Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[CH3:32][O:33][CH2:34][C:35]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from cis-4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A156) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[C:12]1([CH3:23])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[CH:19][C:20](=[O:22])[CH3:21]>[O-]CC.[Na+]>[O:5]=[C:3]1[CH2:21][C:20](=[O:22])[CH2:19][CH:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH3:23])[CH:2]1[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC(=O)C=Cc1ccccc1C
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C1C(=O)CC(=O)CC1c1ccccc1C

Procedure:
To a solution of sodium ethoxide (from 1.9 g.sodium and dry ethanol, 30 ml.) was added dropwise diethyl malonate (13 g.). After the addition the mixture was heated under reflux for 1 minute, cooled and then treated with 4-o-tolyl-3-buten-2-one. (13 g.). After heating under reflux for 17 hrs. the mixture was cooled and the precipitated sodium enolate salt (formula III) was collected by filtration, washed with acetone and then dissolved in cold water. The solution was acidified with 2N-H2SO4 and extracted with dichloromethane. After washing the organic solution with water and drying over Na2SO4, removal of solvents under reduced pressure afforded the corresponding dione II, i.e. ethyl 2,4-dioxo-6-o-tolylcyclohexanecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:30]1([C:28]([C:24]2[N:25]=[CH:26][N:27]=[C:22]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:23]=2)=[O:29])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2ccccc21
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5ccccc54)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
110 mg (0.4 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added to 100 mg (0.39 mmol) (6-chloropyrimidin-4-yl)-(2,3-dihydroindol-1-yl)-methanone and 100 μL (0.58 mmol) DIPEA in 10 mL DMF. The reaction mixture was stirred for 2 h at RT and then evaporated down i. vac. The residue was combined with 20 mL water and stirred for 30 min at RT. The precipitated product was suction filtered, stirred with methanol, suction filtered again and dried at 40° C. in the CAD.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>ClCCCl>[Cl:1][CH2:2][C:3]([C:5]1[N:6]([CH3:10])[CH:7]=[C:8]([C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH:9]=1)=[O:4]
Reactant: Cn1cccc1C(=O)CCl
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1cc(C(=O)c2ccc(Cl)cc2)cc1C(=O)CCl
Reaction time: 0.17 h
Yield: 49.2 %

Procedure:
solution of 30 g (0.19 mole) of 2-chloro-1-(1-methyl-1H-pyrrol-2-yl)-ethanone (10) in 180 mL 1,2-dichloroethane (DCE) under an argon atmosphere was cooled in an ice bath and 60 g AlCl3 (0.45 mole) was added in portions. After stirring for 10 minutes, a solution of 24 mL (0.19 mole) 4-chlorobenzoyl chloride in 110 mL DCE was added dropwise. The ice bath was removed and the reaction was stirred at room temperature overnight. The reaction was poured into 1N HCl/ice and the aqueous layer was extracted three times with methylene chloride. The organics solutions were combined, washed with water, 1N NaOH, water, brine, and dried (MgSO4). Evaporation of the solvent in vacuo gave a solid which was recrystallized from ethyl acetate/methylcyclohexane to give 27.67 g of a solid: mp 130-132° C.; NMR 300 MHz (CDCl3) d 7.8 (m, 2H); 7.6-7.4 (m, 4H); 4.5 (s, 2H); 4.0 (s, 3H). Anal Calcd for C14H11Cl2NO2: C, 56.78; H, 3.74; N, 4.73. Found: C, 56.72; H, 3.76; N, 4.73.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)=[O:4].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Cl)cc1
Temperature: 40 °C

