Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>CN(C)C1C=CN=CC=1.CC(C)=O>[C:19]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:22])[CH:20]=[CH2:21]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: C=CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=CC(=O)OCc1ccccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
153.2 g (1.0 mole) of 2-nitrobenzyl alcohol, 95.7 g (0.94 mole) of triethylamine and 12.9 g (0.11 mole) of 4-(dimethylamino)pyridine were dissolved in 600 ml of acetone and to the resulting solution, there was dropwise added a solution of 95.0 g (1.05 mole) of acryloyl chloride in 150 ml of acetone at 0° C. over one hour with stirring. Then the stirring was continued for additional one hour. After filtering off the resulting salt, the filtrate was concentrated and purified by column chromatography (packed material: silica gel: eluent: hexane/ethyl acetate=10/1). Thus, 141 g of an oily liquid was recovered.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH:5]=[C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8](=O)[O:7]1.O.[NH2:21][NH2:22]>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8](=[O:7])[NH:22][N:21]=1
Reactant: Nc1cc(C=C2OC(=O)C3=C2CCCC3)ccc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(Cc2n[nH]c(=O)c3c2CCCC3)ccc1F
Temperature: 0 °C

Procedure:
To a solution of EXAMPLE 2B (1.42 g) in ethanol (10 mL) was added hydrazine monohydrate (0.27 mL). The mixture stirred at reflux for 1 hour, cooled to 0° C., and filtered. The solid was washed with water and dried. 1H NMR (CD3OD) δ 1.63-1.75 (m, 4H), 2.36-2.45 (m, 2H), 2.46-2.53 (m, 2H), 3.84 (s, 2H), 6.42-6.49 (m, 1H), 6.64 (dd, J=8.6, 2.2 Hz, 1H), 6.86 (dd, J=11.2, 8.1 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1)[C:7]([NH2:9])=[O:8].C=O.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O.N>[CH3:1][N:2]([CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1)[C:7]([NH2:9])=[O:8])[CH3:28]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CNCc1cc(C(N)=O)ccc1Oc1ccc(SC)c(C(F)(F)F)c1
Agent: C=O
Agent: N
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CSc1ccc(Oc2ccc(C(N)=O)cc2CN(C)C)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 79 %

