Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:17])=[C:4]([C:13](=[O:16])[NH:14][CH3:15])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:9])=[O:8].C(OCC(NC1C(I)=C(C(=O)NC)C(I)=C(C=1I)C(Cl)=O)=O)(=O)C.[C:42]([O:45][CH:46]([CH2:50][O:51][C:52](=[O:54])[CH3:53])[C:47](Cl)=[O:48])(=[O:44])[CH3:43]>CC(N(C)C)=O>[C:42]([O:45][CH:46]([CH2:50][O:51][C:52](=[O:54])[CH3:53])[C:47]([NH:1][C:2]1[C:3]([I:17])=[C:4]([C:13](=[O:16])[NH:14][CH3:15])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:9])=[O:8])=[O:48])(=[O:44])[CH3:43]
Reactant: CNC(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reactant: CC(=O)OCC(OC(C)=O)C(=O)Cl
Agent: CNC(=O)c1c(I)c(NC(=O)COC(C)=O)c(I)c(C(=O)Cl)c1I
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1c(I)c(NC(=O)C(COC(C)=O)OC(C)=O)c(I)c(C(=O)Cl)c1I

Procedure:
Compound (11) is prepared from compound (2) in an analogous manner as compound (3) described in Example I, B. Thus, 5-amino-3-methylcarbamoyl-2,4,6-triiodobenzoyl chloride (2) reacted with 2,3-diacetoxypropionyl chloride in DMAc provides 5-(2,3-diacetoxypropionylamino)-3-methylcarbamoyl-2,4,6-triiodobenzoyl chloride (11) in approximately 90% yield.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][NH2:22])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:23][C:24]([CH3:26])=O>CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][N:22]=[C:24]([CH3:26])[CH3:23])[N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)(O)Cn1c(CON)nc2c(N)nc3ccccc3c21
Reactant: CC(C)=O
Solvent: CO
Product: CC(C)=NOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O

Procedure:
A solution of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (800 mg, 2.65 mmol) in acetone (10 mL) and methanol (10 mL) was stirred for 20 hours at room temperature, then was concentrated under reduced pressure. The resulting yellow solid was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 5-15% methanol in chloroform) followed by crystallization from acetonitrile to yield 400 mg of acetone O-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}oxime as pale yellow crystals, mp 212-216° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[C:16]2[N:15]=[CH:14][N:13]([CH2:17][CH2:18][CH3:19])[C:12]=2[C:11](=[O:20])[NH:10][C:9]1=[O:21].Cl[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:37])([CH3:36])[C:28]#[C:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33].O>CN(C)C=O>[CH2:34]([N:31]([CH2:32][CH3:33])[CH2:30][C:29]#[C:28][C:27]([OH:37])([CH3:36])[CH2:26][CH2:25][CH2:24][CH2:23][N:10]1[C:11](=[O:20])[C:12]2[N:13]([CH2:17][CH2:18][CH3:19])[CH:14]=[N:15][C:16]=2[N:8]([CH3:7])[C:9]1=[O:21])[CH3:35]
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCN(CC)CC#CC(C)(O)CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)(O)C#CCN(CC)CC)c(=O)n2C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2.12 g (15.3 mmol) of potassium carbonate were added to a solution of 2.0 g (9.6 mmol) of 3-methyl-7-propylxanthine in 60 ml of dimethylformamide at 60° C. and the mixture was stirred at 60° C. for one hour. Then 3.07 g (12.5 mmol) of 1-chloro-8-diethylamino-5-hydroxy-5-methyl-6-octyne from stage A1) were added dropwise and the mixture was stirred at 80° C. for 12.5 hours. It was then allowed to cool to room temperature, water was added, and three extractions with tert-butyl methyl ether were carried out. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and purified by flash chromatography, dichloromethane/methanol=19/1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][C:9]2=3)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>N1C=CC=CC=1>[Br:25][C:26]1[CH:27]=[C:28]([S:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=5[CH:23]=[CH:24][C:9]3=4)=[CH:6][CH:7]=2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3cccc(Br)c3)cc2)c2ccc3c(c2N1)CCCC3
Yield: 28.5 %

Procedure:
5-(4-Aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione (65 mg, 202 mmol) obtained in Example 55, and 3-bromobenzenesulfonyl chloride (78 mg, 0.305 mmol) were treated by heating in pyridine (2.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to obtain the title compound (47 mg, yield 43%) as white crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:12]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([F:29])=[C:21]3[C:26]=2[NH:25][CH:24]=[C:23]([I:27])[C:22]3=[O:28])[CH2:14][CH2:13]1.[CH2:30](I)[CH3:31]>O>[CH:12]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([F:29])=[C:21]3[C:26]=2[N:25]([CH2:30][CH3:31])[CH:24]=[C:23]([I:27])[C:22]3=[O:28])[CH2:13][CH2:14]1
Reactant: O=c1c(I)c[nH]c2c(OCC3CC3)ccc(F)c12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(I)c(=O)c2c(F)ccc(OCC3CC3)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.6 %