Procedure:
A suspension of 5 g of the acid, prepared in section (a) above, in 50 cm3 of thionyl chloride is heated for 3 hours at 40° C. At the end of the reaction, the reaction medium is homogenized and the solution is concentrated under reduced pressure. The expected acid chloride crystallizes in the form of pink flakes. The yield is quantitative. This solid is employed directly for the condensation reaction.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:2]1=2.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[N+:15]([C:9]1[C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:3]2[O:4][CH2:5][CH2:6][O:1][C:2]=2[CH:10]=1)([O-:17])=[O:16]
Reactant: COC(=O)c1ccc2c(c1)OCCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(cc1[N+](=O)[O-])OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of methyl 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (780 mg, 4.0 mmol) in acetic acid (3 mL) was added dropwise conc. HNO3 (4 mL) while keeping the temperature below 20° C. and the resulting reaction mixture was warmed to room temperature. After stirring for 1 hr, the mixture was poured onto ice-water with vigorous stirring. The resulting white precipitate was collected by vacuum filtration and dried under reduced pressure to yield methyl 7-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (889 mg, 92%). 1H NMR (DMSO-d6, 600 MHz) δ 7.64 (s, 1H), 7.30 (s, 1H), 4.41-4.38 (m, 4H), 3.80 (s, 3H); MS (ES+) m/z 240.0 (M+H)+
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:21]2[C:16](=[C:17]([O:26][CH3:27])[C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1)=[O:7])C.C(O)C.Cl>O1CCCC1>[C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:21]2[C:16](=[C:17]([O:26][CH3:27])[C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)CCCNc1ncnc2c(OC)c(OC)c(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc2c(NCCCC(=O)O)ncnc2c(OC)c1OC
Temperature: 25 °C
Yield: 74.7 %

Procedure:
5 ml of a 1N aqueous solution of sodium hydroxide is added to a solution of 0.52 g (1.5 mmol) of the 4-(3-ethoxycarbonylpropyl)amino-6,7,8-trimethoxyquinazoline obtained in Example 1 in tetrahydrofuran (5 ml)/ethanol (5 ml), followed by stirring at room temperature one whole day and night. The reaction liquid is neutralized with 5 ml of 1N hydrochloric acid, and then concentrated under reduced pressure. The crystals thus precipitated are recovered by filtration, washed with water, and dried with air. Thus, 0.36 g (yield 744%) of a pale-yellow crystal is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][C@@H:34]([CH3:46])[CH2:35][O:36][CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[C@@H:34]([CH3:46])[CH2:35][O:36][CH2:37][CH2:38][CH2:39][C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)=[O:23])=[CH:24][CH:25]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CC(C)N[C@@H](C)COCCCc1ccccc1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COCCCc3ccccc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and N-isopropyl-N—[(S)-1-methyl-2-(3-phenyl-propoxy)-ethyl]-amine as described for example 1.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1>CN(C=O)C>[CH:20]1([CH2:23][N:5]2[C:6]([C:11]([NH2:13])=[O:12])=[C:7]([N+:8]([O-:10])=[O:9])[C:3]([CH2:1][CH3:2])=[N:4]2)[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nn(CC2CC2)c(C(N)=O)c1[N+](=O)[O-]
Yield: 23 %

Procedure:
A suspension of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (40.0 g, 217 mmol, prepared using procedure in WO9849166) in dry DMF (300 ml) was treated with cesium carbonate (77.8 g, 239 mmol). To this, in a single portion, was added cyclopropylmethyl bromide (32.2 g, 239 mmol) and the resultant suspension stirred at 20° C. for 6 h. After concentrating in vacuo, the residue was partitioned between EtOAc (200 ml) and water (200 ml), and the insoluble material removed by filtration. The solid was partitioned between water (200 ml) and DCM (200 ml), and undissolved solid removed by filtration. Combined organics were washed with brine (100 ml), dried (MgSO4), filtered and concentrated in vacuo to a solid (˜40 g). The two regioisomers were separated by crystallisation of the crude mixture. The more lipophilic component (Rf=0.27, DCM:MeOH 98:2) crystallised from a mixture of DCM (50 ml) and diisopropylether (200 ml) to give 1-(cyclopropylmethyl)-3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (11.9 g, 50.0 mmol, 23%). Crystallisation of the mother liquors from MeCN gave the more polar component (Rf=0.19, DCM:MeOH 98:2) (10.0 g, 42.0 mmol) which was confirmed as 1-(cyclopropylmethyl)-5-ethyl-4-nitro-1H-pyrazole-3-carboxamide by nOe studies. The mother liquors contained further material as a mixture of regioisomers (20.0 g, 84.0 mmol). 1-(cyclopropylmethyl)-3-ethyl-4-nitro-1H-pyrazole-5-carboxamide:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([NH:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]#[N:15])[CH:7]=1.O.O.[Sn](Cl)[Cl:22]>C(O)C.Cl>[ClH:22].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]=[C:14]([NH2:15])[C:13]3[CH:12]=[CH:11][S:10][C:9]=3[NH:8][C:6]=2[CH:7]=1
Reactant: Cl[Sn]Cl
Reactant: N#Cc1ccsc1Nc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC1=Nc2ccc(F)cc2Nc2sccc21
Temperature: 25 °C
Yield: 83.3 %

