Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([CH2:9][N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=[C:11]2[NH:19][CH:20]2[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][OH:29])[CH2:22][CH2:21]2)=[CH:6][CH:5]=1.Cl[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1.O>CN(C)C=O>[N:32]1[CH:33]=[CH:34][CH:35]=[N:36][C:31]=1[O:29][CH2:28][CH2:27][N:23]1[CH2:24][CH2:25][CH2:26][CH:20]([NH:19][C:11]2[N:10]([CH2:9][C:7]3[O:8][C:4]([CH3:3])=[CH:5][CH:6]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=2)[CH2:21][CH2:22]1
Reactant: Cc1ccc(Cn2c(NC3CCCN(CCO)CC3)nc3cccnc32)o1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2c(NC3CCCN(CCOc4ncccn4)CC3)nc3cccnc32)o1
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
To a stirred mixture of 1 part of a sodium hydride dispersion 50% and 94 parts of N,N-dimethylformamide is added dropwise a solution of 5.5 parts of hexahydro-4-[[3-[(5-methyl-2-furanyl)methyl]-3H-imidazo[4,5-b]-pyridin-2-yl]amino]-1H-azepine-1-ethanol in N,N-dimethylformamide. Upon complete addition, stirring is continued for 15 minutes at room temperature. 1.9 Parts of 2-chloropyrimidine are added portionwise and upon completion, stirring is continued for 2 hours at room temperature. The reaction mixture is decomposed with water and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent was evaporated. The residue is converted into the ethanedioate salt in ethanol. The salt is filtered off and dried, yielding 3.4 parts (34.8%) of N-[hexahydro-1-[2-(2-pyrimidinyloxy)ethyl]-1H-azepin-4-yl]-3-[(5-methyl-2-furanyl)methyl]-3H-imidazo[4,5-b]pyridin-2-amine (compound 169).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8]([OH:10])=O.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:25])=[O:26])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:10]
Reactant: Nc1ccccc1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(SC)cc3)cc(C(=O)O)cc2OCCO)c1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(SC)cc3)cc(C(=O)Nc3ccccc3)cc2OCCO)c1

Procedure:
Analogously to Example 74, by condensing 3-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonyl-amino)-benzoic acid with aniline there was obtained 3-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonyl-amino)-N-phenyl-benzamide.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:10][C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)=[CH:3][CH:2]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45]>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:43]=[C:44]([NH:45][C:13]([NH:12][C:11]2[N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:26])=[CH:6][CH:5]=3)[N:8]=[C:9]([C:22]([F:23])([F:25])[F:24])[CH:10]=2)=[O:21])[CH:46]=[CH:47][CH:48]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: Cc1ccc(-n2nc(C(F)(F)F)cc2NC(=O)Oc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccc(C)cc4)c3)c2cc1OC
Yield: 59 %

Procedure:
According to the procedure described in Example 162B, the intermediate phenyl 1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate from the previous step (0.145 g, 0.4 mmol) was reacted with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), to afford 1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as a solid (0.134 g, 59%). 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.75 (s, 1H), 8.55 (d, 1H), 7.55 (m, 2H), 7.39 (m, 6H), 7.19 (d, 1H), 6.95 (d, 1H), 6.84 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 2.41 (s, 3H); LC-MS (ESI) m/z 565 (M+H)+.
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:5]=2[NH:4][C:3]1=[O:20].[CH3:21][C:22]1([NH:28][C:29](=[O:32])[CH2:30]I)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:21][C:22]1([NH:28][C:29](=[O:32])[CH2:30][N:4]2[C:5]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:6]=3[CH:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:8][CH:2]([Br:1])[C:3]2=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC1(NC(=O)CI)CCCCC1
Reactant: Cc1ccc2c(c1)NC(=O)C(Br)CC2c1ccccc1
Product: Cc1ccc2c(c1)N(CC(=O)NC1(C)CCCCC1)C(=O)C(Br)CC2c1ccccc1

