Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].[C:11](OCC)(=O)CC(C)=O>>[CH3:11][CH:5]([C:1](=[O:4])[CH2:2][CH3:3])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(=O)CC
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C(C)C(=O)CC
Yield: 45 %

Procedure:
The target product was prepared following the procedure as described in step 1) of Preparation Example 3, except for that ethyl propionylacetate was used to replace for ethyl acetoacetate. Yield 45%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([CH3:9])=[CH:5][N:4]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH3:9][C:6]1[CH:5]=[N:4][C:3]([CH:2]=[O:1])=[N:8][CH:7]=1
Reactant: Cc1cnc(CO)nc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1cnc(C=O)nc1

Procedure:
5-Methylpyrimidine-2-carboxaldehyde was prepared from 2-hydroxymethyl-5-methylpyrimidine by oxidation with excess manganese dioxide in boiling chloroform. The product was obtained as colourless crystals and was characterized by proton nuclear magnetic resonance spectroscopy. Proton nuclear magnetic resonance spectrum (CDCl3 ; δ in ppm): 2.44 (3H,s); 8.80 (2H,s); 10.06 (1H,s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CSc1ccc(O)cc1

Procedure:
After 25.42 g of p-hydroxythiophenol was dissolved in 100 ml of methylene chloride, 20.2 g of triethylamine was dropwise added to the solution under ice cooling. Then, 39.2 g of tert-butyl bromoacetate was added to the mixture followed by reacting at room temperature for an hour. After completion of the reaction, the reaction mixture was washed with 3 times with 1N-HCl and once with saturated sodium chloride aqueous solution. After the organic phase was dried over magnesium sulfate, methylene chloride was distilled off to give tert-butyl (4-hydroxyphenylthio)acetate (quantitative).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20].[OH-].[Na+].CO>O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:12]([N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:21]
Reactant: COC(=O)CCCCCCCN(C(=O)c1ccc(Cl)cc1Cl)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(N(CCCCCCCC(=O)O)C(=O)c2ccc(Cl)cc2Cl)cc1

Procedure:
As described in example 1(b), the reaction is carried out with 35 g (77 mmol), of 8-[2.4-dichloro-N-(4-methoxyphenyl)-benzamido]-caprylic acid methyl ester, 4 g (0.1 mol) of sodium hydroxide, 150 cc. of methanol and 5 cc. of water. Reaction time: 24 hours, reaction temperature: 25° C. The crude product is further purified chromatographically on silicic acid gel using a mixture of n-hexane and ethyl acetate (2:1) as eluant.
Reaction SMILES: [CH2:1]([N:8]([CH2:12]Cl)[C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][NH:15][C:16]([NH:18][CH3:19])=[S:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:14][N:15]=[C:16]1[N:18]([CH3:19])[C:9](=[O:10])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][S:17]1
Reactant: CNC(=S)NC
Reactant: O=C(Cl)N(CCl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN=C1SCN(Cc2ccccc2)C(=O)N1C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A mixture of 4.4 g (0.02 mole) of N-benzyl-N-chloromethylcarbamoyl chloride and 2.0 g (0.02 mole) of 1,3-dimethylthiourea was dissolved in 50 ml of ethyl alcohol and heated under reflux with stirring for 2 hours. After addition of 20 ml of a saturated aqueous potassium carbonate solution, the mixture was extracted with 100 ml of benzene. The benzene layer was washed with water, dried, and freed from the benzene by distillation under reduced pressure to obtain 4.0 g of crude crystals which were recrystallized from ether. Yield 3.2 g (63%); m.p. 93°-95° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2.C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:37][CH2:38][C:39](Cl)=[O:40].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:37][CH2:38][C:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2)=[O:40]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cc(F)ccc3N)[nH]c2c1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cc(F)ccc3NC(=O)CCl)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a suspension of methyl 2-(2-amino-5-fluorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate (2.44 g, 6.68 mmol), sodium acetate (602 mg, 7.3 mmol) and acetic acid (0.45 ml, 7.86 mmol) in tetrahydrofuran (20 ml) was added dropwise chloroacetyl chloride (0.60 ml, 7.53 mmol), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium carbonate solution and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and a mixed solvent of hexane:ethyl acetate (4:1) was added to the residue. The precipitated solid was collected by filtration to give methyl 2-[2-(2-chloroacetylamino)-5-fluorophenyl]-3-cyclohexyl-1H-indole-6-carboxylate (2.5 g, yield 84.7%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([OH:10])=[C:5]([Cl:11])[CH:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[Cl:9][C:7]1[CH:8]=[C:3]([CH:4]=[C:5]([Cl:11])[C:6]=1[OH:10])[NH:2][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Agent: Cl
Solvent: O
Product: CC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Into a 500 ml round bottom flask (fitted with a magnetic stirrer), water (200 ml) was mixed with 4-amino-2,6-dichlorophenol hydrochloride (20 g) until the solid was completely dissolved. The resulting solution was warmed to 70° C., and to it was added acetic anhydride (11 g) and the resulting solution was stirred for 1 hour. Upon cooling, crystals of 3',5'-dichloro-4'-hydroxyacetanilide were formed (19.6 g, 95% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:5]=[CH:6][C:7](Cl)=[O:8].[C@H:14]1([O:25][C@@H:26]2[C@@H:31]([CH2:32][OH:33])[O:30][C@@H:29]([N:34]=[N+]=[N-])[C@H:28]([OH:37])[C@H:27]2[OH:38])[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]([OH:18])[C@H:15]1[OH:16]>CN(C)C=O.N1C=CC=CC=1>[C@H:14]1([O:25][C@@H:26]2[C@@H:31]([CH2:32][OH:33])[O:30][C@@H:29]([NH:34][C:7](=[O:8])[CH:6]=[CH:5][C:4]3[CH:10]=[CH:11][C:12]([OH:13])=[C:2]([OH:1])[CH:3]=3)[C@H:28]([OH:37])[C@H:27]2[OH:38])[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]([OH:18])[C@H:15]1[OH:16]
Reactant: O=C(Cl)C=Cc1ccc(O)c(O)c1
Reactant: [N-]=[N+]=N[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(C=Cc1ccc(O)c(O)c1)N[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Reaction time: 1.5 h