Procedure:
Suspend 2-(5-fluoro-2-nitro-phenylamino)-thiophene-3-carbonitrile (3.89 g, 14.78 mmol) in ethanol (40.0 ml). Dissolve tin(II) chloride dihydrate (10.00 g, 44.33 mmol) in 5N HCl (40.0 ml) and then add it to the suspension. Heat the reaction at reflux for 2.5 hours and then cool it to ambient temperature. Collect the resulting precipitate by vacuum filtration and then dry it under vacuum to give 3.32 g (83%) of the title compound: mass spectrum (ion spray): m/z=234.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:23])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]=O>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:23]=[CH:29][C:25]2[O:24][CH:28]=[CH:27][CH:26]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N
Reactant: O=Cc1ccco1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N=Cc1ccco1

Procedure:
The present compound was synthesized by a method similar to that in Example 210 and using 2-amino-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (210 mg) and furan-2-carbaldehyde. A colorless powder (125 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)=[O:4].[CH2:17]([N:21]([CH2:47][CH:48]([CH3:50])[CH3:49])[C:22]([C:24]1[CH:46]=[CH:45][C:27]2[N:28]([CH2:32][CH2:33][CH2:34][N:35]([CH3:44])[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[C:29](=[S:31])[NH:30][C:26]=2[CH:25]=1)=[O:23])[CH:18]([CH3:20])[CH3:19]>O1CCCC1>[CH2:47]([N:21]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:22]([C:24]1[CH:46]=[CH:45][C:27]2[N:28]([CH2:32][CH2:33][CH2:34][N:35]([CH3:44])[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[C:29]([S:31][CH2:2][C:3](=[O:4])[C:5]3[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=3)=[N:30][C:26]=2[CH:25]=1)=[O:23])[CH:48]([CH3:49])[CH3:50]
Reactant: CC(C)CN(CC(C)C)C(=O)c1ccc2c(c1)[nH]c(=S)n2CCCN(C)CCc1ccccn1
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Solvent: C1CCOC1
Product: COc1cc(C(=O)CSc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCCN(C)CCc2ccccn2)cc(OC)c1OC
Temperature: 20 °C
Reaction time: 15 h

Procedure:
Morpholinomethylpolystyrene resin (acquired from Novabiochem, 2 eq) and 2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone are added successively to a solution of N,N-diisobutyl-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-2-thioxo-2,3-dihydro-1H-benzimidazole-5-carboxamide in tetrahydrofuran. The mixture is stirred for 15 hours at approximately 20° C. then tetrahydrofuran, aminomethylpoystyrene resin (2 eq, acquired from Novabiochem) and 4-bromomethylphenoxymethyl-polystyrene resin (3 eq, acquired from Novabiochem) are added. After stirring for 6 hours, the mixture is filtered on frit. The filtrate is then concentrated to dryness under reduced pressure at 40° C. in order to produce the expected compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([F:16])=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([F:24])[CH:23]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:16][C:5]1[CH:6]=[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[C:2]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[C:22]([F:24])[CH:23]=2)=[N:3][CH:4]=1
Reactant: Cc1nc(N)nc(-c2cc(F)cnc2Cl)n1
Reactant: Nc1cncc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cc(F)cnc2Nc2cncc(F)c2)n1
Reaction time: 0.08 h
Yield: 16.1 %

