]=1
Reactant: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](NC2CCNCC2)CC1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1)N1CCC(N[C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Reaction time: 12 h

Procedure:
To a stirred solution of 0.050 g of 1,3-dihydro-1-{trans-4-[4-piperidinylamino]-1-cyclohexyl}-2H-benzimidazol-2-one and 0.023 mL of triethylamine in 1.5mL of dichloromethane was added 0.024 g of nicotinoyl chloride hydrochloride. After 12 h, 20 mL of saturated sodium carbonate was added, the organic layer was separated, and the aqueous layer extracted with two addtional 20 mL portions of chloroform. The combined organic extracts dried over MgSO4 and concentrated under reduced pressure. Chromatography over silica gel eluting with 10% methanol/10% conc. NH4OH in chloroform gave 0.024 g of 1,3-dihydro-1-{trans -4-[1-(3-pyridinecarbonyl)-4-piperidinylamino]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: 1H NMR (400 MHz, CDCl3) 9.04 (s, 1H), 8.68 (dd, 2H), 7.77 (m, 1H), 7.38 (m, 1H), 7.26 (m, 1H), 7.06 (m, 3H), 4.67 (br s, 1H), 3.75 (br s, 1H), 3.18 (br s, 2H), 2.99 (br s, 1H), 2.87 (br s, 1H), 2.55 (q, 2H), 2.13-1.9 (m, 4 H), 1.72-1.3 (m, 7H). The dihydrochloride salt was precipitated from chloroform/ethyl acetate: Analysis calculated for C24H29N5O2.2HCl.0.90 CHCl3.0.25 CH3CO2CH2CH3C: 50.02, H: 5.95, N: 11.26 found C: 51.28, H: 5.49, N: 11.53.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][CH2:11][CH:12]([OH:22])[C:13](=[O:21])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N)C1C=CC=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:23])[NH:10][CH2:11][CH:12]([C:13](=[O:21])[NH:14][CH2:15][C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:24]=1)[OH:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCC(O)C(=O)Nc1ccccc1)OCc1ccccc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: NCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(O)C(=O)NCc1ccccc1)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
The (2-hydroxy-2-phenylcarbamoyl-ethyl)-carbamic acid benzyl ester (250 mg, 1.045 mmol) was dissolved into 2 mL of dry DMF. To this was added PyBOP (652.3 mg, 1.254 mmol), HOBT (169.4 mg, 1.254 mmol), benzylamine (0.228 mL, 2.090 mmol) and DIPEA (0.728 mL, 4.18 mmol). The reaction stirred for 1.5 h. LC-MS analysis of the crude indicated complete consumption of the S.M. and the presence of the product. 40 mL of EtOAc was added and the organic mixture washed with 2×20 mL NH4Cl, 2×20 mL of H2O and 1×20 mL of brine. Dried organic phase with MgSO4, filtered and concentrated to a yellow film. Dissolved in CH2Cl2, applied to a SiO2 Column and purified (10-30% EtOAc/hexanes) to give a quantitative yield of (2-benzylcarbamoyl-2-hydroxy-ethyl)-carbamic acid benzyl ester.
Reaction SMILES: [CH:1]1([N:7]2[CH:11]=[C:10](B3OC(C)(C)C(C)(C)O3)[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:28]1[CH:29]=[C:30]([NH:35][C:36]2[N:41]=[C:40]([CH:42]([F:44])[F:43])[CH:39]=[CH:38][N:37]=2)[CH:31]=[C:32]([CH3:34])[CH:33]=1>O1CCOCC1>[CH:1]1([N:7]2[CH:11]=[C:10]([C:28]3[CH:29]=[C:30]([NH:35][C:36]4[N:41]=[C:40]([CH:42]([F:43])[F:44])[CH:39]=[CH:38][N:37]=4)[CH:31]=[C:32]([CH3:34])[CH:33]=3)[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CC1(C)OB(c2cnn(C3C=CCCC3)c2)OC1(C)C
Reactant: Cc1cc(Br)cc(Nc2nccc(C(F)F)n2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(C3C=CCCC3)c2)c1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
1-(Cyclohex-2-en-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (436 mg, 1.59 mmol), sodium carbonate (337 mg, 3.18 mmol), and 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (130 mg, 0.159 mmol) were added to a solution of N-(3-bromo-5-methylphenyl)-4-(difluoromethyl)pyrimidin-2-amine (500 mg, 1.59 mmol) in dioxane (7.5 mL). The mixture was purged with nitrogen for 5 minutes and stirred at 110° C. for 18 h. The mixture was allowed to cool to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/hexane) to afford N-(3-(1-(cyclohex-2-en-1-yl)-1H-pyrazol-4-yl)-5-methylphenyl)-4-(difluoromethyl)pyrimidin-2-amine ESI calc'd. for C21H22F2N5 [M+H]+ 382. found 382.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[N:11]([N:13]=[CH:14][C:15]=3[C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=3)[CH:12]=2)[CH:4]=[N:3]1.[OH-].[K+].Cl>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[N:11]([N:13]=[CH:14][C:15]=3[C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH:12]=2)[CH:4]=[N:3]1
Reactant: COC(=O)c1ccc(-c2cnn3cc(-c4cnn(C)c4)cnc23)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(-c2cnc3c(-c4ccc(C(=O)O)cc4)cnn3c2)cn1
Temperature: 60 °C