Procedure:
A method for producing compounds of the formula: ##STR8## wherein A is selected from the group consisting of alkali metal cations and alkaline earth metal cations which comprises reacting 3,4-dihydroxycinnamic acid with acetic anhydride in pyridine for 18-30 hours, in organic solvents, giving 3,4-dihydroxycinnamic acid, diacetate, then converting to 3,4-dihydroxycinnamic acid chloride by treating with thionyl chloride in dimethylformamide at -20° to -18° C. for 30-90 minutes; reacting 4-O-α-D-glucopyranosyl-β-D-glucopyranosyl bromide, heptaacetate with sodium azide in dimethylsulfoxide at 55°-65° C. for 10-30 minutes, extracting in organic solvents, giving 4-O-α-D-glucopyranosyl-β-D-glucopyranosylazide, heptaacetate, then catalytically reducing, giving 4-Oα-D-glucopyranosyl-β-D-glucopyranosylamine, heptaacetate (heptaester); reacting a solution of the 3,4-dihydroxycinnamic acid chloride in dimethylformamide at -20° to -15° C. with a solution of the 4-O-α-D-glucopyranosyl-β-D-glucopyranosylamine, heptaacetate in pyridine at -15° to -5° C. for 20-40 minutes, then at -5° to 20° C. for 1-2 hours followed by extracting with organic solvents, giving N-(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)-3,4-dihydroxycinnamamide, nonaacetate (nonaester), then converting to N-(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)-3,4-dihydroxycinnamamide by reacting in a mixture of methanol, triethylamine and water, under an inert atmosphere for 20-30 hours followed by heating at reflux for 2-6 hours and extracting in organic solvents, reacting this derivative with triethylamine sulfur trioxide in N,N-dimethylacetamide under an inert atmosphere at 50°-70° C. for 15-20 hours, and then treating with an alkali metal or alkaline earth metal acetate in water.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24](O)=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[CH2:35]([N:37](CC)[CH2:38]C)C.CNC>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24](=[O:25])[N:37]([CH3:38])[CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)c1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-carboxynitrobenzene (3.4 g) in dichloromethane (60 ml) were added isobutyl chloroformate (1.4 ml) and triethylamine (1.5 ml) in an ice bath and the mixture was stirred at the same temperature for 0.5 hours. To the reaction mixture was added 50% aqueous dimethylamine (1.1 ml) and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/methanol=19/1 as an eluant to give the desired compound (3.1 g, yield 83%) as a pale yellow amorphous solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][N:39]([CH3:65])[CH2:40][CH2:41][C@@H:42]([NH:51][C:52]1[CH:57]=[CH:56][C:55]([S:58]([NH2:61])(=[O:60])=[O:59])=[CH:54][C:53]=1[N+:62]([O-:64])=[O:63])[CH2:43][S:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:61][S:58]([C:55]3[CH:56]=[CH:57][C:52]([NH:51][C@H:42]([CH2:41][CH2:40][N:39]([CH3:38])[CH3:65])[CH2:43][S:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[C:53]([N+:62]([O-:64])=[O:63])[CH:54]=3)(=[O:59])=[O:60])=[O:22])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O[Si](C)(C)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1[N+](=O)[O-]
Yield: 36.7 %