Procedure:
Potassium carbonate (450 mg, 3.26 mmol) was added to a DMF solution (5 ml) of 8-cyclopropylmethoxy-5-fluoro-3-iodo-1H-quinolin-4-one (910 mg, 2.53 mmol). The mixture was stirred for 15 minutes at room temperature. Ethyl iodide (0.31 ml, 3.87 mmol) was added thereto, and the resulting mixture was stirred at 60° C. for 2 hours. After the reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was then purified by silica gel column chromatography (dichloromethane:ethyl acetate=40:1→15:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 750 mg of powdery pale dark brown 8-cyclopropylmethoxy-1-ethyl-5-fluoro-3-iodo-1H-quinolin-4-one (yield: 77%).
Reaction SMILES: [CH2:1]([N:3]([CH2:61][CH3:62])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:19](=[O:40])[N:20]([CH3:39])[CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:6]([C:41]2[CH:46]=[C:45]([C:47](=[O:60])[NH:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=3)[CH:44]=[CH:43][N:42]=2)[CH:5]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:61]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:19](=[O:40])[N:20]([CH3:39])[CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:6]([C:41]2[CH:46]=[C:45]([C:47](=[O:60])[NH:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:57])([F:59])[F:58])[CH:51]=3)[CH:44]=[CH:43][N:42]=2)[CH:5]=1)[CH3:62]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCOCCOCCOCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCOCCOCCOCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 1-(3-((4-(diethylamino)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)phenyl)-2-methyl-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oate (1.17 g) in DCM (20 mL) was added TFA (20 mL). The mixture was stirred for 1 hour, concentrated and lyophilized to give a think brown syrup. MS (ES, m/z): 808.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:21])[CH3:20])[CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])=[O:10])[C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:5][CH:4]=[C:3]1[NH:28][C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)=[O:30]>CO.ClCCl>[O:1]=[C:2]1[N:7]([CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:21])[CH3:20])[C:13](=[O:18])[C:14]([F:15])([F:17])[F:16])=[O:10])[C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:5][CH:4]=[C:3]1[NH:28][C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)=[O:30]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)NCc2ccncc2)c1=O)C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)NCc2ccncc2)c1=O)C(=O)C(F)(F)F

Procedure:
2-[6-Oxo-2-phenyl-5-[3-(4-pyridylmethyl)ureido]-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide was subjected to a procedure similar to that described in Example 1. Chromatography, with methanol:dichloromethane (10:90) as the eluent, gave 2-[6-oxo-2-phenyl-5-[3-(4-pyridylmethyl)ureido]-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide as a white solid; NMR (DMSO/D2O): 8.58 (s,1), 8.46 (bs, 2), 7.41 (m,5), 7.27 (d,2), 4.56 (d,1), 4.37 (d,1), 4.32 (s,2), 4.00 (d,1), 2.20 (m,1), 0.79 (d,3), 0.73 (d,3); MS: m/z=531(M+1).
Reaction SMILES: [Li+].[BH4-].C([O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:15][C@H:14]2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9][CH:8]=1)C=C>C1COCC1.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>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:15][C@H:14]2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:9][CH:8]=1
Reactant: C=CCOc1ccc([C@@H]2C[C@H]2NC(=O)OC(C)(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
LiBH4 (0.34 g, 15.54 mmol) was added to a solution of Pd(PPh3)4 (0.15 g, 0.13 mmol) and tert-butyl(trans)-2-[4-(allyloxy)phenyl]cyclopropylcarbamate (Intermediate I, 0.75 g, 2.59 mmol) in dry THF (20 mL) and stirred at room temperature for 1 h. After removal of the solvent, the residue was dissolved in EtOAc (25 mL), acidified with HCl (10% aqueous solution, 2 mL), and washed with water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (10%-20% EtOAc/Hexanes), affording 0.58 g of tert-butyl(trans)-2-(4-hydroxyphenyl)cyclopropylcarbamate [Rf=0.3 (30% EtOAc/Hexanes), pale yellow foam, 90% yield].
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]4[CH:26]=[C:25]5[C:21]([CH:22]=[CH:23][N:24]5S(C5C=CC(C)=CC=5)(=O)=O)=[CH:20][CH:19]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[NH:24]1[C:25]2[C:21](=[CH:20][CH:19]=[C:18]([CH2:17][NH:16][C:12]3[N:11]=[C:10]([NH:9][C:6]4[CH:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[NH:8][N:7]=4)[CH:15]=[CH:14][N:13]=3)[CH:26]=2)[CH:22]=[CH:23]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(CNc4nccc(Nc5cc(C6CC6)[nH]n5)n4)cc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1cc(Nc2cc(C3CC3)[nH]n2)nc(NCc2ccc3cc[nH]c3c2)n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 38 (130 mg, 0.25 mmol) in MeOH (2 mL) was added a 2.0 N solution of KOH in water (2 mL). The mixture was stirred at 100° C. for 18 h. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC to afford 20 mg (22%) of I-35 as white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[N:13]=[CH:12][C:11]([S:14][C:15]3[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=3)=[CH:10][C:9]=2[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:5][CH:6]=1.Cl.Cl[CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35]>>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][CH2:31][O:21][C:17]1[CH:16]=[C:15]([S:14][C:11]2[CH:10]=[C:9]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:8]([NH:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)=[N:13][CH:12]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)CCCCl
Reactant: Cc1csc(Nc2ncc(Sc3cccc(O)c3)cc2Oc2ccccc2)n1
Agent: Cl
Product: Cc1csc(Nc2ncc(Sc3cccc(OCCCN(C)C)c3)cc2Oc2ccccc2)n1