Procedure:
Prepared as in Example 20I from 3-bromo-5-phenyl-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one using N-(1-methylcyclohexyl)-iodoacetamide, M.P. x° C., x% yield for the trans isomer.
Reaction SMILES: [Na].[H-].[Na+].[C:4]1(=[N:16][OH:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(O)(=O)/C=C/C([O-])=O>>[O:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][O:17][N:16]=[C:4]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:23][CH2:24]1
Reactant: ClCCCN1CCOCC1
Reactant: ON=C1CCCCCCCCCCC1
Agent: O=C([O-])/C=C/C(=O)O
Agent: [H-]
Agent: [Na+]
Product: C1CCCCCC(=NOCCCN2CCOCC2)CCCCC1

Procedure:
The sodium salt is formed from 2.4 g. (0.1 moles) of sodium hydride and 19.73 g. (0.1 moles) of cyclododecanone oxime in a toluenic medium, then it is reacted with 18.0 g. (0.11 moles) of 1-chloro-3-morpholinopropane. Thereafter one proceeds as in Example 1. Yield: 22.22 g. (68.5%). Hydrogen fumarate, m.p.: 118°-120° C.
Reaction SMILES: C(CCC(ONC([CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)=N)=O)(OC)=O.[C:26]([CH2:30][CH2:31][C:32]([O:34][NH:35][C:36](C1CCCN1C(OC(C)(C)C)=O)=[NH:37])=[O:33])([O:28][CH3:29])=[O:27].C(CCC(ONC(C1C=C(NC(=O)OC(C)(C)C)SC=1)=N)=O)(OC)=O.C(CCC(ONC(C1SC(NC(=O)OC(C)(C)C)=CC=1)=N)=O)(OC)=O.C(CCC(ONC(C1C=NN(C)C=1NC(=O)OC(C)(C)C)=N)=O)(OC)=O.C(CCC(ONC(C1NC=CC=1)=N)=O)(OC)=O.C(CCC(ONC(C1N(C)C=CC=1)=N)=O)(OC)=O.C(CCC(ONC(=N)C1C=CC=C(CO[Si](C(C)C)(C(C)C)C(C)C)C=1)=O)(OC)=O.C(CCC(ONC(=N)C1C=CC(CO[Si](C(C)C)(C(C)C)C(C)C)=CC=1)=O)(OC)=O.C(CCC(ONC(C1C=C(NC(=O)NCC(C)C)SC=1)=N)=O)(OC)=O.C(S(C1SC(N)=C(C(NOC(=O)CCC(OC)=O)=N)C=1)(=O)=O)C.ClCC(NOC(=O)CCC(OC)=O)=N.C(CCC(ONC(C1C(C)=NOC=1NC(=O)OC(C)(C)C)=N)=O)(OC)=O>>[C:26]([CH2:30][CH2:31][C:32]([O:34][NH:35][C:36]([CH:18]1[CH2:13][CH2:14][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16][CH2:17]1)=[NH:37])=[O:33])([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CCC(=O)ONC(=N)C1CCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)CCC(=O)ONC(=N)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: CCS(=O)(=O)c1cc(C(=N)NOC(=O)CCC(=O)OC)c(N)s1
Agent: COC(=O)CCC(=O)ONC(=N)CCl
Agent: COC(=O)CCC(=O)ONC(=N)c1c(C)noc1NC(=O)OC(C)(C)C
Product: COC(=O)CCC(=O)ONC(=N)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl 3-[N-(3-Carbomethoxypropionyloxy)carbamimidoyl]-piperidine-1-carboxylate; tert-Butyl 2-[N-(3-Carbomethoxypropionyloxy)carbamamidoyl]piperidine-1-carboxylate; tert-Butyl 2-[N-(3-Carbomethoxypropionyloxy)carbamimidoyl]pyrrolidine-1-carboxylate; tert-Butyl 4-[N-(3-Carbomethoxypropionyloxy)carbamimidoyl]thiophen-2-ylcarbamate; tert-Butyl 