Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([NH:18][CH2:19][CH2:20]O)[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O>CC1C=CC=CC=1>[ClH:24].[Cl:24][CH2:20][CH2:19][NH:18][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1
Reactant: OCCNC(c1ccccc1)c1cccc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cl
Product: FC(F)(F)c1cccc(C(NCCCl)c2ccccc2)c1
Temperature: 10 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a stirred and cooled (5°-10° C) mixture of 60 parts of 2-[{phenyl[3-(trifluoromethyl)phenyl]methyl}amino]-ethanol and 540 parts of methylbenzene are added dropwise 40 parts of sulfinyl chloride. Upon completion, stirring is continued first till room temperature is reached and further overnight at reflux temperature. The reaction mixture is concentrated to one third its volume. After cooling to 10° C, the solid product is filtered off, washed with 2,2'-oxybispropane and dried in vacuo at 75° C, yielding 28.5 parts (40%) of N-(2-chloroethyl)-α-phenyl-3-(trifluoromethyl)benzenemethanamine hydrochloride; mp. 187° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[O:18][C:17](=[O:19])[C:16]([C:20](=[O:23])[CH2:21][CH3:22])=[C:15]([OH:24])[CH:14]=1)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>CC(O)=O.C1COCC1.O>[OH:24][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[O:18][C:17](=[O:19])[C:16]=1[C:20](=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)c1c(O)cc(CCCCO[Si](C)(C)C(C)(C)C)oc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(=O)c1c(O)cc(CCCCO)oc1=O

Procedure:
6-(4-((t-Butyldimethylsilyl)oxy)butyl)-4-hydroxy-3-propionyl-2H-pyran-2-one (XIV; 5 g; 14.1 mmol) in 150 ml AcOH/THF/water (3/1/1, v/v/v) was stirred at 28° C. for 18 h. The reaction mixture was neutralized with saturated NaHCO3, extracted with 3×150 ml EtOAc, dried with Na2SO4, and evaporated to an oil. The product was purified via silica chromatography (40% EtOAc in hexanes).
Reaction SMILES: [NH2:1][C:2](=[O:43])[CH2:3][C:4]1[CH:42]=[CH:41][CH:40]=[CH:39][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][C:20]=2[F:38])[N:9]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>C1COCC1>[F:38][C:20]1[CH:21]=[C:22]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:24][C:19]=1[NH:18][C:10]1[N:9]=[C:8]([CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[CH2:3][C:2]([NH2:1])=[O:43])[C:13]([C:14]([F:16])([F:15])[F:17])=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)c(F)c2)CC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2F)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.1 %

Procedure:
To a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluorophenyl)piperidine-1-carboxylate (I61) (0.049 g, 0.081 mmol) in THF (3 mL) was added TFA (0.20 mL, 2.6 mmol). The resulting mixture was then stirred at room temperature for 20 hours then 40° C. for 24 hours. The volatiles were removed by evaporation under reduced and DCM (2 mL) and TFA (1.00 mL, 13.1 mmol) were added. After stirring at 30° C. for 18 hours the mixture was concentrated under reduced pressure and the residue azeotroped twice with toluene (10 mL) to give the title compound (I62) (0.037 g, 91%). LCMS Method C: rt 4.84 min; m/z 502.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].Br[CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: BrCCc1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc3c(c2)OCCO3)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.3 g--see Preparation 8), 6-(2-bromoethyl)-1,4-benzodioxan (0.26 g--see Preparation 21), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 3 hours. On cooling to room temperature, water (40 ml) was added and the mixture was extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.21 g.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].Cl.[CH2:18]([O:25][C:26](=[O:31])[C@@H:27]([OH:30])[CH2:28][NH2:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH2:18]([O:25][C:26](=[O:31])[C@@H:27]([OH:30])[CH2:28][NH:29][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: NC[C@H](O)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)SCC(Cc1ccccc1)C(=O)NC[C@H](O)C(=O)OCc1ccccc1
Reaction time: 20 h

