Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[C:17]1([CH2:23][S:24](Cl)(=[O:26])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][N:13]([S:24]([CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:26])=[O:25])[CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)Cc2ccccc2)c1

Procedure:
Starting materials: sodium hydride 60% (0.240 g), (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) (1.01 g), α-toluenesulfonylchloride (1.19 g). Reaction conditions: −30° C., 30 min; 30° C., 2.5 hours.
Reaction SMILES: [Cl:1][C:2]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:27])[N:19]2[CH3:26])(C(OCC)=O)[C:3]([O:5]CC)=[O:4].C(O)(=O)C.Cl>O>[Cl:1][CH:2]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:27])[N:19]2[CH3:26])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(Cl)(Cc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CC(Cl)C(=O)O)c2ccc(=O)n(C)c12
Temperature: 25 °C
Yield: 81.4 %

Procedure:
Diethyl 2-chloro-2-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-ylmethyl)malonate (5.1 g) was added to a mixture of 20 ml of acetic acid and 15 ml of 6N hydrochloric acid, followed by heating under reflux for 9 hours. After cooling to room temperature, water was added to the reaction mixture, followed by cooling with ice. The precipitated solid was collected by filtration, washed with water and dried to thereby obtain 3.1 g of 2-chloro-3-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)propionic acid as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.[CH:13](NC(C)C)(C)[CH3:14].[Li]CCCC.ICC.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[C:3]=1[CH2:13][CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1c(Cl)ccc(NC(C)=O)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of N-(4-chloro-2-fluorophenyl)acetamide (10.0 g, 53.3 mmol) and diisopropylamine (7.5 mL, 53.3 mmol) in THF (300 mL) at −78° C. is added dropwise n-BuLi (2.5 M in hexanes, 42.6 mL, 106.6 mmol) keeping the reaction temperature below −60° C. After 2 hours, iodoethane (12.4 g, 80 mmol) is added dropwise at −78° C. The reaction mixture is stirred at −78° C. for additional 1.5 hours. A 1N solution of aqueous HCl is added slowly until a pH between 4 and 5 is reached. The mixture is extracted with EtOAc (200 mL×3) and the organic layers are combined washed with water and brine, then dried over MgSO4. The solvent is removed under reduced pressure and the solid residue is stirred in ether and hexane (1:4, 80 mL) for 1 hour. The filtered solid is dried to give N-(4-chloro-3-ethyl-2-fluorophenyl)acetamide.
Reaction SMILES: [S:1]([NH:5][C:6](=[NH:12])[CH2:7][CH2:8]S(C)=O)(=[O:4])(=[O:3])[NH2:2].C(N(CC)CC)C>C(O)C>[S:1]([NH:5][C:6](=[NH:12])[CH:7]=[CH2:8])(=[O:4])(=[O:3])[NH2:2]
Reactant: CS(=O)CCC(=N)NS(N)(=O)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=CC(=N)NS(N)(=O)=O
Yield: 97 %

Procedure:
A suspension of N-sulfamyl-3-(methylsulfinyl)propionamidine (5.0 g, 23.5 mmol) in ethanol (100 ml) containing triethylamine (3.6 ml) was refluxed for 20-40 hours. Upon cooling, suspended solids were removed by filtration and the solvent evaporated to give a residue (3.4 g) which was chromatographed on silica gel and eluted with 3-7% methanol/chloroform. Upon concentration of appropriate fractions, the title compound crystallized to give 1.3 g, mp 72°-75°.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([N+:21]([O-])=O)[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]>CO.CCOC(C)=O>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:21])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)ccn1
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)c1cc(Oc2ccc(N)c(N)c2)ccn1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
4-(3,4-Dinitro-phenoxy)-pyridine-2-carboxylic acid methylamide (Step A) (0.71 g, 2.23 mmol) was dissolved in 40 mL MeOH and 80 mL EtOAc. To the argon-degassed solution was added 10% Pd/C (0.20 g). The reaction was vigorously stirred for 42 h at RT under 1 atm of H2 gas. The reaction was filtered through a Celite® plug. The solvent was removed under reduced pressure to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:27][CH2:28][CH3:29])=[C:16]([C:22]([CH3:26])=[C:23]([Cl:25])[CH:24]=3)[C:17]([NH:19][CH2:20][CH3:21])=[O:18])[CH3:13])[N:9]=[C:10](I)[C:3]=12.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][NH:41][CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:27][CH2:28][CH3:29])=[C:16]([C:22]([CH3:26])=[C:23]([Cl:25])[CH:24]=3)[C:17]([NH:19][CH2:20][CH3:21])=[O:18])[CH3:13])[N:9]=[C:10]([C:38]3[CH:39]=[N:40][NH:41][CH:42]=3)[C:3]=12
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCNC(=O)c1c(C)c(Cl)cc(C(C)n2nc(I)c3c(N)ncnc32)c1OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)n2nc(-c3cn[nH]c3)c3c(N)ncnc32)c1OCC
Temperature: 100 °C
Yield: 11.3 %