5-[N-(3-Carbomethoxypropionyloxy)carbamimidoyl]thiophen-2-ylcarbamate; tert-Butyl 5-[N-(3-Carbomethoxypropionyloxy)carbamimidoyl]thiophen-2-ylcarbamate; tert-Butyl 4-[N-(3-Carbomethoxypropionyloxy)carbamimidoyl]-2-methyl-2H-pyrazol-3-ylcarbamate; tert-Butyl 5-[N-(3-Carbomethoxypropionyloxy)carbamimidoyl]-1-(2-trimethylsilyl)ethoxymethyl-1H-imidazol-4-ylcarbamate; tert-Butyl 4-[N-(3-Carbomethoxypropionyloxy)carbamimidoyl]-1-(2-trimethylsilyl)-ethoxymethyl-1H-imidazol-5-ylcarbamate; N-(3-Carbomethoxypropionyloxy)-1H-pyrrole-2-carboxamidine; N-(3-Carbomethoxypropionyloxy)-1-methyl-1H-pyrrole-2-carboxamidine; tert-Butyl 4-[N-(3-Carbomethoxypropionyloxy)carbamimidoyl]-1-(2-trimethylsilyl)ethoxymethyl-1H-pyrazol-3-ylcarbamate; N-(3-Carbomethoxypropionyloxy)-3-triisopropylsilyloxymethylbenzamidine; N-(3-Carbomethoxypropionyloxy)-4-triisopropylsilyloxymethylbenzamidine; 3-{4-[N-(3-Carbomethoxypropionyloxy)carbamimidoyl]thiophen-2-yl}-1-isobutylurea.; 5-Ethanesulfonyl-amino-N-(3-carbomethoxypropionyloxy)thiophene-3-carboxamidine; 2-Chloro-N-(3-carbomethoxypropionyloxy)acetamidine; and tert-Butyl [4-(N-(3-Carbomethoxypropionyloxy)carbamimidoyl)-3-methylisoxazol-5-yl]carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:10][CH:11]([CH3:19])[C:12](=O)[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.CS(O)(=O)=O>O>[CH3:17][O:16][C:14](=[O:15])[CH2:13][C:12]1[C:3]2[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=2[S:10][C:11]=1[CH3:19]
Reactant: COC(=O)CC(=O)C(C)Sc1cc(Cl)cc(OC)c1
Agent: CS(=O)(=O)O
Solvent: O
Product: COC(=O)Cc1c(C)sc2cc(OC)cc(Cl)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
To methyl 4-((3-chloro-5-methoxyphenyl)sulfanyl)-3-oxopentanoate (1.86 g) was added methanesulfonic acid (5.98 mL) at 0° C. The mixture was stirred at 0° C. under nitrogen atmosphere for 15 min. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.01 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[CH:4][C:3]=1[O:13][CH3:14].Cl.[N:16]1[O:17][N:18]=[C:19]2[CH:24]=[C:23]([CH2:25][O:26][NH2:27])[CH:22]=[CH:21][C:20]=12.N1C=CC=CC=1.[N+](C1C=CC(CO/N=C2\CCCC3C\2=CC(OC)=C(OC)C=3)=CC=1)([O-])=O>C(O)C.C(OCC)(=O)C.CCCCCC>[N:16]1[O:17][N:18]=[C:19]2[CH:24]=[C:23]([CH2:25][O:26]/[N:27]=[C:9]3\[CH2:8][CH2:7][CH2:6][C:5]4[C:10]\3=[CH:11][C:2]([OH:1])=[C:3]([O:13][CH3:14])[CH:4]=4)[CH:22]=[CH:21][C:20]=12
Reactant: NOCc1ccc2nonc2c1
Reactant: COc1cc2c(cc1O)C(=O)CCC2
Agent: COc1cc2c(cc1OC)/C(=N/OCc1ccc([N+](=O)[O-])cc1)CCC2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1O)/C(=N/OCc1ccc3nonc3c1)CCC2
Yield: 8.9 %