Procedure:
Add 2(R,S)-acetylthiomethyl-3-phenylpropionic acid (0.59 g) to (S)-isoserine benzyl ester, hydrochloride (0.578 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (0.53 g), 1-hydroxybenzotriazole (HOBT) (0.37 g) and N-methylmorpholine (0.80 ml) in dimethylformamide (DMF) (10 ml), and stir the resulting mixture for 20 hours. Concentrate the reaction mixture in vacuo and partition the residue between dichloromethane/water. Concentrate the dried (MgSO4) dichloromethane solution in vacuo. Chromatograph the resulting residue on a column of silica gel (1 L) using chloroform:methanol 19.5:1 as eluant to give the title compound, a colorless oil, [α]D26 =+12.3° (MeOH).
Reaction SMILES: [Cl:1][CH2:2][C@H:3]([OH:7])[CH2:4][CH2:5][OH:6].ClC[C@H](O)CC(OC)=O.C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:1][CH2:2][C@H:3]([OH:7])[CH2:4][CH2:5][O:6][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: OCC[C@@H](O)CCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: COC(=O)C[C@@H](O)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@@H](O)CCl)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
A solution of 5 g (40 mmole) of (3R)-4-chloro-1,3-butanediol in 30 ml of methylene chloride, said (3R)-4-chloro-1,3-butanediol being obtainable in a similar manner as in Example 1 starting from methyl (3R)-4-chloro-3-hydroxybutyrate, was cooled to -20° C. on a dry ice-acetone bath, and 8.13 g (80 mmole) of triethylamine was added dropwise thereto over 30 minutes. A solution of 7.66 g (40.2 mmole) of p-toluenesulfonyl chloride in 100 ml of methylene chloride was added dropwise thereto over 50 minutes. After returning to room temperature, the mixture was stirred for 20 hours. The reaction mixture was poured into 200 ml of ice-water for liquid separation. The organic layer was washed successively with 100 ml of 1N hydrochloric acid, 100 ml ×2 of a saturated sodium hydrogencarbonate aqueous solution and 100 ml of a saturated sodium chloride aqueous solution and then freed of the solvent by distillation to obtain 7.8 g of a concentrate. The concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=2:1 by volume) to obtain 6.1 g (yield: 54%) of the titled compound. 1H-NMR (CDCl3) δ ppm: 1.78-2.00 (m, 2H), 2.46 (s, 3H), 3.45-3.65 (dd, 2H), 3.95 (m, 1H), 4.20 (m, 2H), 7.40 (d, 2H), 7.80 (d, 2H)
Reaction SMILES: [C:1]1([CH:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]3[CH:20]=[C:21]([O:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[CH:23][C:10]=3[NH:9][C:8]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[CH2:32](I)[CH3:33]>>[C:1]1([CH:7]2[N:13]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:11]3[CH:20]=[C:21]([O:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[CH:23][C:10]=3[N:9]([CH2:32][CH3:33])[C:8]2=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(c1ccccc1)C(=O)N2
Reactant: CCI
Solvent: CI
Product: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(c1ccccc1)C(=O)N2CC
Yield: 65 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 3,5-diphenyl-8-ethoxy-7-methoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIba), and methyl iodide by ethyl iodide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 65%. M: 178–180° C. 1H-NMR (CDCl3, 300 MHz): d 1.06–1.11 (m, 3H, NCH2CH3), 1.55–1.59 (m, 3H, OCH2CH3), 3.77 (s, 3H, OCH3), 4.19–4.26 (m, 2H, OCH2), 4.01 (AB system, ? d=0.70, JAB=13.7, 2H, NCH2), 6.77 (s, 1H Ar), 6.92 (s, 1H Ar), 7.35–7.74 (m, 10H Ar).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15](O)=[O:16])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:35][NH2:36]>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15](=[O:16])[NH:36][CH3:35])=[C:11]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[C:10]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nn(Cc3ccccc3)c(=O)c(C(=O)O)c2-c2ccc(OC)cc2)cc1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nn(Cc2ccccc2)c1=O
Yield: 90.9 %