Procedure:
The title product (162.8 mg, yield: 32%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 32 utilizing (R)-4-(4-((tert-butyldimethylsilyloxy)(4 ′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 249.6 mg, 0.47 mmol) and (R)-4-(4-(dimethylamino)-1-(phenylthio)butan-2-ylamino)-3-nitrobenzenesulfonamide (INTERMEDIATE 19, 208.8 mg, 0.49 mmol). The title product was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→10% MeOH/DCM).
Reaction SMILES: [O:1]=[C:2]([CH3:24])[C:3](=[CH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]>[Pd].C(OCC)(=O)C>[O:1]=[C:2]([CH3:24])[CH:3]([CH2:9][C:10]1[CH:11]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)=O

Procedure:
This compound is prepared in a manner analogous to that of Step B of Example 2, using 44.6 grams (0.126 mole) of ethyl 3-oxo-2-[3,5-di(trifluoromethyl)phenylmethylidene]butanoate and 1.5 grams (catalyst) of 5% palladium on charcoal in 250 mL of ethyl acetate, yielding ethyl 3-oxo-2-[3,5-di(trifluoromethyl)phenylmethyl]butanoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13][N:12]([C:22](=[O:24])[CH3:23])[CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1(c2ccccc2)CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(CNC(=O)OC(C)(C)C)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of (4-phenylpiperidin-4-ylmethyl) carbamic acid tert-butyl ester (2.1 mmol) in CH2Cl2 is added acetic anhydride (3.1 mmol) and triethylamine (3.1 mmol) at 0° C. The reaction mixture is stirred at room temperature for 2.5 h then the bulk of solvent is concentrated in vacuo. After the residue is suspended in AcOEt, the mixture is washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give (1-acetyl-4-phenylpiperidin-4-ylmethyl)carbamic acid tert-butyl ester, which is directly used for the next reaction without further purification.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:20][CH2:21][CH:22]1[CH2:24][CH2:23]1>>[CH:22]1([CH2:21][NH:20][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH2:24][CH2:23]1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCC1CC1
Product: c1ccc2c(c1)ncn2-c1ccnc(NCC2CC2)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 1) was reacted with aminomethylcyclopropane according to the procedure described in EXAMPLE 11, Step C to afford the title compound. Mass Spectrum (CI): 266.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.65 (s, 1H); 8.38 (br s, 1H); 8.23 (d, J=7.8 Hz, 1H); 7.88 (d, J.=7.8 Hz, 1H); 7.42 (m, 2H); 6.82 (d, J=5.5 Hz, 1H); 5.30-6.25 (br, 1H); 3.42 (br s, 2H); 1.19 (br s, 1H); 0.62 (m, 2H); 0.35 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][CH:13]1[CH:17]([O:18][CH2:19][S:20][CH3:21])[CH2:16][O:15][CH2:14]1.[NH2:22][C:23]1[C:28]([Cl:29])=[CH:27][N:26]=[CH:25][C:24]=1[Cl:30].[H-].[Na+]>C(Cl)(=O)C(Cl)=O.O1CCCC1>[Cl:30][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:29])[C:23]=1[NH:22][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([O:12][CH:13]2[CH:17]([O:18][CH2:19][S:20][CH3:21])[CH2:16][O:15][CH2:14]2)[CH:5]=1
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)O)cc1OC1COCC1OCSC
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1COCC1OCSC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.4 %

Procedure:
1.0 g (3.2 mmol) of 4-methoxy-3-(4-methylthiomethyloxytetrahydrofuran-3-yloxy)benzoic acid (starting compound A19) are heated to reflux for 90 min in 4 ml of oxalyl chloride. Excess oxalyl chloride is removed in vacuo and coevaporated using 2×20 ml of toluene. A solution of 520 mg (3.2 mmol) of 4-amino-3,5-dichloropyridine in 10 ml of tetrahydrofuran is added dropwise to a suspension of 200 mg (6.9 mmol) of 80% strength sodium hydride in 10 ml of tetrahydrofuran. The mixture is stirred at RT for 90 min, then the acid chloride is added dropwise in a further 10 ml of tetrahydrofuran and the reaction mixture is stirred at RT for 2 h. It is concentrated, the residue is treated with 25 ml of water and the mixture is extracted with 3×25 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, concentrated and the residue is chromatographed on silica gel. The product-containing fractions are concentrated and the residue is crystallized from acetonitrile. 300 mg of the title compound of m.p. 195-198° C. are obtained.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:9])(C)(C)C.[CH3:28]C(O)=O>>[F:18][C:15]1[CH:16]=[CH:17][C:12]2[N:11]=[C:10]([C@@H:8]([NH:7][C:6](=[O:5])[CH3:28])[CH3:9])[N:19]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:13]=2[CH:14]=1
Reactant: CC(=O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1cccnc1
Product: CC(=O)N[C@@H](C)c1nc2ccc(F)cc2n1-c1cccnc1
Temperature: 100 °C
Yield: 57 %

