Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[S:18][C:17]([CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[C:16]([CH3:25])[CH:15]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH2:21]([N:20]([CH2:19][C:17]1[S:18][C:14]([C:12]2[O:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:4][CH:5]=3)[N:13]=2)=[CH:15][C:16]=1[CH3:25])[CH2:23][CH3:24])[CH3:22]
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CN)cc3)no2)cc1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CNS(C)(=O)=O)cc3)no2)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.7 %

Procedure:
To a solution of {5-[3-(4-aminomethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-diethyl-amine (60 mg, 168 μmol) and DIPEA (33 mg, 252 μmol) in DCM (10 mL), methanesulfonyl chloride (23 mg, 202 μmol) is added. The mixture is stirred at rt for 15 h before it is diluted with DCM and washed with sat. aq. NaHCO3 solution. The washing is extracted back three times with DCM, the organic extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC. The product containing fractions are combined and concentrated. The product is dissolved in methanol and filtered over Amberlyst A21. The filtrate is evaporated and dried to give the title compound (10 mg) as a colourless resin; LC-MS: tR=0.52 min; [M+1]+=435.03; 1H NMR (CDCl3): δ1.14 (t, J=7.0 Hz, 6H), 2.27 (s, 3H), 2.68 (q, J=6.8 Hz, 4H), 2.93 (s, 3H), 3.79 (s, 2H), 4.42 (d, J=5.8 Hz, 2H), 5.04-5.10 (m, 1H), 7.51 (d, J=8.3 Hz, 2H), 7.68 (s, 1H), 8.15 (d, J=8.3 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[C:16]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][CH:32]=[C:33]([CH2:35]Cl)[N:34]=2)=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][CH:32]=[C:33]([CH2:35][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:34]=2)=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(c1ccccc1)c1ccc(-c2nc(CCl)co2)cc1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: O=C(c1ccccc1)c1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)cc1
Yield: 78 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(4-benzoylphenyl)-4-chloromethyloxazole to give 2-(4-benzoylphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 78%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 112-113° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1[CH:26]=[C:25]([CH:27]=O)[CH:24]=[N:23][CH:22]=1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:25]3[CH:26]=[N:21][CH:22]=[N:23][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1cncnc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4cncnc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 14.3 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and Pyrimidine-5-carbaldehyde (17.6 mg, 0.163 mmol) were reacted to produce 9.0 mg (14%) of the title compound. mp: >300° C., 1H NMR (300 MHz, DMSO-d6): 13.7 (s, 1H), 9.42 (s, 2H), 9.28 (s, 1H), 8.10 (s, 1H), 7.77 (s, 1H), 7.35 (m, 1H), 7.23 (s, 1H), 6.39 (d, J=8 Hz, 1H), 5.22 (t, J=8 Hz, 1H), 3.3 (s, 1H), 2.90 (s, 1H), 2.78 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 1.40 (d, J=9 Hz, 1H). MS: 426, 428 (M+H), HPLC: 1.91 min (G method).
Reaction SMILES: Cl.C([O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[NH:16][C:17]([NH2:19])=[NH:18])=O)C.[OH-].[Na+].Cl>O>[NH2:18][CH:17]1[N:16]=[C:8]2[N:9]=[C:10]3[C:15]([CH:14]=[CH:13][CH:12]=[CH:11]3)=[C:7]2[C:5](=[O:4])[NH:19]1
Reactant: CCOC(=O)c1c(NC(=N)N)[nH]c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC1N=C2N=c3ccccc3=C2C(=O)N1
Yield: 80.1 %

Procedure:
A mixture of 2-guanidinoindole-3-carboxylic acid ethyl ester hydrochloride (1.00 g, 3.5 mmol) and sodium hydroxide (1.5 g) in water (50 mL) is heated to gentle reflux for 6 hr followed by the addition of sufficient 5% HCl to adjust the solution to pH 1, and filtration of the resulting mixture through celite, washing the pad with water. The filtrate is extracted with ethyl acetate (3×25 mL), and then basified with solid sodium carbonate. The tan precipitate which slowly forms is collected by filtration, washed with water, and dried in vacuo affording 2-amino-4-oxo-3H-indolo[2,3-d]pyrimidine (561 mg, 78%) as light tan crystals, mp >275 C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[C:14](N)=[O:15].[OH-:17].[K+].CO>O>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[C:14]([OH:15])=[O:17]
Reactant: COc1ccc2c(c1OC)CCC2C(N)=O
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1OC)CCC2C(=O)O
Temperature: 25 °C
Yield: 91.2 %