Procedure:
A solution of 4-(2-chloro-5-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (85 mg, 0.355 mmol) and 3-amino-5-fluoropyridine (118 mg, 1.053 mmol) in THF (3 mL) was cooled in an ice bath under nitrogen. After 5 min, a solution of LiHMDS (1 M in THF, 2500 μL, 2.500 mmol) was added. After 10 min, the cooling bath was removed. After 2 h, HCl (5 N, 0.5 mL) was added. EtOAc (10 mL) and saturated NH4Cl (10 mL) were added. The mixture was vigorously stirred for 15 min. The resulting emulsion was filtered through a glass frit. The collected solid was dissolved in warm DMSO and purified by prep HPLC (30-75% MeCN/water/w 0.1% TFA over 20min). The collected product fractions were concentrated to dryness. Saturated NaHCO3 (10 mL) was added. The mixture was neutralized with HCl (5 N) and filtered. The filtrate was extracted with iPrOH (5%) in CHCl3 (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated to a yellow solid which was filtered as a suspension in ether to give the product as a yellow powder (18 mg). LCMS (ES, pos.): calcd for C14H11F2N7: 315.1; found: 316.1 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.18 (s, 1H); 8.82 (s, 1H); 8.62 (dd, J=9.78, 3.13 Hz, 1H); 8.44-8.53 (m, 2H); 8.18 (d, J=2.54 Hz, 1H); 8.04 (br. s., 1H); 7.90 (br. s., 1H); 2.46 (s, 3H). 19F NMR (377 MHz, d6-DMSO) δ −139.21 (s, 1 F); −127.41 (s, 1 F).
Reaction SMILES: [CH2:1]([CH:3]1[CH:7]([C:8]([OH:10])=O)[NH:6][C:5](=[O:11])[NH:4]1)[CH3:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21]>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:8]([CH:7]1[CH:3]([CH2:1][CH3:2])[NH:4][C:5](=[O:11])[NH:6]1)=[O:10]
Reactant: COc1ccccc1OC
Reactant: CCC1NC(=O)NC1C(=O)O
Product: CCC1NC(=O)NC1C(=O)c1ccc(OC)c(OC)c1
Temperature: 100 °C

Procedure:
In 100 g PPA are suspended 15.8 g 4-ethyl-2-oxoimidazolidine-5-carboxylic acid and 13.8 g 1,2-dimethoxybenzene. The mixture is rapidly stirred and heated for 5 hours at 100° C. The reaction mixture is quenched with water and the product separates as a solid. The solid is collected and washed with water and dried. Purification is effected by chromatography over silica gel.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[C:8]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:7]=1>CO.C(#N)C>[Cl:5][C:6]1[N:11]=[C:10]([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:9]=[C:8]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:7]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: NC1CC1
Solvent: CO
Solvent: CC#N
Product: FC(F)(F)COCc1cc(NC2CC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A solution of cyclopropanamine (68 mg, 1.20 mmol) in MeOH (2 mL) was added dropwise to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (104 mg, 0.40 mmol) in acetonitrile (2 mL). The mixture was stirred at rt overnight. The mixture was purified by preparative HPLC yielding to give the title compound (64 mg, 57%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([NH2:13])=[C:5]([NH2:14])[CH:4]=1.[C:17](O)(=[O:21])[C:18](O)=[O:19]>Cl>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[NH:13][C:18](=[O:19])[C:17](=[O:21])[NH:14]2
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(C(F)(F)F)c(C(F)(F)F)cc1N
Agent: Cl
Product: O=c1[nH]c2cc(C(F)(F)F)c(C(F)(F)F)cc2[nH]c1=O
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A mixture of 102 mg (0.418 mmol) of 4,5-bis(trifluoromethyl)-1,2-phenylenediamine and 37 mg (0.411 mmol) of oxalic acid in 2 mL of 2N HCl was refluxed for 6 h and cooled to room temperature. The mixture was filtered and washed by water, CHCl3 and dried to leave a colorless solid (43 mg, 35%), mp>250° C. 1H NMR (DMSO-d6), 7.629 (s, 2) 12.293 (s, 2). 19F NMR (DMSO-d6), 62.185 (s).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>O1CCCC1>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:25]
Reactant: COC(=O)c1c(N)cccc1Cl
Reactant: O=C(Cl)CCCCBr
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1c(Cl)cccc1NC(=O)CCCCBr
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 750 mg of methyl 2-amino-6-chlorobenzoate as synthesized in above Step 7-18-A in 10 ml of tetrahydrofuran, first 700 mg of pyridine and then 800 mg of 5-bromovaleryl chloride were added under cooling with ice. The solution was warmed to room temperature, stirred for an hour and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to provide 1.34 g (96%) of methyl 2-(5-bromopentanoylamino)-6-chlorobenzoate.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:22])([F:21])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].Cl>CCCCCC.ClCCl>[CH3:24][C:23]([C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:6]([F:21])([F:22])[F:5])[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:25]
Reactant: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Yield: 90 %