Procedure:
A solution of methyl 4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]benzoate (0.5 g, 1.5 mmol) in methanol (7.0 mL) was treated with 1M potassium hydroxide in methanol (6.0 mmol, 6.0 mL) and the resulting solution was heated to 60° C. for 48 hours. The reaction was cooled to room temperature and treated with conc. HCl and evaporated to dryness. The solids were washed with water, filtered and dried in vacuo to give 4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]benzoic acid as a yellow solid: LC/MS [M+H]=320.0
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5].ClC(Cl)(Cl)C(=N)O[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.FC(F)(F)S(O)(=O)=O>C1CCCCC1>[CH2:23]([O:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Product: CCCCCCCCCCC[C@H](CC(=O)OC)OCc1ccccc1
Yield: 112.8 %

Procedure:
A suspension of 206.7 g of methyl (R)-3-hydroxytetradecanoate in 1000 ml of cyclohexane was treated under nitrogen and while stirring with 214.2 g of benzyl trichloroacetimidate and dissolved at 20°. 10 ml of trifluoromethanesulphonic acid were added dropwise while cooling in an ice/water bath in such a manner that the temperature remains between 20°-23°. The resulting suspension was stirred at 25°-30°. The precipitate was filtered off, the filter cake was washed with cyclohexane, the filtrates were extracted with sat. NaHCO3 solution, water and sat. NaCl solution. The organic phase was dried over magnesium sulphate, filtered, the filter cake was washed with cyclohexane and the filtrates were evaporated. 314.5 g of methyl (R)-3-(benzyloxy)-tetradecanoate were obtained.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].CC(C)=O.[SH2]=N.[C:11]1([NH:17][C:18](C2C=CC=CC=2C(O)=O)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[C:11]1([NH:17][C:18]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Reactant: CC(C)N
Agent: N=[SH2]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)NC(=O)Nc1ccccc1
Yield: 81.4 %

Procedure:
A solution of 0.75 g i-propylamine with 5 ml aceton was added dropwise to a suspension of 1,5 g phenylcarbamoyl-benzoic acid sulfimide with 10 ml acetone, under stirring. The reaction mixture was stirred for 30 minutes at ambient temperature, then diluted with 50 ml water and cooled. The 0.75 g crystalline 1-phenyl-3-i-propylurea was isolated by filtration (melting point: 158°-160° C.).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([O:20][CH2:21][CH:22]([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>>[F:23][CH:22]([F:24])[CH2:21][O:20][C:16]1[N:15]=[CH:14][C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:25]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:26])[C:7]=3[CH2:8]2)=[CH:18][C:17]=1[CH3:19]
Reactant: O=COc1ccccc1
Reactant: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)F
Product: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC(F)F
Yield: 87 %