Procedure:
The mixture of 4,5-dimethoxyindane-1-carboxamide (8.4 g, 38.0 mmol), KOH (6.4 g, 114.0 mmol), MeOH (31.0 mL) and water (62 mL) was heated to refluxed for 14 h. The reaction mixture was cooled to room temperature, and MeOH was removed in vacuo. The residue was diluted by 50 mL of water, and the aqueous mixture was extracted with EtOAc (50×2). The aqueous layer was added conc. HCl to adjusted pH ˜1. The solid was filtered, washed by water (100 mL), and dried over P2O5 to afford 4,5-dimethoxyindane-1-carboxylic acid as off-white solid (7.7 g, 92%). M. P.: 128-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:31][NH:32][C:33]([NH:35][OH:36])=[NH:34].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[N:31][NH:32][C:33](=[NH:34])[NH:35][OH:36])[CH2:9]1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(NN)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)NO)CC(c1ccccc1Cl)C2
Temperature: 90 °C
Reaction time: 3 h
Yield: 166.3 %

Procedure:
A mixture of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (679 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (917 mg) and concentrated hydrochloric acid (0.3 ml) in ethanol (10 ml) was stirred at 90° C. (bath temperature) for 3 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (40 ml), tetrahydrofuran (30 ml) and 0.2 N sodium hydroxide (50 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (20 ml) and water (15 ml, thrice). To the upper layer was added 2 N hydrochloric acid (2.5 ml), and the mixture was concentrated under reduced pressure. To the residue was added ethanol (10 ml), and the mixture was stirred at 900° C. (bath temperature) for 3 hours and cooled to give crystals, which were filtered to give 7-(2-chlorophenyl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 106) (790 mg) as pale yellow crystals.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.[Br:9][C:10]1[CH:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]([C:25](OCC)=[O:26])[CH2:20][CH2:21][CH2:22][C:23]=2[CH3:24])=[O:16])[N:12]([C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[N:11]=1>ClCCl>[Br:9][C:10]1[CH:14]=[C:13]([C:15]([NH:17][C:18]2[CH:23]([CH3:24])[CH2:22][CH2:21][CH2:20][C:19]=2[C:25]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:26])=[O:16])[N:12]([C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[N:11]=1
Reactant: CC(C)N
Reactant: CCOC(=O)C1CCCC(C)=C1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)NC(=O)C1=C(NC(=O)c2cc(Br)nn2-c2ncccc2Cl)C(C)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isopropyl amine (77 μL, 0.9 mmol) was added to a solution of trimethylaluminum (0.45 mL, 2M solution in hexanes, 0.9 mmol) in dichloromethane (10 mL). After stirring at ambient temperature for 1 h, ethyl 2-[[[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]carbonyl]amino]-3-methyl-2-cyclohexene-1-carboxylate (i.e. the product of Step G) was added (425 mg, 0.9 mmol) in dichloromethane (5 mL) and the solution was heated at reflux for 24 hours and then overnight at ambient temperature. The reaction was quenched with water and the mixture was filtered through a column of celite and washed with dichloromethane. The eluent was concentrated and purified by silica gel column chromatography (eluted with 60% then 80% ethyl ether in petroleum ether then ethyl ether then ethyl acetate) to give the title compound, a compound of present invention, as a colorless oil (100 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH:12]1([CH2:15][OH:16])[CH2:14][CH2:13]1.CC([O-])(C)C.[K+].O>C1COCC1>[Br:1][C:2]1[C:3]([O:16][CH2:15][CH:12]2[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: OCC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cnc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.6 %