Procedure:
To a mixture of 2.43 moles (324 g.) of aluminum chloride in 648 ml. of dichloromethane is added a solution 0.88 mole (274 g.) of 1,4-bis(2,2,2-trifluoroethoxy)benzene and 0.97 mole (92 ml.) of acetic anhydride in 880 ml. of dichloromethane over a 3 hour period while maintaining the temperature at above 0° C. The reaction mixture is then heated to its reflux temperature and stirred at reflux for 5 hours. The progress of the reaction is followed using thin-layer chromatography. The reaction mixture is placed in an ice bath and ice and 10 percent hydrochloric acid are added slowly to decompose the aluminum chloride complex. The temperature of the reaction mixture is not allowed to exceed 25° C. The organic phase is separated and washed once with 2 liters of 10 percent hydrochloric acid and then with 2 liters of water. The combined aqueous phase is extracted with several liters of dichloromethane. The organic phase is dried over magnesium sulfate, then evaporated to provide a moist residue. Hexane is added to the residue and the resulting solid is collected by filtration and washed with hexane. Upon drying, 250 g. of light yellow crystalline 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is obtained. The yield is 90 percent, the m.p is 84° to 86° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:24]2[O:23][CH2:22][CH2:21][C:20]([C:25]([NH:27][C:28]([NH2:30])=[NH:29])=[O:26])=[CH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1)=[O:13])=O)(C)(C)C.[ClH:31].C(OC(C)C)(C)C>O1CCOCC1>[ClH:31].[ClH:31].[NH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:24]2[O:23][CH2:22][CH2:21][C:20]([C:25]([NH:27][C:28]([NH2:30])=[NH:29])=[O:26])=[CH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cccc2c1OCCC(C(=O)NC(=N)N)=C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: N=C(N)NC(=O)C1=Cc2cccc(C(=O)NCCN)c2OCC1
Reaction time: 18 h

Procedure:
To a solution of {2,3-dihydro-9-[2-(tert-butoxycarbonylamino)ethylaminocarbonyl]-1-benzoxepin-4-carbonyl}guanidine (0.8 g) in 1,4-dioxane (8 ml) was added 4N hydrogen chloride in 1,4-dioxane (8 ml) at ambient temperature and the mixture was stirred at the same temperature for 18 hours. Diisopropyl ether (10 ml) was added to the mixture and the precipitate was collected by filtration. The precipitate was recrystallized from a mixture of methanol and diisopropyl ether to give [2,3-dihydro-9-(2-aminoethylaminocarbonyl)-1-benzoxepin-4-carbonyl]guanidine dihydrochloride (0.57 g).