Procedure:
7-Hydroxy-6-methoxy-1-tetralone (83 mg, 0.43 mmol) was subjected to reaction with O-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)hydroxylamine hydrochloride (96 mg, 0.48 mmol) in ethanol (2 mL) and pyridine (0.2 mL, 2.58 mmol) under the same conditions as described for (E)-6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one O-4-nitrobenzyl oxime. Subjection of the material obtained on work up to flash chromatography (3:7 v/v ethyl acetate/hexane elution) afforded the title compound as off-white crystals (13 mg, 9%), m.p. 138° C. (with decomposition), Rf 0.4.
Reaction SMILES: [CH:1]([O:4][CH:5]1[CH2:14][CH2:13][C:8]2(OCC[O:9]2)[CH2:7][CH2:6]1)([CH3:3])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.O>[CH:1]([O:4][CH:5]1[CH2:14][CH2:13][C:8](=[O:9])[CH2:7][CH2:6]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC1CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC1CCC(=O)CC1
Temperature: 100 °C

Procedure:
To a stirred solution of 8-isopropoxy-1,4-dioxaspiro[4.5]decane (0.464 g, 2.317 mmol) in THF (2 mL) and water (2 mL), p-TsOH (0.080 g, 0.463 mmol) was added. The mixture was heated to 100° C. overnight. The resulting mixture was allowed to cool to room temperature and partitioned between EtOAc (30 mL) and water (30 mL). The organic phase was washed with brine (30 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH3:22]>CC(C)=O>[CH2:21]([O:12][C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([CH3:13])=[N:8]2)=[CH:3][C:2]=1[F:1])[CH3:22]
Reactant: Cc1ccc2cc(F)c(O)cc2n1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc2nc(C)ccc2cc1F
Yield: 65.7 %

Procedure:
6-fluoro-2-methylquinolin-7-ol (500 mg, 1.41 mmol) (Example 119, Step B), potassium carbonate (585 mg, 4.23 mmol) and bromoethane (308 mg, 2.82 mmol) in acetone (10 mL) were stirred at 70° C. in a sealed tube for 20 hours. After dilution with water (50 mL) the reaction was extracted with DCM. The organic phases were concentrated and the residue purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-ethoxy-6-fluoro-2-methylquinoline (190 mg, 65.6% yield) as a solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][S:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25].O.[CH:27]([OH:30])(C)C>CN(C)C=O>[CH:27]([C:10]1[O:6][C:7]([CH2:11][S:12][CH2:13][CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])=[CH:8][CH:9]=1)=[O:30]
Reactant: CC(C)O
Reactant: O=C1c2ccccc2C(=O)N1CCSCc1ccco1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(CSCCN2C(=O)c3ccccc3C2=O)o1
Reaction time: 5 h

Procedure:
A solution of phosphoryl chloride (21.4 g) in dry dimethylformamide (40 ml), cooled in ice, was added portionwise to a solution of N-[2-[(2-furanylmethyl)thio]ethyl]-1H-isoindole-1,3(2H)-dione (21.4 g) in dry dimethylformamide (70 ml). After 5 hours at room temperature, the solution was poured into iced water (1.7 l). Isopropyl alcohol (150 ml) was added and after 18 hours the solid which separated was filtered and crystallised from ethyl acetate-ether to give the title compound (22.3 g) m.p. 76°-77°.
Reaction SMILES: CO[C:3](=[O:25])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F:26][C:27]([F:32])([F:31])C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CCOCC>C(Cl)Cl>[C:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([N:5]1[CH2:6][CH2:7][CH2:8][CH:4]1[C:3](=[O:25])[C:27]([F:32])([F:31])[F:26])=[O:24])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)[C@@H]1CCCN1C(=O)c1ccccc1C(=O)c1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccccc1C(=O)N1CCCC1C(=O)C(F)(F)F
Reaction time: 12 h
Yield: 2 %