Procedure:
Prepared according to the method of Example 60 using 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenol and 3-chloro-N,N-dimethylpropan-1-amine hydrochloride. 1H NMR (d6-DMSO) δ 9.55 (s, 1H), 8.28 (dd, 1H), 7.49 (dd, 1H), 7.29 (m, 2H), 7.11 (t, 1H), 7.00 (t, 1H), 6.85 (m, 2H), 6.65 (m, 1H), 6.58 (m, 1H), 6.54 (m, 1H), 6.38 (m, 1H), 3.70 (m, 2H), 2.21 (s, 3H), 2.04 (s, 6H) 1.96 (t, 2H), 1.44 (m, 2H); Mass spectrum (esi) m/z=−493.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:27])([CH3:26])[O:19][C:20]=3[C:21]([C:23](O)=[O:24])=[CH:22][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[CH:32]1([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:26])([CH3:27])[O:19][C:20]=3[C:21]([C:23]([NH:39][C:38]3[CH:40]=[CH:41][C:35]([CH:32]4[CH2:34][CH2:33]4)=[CH:36][CH:37]=3)=[O:24])=[CH:22][C:12]=2[N:11]=1
Reactant: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)O)c3c(c21)CC(C)(C)O3
Reactant: Nc1ccc(C2CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)Nc3ccc(C4CC4)cc3)c3c(c21)CC(C)(C)O3
Yield: 13.2 %

Procedure:
The title compound was prepared following the procedure described for Example-108 using 2-((2-chloro-6-fluorophenyl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylic acid (Intermediate-49, 0.100 g, 0.256 mmol), thionyl chloride (2.0 mL), 4-cyclopropyl aniline (0.102 g, 0.769 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.017 g of the desired product. 1HNMR (DMSO-d6): δ 0.62 (d, J=3.9 Hz, 2H), 0.91 (d, J=6.3 Hz, 2H), 1.60 (s, 6H), 1.88 (m, 1H), 3.45 (s, 2H), 3.55 (s, 3H), 6.98-7.16 (m, 3H), 7.19-7.36 (m, 3H), 7.53 (d, J=8.1 Hz, 2H), 9.60 (s, 1H), 10.48 (s, 1H); MS [M+H]+: 505.26.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([C:20]4[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=4)=[N:14][N:15]([CH2:17][CH:18]=[O:19])[CH:16]=3)=[CH:11][C:6]=2[N:5]([CH2:27][CH3:28])[C:4]1=[O:29])[CH3:2].C(I)C=C.[CH2:34]([NH:36][CH2:37]C)[CH3:35]>O>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([C:20]4[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=4)=[N:14][N:15]([CH2:17][CH:18]([OH:19])[CH2:37][NH:36][CH2:34][CH3:35])[CH:16]=3)=[CH:11][C:6]=2[N:5]([CH2:27][CH3:28])[C:4]1=[O:29])[CH3:2]
Reactant: CCNCC
Reactant: CCn1c(=O)n(CC)c2cc(-c3cn(CC=O)nc3-c3cccc(C)c3)ccc21
Agent: C=CCI
Solvent: O
Product: CCNCC(O)Cn1cc(-c2ccc3c(c2)n(CC)c(=O)n3CC)c(-c2cccc(C)c2)n1