Procedure:
The amide from example 177 (105 mg, 0.28 mmol) was suspended in DCM (3 mL) and treated with formaldehyde (37% aqueous, 35 μL, 0.425 mmol). The mixture was stirred for 30 minutes (dissolution had occurred by this stage) and then treated with sodium tri(acetoxy)borohydride (120 mg, 0.567 mmol). The reaction was stirred overnight and then diluted with water (5 mL), basified with 880 ammonia (1 mL) and extracted with DCM (3×10 mL). The combined organic extracts were washed with brine (5 mL), dried (MgSO4) and evaporated to a white solid. Purification by flash chromatography [SiO2; DCM, MeOH, 880 NH3 (95:5:0.5)] afforded the title amide as a white powder (85 mg, 78%); Free base: δH (CDCI3, 400 MHz) 2.24 (6 H, s), 2.46 (3 H, s), 3.50 (2 H, s), 5.47-6.15 (2 H, brm), 6.85 (1 H, d), 7.03 (1 H, d), 7.23 (1 H, s), 7.35 (1 H, d), 7.71 (1 H, d), 7.90 (1 H, s); MS m/z (TS+) 385 (MH+)
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]OCC2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[O:50]1[CH2:55][CH2:54]CCN1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:54][CH2:55][O:50]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: C1CCONC1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCCCO2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and [1,2]oxazinane and isolated as light-yellow gum (13.6 mg, 75%). MS(m/c): 387.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[Cl:13][C:14]1[C:22]([Cl:23])=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([O:24][CH3:25])[CH:15]=1>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([Cl:23])[C:14]([Cl:13])=[CH:15][C:16]=2[O:24][CH3:25])[CH2:7]1
Reactant: COc1cc(Cl)c(Cl)cc1C(=O)O
Reactant: CN1CCc2c(N)cccc2C1
Product: COc1cc(Cl)c(Cl)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4,5-dichloro-2-methoxybenzoic acid
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[CH:3][CH:2]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: COC(=O)CCNC(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1ccc(-c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCNC(=O)[C@@H](CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of (R)-tert-butyl 3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoate (40 mg, 0.094 mmol) in DCM (0.5 mL), TFA (0.15 mL) is added at room temperature. The mixture is allowed to stir for 2 hours, and then concentrated under reduced pressure to give (R)-3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoic acid (33.5 mg, 96%). HPLC retention time=1.20 minutes (condition A); MS (m+1)=370.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.21-2.29 (m, 1 H) 2.38-2.45 (m, 1 H) 2.62-2.66 (m, 1 H) 2.75-3.00 (m, 4 H) 3.29-3.37 (m, 1 H) 3.45-3.53 (m, 4 H) 6.12 (br s, 1 H) 7.23 (d, J=8 Hz, 2 H) 7.32-7.35 (m, 1 H) 7.41-7.45 (m, 2 H) 7.53 (d, J=8.1 Hz, 2 H) 7.56-7.59 (m, 2 H).
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].O(Br)[Br:16].[P+5]>C(#N)C>[Br:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Reactant: BrOBr
Agent: [P+5]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Nitro-5-(trifluoromethyl)pyridin-2-ol (31.00 g, 149 mmol) was dissolved in acetonitrile (250 ml) to give a dark brown solution. Phosphorus(V) oxybromide (85 g, 298 mmol) was added and the mixture was heated at reflux for 4 hours and then stirred at RT overnight. The reaction mixture was quenched by pouring into vigorously stirring water (600 ml) containing sodium hydrogencarbonate (110 g). The dark brown mixture was extracted with DCM (3×200 ml) and the organic phase was washed with water (200 ml) and brine (100 ml), dried (MgSO4) and concentrated in vacuo to afford the title product as a brown oil. 1H-NMR: [400 MHz, CDCl3, δH 8.87 (1H, d, J=1.4 Hz, ArH), 8.39 (1H, d, J=1.9 Hz, ArH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9](O)=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ClC(OCC(C)C)=O.C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[CH2:9][OH:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CO)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a chilled (0° C.) solution of 2-(2-fluoro-biphenyl-4-yl)propionic acid in THF was added isobutyl chloroformate followed by dropwise addition of TEA. The resulting white slurry was allowed to stir for 1 hour and then diluted with THF (50 mL) and filtered. The filter cake was washed with additional THF (50 mL) and the filtrate was concentrated to approximately 50 mL using a rotary evaporator. The concentrated filtrate was then stirred at −20° C. and a solution of NaBH4 in H2O (20 mL) was dropwise added over a period of 15 minutes. The resulting suspension was stirred for 2 hours at 0° C., diluted with water (200 mL), and extracted with ethyl acetate (2×100 mL). The ethyl acetate layers were combined and washed with 1.0 N HCl solution (100 mL) followed by a 5% bicarbonate solution wash (100 mL). The ethyl acetate solution was then concentrated to an oily residue of 2-(2-fluoro-biphenyl-4-yl)propanol (4.47 g, 95% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:24][NH:23][CH2:22][CH2:21][N:20]3[C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:35](=O)[CH3:36].ClC1C=C(NC(N2CCN(C[C@@H]3OCCN(CCC4C=NC=CC=4)C3)CC2)=O)C=CC=1Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH:19]3[CH2:24][N:23]([CH2:35][CH3:36])[CH2:22][CH2:21][N:20]3[C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])[CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC=O
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(CC2CNCCN2C(=O)OCc2ccccc2)CC1
Agent: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@H]2CN(CCc3cccnc3)CCO2)CC1
Product: CCN1CCN(C(=O)OCc2ccccc2)C(CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Yield: 18 %

Procedure:
Benzyl 2-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)methyl]piperazine-1-carboxylate and acetaldehyde were used in a similar manner to N-(3,4-dichlorophenyl)-4-{[(25)-4-(2-pyridin-3-ylethyl)morpholin-2-yl]methyl}piperazine-1-carboxamide, except that after purification of the residue on a Redisep® silica column, eluting with ethyl acetate/MeOH (30:70), the solid, after precipitation from CH2Cl2 with isohexane, was further purified on an SCX column, eluting sequentially with ethyl acetate, MeOH and 1% ammonia/MeOH to give the title product (20 mg, 18%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([CH2:14][CH:15]=[CH2:16])[C:5]=1[OH:17].B1C2CCCC1CCC2.[OH-:28].[Na+].OO>C1COCC1>[C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:18])=[C:5]([OH:17])[C:6]=1[CH2:14][CH2:15][CH2:16][OH:28])(=[O:13])[CH3:12]
Reactant: C=CCc1c(NC(C)=O)ccc(C(=O)OC)c1O
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(C)=O)c(CCCO)c1O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 4-acetylamino-3-allyl-2-hydroxy-benzoic acid methyl ester (2.49 g, 10 mmol, prepared as described in Takuji Kakigami et. al., Chem. Pharm. Bull, 46 (1), 42-52, (1998)) in THF (10 mL) at 0° C. under Argon was added a 0.5 M solution of 9-BBN in THF (80 mL, 40 mmol). The reaction mixture was stirred at 0° C. for 40 min, then at rt for 2 h. The reaction mixture was then cooled to 0° C., and 1 N aqueous NaOH (25 mL) was added dropwise over 5 min, followed by 30% aqueous H2O2 (20 mL) over 5 min. After addition, the reaction mixture was stirred at rt for 2 h, then extracted with EtOAc (3×60 mL). The combined EtOAc extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure to give a crude product, which was chromatographed (silica gel) eluting with 30% to 80% EtOAc/hexane to afford the title compound (1.82 g) as a foam.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(O)[CH:10]([OH:22])[CH2:9]1)=O)(C)(C)C.C(N(S(F)(F)[F:29])CC)C.CO>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2([F:29])[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[OH:22])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(O)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: OC1CNCCC1(F)c1ccc(Cl)cc1
Temperature: -78 °C
Yield: 24 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-3,4-dihydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.213 g, 3.34 mmol) in methylene chloride (30 mL) at −78° C. was added diethylaminosulfur trifluoride (DAST, 3 mL). The resulting solution was stirred at −78° C. 4 h. Methanol (20 mL) was added to quench excess DAST and the mixture was allowed to remain at −78° C. 5 min before warming to rt. The mixture was concentrated and purified by silica gel chromatography (80% hexanes/20% ethyl acetate gradient) to afford 4-(4-chloro-phenyl)-4-fluoro-piperidin-3-ol (262 mg, 24%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[N+:21]([O-])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:21][C:20]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Yield: 109.7 %