Procedure:
The title compound is prepared in 87% yield (300 mg, brown solid) from 4-chloro-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (280 mg, 0.79 mmol, Intermediate-4) and phenyl formate (190 mg, 1.5 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C)C=O.S(Cl)(Cl)=O.[CH2:23]([NH2:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:23]([NH:41][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCNC(=O)c1ccc(OC(C)=O)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
Under a nitrogen atmosphere, 4-acetoxybenzoic acid (100.0 g) and N,N-dimethylformamide (3 ml) were suspended in chloroform (500 ml) and thereto was added dropwise thionyl chloride (79.2 g) for a period of about 30 minutes. After completion of the addition, the suspension was refluxed with heating for 1 hour to prepare the corresponding acid chloride. The reaction mixture was cooled and thereto were added n-octadecylamine (149.6 g) and triethylamine (67.4 g), followed by refluxing with heating for 3 hours. The reaction mixture was cooled to room temperature to precipitate a white crystal. This crystal was filtered off under reduced pressure and washed with distilled water and then recrystallized from isopropanol to obtain N-n-octadecyl-4-acetoxybenzamide (206.0 g). Yield 86%; m.p. 106° C. This was suspended in 1,4-dioxane (1000 ml) and thereto was added aqueous KOH solution 50%) (160.7 g). The reaction mixture was kept at 40°-45° C. and the reaction was allowed to proceed for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and thereto was added dilute hydrochloric acid to precipitate a white crystal, which was filtered off under reduced pressure. This crystal was washed with distilled water and recrystallized from chloroform to obtain the desired product (137.6 g). Yield 74 %; m.p. 105° C.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[CH2:28]([NH2:33])[CH2:29][CH:30]([CH3:32])[CH3:31]>>[CH3:31][CH:30]([CH3:32])[CH2:29][CH2:28][NH:33][C:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)=[O:27]
Reactant: CC(C)CCN
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Product: CC(C)CCNC(=O)c1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and iso-amylamine. The crude product was used without further purification (95%, oil). HPLC-MS: m/z=341.2 (M+1); Rt: 3.99 min.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=1[Cl:24].[NH+]1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=3[Cl:24])[S:3][C:4]=2[CH:10]=1
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: Clc1ccc2nc(Br)sc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1ccc(Nc2nc3ccc(Cl)cc3s2)c(Cl)c1
Yield: 24.1 %

Procedure:
In xylene (10 ml), 2-bromo-6-chlorobenzothiazole (760 mg, 3.06 mmol), methyl 4-amino-3-chlorophenylacetate (610 mg, 3.06 mmol), and pyridinium•p-toluenesulfonate (PPTS) (230 mg, 0.92 mmol) were heated under reflux for 1 hour. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (6:1, v/v) eluate fractions, methyl (4-(6-chloro-2-benzothiazolyl)amino-3-chlorophenyl)acetate (271 mg, 24%) was obtained as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])C.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:30][CH:31]1[CH2:33][CH2:32]1>CN(C)C=O>[CH:33]1([CH2:32][N:3]([CH3:1])[CH2:4][CH:5]([N:7]2[C:20]3[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=3[S:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH3:6])[CH2:31][CH2:30]1
Reactant: CCNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CN(C)CC1CC1)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 150 °C

Procedure:
A mixture of 10-(1-ethylamino-2-propyl)-2-phenothiazinecarbonitrile, L series (3.1 g), sodium carbonate (1.19 g) and bromomethylcyclopropane (2.7 g) in dimethylformamide (32 cc) is heated to 150° C. for 9 hours. After cooling, the reaction mixture is poured into distilled water (300 cc) and extracted with ethyl acetate (3×150 cc). The combined organic phases are washed with distilled water (4×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The brown oily residue (3.38 g) is purified by chromatography on a column (height: 30 cm; diameter: 2.5 cm) of silica gel (0.06-0.20 mm), eluting with a mixture (80:20 by volume) (2 liters) of methylene chloride and ethyl acetate and collecting 60-cc fractions. Fractions 4 to 12 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-{1-[N-(Cyclopropylmethyl)-methylamino]-2-propyl}-2-phenothiazinecarbonitrile, L series (1.83 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C@@H:19]([NH2:22])[C@H:18]([OH:23])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C@@H:19]([NH:22][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:18]([OH:23])[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
Add benzaldehyde (0.24 mol, 26.3 g) to a solution of racemic trans-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.24 mol, 53.7 g), and acetic acid (92 mL) in ethanol (400 mL) and stir the reaction mixture at room temperature for 30 min. Add sodium cyanoborohydride (0.49 mol, 31.2 g) and stir the reaction mixture for 3 h. Quench the reaction mixture with sodium bicarbonate solution and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Dissolve the residue in a minimum amount of dichloromethane and add 0.1 N aqueous hydrochloric acid to maintain the pH between 4-5. Discard the organic layer. Wash the acidic aqueous layer three times with dichloromethane and discard the organic layer. Adjust the pH of the aqueous layer between 10-12 and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (35.7 g, 46%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.35-1.40 (m, 2H), 1.45 (s, 9H), 2.05 (br s 1H), 2.43 (t, 1H), 2.57 (t, 1H), 2.69 (br s, 1H), 3.27 (br s, 1H), 3.70 (d, 1H), 3.94 (d, 1H), 4.15 (br s, 1H), 4.26 (d, 1H), 7.23-7.29 (m, 1H), 7.30-7.32 (m, 2H), 7.33-7.36 (m, 2H).