Procedure:
To a solution of 3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide (9.0 mg, 0.017 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.6 mg, 0.034 mmol), sodium carbonate (11 mg, 0.10 mmol) in N,N-dimethylformamide (0.1 mL)/water (51 μL) under N2 was added tetrakis(triphenylphosphine)palladium(0) (2.0 mg, 0.0017 mmol). The mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was filtered and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (0.9 mg, 10%). The product was isolated as a racemic mixture. LCMS calculated for C22H26ClN8O2 (M+H)+: m/z=469.2; Found: 469.0.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[N:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1>>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[N:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: Cc1cnc(Cl)nc1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Product: Cc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-chloro-5-methyl-pyrimidine following a procedure analogous to that described in Example 88. LC (method 18): tR=1.30 min; Mass spectrum (ESI+): m/z=404 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:42])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][C:38]1[N:37]=[CH:36][C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:42])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:23])[F:21])[C:12]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:40][CH:39]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M219) (191 mg, 0.31 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (95 mg, 62%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[NH:27][C:28]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:29]
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Reactant: COc1cccc(N=C=O)c1
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2cccc(OC)c2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and 3-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-:3])=[O:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH:18]=[N:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:17]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1ccccc1[N+](=O)[O-]
Product: CN(C)C=NC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Nitrobenzamide (2.5 g, 15 mmol) was dissolved in dimethylformamide-dimethylacetal (10 mL) and heated to 100° C. for 1 hour. Upon cooling, the reaction mixture was placed in a freezer at −23° C. overnight. The white precipitate was collected by filtration and rinsed with hexane to provide N-[(dimethylamino)methylene]-2-nitrobenzamide (3.06 g), which was used without further purification.
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:10][C:9]2[CH:11]=[C:12]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:13]([CH3:15])=[CH:14][C:8]=2[O:7]1)=[O:5])C.[OH-].[Na+].Cl>CO>[CH3:15][C:13]1[C:12]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:11][C:9]2[O:10][CH:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:14]=1
Reactant: CCOC(=O)C1Oc2cc(C)c(S(=O)(=O)c3ccccc3)cc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(cc1S(=O)(=O)c1ccccc1)OC(C(=O)O)O2

Procedure:
8.6 g (24.7 mmol) of 5-methyl-6-phenylsulphonyl-1,3-benzodioxole-2-carboxylic acid ethyl ester are suspended in 37 ml of methanol. 37 ml of 1N sodium hydroxide solution are then slowly added at room temperature, the starting material soon dissolving. After one hour the reaction mixture is cooled, concentrated hydrochloric acid is added and the whole is extracted three times with ethyl acetate. The combined organic phases are washed with water and then with a saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. 50 ml of methylene chloride are added to the yellow oil remaining, and the whole is stirred until crystallisation occurs. The filtered crystals are recrystallised from a small amount of 1,2-dichloroethane, yielding 5-methyl-6-phenylsulphonyl-1,3-benzodioxole-2-carboxylic acid in the form of white crystals having a melting point of 169°-171°.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](=[O:37])[NH:28][CH:29]([CH3:36])[CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.[F:47][C:48]([F:54])([F:53])[S:49]([OH:52])(=[O:51])=[O:50]>C1(OC)C=CC=CC=1>[F:47][C:48]([F:54])([F:53])[S:49]([OH:52])(=[O:51])=[O:50].[F:47][C:48]([F:54])([F:53])[S:49]([OH:52])(=[O:51])=[O:50].[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27](=[O:37])[NH:28][CH:29]([CH3:36])[CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)NC(C)CN3CCCC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(CN1CCCC1)NC(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
369 mg of (2S, 4S)-4-(4-methoxybenzylthio)-2-(1-methyl-2-pyrrolidinylethylcarbamoyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 2) were suspended in 720 μl of anisole, and the suspension was placed on an ice bath. Maintaining the suspension on the ice bath, 3.6 ml of trifluoroacetic acid and 128 μl of trifluoromethanesulfonic acid were added to it, and it was then stirred for 1 hour at room temperature. At the end of this time, the solvent was removed by distillation under reduced pressure. The residue was washed with diethyl ether by repeated decantation and dried under reduced pressure, to give 440 mg of the title compound.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:36][C:37]([O-:40])([CH3:39])[CH3:38].[K+]>>[C:37]([O:40][C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:17]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)([CH3:39])([CH3:38])[CH3:36]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(F)nc3)CC2)C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: CC(C)(C)Oc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from N-({1-[4-(6-fluoro-pyridin-3-yl)-4-hydroxy-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide 6a and t-BuOK using the procedure described in Example 8.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:24])([CH3:23])[C:13](=[O:22])[N:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>>[OH:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:24])([CH3:23])[C:13](=[O:22])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:29]([C:28]4[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=4[O:26][CH3:25])=[O:30])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1O
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4OC)CC3)C(=O)C2(C)C)cc1O