Procedure:
4.0 g (10.6 mmol) of the title compound of Example 25 was dissolved in 50 ml of methylene chloride at room temperature under an atmosphere of nitrogen. 20 ml (260 mmol) trifluoroacetic acid (TFA) was added and the solution refluxed for 2 hours to hydrolyze the ester. Solvent and excess TFA were then removed under reduced pressure, the residue was redissolved in 22.5 ml (159 mmol) of trifluoroacetic anhydride (TFAA), and the solution ref luxed for 12 hours. The TFAA was evaporated under high vacuum at 80° C. to give an impure yellow gum. Flash chromatography on silica gel with 100% ether afforded 80 mg (2%) of the title compound as a yellow foam. TLC (Ether): Rf =0.50. 1H NMR (CDCl3) δ: 7.32-7.84(m,9H); 4.30-4.96(m,1H); 3.20-3.54 (M,2H); 1.68-2.48(m,4H). High Resolution Mass Spectrum: 376.1170±0.9 ppm (calculated for C20H17NO3F3). 2,4-DNP test: positive
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:28])=[CH:20][N:21]=[C:22]([NH2:27])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.[ClH:29].CO>>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:28])=[CH:20][N:21]=[C:22]([NH2:27])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:15])=[O:16])[CH2:10]1.[ClH:29]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3c(N)ncc(Cl)c23)C1
Agent: Cl
Solvent: CO
Product: Nc1ncc(Cl)c2c(S(=O)(=O)N3CCC(N)C3)cccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Intermediate 28 (30 mg) obtained in Step A mentioned above is added with 10% hydrogen chloride/methanol (4 ml), and the mixture is stirred at room temperature for 20 hours. The solvent is evaporated under reduced pressure to obtain the title compound as hydrochloride (25 mg (predictive yield)).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[CH3:21][N:20]([CH3:22])[C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:33]4[CH:34]=[N:29][CH:30]=[N:31][CH:32]=4)[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: OB(O)c1cncnc1
Reactant: CN(C)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CN(C)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cncnc4)nc3s2)CC1

Procedure:
4-((2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperazine-1-carboxamide was reacted with pyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 268. NMR (CDCl3): 2.55-2.57 (m, 4H, 2×CH2), 2.84 (s, 6H, 2×CH3), 3.31-3.33 (m, 4H, 2×CH2), 3.80 (s, 2H, CH2), 3.90-3.92 (m, 4H, 2×CH2), 3.99-4.02 (m, 4H, 2×CH2), 7.19 (s, H, ArH), 9.28 (s, H, ArH), 9.69 (s, 2H, 2×ArH). MS: (ESI+): MH+=469.24
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[OH-].[K+].O.[Cl:16][C:17]1[CH:18]=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:21][C:22]=1Cl>C1(C)C=CC=CC=1.CS(C)=O.[Cu].[I-].[K+]>[Cl:16][C:17]1[CH:18]=[C:19]([C:24]([F:25])([F:26])[F:27])[CH:20]=[CH:21][C:22]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: [Cu]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C(=O)O)cc1Oc1ccc(C(F)(F)F)cc1Cl
Temperature: 90 °C
Reaction time: 30 h
Yield: 83.6 %

Procedure:
A mixture of 33.6 g (0.2 mol) of 3-hydroxy-4-methoxybenzoic acid and 26.8 g (0.4 mol) of potassium hydroxide (85%) in 200 ml of toluene and 200 ml of dimethyl sulfoxide is dewatered at 140° C. in a sulfonating flask equipped with a water separator. The toluene is distilled off and the mixture is then cooled to 90° C. and 43 g (0.2 mol) of 3,4-dichlorobenzotrifluoride, 1.1 g of potassium iodide and 0.2 g of copper filings in 20 ml of dimethyl sulfoxide are added. The mixture is kept for 30 hours at 150° C. and the solvent is then distilled off under a high vacuum. The residue is dissolved in 250 ml of water, the solution is filtered, the filtrate is acidified with 100 ml of 2N HCl in 200 g of ice and the precipitate obtained is filtered with suction, then washed with water and vacuum-dried at 80° C., affording 58 g of 3-(2-chloro-4-trifluoromethylphenoxy)-4-methoxybenzoic acid. Melting point 162°-165° C.
Reaction SMILES: [Na].Cl[C:3]1[C:8]([C:9]#[N:10])=[C:7]([NH:11][CH2:12][CH3:13])[N:6]=[C:5]([NH:14][C:15]([C:18]#N)([CH3:17])C)[N:4]=1.[CH2:20]([OH:22])[CH3:21]>CO>[CH2:20]([O:22][C:3]1[C:8]([C:9]#[N:10])=[C:7]([NH:11][CH2:12][CH3:13])[N:6]=[C:5]([NH:14][CH:15]([CH3:17])[CH3:18])[N:4]=1)[CH3:21]
Reactant: CCNc1nc(NC(C)(C)C#N)nc(Cl)c1C#N
Reactant: CCO
Agent: [Na]
Solvent: CO
Product: CCNc1nc(NC(C)C)nc(OCC)c1C#N