Procedure:
A solution of 3-bromo-2-chloro-5-nitropyridine (2.4 g, 10 mmol) and cyclopropylmethanol (970 uL, 12 mmol) in THF (50 ml) was treated with KOtBu (3.3 g, 15 mmol). After stirring at rt for 12 h, the mixture was treated with water (150 ml) and extracted with EtOAc (3×50 ml); the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow solid. The solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 30%) in hexanes to afford the title compound (1.3 g, 48%) as a yellow solid. LCMS (M+H)+=274.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21].[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25]>CO>[CH3:28][O:27][C:23](=[O:26])[CH2:24][CH2:25][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: Cc1c(CC(N)=O)c2cc(N)ccc2n1Cc1ccccc1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCNc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1
Yield: 55 %

Procedure:
A solution of 147 mg (0.5 mmol) of 5-amino-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide (Example 18) and 2 mL of methyl acrylate in 5 mL of MeOH was stirred for 65 hours, then concentrated at reduced pressure. The residue was chromatographed on silica and eluted with a gradient (EtOAc→45% MeOH/EtOAc) to give a major product and a minor product in the later fractions. The major product was 105 mg (55% yield) of 3-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]amino]propanoic acid methyl ester.
Reaction SMILES: C(OC([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][C:25]=3[CH3:37])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[N:10]=[C:9]1[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][N:57](C(OC(C)(C)C)=O)[CH3:58])[CH:39]=1)=O)(C)(C)C.O.[ClH:67].O1CCOCC1>>[ClH:67].[CH3:37][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][S:19]([N:16]1[CH2:15][CH2:14][C:11]2([N:10]=[C:9]([C:38]3[CH:43]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:41]=[C:40]([O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][NH:57][CH3:58])[CH:39]=3)[NH:8][C:12]2=[O:13])[CH2:18][CH2:17]1)(=[O:20])=[O:21])[C:30]([OH:32])=[O:31]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(OCCOCCOCCN(C)C(=O)OC(C)(C)C)cc(C(F)(F)F)c1)N(C(=O)OC(C)(C)C)C2=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CNCCOCCOCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)O)cc4C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
2-[3-(2-{2-[2-(tert-Butoxycarbonyl-methyl-amino)-ethoxy]-ethoxy}-ethoxy)-5-trifluoromethyl-phenyl]-8-[2-(4-tert-butoxycarbonyl-2-methyl-phenyl)-ethanesulfonyl]-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-3-carboxylic acid tert-butyl ester (37.4 mg, 39.7 μmol) was dissolved in 4 N hydrochloric acid-dioxane (0.79 mL). Water (14.3 μL, 795 μmol) was added and the mixture was stirred at room temperature for three hours. The reaction solution was concentrated under reduced pressure to give 3-methyl-4-{2-[2-(3-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethoxy}-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-benzoic acid hydrochloride (28.0 mg, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=O)[S:27][CH:28]=1.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:10]([O:9][C:7]([NH:6]/[C:5](=[CH:29]\[C:26]1[S:27][CH:28]=[C:24]([CH3:23])[CH:25]=1)/[C:3]([O:2][CH3:1])=[O:4])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1csc(C=O)c1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)/C(=C/c1cc(C)cs1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A stirred solution of N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (5.01 g, 15.1 mmol) and 4-methylthiophene-2-carbaldehyde (95a) (2.50 g, 19.8 mmol) in dry dichloromethane (100 mL) was cooled to 0° C. and treated dropwise with DBU (2.76 g, 18.1 mmol). The mixture was warmed to ambient temperature and stirred overnight. The solution was concentrated, taken up in ethyl acetate (150 mL) and washed with 5% hydrochloric acid (2×100 mL). The organic extract was washed with saturated aqueous sodium bicarbonate (2×150 mL), water (200 mL), dried (magnesium sulfate), filtered and evaporated. The residue was purified by crystallization from 4:1 (v/v) ethyl acetate/hexanes to afford the title compound (3.38 g, 67%) as the sole product. 1H NMR (300 MHz, d6-DMSO) δ2.20 (s, 3H), 3.70, (s, 3H), 5.12 (s, 2H), 7.20-7.52 (m, 7H), 7.69 (s, 1H), 8.82 (s, 1H). MS APCI, m/z=354 (M+Na). LC/MS: 2.43 min.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:13])([F:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C.[NH3:15]>CO>[F:12][C:5]([F:13])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]([NH2:15])=[O:3]
Reactant: CCOC(=O)C(F)(F)c1ccccc1
Reactant: N
Solvent: CO
Product: NC(=O)C(F)(F)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of the above difluoro-phenyl-acetic acid ethyl ester and NH3 in MeOH (7 M, 10 mL) is heated to 60° C. for 2 h in a pressure tube. The mixture is cooled to room temperature, and concentrated to afford 2,2-difluoro-2-phenyl-acetamide (0.33 g). LCMS: RT=1.7 minutes; MS: 172 (M+H).
Reaction SMILES: FC1C=[C:4]([NH:9][C:10]2[C:11](=[O:23])[NH:12][C:13](=[O:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=2)[CH:5]=CC=1C.CN([CH:27]=[O:28])C>Cl>[CH3:27][O:28][CH2:5][CH2:4][NH:9][C:10]1[C:11](=[O:23])[NH:12][C:13](=[O:22])[C:14]=1[C:15]1[CH:16]=[CH:17][C:18]([I:21])=[CH:19][CH:20]=1
Reactant: Cc1ccc(NC2=C(c3ccc(I)cc3)C(=O)NC2=O)cc1F
Reactant: CN(C)C=O
Agent: Cl
Product: COCCNC1=C(c2ccc(I)cc2)C(=O)NC1=O