Procedure:
Using 2-benzyl-5,6-bis(4-methoxyphenyl)-4-carboxy-2H-pyridazin-3-one and methylamine hydrochloride as starting materials, the procedures of Example 22 were repeated likewise, whereby the title compound was obtained in a yield of 90.9%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][C:38]1[C:39]([N:48]2[CH2:53][CH2:52][N:51]([CH2:54][CH2:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:50][CH2:49]2)=[CH:40][C:41]([O:45][CH2:46][CH3:47])=[C:42]([NH2:44])[CH:43]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(O)C(F)(F)F.CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:42]3[CH:43]=[C:38]([CH3:37])[C:39]([N:48]4[CH2:53][CH2:52][N:51]([CH2:54][CH2:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:50][CH2:49]4)=[CH:40][C:41]=3[O:45][CH2:46][CH3:47])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: CO
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OCC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 80 °C
Yield: 54.4 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (2.9 g, 5.7 mmol) and (5-methyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amine (2.0 g, 5.7 mmol) in trifluoroethanol (100 mL) was added p-toluene sulfonic acid (2.2 g, 11 mmol), and the vial was sealed and heated to 80° C. overnight. The reaction was then cooled to rt and excess 0.5 M NaOMe in MeOH was added. The solution was transferred to a roundbottom flask and silica was added. The solvent was removed on a rotovap and the product purified on a 120 g ISCO column. Desired fractions were combined and rotovaped down. The resulting foam was dissolved in DCM and ether was added to provide the title compound 2.5 g, 3.1 mmol, 54% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 9.33 (d, J=6.7 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J=5.4 Hz, 1H), 8.02 (s, 1H), 7.73-7.70 (m, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.53 (s, 1H), 7.43-7.31 (m, 2H), 7.23 (d, J=8.6 Hz, 1H), 7.16 (t, J=8.0 Hz, 2H), 6.92 (t, J=6.6 Hz, 1H), 6.71 (s, 1H), 6.56 (d, J=5.1 Hz, 1H), 4.23 (q, J=7.2 Hz, 2H), 4.04 (q, J=7.0 Hz, 2H), 3.33-3.25 (m, 2H), 3.03 (s, 3H), 2.84-2.78 (m, 4H), 2.74 (t, J=6.6 Hz, 2H), 2.63-2.46 (m, 4H), 2.11 (s, 3H), 1.40 (t, J=6.8 Hz, 3H), 1.23 (t, J=7.0 Hz, 3H). MS (ESI) m/z=811 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:19]1[C:30]2[C:29]3[CH2:28][CH2:27][CH2:26][C:25]=3[S:24][C:23]=2[N:22]=[CH:21][N:20]=1>O1CCCC1>[C:30]12[C:19]([O:1][CH:2]3[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]3)=[N:20][CH:21]=[N:22][C:23]=1[S:24][C:25]1[CH2:26][CH2:27][CH2:28][C:29]2=1
Reactant: Clc1ncnc2sc3c(c12)CCC3
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (194 mg, 0.90 mmol, 1.40 equiv) in anhydrous tetrahydrofuran (5 mL) was added sodium hydride (60% dispersion in mineral oil, 77 mg, 1.92 mmol, 3.00 equiv) at 0° C. under nitrogen. After stirred at room temperature for 1 h, 12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraene (200 mg, 0.95 mmol, 1.00 equiv) was added and the resulting solution was stirred overnight at ambient temperature for additional 5 h. The reaction was then quenched with water and extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to give the resulted tert-butyl N-(4-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yloxy]cyclohexyl)carbamate (308 mg, 83%) as a yellow solid. MS (ES, m/z): 390 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[N:8]=[CH:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25]([BH3-])#N.[Na+]>C(O)=O.O1CCCC1>[CH3:25][N:8]1[CH2:9][C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:2](=[O:1])[N:7]12
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2ncc3ccsc3c12
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=CO
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CN2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.34 g of methyl 7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]pyridazine-10-carboxylate in 10 ml of formic acid are treated dropwise under argon at 25°-30° with 0.31 g of sodium cyanoborohydride in 2 ml of tetrahydrofuran. The mixture is left to stir at room temperature for 24 hours. The solution is poured into 50 ml of ice-water. The yellowish crystals are removed by filtration and washed with water. After drying in vacuo, recrystallization is carried out from ethyl acetate. There is obtained methyl 4,5-dihydro-5-methyl-7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]-pyridazine-10-carboxylate of m.p. 180°-181°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:22])([CH3:21])[CH2:15]OS(C)(=O)=O)[CH2:11][O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:25]#[N:26].[Na+]>CS(C)=O.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:22])([CH3:21])[CH2:15][C:25]#[N:26])[CH2:11][O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(COS(C)(=O)=O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(CC#N)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 135 °C