Procedure:
This compound was prepared in the manner of Example XXXIII, substituting 4-chloro-6-ethylamino-2-isopropylamino-5-pyrimidinecarbonitrile and a solution of sodium in ethanol for 4-chloro-2-(1-cyano-1-methylethylamino)-6-ethylamino-5-pyrimidinecarbonitrile and a solution of sodium in methanol. The reaction product was recrystallized from petroleum ether to give 4-ethoxy-6-ethylamino-2-isopropylamino-5-pyrimidinecarbonitrile; mp, 98°-99°.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(OC([N:26]1[CH2:31][CH2:30][N:29]([CH:32]2[CH2:35][NH:34][CH2:33]2)[CH2:28][CH2:27]1)=O)(C)(C)C.[ClH:36]>>[ClH:36].[CH3:18][O:17][C:6]1[C:5]2[C:9](=[CH:10][C:2]([N:34]3[CH2:35][CH:32]([N:29]4[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]4)[CH2:33]3)=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCN(C2CNC2)CC1
Agent: Cl
Product: COc1nn(-c2ccccc2)c2cc(N3CC(N4CCNCC4)C3)ccc12

Procedure:
The title compound was prepared according to the procedure as described in Example 57 reacting 6-bromo-3-methoxy-1-phenyl-1H-indazole and 4-azetidin-3-yl-piperazine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12](C(OCC)=O)[CH2:11][C@H:10]2[O:20][CH3:21])=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[OH-].[K+]>CC(O)C>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[O:20][CH3:21])=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: CCOC(=O)N1CC[C@H](NC(=O)c2cc(Cl)c(N)cc2OC)[C@H](OC)C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Yield: 46 %

Procedure:
A mixture of 16.6 parts of cis-ethyl 4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-1-piperidinecarboxylate, 26.36 parts of potassium hydroxide and 160 parts of 2-propanol was stirred and refluxed for 3 hours. The reaction mixture was evaporated in vacuo on a boiling water-bath. Water was added to the residue and the whole was evaporated again. The residue was boiled in water on a warm water-bath. The precipitated product was filtered off and taken up in trichloromethane. The organic phase was separated, dried, filtered and evaporated. The residue was taken up in methylbenzene. The solid residue was filtered off and dried, yielding 6.7 parts (46%) of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4piperidinyl)benzamide; mp. 184.3° C. (compound 211).
Reaction SMILES: ClC1C=C[C:5]([CH:8]2[NH:12][C:11]([C:13]3C=CC(OC)=[CH:15][C:14]=3OCC)=N[CH:9]2[CH:24]2CCCCC2)=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[N:41]([C:42]([N:44]3CCN(C)C[CH2:45]3)=[O:43])[C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=3[O:59][CH2:60][CH3:61])=[N:39][CH:38]2[CH2:62][CH:63]2[CH2:67][CH2:66][CH2:65][CH2:64]2)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[N:41]([C:42]([N:44]3[CH2:24][CH2:9][CH:8]([N:12]4[CH2:15][CH2:14][CH2:13][CH2:11]4)[CH2:5][CH2:45]3)=[O:43])[C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=3[O:59][CH2:60][CH3:61])=[N:39][CH:38]2[CH:62]2[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]2)=[CH:33][CH:32]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(C2CCCCC2)C(c2ccc(Cl)cc2)N1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Product: CCOc1cc(OC)ccc1C1=NC(C2CCCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
[5-(4-Chloro-phenyl)-4-cyclohexyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone was prepared from 5-(4-chloro-phenyl)-4-cyclohexyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 11) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 593.3260, calculated for C36H46N4O3Cl [(M+H)+]593.3253.