Procedure:
A solution of 3-(3-fluoro-4-methylphenylamino)-4-(4-iodophenyl)-1H-pyrrole-2,5-dione (Example A705, 126 mg, 0.3 mmol) and 2-methoxyethylazine (0.2 mL, 2,3 mmol) in DMF (2 mL) was stirred at room temperature for 113 hours then diluted with hydrochloric acid (0.5M, 50 mL) and extracted with ethyl acetate (50 mL). The ethyl acetate solution was washed with water (2×50 mL) and brine (50 mL), dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel using dichloromethane-diethyl ether (99:1 v/v) as eluent to afford the title compound, a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C@H:11]([N:15]1[CH:19]=[C:18]([C:20]([O:22]CC)=O)[N:17]=[CH:16]1)[C@@H:12]([OH:14])[CH3:13].[OH-].[NH4+:26]>COCCOC>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C@H:11]([N:15]1[CH:19]=[C:18]([C:20]([NH2:26])=[O:22])[N:17]=[CH:16]1)[C@@H:12]([OH:14])[CH3:13]
Reactant: CCOC(=O)c1cn([C@@H](CSc2cccc(Cl)c2Cl)[C@H](C)O)cn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: COCCOC
Product: C[C@H](O)[C@H](CSc1cccc(Cl)c1Cl)n1cnc(C(N)=O)c1