Procedure:
A mixture of ethyl 3-(2,4-difluorophenylthio)-4-nitrobenzoate (1.1 g), iron powder (1.1 g) and ammonium chloride (0.11 g) in ethanol (10 ml) and water (5 ml) was stirred and refluxed for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried and evaporated to give crystals of ethyl 4-amino-3-(2,4-difluorophenylthio)benzoate (1.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:9][Si:10]([CH3:15])([O:13][CH3:14])[O:11][CH3:12].N.[Cl-]>>[C:2]1([NH:1][CH2:9][Si:10]([O:13][CH3:14])([O:11][CH3:12])[CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CO[Si](C)(CCl)OC
Agent: N
Agent: [Cl-]
Product: CO[Si](C)(CNc1ccccc1)OC
Temperature: 30 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
In a 500 ml four-neck flask with reflux condenser, precision glass stirrer, thermometer and gas inlet tube, 298 g of dry aniline were heated to 130° C. and admixed with 124 g of (chloromethyl)methyl-dimethoxysilane with stirring within 60 min. When the addition had ended, ammonia was passed through the mixture with uniform temperature with stirring until no further reaction was observed (approx. 60 min). Thereafter, excess aniline was removed under reduced pressure, and the suspension was cooled to 30° C. and then admixed with 150 ml of isohexane. Subsequently, the white precipitate formed was filtered through a suction filter and washed with 2×80 ml of isohexane. Filtrate and wash solutions were combined and freed from the solvent under reduced pressure. The subsequent fractional distillation gave 160 g (95% yield) of (N-phenylaminomethyl)dimethoxy(methyl)silane with a chloride content of <20 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[Se:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[C:23]([CH3:25])([CH3:24])[O:22][C:21]([CH3:27])([CH3:26])[C:20](=[O:28])[CH:19]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[Se:9][C:10]([CH2:13][O:14][C:18]3[C:23]([CH3:24])([CH3:25])[O:22][C:21]([CH3:27])([CH3:26])[C:20](=[O:28])[CH:19]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: OCc1cnc(-c2ccc(Cl)cc2)[se]1
Reactant: CC1(C)OC(C)(C)C(Cl)=CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OC(C)(C)C(OCc2cnc(-c3ccc(Cl)cc3)[se]2)=CC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
To a solution of [2-(4-chlorophenyl)selenazol-5-yl]methanol (300 mg, 1.1 mmol) in dry tetrahydrofuran (5 ml) under an atmosphere of nitrogen is added, in one portion, the sodium hydride (44 mg, 1.1 mmol). The reaction mixture is stirred for 5 minutes at room temperature and 5-chloro-2,2,6,6-tetramethyl-6H-pyran-3-one (208 mg, 1.1 mmol) is added in one portion. The reaction mixture is stirred at room temperature overnight. Silica gel is added to the crude reaction mixture, and the solvent is evaporated under reduced pressure. The residue is purified by flash chromatography on silica gel to give 5-[2-(4-chlorophenyl)selenazol-5-ylmethoxy]-2,2,6,6-tetramethyl-6H-pyran-3-one (261 mg).
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][NH2:32])[CH:26]=1.ClC1C=C(N2C(C3C=C(OC(F)(F)F)C=C(F)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:31]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)[N:32]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: NNc1cccnc1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1