Procedure:
A mixture of 2.04 g of 4(S)-(3-methanesulfonyloxy-2,2-dimethyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and 2.17 g of sodium cyanide in 12 ml of dimethylsulfoxide is heated to 135° C. for 15 hours. The mixture is cooled to room temperature and diluted with water and ethyl acetate. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried over sodium sulphate, filtered and concentrated. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60 F). Rf=0.32 (1:1 EtOAc-heptane); Rt=4.82 (gradient I).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4].Cl.[C:22]([O:26][C:27](=[O:36])[NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>CN(C)C=O.ClCCl>[C:22]([O:26][C:27](=[O:36])[NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:2][C:3](=[O:4])[NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
To a stirred suspension of 65 mg of 2-chloro-N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-acetamide (XV) (0.23 mmol) in N,N-dimethylformamide (2 mL), 175 mg of (6-amino-hexyl)-carbamic acid tert-butyl ester hydrochloride (0.69 mmol) and 0.097 mL of triethylamine (0.69 mmol) were added. The reaction mixture was stirred at room temperature overnight, diluted with dichloromethane, and the resulting solution was washed first with water then with brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by preparative HPLC on Waters X Terra RP 18 (19×250 mm, 5 m) column. Mobile phase A was 0.05% ammonia/acetonitrile:95/5 and mobile phase B was acetonitrile/water:95/5. Gradient from 10 to 75% B in 15 min. Fractions containing the desired compound were dried, affording 50 mg (47% yield) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])[CH:6]=[CH:7][CH:8]=1.[OH:32][CH:33]([CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])[C:34]([NH:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][C:44](O)=[O:45])=[O:35].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][C:44]([CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][NH:36][C:34](=[O:35])[CH:33]([OH:32])[CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])=[O:45])=[CH:18][CH:17]=1
Reactant: O=C(O)COCCOCCNC(=O)C(O)C(O)C(O)C(O)CO
Reactant: NCc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(COCCOCCNC(=O)C(O)C(O)C(O)C(O)CO)NCc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1

Procedure:
21 is prepared similarly to 18 starting from 100 mg of 4-(3-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (1/1), 122 mg of {2-[2-(2,3,4,5,6-pentahydroxyhexanoylamino)ethoxy]ethoxy}acetic acid (20), 93 μl of diisopropylcarbodiimide and 65 mg of hydroxybenzotriazole in 2 ml of dimethylformamide. This gives 21: C37H45F2N3O11 (745.78) MS (ESI) 746 (M+H)
Reaction SMILES: CSC(=S)NN=CC1N=C(C2C=CC=CC=2)NC=1C.C[S:21][C:22](=S)[NH:23][N:24]=[CH:25][C:26]1[N:27]=[C:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:29][C:30]=1[CH2:31][CH3:32]>>[CH2:31]([C:30]1[N:29]=[C:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]2[C:26]=1[CH:25]=[N:24][NH:23][C:22]2=[S:21])[CH3:32]
Reactant: CCc1[nH]c(-c2ccccc2)nc1C=NNC(=S)SC
Agent: CSC(=S)NN=Cc1nc(-c2ccccc2)[nH]c1C
Product: CCc1nc(-c2ccccc2)n2c(=S)[nH]ncc12

Procedure:
The general procedure of Example 62 is repeated but replacing the 3-[(5-methyl-2-phenyl-4-imidazolyl)methylene]-dithiocarbazic acid methyl ester employed in that example with 3-[(5-ethyl-2-phenyl-4-imidazolyl)methylene]-dithiocarbazic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][S:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:11]=[CH:10][C:9]=2[NH:25][C:26]([C:28]2[N:29](COCC[Si](C)(C)C)[CH:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[O:27])=[CH:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCO>[CH3:1][C:2]1([CH3:43])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][S:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:17])=[O:18])[CH:11]=[CH:10][C:9]=2[NH:25][C:26]([C:28]2[NH:29][CH:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[O:27])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(CCS(=O)(=O)N3CCOCC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC=C(c2cc(CCS(=O)(=O)N3CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 60.3 mg of crude 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid {2-(4,4-dimethyl-cyclohex-1-enyl)-4-[2-(morpholine-4-sulfonyl)-ethyl]-phenyl}-amide (as prepared in the previous step) in CH2Cl2 (5 mL) was treated with EtOH (2 drops) and TFA (1 mL) and stirred at RT for 1.5 h. Solvents were evaporated in vacuo, and the residue was purified by RP-HPLC(C18) with 20-100% CH3CN in 0.1% TFA/H2O over 30 min to afford 11.2 mg (20% over three steps) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.16 (d, 1H, J=8.4 Hz), 7.91 (s, 1H), 7.21 (dd, 1H, J=8.4, 2.4 Hz), 5.76-5.71 (m, 1H), 3.71-3.65 (m, 4H), 3.50-3.46 (m, 1H), 3.26-3.20 (m, 4H), 3.14-3.11 (m, 1H), 3.10-3.04 (m, 2H), 3.35-2.27 (m, 2H), 2.10-2.05 (m, 2H), 1.59 (t, 2H, J=6.4 Hz), 1.08 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C25H31N5O4S, 498.2 (M+H). found 498.0.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32]>>[OH:32][C@@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[NH:25][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N[C@@H]2CCCC[C@H]2O)cn1
Yield: 91 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using (1R,2R)-2-amino-cyclohexanol hydrochloride (1:1) instead of 2-aminoethyl isopropylether, to the title compound (240 mg, 91%) which was obtained as a white solid. MS: m/e=406.2 [M−H]−.