Procedure:
A mixture of ethyl 1-{(1R,2S)-1-{[(2,3-dichlorophenyl)thio]methyl}-2-hydroxypropyl}-1H-imidazole-4-carboxylate (0.17 g), 28% ammonium hydroxide (10 mL) and 1,2-dimethoxyethane (20 mL) was heated at 100° C. in the stainless steel bottle for 24 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (elution; 10:1 chloroform-1% ammonium hydroxide/methanol) to give the product, which was recrystallized from 1:1 n-hexane-ethyl acetate (10 mL) to give 1-{(1R,2S)-1-{[(2,3-dichlorophenyl)thio]methyl}-2-hydroxypropyl}-1H-imidazole-4-carboxamide (104) (0.10 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][N:26]1[C:30]2[CH:31]=[C:32]([C:35]([OH:37])=O)[CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1.CN(C=O)C.[CH3:43][C:44]1[O:48][C:47](=[O:49])[O:46][C:45]=1[CH2:50][O:51][C:52](=[O:72])[C@H:53]([OH:71])[CH2:54][C@H:55]([NH2:70])[CH2:56][C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([Cl:69])[CH:64]=2)=[CH:59][CH:58]=1.CCN(C(C)C)C(C)C>>[CH3:43][C:44]1[O:48][C:47](=[O:49])[O:46][C:45]=1[CH2:50][O:51][C:52](=[O:72])[C@H:53]([OH:71])[CH2:54][C@H:55]([NH:70][C:35]([C:32]1[CH:33]=[CH:34][C:29]2[N:28]=[N:27][N:26]([OH:25])[C:30]=2[CH:31]=1)=[O:37])[CH2:56][C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([Cl:69])[CH:64]=2)=[CH:59][CH:58]=1
Reactant: O=C(O)c1ccc2nnn(O)c2c1
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1ccc2nnn(O)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
HATU (37.9 mg, 99.6 μmol) was added to a solution of 1-hydroxy-1H-1,2,3-benzotriazole-6-carboxylic acid (14.9 mg, 83 μmol) in DMF (0.5 mL, 6.4 mmol) and the resulting mixture was stirred at room temperature for 5 minutes. (2R,4R)-4-Amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid 5-methyl-2-oxo[1,3]dioxol-4-ylmethyl ester (28.7 mg, 66.4 μmol) was added to the mixture, followed by DIPEA (35 μL, 0.2 mmol) dropwise over 5 minutes, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo to yield a yellow liquid, which was purified by preparative HPLC to yield the title compound as a white solid (37.8 mg, purity 98.5%). MS m/z [M+H]+ calc'd for C29H25ClN4O8, 593.14. found 593.0.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH3:10]
Reactant: OCCCCBr
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(C)c1OCCCCO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-hydroxy-3,5-dimethyl benzaldehyde (5.00 g, 33.3 mmol) in DMF (30 mL) were added 4-bromo-butan-1-ol (6.11 g, 39.9 mmol) and Cs2CO3 (16.2 g, 50.0 mmol). The reaction mixture was stirred at room temperature for 48 hours, then water (100 mL) was added, and the products were extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. Solvent was removed and the crude product was purified by the Simpliflash system, using 40% ethyl acetate in hexane as eluent, to give 4-(4-hydroxybutoxy)-3,5-dimethyl benzaldehyde as a colorless liquid. Yield: 0.66 g (7%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C:15]4[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1>>[CH3:22][N:12]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([C:28]4[CH:27]=[N:26][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:30][CH:29]=4)=[CH:3][C:4]=3[C:5]=2[N:14]([C:15]2[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=2)[C:13]1=[O:21]
Reactant: Cn1nccc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Product: Cn1nccc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(C(F)(F)F)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate E, 58 mg, 0.163 mmol) and 2-trifluoromethylpyridine-5-boronic acid (Frontier Scientific, Logan, USA, 40.5 mg, 0.212 mmol) to give the title compound as a red solid. (HPLC: tR 2.87 min (Method A); M+H=425 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.08 (s, 1H), 8.82 (d, 1H), 8.27-8.16 (m, 2H), 8.10-7.98 (m, 2H), 7.82 (d, 1H), 7.18-7.16 (m, 1H), 6.72 (s, 1H), 3.72 (s, 3H), 3.63 (s, 3H))
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.CS(O)(=O)=O.N1CCCC1>>[NH2:20][C:8]([N:4]1[CH2:1][CH2:2][CH2:6][CH2:5]1)=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Agent: CS(=O)(=O)O
Solvent: C1CCNC1
Product: Cc1ccc(S(=O)(=O)N=C(N)N2CCCC2)cc1

Procedure:
The compound of Example 18 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of pyrrolidine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 267.35; found mol. wt. (M+H) 268.2; 534.9 (Dimer)
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:13])([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].O>CN(C)C=O>[CH3:12][Si:3]([CH2:2][N:18]1[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]2[C:14]1=[O:24])([CH3:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1
Reactant: C[Si](C)(CCl)Cc1ccc(F)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Yield: 94.9 %

Procedure:
Chloromethyl-dimethyl-4-fluorobenzylsilane (2.01 g, 9.33 mmol) and potassium phthalimide (1.90 g), 10.27 mmol) were heated in dry dimethylformamide (30 ml) at 70° C. for 5 hours and then the mixture was poured into water and extracted with ether. The ether solution was washed with water, brine, dried and evaporated. Chromatography (silica gel, ether/hexane-20/80) afforded N[(dimethyl-4-fluorobenzylsilyl)methyl]phthalimide as a white powder (2.90 g, 95% yield) 1H NMR (CDCl3, TMS) δ:0.20 (s,6H), 2.25 (s,2H), 3.27 (s,2H), 6.83-7.13 (m,4H), 7.67-7.97 (m,4H).