Procedure:
A solution of {(S)-1-[4-fluoro-2-(pyridin-3-ylamino)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester (47 mg, 0.126 mmol) in AcOH (1 mL) was heated at 100° C. for 28 h in a sealed tube. In a separate vial, {(S)-1-[4-fluoro-2-(pyridin-3-ylamino)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester (228 mg, 0.61 mmol) was dissolved in AcOH (2 mL) and heated at 100° C. for 17 h. After cooling to RT, the two reaction mixtures were combined and the volatiles were removed in vacuo. The resulting residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic fraction was washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound as an orange oil (126 mg, 57%). LCMS (Method C): RT 2.16 min [M+H]+ 299.3. 1H NMR (CDCl3, 400 MHz): δ 8.84 (1H, dd, J=4.82, 1.02 Hz), 8.75 (1H, s), 7.95 (1H, s), 7.72-7.57 (2H, m), 7.47 (1H, s), 7.07 (1H, td, J=9.15, 2.31 Hz), 6.80 (1H, d, J=8.61 Hz), 5.21-5.09 (1H, m), 1.96 (3H, s), 1.50 (3H, d, J=6.99 Hz)
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[C:17]([CH:21]1[CH2:26][CH2:25][CH:24]([C:27](Cl)=[O:28])[CH2:23][CH2:22]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([CH:21]1[CH2:22][CH2:23][CH:24]([C:27]([NH:1][CH:2]([C:5]2[C:6](=[O:16])[NH:7][C:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH2:3][CH3:4])=[O:28])[CH2:25][CH2:26]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: CC(C)(C)C1CCC(C(=O)Cl)CC1
Product: CCC(NC(=O)C1CCC(C(C)(C)C)CC1)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 200 mg (0.90 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 180 mg (0.90 mmol) 4-tert-butylcyclohexanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH2:12][O:11][CH:10]([C:15]2([CH3:20])[O:19][CH2:18][CH2:17][O:16]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.C(OCC)(=O)C>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:15]2([CH3:20])[O:16][CH2:17][CH2:18][O:19]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C2CN(Cc3ccccc3)C(=O)CO2)OCCO1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C2CN(Cc3ccccc3)CCO2)OCCO1
Temperature: 25 °C
Reaction time: 40 h
Yield: 45.8 %

Procedure:
Borane-dimethyl sulfide complex (2.2 ml) was added to a solution of 4-benzyl-2-(2-methyl-1,3-dioxolan-2-yl)-5-oxomorpholine (4.6 g) in tetrahydrofuran (60 ml) under ice-cooling. The mixture was stirred at ambient temperature for 40 hours and methanol (5 ml) was added to the mixture. After 2 hours, the mixture was concentrated under reduced pressure to give a syrup. The syrup was poured into a mixture of water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (50 g) and eluted with chloroform to give 4-benzyl-2-(2-methyl-1,3-dioxolan-2-yl)morpholine (2.00 g) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][N:6]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:5]2=[O:20].[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.CS(C)=O>[CH2:23]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[C:5](=[O:20])[N:6]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:7]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1c2cc(Cl)ccc2NCN1CCN1CCOCC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: O=C1c2cc(Cl)ccc2N(Cc2ccccc2)CN1CCN1CCOCC1
Reaction time: 0.5 h

Procedure:
3.50 Grammes (11.8 mmoles) of 6-chloro-2,3-dihydro-3-[2-(4morpholinyl)ethyl]-4(1H)-quinazolinone are dissolved in 20 ml of a mixture of toluene and dimethylsulfoxide in a ratio 5:1. The solution is dripped into a suspension containing 340 mg (14.2 mmoles) of 95% sodium hydride in 30 ml of dimethylsulfoxide and the reaction mixture is kept at 40° C. for 30 minutes. Afterwards a mixture containing 2.11 ml (17.7 mmoles) of benzylbromide and 60 ml of toluene is dripped into the solution and the suspension is kept at 40° C. for 4 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>S(Cl)(Cl)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]([N:26]2[CH2:31][CH2:30][S:29][CH2:28][CH2:27]2)=[O:9])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: C1CSCCN1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCSCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Nitro-5-(trifluoromethyl)benzoic acid (2.96 g, 12.6 mmol) was allowed to reflux in thionyl chloride (6 mL) for 6 h. The resulting solution was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting solid was taken up in CH2Cl2 (20 mL) and iPr2NEt (2.6 mL, 15.1 mmol) and thiomorpholine (1.4 mL, 13.8 mmol) was added. The reaction was stirred at RT for 1 h and then diluted with CH2Cl2 (50 mL). The organic layer was washed with aq. HCl (1 M, 25 mL), 9% aq. Na2CO3 (25 mL)), brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (3-nitro-5-(trifluoromethyl)phenyl)(thiomorpholino)-methanone.