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3-hydroxy-4-methoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B11*HCl) and 2-methoxybenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield 5-(3-hydroxy-4-methoxyphenyl)-2-{1-[(2-methoxyphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one as the product.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C@H:5]([CH:46]([CH3:48])[CH3:47])[CH2:6][C@H:7]([OH:45])[C@@H:8]([NH:16][C:17]([C@@H:19]([NH:26][C:27]([C@@H:29]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)=[O:18])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CS[C:51]([NH:53][C:54](=[O:63])[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[NH:52].CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:40]([O:39][C:38]([NH:37][C@H:29]([C:27]([NH:26][C@H:19]([C:17]([NH:16][C@@H:8]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[C@@H:7]([OH:45])[CH2:6][C@@H:5]([CH:46]([CH3:48])[CH3:47])[CH2:4][CH2:3][NH:2][C:51]([NH:53][C:54](=[O:63])[O:55][CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)=[NH:52])=[O:18])[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)=[O:28])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:44])([CH3:43])([CH3:41])[CH3:42]
Reactant: CSC(=N)NC(=O)OCc1ccccc1
Reactant: CC(C)[C@@H](CCN)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)[C@@H](CCNC(=N)NC(=O)OCc1ccccc1)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 80 %

Procedure:
0.136 g (0.197 mmol) of t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-6-amino-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate hydrochloride, 0.051 g (0.2 mmol) of benzyl [(methylthio)formimidoyl]carbamate and 0.07 ml (0.34 mmol) of Hunig base in 1 ml of absolute ethanol are stirred at 70° under argon for 3 hours. Thereafter, the reaction mixture is cooled, poured into 2N potassium carbonate solution and extracted with methylene chloride. The methylene chloride extracts are dried over magnesium sulphate and evaporated under reduced pressure. Chromatography of the residue obtained on 2 g of silica gel with a mixture of methylene chloride and isopropanol as the eluting agent yields 0.131 g of benzyl [N-[(3S,5S,6S)-6-[[N-[N-(t-butoxycarbonyl)-3-phenyl-L-alanyl]-L-histidyl]amino]-7-cyclohexyl-5-hydroxy-3-isopropylheptyl]amidino]carbamate as a colourless oil, MS: 831 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.C(N1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])(OCC)=O.C([O-])([O-])=O.[Na+].[Na+]>O.C(OCC)(=O)C>[OH:9][CH:6]1[CH2:7][CH2:8][CH:3]([N:2]2[C:19](=[O:20])[C:18]3[C:17](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]2=[O:25])[CH2:4][CH2:5]1
Reactant: NC1CCC(O)CC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 15.6 h
Yield: 76.1 %