Procedure:
1,3-Diethyl-5-(1-oxiranylmethyl-3-m-tolyl-1H-pyrazol-4-yl)-1,3-dihydro-benzoimidazol-2-one (obtained using a method similar to that for [4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-m-tolyl-pyrazol-1-yl]-acetaldehyde, substituting epibromohydrin for allyl iodide) (0.016 g) was diluted with diethylamine (0.3 mL, as a 70% solution in water) and stirred at 23° C. for 0.5 hours. Azeotropic removal of the water with toluene gave 1,3-Diethyl-5-[1-(3-ethylamino-2-hydroxy-propyl)-3-m-tolyl-1H-pyrazol-4-yl]-1,3-dihydro-benzoimidazol-2-one.
Reaction SMILES: [Cl:1]/[C:2](/[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[C:3](\Cl)/[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].C([O-])(=O)C.[NH4+:21]>CN(C)C=O>[NH2:21]/[C:3](/[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5])=[C:2](\[Cl:1])/[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)OC(=O)/C(Cl)=C(/Cl)C(=O)OC(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)/C(N)=C(/Cl)C(=O)OC(C)C
Yield: 118.7 %

Procedure:
26.9 g (0.1 mol) of diisopropyl dichloromaleate, 19.27 g (0.25 mol) of ammonium acetate and 40 ml of dimethylformamide were reacted under the same conditions as described in Example 1. 29.65 g (85.6% yield) of diisopropyl aminochloromaleate were obtained as a reddish-yellow, viscous liquid (purity according to GC analysis 83%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.O.Cl.[O:14]([NH2:16])[CH3:15]>CO>[CH3:15][O:14][N:16]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)[CH2:2][Br:1]
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: O
Product: CON=C(CBr)c1ccc(C)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-4′-methyl-acetophenone (6.514 g, 27.5 mmol) in methanol at 50° C. was added water until the solution turned slightly cloudy. Methoxylamine hydrochloride (7.037, 85.7 mmol) was added and the mixture was stirred overnight. The solvent was removed under high vacuum and the residue was extracted with EtOAc and dried over MgSO4. The product was purified by flash chromatography on silicagel (CH2Cl2/hexanes) to give 2 isomers in 87% total yield: 2 isomers in 87% total yield: Z-isomer 1H NMR 500 MHz (DMSO-d6) δ 2.33 (s, 3H), 3.83 (s, 3H), 4.62 (s, 2H), 7.26 (dd, 2H, J=1.8, 8.2 Hz), 7.51 (d, 2H, J=7.6 Hz); FABHRMS: found M+, 242.0177 (calcd for C10H13ONBr: M+, 242.0175). E-isomer 1H-NMR 500 MHz (DMSO-d6) d 2.33 (s, 3H), 3.99 (s, 3H), 4.68 (s, 2H), 7.25 (d, 2H, J=8.2 Hz), 7.61 (d, 2H, J=7.3 Hz); FABHRMS: found M+, 242.0175 (calcd for C10H13ONBr: M+, 242.0175).
Reaction SMILES: CC#N.[CH3:4][O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:29][Si:30]([CH2:33][CH2:34][O:35][CH2:36]Cl)([CH3:32])[CH3:31]>C(OCC)(=O)C>[CH3:4][O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:21])[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:36][O:35][CH2:34][CH2:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccccc1C(=O)c1ccc(OCOCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
Dry CH3CN (50 mL) was added to 2-(4-hydroxybenzoyl)benzoic acid methyl ester (3.65 g, 15 mmol) followed by cesium carbonate (5.4 g, 16.5 mmol) and trimethylsilylethoxymethylchloride (2.9 mL, 16.5 mmol). The system was stirred at room temperature under nitrogen for 24 h and monitored by TLC. Removal of the solvent gave a light yellow oil that was taken up into ethyl acetate (100 mL), washed with water (3×50 mL), brine (40 mL) and dried with MgSO4. The solvent was removed and the crude product was purified by flash column chromatography (5:95 EtOAc:petrol) to give 2-[4-(2-trimethylsilanylethoxymethoxy)benzoyl]benzoic acid methyl ester as a yellow oil (3.94 g, 10.2 mmol, 67%); Rf 0.79 (40:60 EtOAc:petrol). λmax (CH3OH)/nm 282, Abs 1.072. IR: 2939, 1720, 1666, 1589, 1489 cm−1. 1H NMR: (300 MHz, CDCl3) δ 0.00 (s, 9H, Si—(CH3)3), 0.94 (m, 2H, R—O—CH2—CH2—Si), 3.66 (s, 3H, COOCH3), 3.75 (m, 2H, O—CH2—CH2—Si), 5.27 (s, 2H, O—CH2—O), 7.05 (m, 2H, Ar—H), 7.37 (m, 1H, Ar—H), 7.53-7.66 (dtd, 2H, J=22.6, 7.4, 1.4 Hz, Ar—H), 7.72 (m, 2H, Ar—H), 8.05 (m, 1H, Ar—H). 13C NMR: (75 MHz, d6-DMSO) δ −2, 16.8, 51.5, 65.3, 91.5, 115.1, 127, 128, 129, 129.2, 129.6, 130.4, 132, 140.7, 160.2, 165.2, 194. LC/MS-ES+ m/z 163.2, 297.1, 387.1 [MH+], 409 [MNa+]. HRMS (EI) m/z Calcd. for C21H26O5Si: 386.1549. Found 386.1562.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[CH:7]=[C:8]1/[C:9](=[O:23])[CH:10]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[C:11](=[O:13])[CH2:12]/1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH:8]1[CH2:12][C:11](=[O:13])[CH:10]([C:14]2[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])[C:9]1=[O:23]
Reactant: Cc1cc(C)c(C2C(=O)C/C(=C\c3sccc3C)C2=O)c(C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(C2C(=O)CC(Cc3sccc3C)C2=O)c(C)c1