Procedure:
1.10 g (2.40 mmol) of the compound from example 3A is reacted with 525 mg (3.61 mmol) 3-pyridylhydrazine hydrochloride in a manner analogous to the synthesis of the compound from example 8A. Following hydrolysis, 557 mg (54% of theoretical yield) of the title compound is produced.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[NH:5][C:6](=[O:15])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.[H-].[Na+].[CH3:18]I>CN(C)C=O>[CH3:1][C:2]1[S:3][C:4]2[N:5]([CH3:18])[C:6](=[O:15])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1
Reactant: CI
Reactant: Cc1nc2c([nH]c(=O)c3ccccc32)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c3ccccc3c(=O)n(C)c2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 6.48 g. (0.030 mole) of 2-methyl-thiazolo[5,4-c]isoquinoline-5(4H)-one in 64 ml of dimethylformamide was added with 1.45 g of a 50% (by weight) suspension of sodium hydride in mineral oil (0.030 mole of sodium hydride). The resulting mixture was kept at 60° C. for 2 hours and, after cooling to room temperature, was added with 2.37 ml (0.038 mole) of methyl iodide and heated for 1 hour at 60° C. After evaporating the solvent, the residue was taken up with water and the obtained solid was collected, washed with water, dried and finally crystallized from methylene chloride/methanol. Yield 4.5 (65%) of the title compound. M.p. 174-176. The compound is the N-isomer.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:6]([CH3:22])=[C:7]2[C:11](=[C:12]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]=1[CH3:14])[NH:10][CH2:9][CH2:8]2)[CH3:3].[H-].[Na+].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].CCOC(C)=O>CN(C=O)C>[CH2:26]([N:10]1[C:11]2[C:7](=[C:6]([CH3:22])[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])=[C:13]([CH3:14])[C:12]=2[NH:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:8][CH2:9]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: Cc1c(CN(C)C)c(C)c(NC(=O)C(C)(C)C)c2c1CCN2
Reactant: CCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCN1CCc2c(C)c(CN(C)C)c(C)c(NC(=O)C(C)(C)C)c21
Reaction time: 0.5 h
Yield: 120.4 %

Procedure:
N-(5-Dimethylaminomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (700 mg) was dissolved in DMF (7 ml) and NaH (P=60%, 160 mg) was added under a nitrogen atmosphere at 5° C. After stirring at the same temperature for 30 min, 1-iodooctane (240 mg) was added, which was followed by stirring at 30° C. for 3 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=10/1−3/1) to give 500 mg of the title compound.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)c(OC)c1
Yield: 55 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-heptyl chloroformate. Yield: 55% of theory, C36H45N7O6 (671.8) Rf value: 0.54 (silica gel; dichloromethane/ethanol=9:1) ##EQU144##
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH:14]1[C:22]2[C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][C:18]=2[C:17]([C:27]2[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=3)[CH:30]=[CH:31][CH:32]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C>[CH:14]1[C:22]2[C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][C:18]=2[C:17]([C:27]2[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:2]4[CH:7]=[C:6]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[N:5]=[CH:4][N:3]=4)[CH:34]=3)[CH:30]=[CH:31][CH:32]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(-c2cccc(-c3cccc4c3sc3ccccc34)c2)c1
Reactant: Clc1cc(-c2ccccc2)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2cc(-c3cccc(-c4cccc(-c5cccc6c5sc5ccccc56)c4)c3)ncn2)cc1
Temperature: 80 °C
Yield: 71 %

Procedure:
Then, 1.0 g of 4-chloro-6-phenylpyrimidine obtained in Step 1, 2.0 g of 3′-(dibenzothiophen-4-yl)-3-biphenylboronic acid, 5.3 mL of a 2M aqueous solution of potassium carbonate, 24 mL of toluene, and 3.0 mL of ethanol were put into a 100-mL three-neck flask equipped with a reflux pipe. Degasification by stirring under a reduced pressure was performed and the air in the flask was replaced with nitrogen. To this mixture, 61 mg of tetrakis(triphenylphosphine)palladium(0) (abbreviation: Pd(PPh3)4) was added and the mixture was heated at 80° C. for 7 hours to cause a reaction. An organic layer was extracted from the obtained mixture with the use of toluene and was washed with water and a saturated aqueous solution of sodium chloride. Anhydrous magnesium sulfate was added and gravity filtration was performed. After the solvent in this solution was distilled off, the obtained residue was dissolved in hot toluene and subjected to hot filtration through a filter aid in which Celite, alumina, Celite, Florisil, and Celite were stacked in this order. The solvent was distilled off and the obtained solid was recrystallized with toluene, so that 1.9 g of a white solid was obtained in a yield of 71%. Synthesis Scheme (D-2) of Step 2 is shown below.