Procedure:
A solution of 4-aminocyclohexanol hydrochloride (2.52 g, 16.6 mmol) in water (20.0 mL) was treated with N-carbethoxyphthalimide (3.82 g, 17.4 mmol) and Na2CO3 (3.77 g, 35.6 mmol). The reaction was stirred at room temperature for 15.6 hours. The reaction was cooled to 0° C. and quenched with 10% HCl, filtered, and washed with water to give a white solid. The solid was dissolved in ethyl acetate washed with water, brine, dried over MgSO4 and concentrated in vacuo to give 3.10 g (76%) of 2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione as a colorless solid: mp 176.9-177.0° C.; 1H NMR (400 MHz, Acetone-d6) δ 7.82 4.09, 3.74, 3.62, 2.28, 2.04, 1.76, 1.39; 13C NMR (100 MHz, acetone-d6) δ 168.7, 135.1, 133.0, 123.6, 69.5, 50.8, 35.7, 28.3; IR (mull) 3389, 3318, 2953, 2930, 2876, 2861, 1767, 1703, 1463, 1393, 1377, 1088, 1075, 1061, 720 cm−1; HRMS (FAB) calcd for C14H16NO3: 246.1130, found 246.1128; Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.39; H, 6.21; N, 5.70.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34]>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:31]5[CH2:32][CH2:33][N:29]([CH3:28])[C:30]5=[O:34])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CN1CCNC1=O
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: CN1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)cc2)C1=O
Yield: 75.5 %

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 186 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (336 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[S:13][C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=3)=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[C:28]1(B2OC(C)(C)C(C)(C)O2)[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O>[C:28]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:12]4[S:13][C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:15]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[N:16]=4)=[C:9]([CH3:11])[N:10]=3)[CH:7]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: CCOC(=O)c1sc(-c2c(C)nc3ccc(Br)cn23)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1sc(-c2c(C)nc3ccc(C4=CCCCC4)cn23)nc1-c1ccccc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
To a mixture of ethyl 2-(6-bromo-2-methylimidazo[1,2-a]pyridin-3-yl)-4-phenyl-1,3-thiazole-5-carboxylate (267 mg, 0.6 mmol) obtained above in DME (18 mL) and water (3.6 mL), were added 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (250 mg, 1.2 mmol), cesium carbonate (586 mg, 1.8 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (49.1 mg, 0.06 mmol) under a nitrogen atmosphere, and the mixture was stirred at 95° C. for 3 h. The reaction mixture was allowed to cool to rt. The resulting precipitate was collected by filtration and washed with water and diethyl ether to give the title compound (223 mg, 84%) as a white solid.
Reaction SMILES: [CH2:1]=[O:2].[N:3]1[C:10]([NH2:11])=[N:9][C:7]([NH2:8])=[N:6][C:4]=1[NH2:5].[OH-].[Na+]>O>[CH2:1]([NH:5][C:4]1[N:6]=[C:7]([NH2:8])[N:9]=[C:10]([NH2:11])[N:3]=1)[OH:2]
Reactant: C=O
Reactant: Nc1nc(N)nc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(N)nc(NCO)n1
Temperature: 70 °C

Procedure:
Formaldehyde (50%, 12.0 g, 0.2 mol) was added to a mixture of melamine (12.6 g, 0.1 mol) and water (40 ml) with stirring. The pH of the mixture was adjusted to 9.0-9.2 by addition of NaOH (0.5N). The mixture was heated to 70° C. and a dyestuff (Direct red 252 mg, 2000 ppm based on melamine) was added to give a colored methylolmelaminersolution. In this procedure, other dyestuffs can be used such as direct dyes, fluorescent dyes, dispersion dyes, and mixtures thereof. See Table 1.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[CH3:18])[C:8]([CH:19]=O)=[C:7]([NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:6]=1.C1C[O:31][CH2:30][CH2:29]1>C(OCC)C>[CH:22]1([N:21]2[C:7]3[N:6]=[C:5]([S:4][CH3:3])[N:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=4[CH3:18])[C:8]=3[CH:19]=[CH:29][C:30]2=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCOC1
Reactant: CSc1nc(NC2CCCCC2)c(C=O)c(-c2ccc(F)cc2C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CSc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(C3CCCCC3)c2n1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
Triethylphosphonoacetate (3.87 mL, 0.01953 mol) in dry THF (56 mL) was treated with NaH (60% in mineral oil) (967.5 mg, 0.0243 mol). The mixture was stirred for 30 min giving a clear solution. The title compound from Example 180 (4.5 g, 0.0125 mol) in dry THF (75 mL) was added in one portion and the solution gently refluxed for 72 h. After cooling to 23°, the reaction mixture was diluted with ethyl ether, then washed in turn with satd aq NH4Cl and H2O. Organic layer was dried (Na2SO4), then evaporated to a viscous syrup which was flash chromatographed in methylene chloride-hexane gradient (20% to 0% hexane) to afford first 920 mg (19%) of the title compound as a white solid. LC MS (m/e)=384 (MH+). Rt=2.79 min.