Procedure:
To a solution of 4-[1-(3-methylthiophen-2-yl)-meth-(E)-ylidene]-2-(2,4,6-trimethylphenyl)cyclopentane-1,3-dione (100 mg, 0.31 mmol) in methanol (10 ml) is hydrogenated in a H-Cube using 10% palladium on charcoal at 40° C. and 10 bar hydrogen pressure with a flow rate of 0.5 ml/min. The eluate collected is concentrated under vacuum to give a residue which is purified by silica gel column chromatography to give 4-(3-methylthiophen-2-ylmethyl)-2-(2,4,6-trimethylphenyl)cyclopentane-1,3-dione.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2nc(C)ccc2N)ccn1
Reactant: Brc1cncnc1
Product: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cncnc2)ccn1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide in accordance with the general method of example 20 using 5-bromopyrimidine instead of 3-Bromopyridine to yield the final compound as a beige solid, MS (ISP): m/e=321.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[Cl:7][CH2:8][CH2:9]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][CH2:8][Cl:7])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: OCCCl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClCCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-1H-pyrazole (5 g, 34.02 mmol), 2-chloroethanol (2.7 mL, 40.82 mmol) and PPh3 (10.71 g, 40.82 mmol) and in THF (68 mL) at 0° C. was added DEAD (6.4 mL, 40.8 mmol). The mixture was allowed to warm-up to room temperature and stirred overnight. It was then concentrated under reduced pressure, the residue was treated with ether and the resultant suspension was filtered. The filtrate was collected and concentrated under reduced pressure to afford the title compound 75 which was used in the next step without further purification. MS (m/z): 209.0 (M+H).
Reaction SMILES: [C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[CH:24]=[C:25]([C:32]([F:35])([F:34])[F:33])[CH:26]=[C:27]4[C:31]=3[NH:30][N:29]=[CH:28]4)[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O>[C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[CH:24]=[C:25]([C:32]([F:33])([F:35])[F:34])[CH:26]=[C:27]4[C:31]=3[NH:30][N:29]=[CH:28]4)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3cn[nH]c23)(c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CCNCC2)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 4-phenyl-4-(((5-(trifluoromethyl)-1H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (120 mg, 0.245 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 1 mL) and stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 71 mg (74%). 1H-NMR (CDCl3, 500 MHz) δ 8.04 (s, 1H), 7.92 (s, 1H), 7.45 (m, 2H), 7.32-7.42 (m, 3H), 7.26 (s, 1H), 4.70 (s, 2H), 3.57 (s, 2H), 2.90 (m, 2H), 2.76 (m, 2H), 2.20 (m, 2H), 1.86 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 144.1, 139.6, 135.2, 129.0, 127.0, 126.9, 124.7 (q, J=272 Hz), 123.1 (q, J=33 Hz), 122.9, 121.9, 120.3, 118.4, 80.7, 71.8, 50.4, 42.6, 41.7, 33.8. Mass spec.: 390.08 (MH)+. Accurate mass spec.: m/z 390.1801 [MH]+, Δ=2.0 ppm.