Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC1C=CC=CC=1)[C:9](=[O:35])[CH:10]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:14][C:13]=1[OH:34])[CH3:11])C1C=CC=CC=1.C(O)(=[O:45])C>Cl>[CH2:27]([N:19]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[C:16]([CH3:18])=[CH:17][C:12]([CH:10]([CH3:11])[C:9]([OH:35])=[O:45])=[C:13]([OH:34])[CH:14]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)O
Reactant: Cc1cc(C(C)C(=O)N(Cc2ccccc2)Cc2ccccc2)c(O)cc1N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Product: Cc1cc(C(C)C(=O)O)c(O)cc1N(Cc1ccccc1)Cc1ccccc1

Procedure:
20 g of 2-(4-dibenzylamino-2-hydroxy-5-methylphenyl)-propionic acid dibenzylamide are heated under reflux for 3 hours in 40 ml of 2N hydrochloric acid and 40 ml of glacial acetic acid. The mixture is then concentrated to dryness by evaporation in vacuo and the residue is partitioned between ether and 1N sodium hydroxide solution. Acidification to a pH of 1 with hydrochloric acid and extraction yields 2-(4-dibenzylamino-2-hydroxy-5-methylphenyl)-propionic acid which, for purification, is chromatographed over silica gel in methylene chloride. The colourless crystals melt at 174°-175°. 15 g of the crystals are dissolved in 50 ml of ether and 6 g of dicyclohexylcarbodiimide are added thereto. After 30 minutes the urea formed is filtered off and the filtrate is concentrated to dryness by evaporation. In this manner 6-dibenzylamino-3,5-dimethylbenzofuran-2(3H)-one having a melting point of 122°-123° is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:12][NH:11][CH2:10][CH2:9][C:5]=2[N:6]=[CH:7][N:8]=1.Br[C:14]1[CH:15]=[C:16]([CH3:22])[C:17]([O:20][CH3:21])=[N:18][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O.CO.O1CCOCC1>[CH3:1][O:2][C:3]1[C:4]2[CH2:12][N:11]([C:14]3[CH:19]=[N:18][C:17]([O:20][CH3:21])=[C:16]([CH3:22])[CH:15]=3)[CH2:10][CH2:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: COc1ncnc2c1CNCC2
Reactant: COc1ncc(Br)cc1C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ncc(N2CCc3ncnc(OC)c3C2)cc1C
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 36.4 %

Procedure:
To a glass vial was added 4-methoxy-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (WO 2008/130481, p 47) (0.570 g, 3.45 mmol), 5-bromo-2-methoxy-3-methylpyridine (0.697 g, 3.45 mmol), cesium carbonate (2.25 g, 6.90 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.316 g, 0.345 mmol), X-Phos (0.493 g, 1.04 mmol) and anhydrous dioxane (5 mL). The vial was flushed with a stream of argon for 15 sec and capped. The mixture was heated with stirring for 1 h 45 min at 110° C. then allowed to cool to room temperature and stirred at RT for 3 days. The reaction mixture was filtered through a celite pad and concentrated in vacuo. Purified by flash chromatography on silica gel with heptane/EtOAc, 100/0 to 0/100 then EtOAc/MeOH, 90/10 to give 4-methoxy-6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine as a brown gum (0.36 g, 36% yield) LCMS: [M+H]+=287.0, Rt(7)=0.80 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:7]([F:14])[C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[C:22](=[O:29])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[NH2:23]>>[F:14][C:7]1[C:8]([CH3:13])([CH3:12])[O:9][C:10]2[C:5]([C:6]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[CH:4][CH:3]=[C:2]([NH:23][C:22](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:11]=2
Reactant: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1F
Reactant: CC(C)(C)OC(N)=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)OC(C)(C)C(F)=C2c1ccc(F)cc1

Procedure:
The compound obtained in (5) described above (125 mg) and tert-butyl carbamate (145 mg) were treated in the same manner as Reference Example 5(4) to give the titled compound (157 mg) as a brown viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](Br)[C:5]([F:8])=[N:6][CH:7]=1.[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH2:11])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: Nc1cnc(F)c(Br)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(N)cnc1F
Temperature: 100 °C
Yield: 98 %

Procedure:
To a stirred solution of 5-amino-2-fluoro-3-bromopyridine from step 126b above (3.25 g, 17.0 mmol) in toluene (20 mL) was added tributyl(vinyl)tin (Aldrich, 7.64 g, 20.4 mmol) followed by tetrakis(triphenylphosphine) palladium (Aldrich, 0.63 g, 1.7 mmol). The reaction mixture was heated at 100° C. for 24 h. The solvent was removed in vacuo and the residue was purified by column chromatography (silica gel; EtOAc/hexane, 4:6) to afford the desired material as beige solids (2.30 g, 98%): 1H NMR (CDCl3, 300 MHz) δ 3.61 (br s, 2H), 5.44 (d, J=11.5 Hz, 1H), 5.83 (d, J=17.5 Hz, 1H), 6.66 (m, 1H), 7.18 (dd, J=3.0 Hz, 5.0 Hz, 1H), 7.52 (m, 1H); MS (CI/NH3) m/z 139 (M+H)+, 156 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:30])[C:14]([C:15]([NH:17][C:18]34[CH2:25][CH2:24][C:21]([C:26]([O:28]C)=[O:27])([CH2:22][CH2:23]3)[CH2:20][CH2:19]4)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:31])[CH:7]=1.[OH-].[Li+].C(O)=O>C1COCC1.CO>[F:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:30])[C:14]([C:15]([NH:17][C:18]34[CH2:19][CH2:20][C:21]([C:26]([OH:28])=[O:27])([CH2:22][CH2:23]3)[CH2:24][CH2:25]4)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:31])[CH:7]=1
Reactant: COC(=O)C12CCC(NC(=O)c3c(C)nn4c(OCc5c(F)cccc5F)cc(C)cc34)(CC1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O=CO
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NC34CCC(C(=O)O)(CC3)CC4)c2c1
Temperature: 40 °C
Reaction time: 10 h
Yield: 75 %

Procedure:
56 mg (0.113 mmol) of methyl 4-[({7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]bicyclo[2.2.2]octane-1-carboxylate from Example 152 were dissolved in 1.1 ml of THF/methanol (5/1), and 8.1 mg (0.339 mmol) of lithium hydroxide were added. The mixture was stirred at 40° C. for 10 h. After cooling, the mixture was acidified with 20 μl of formic acid and purified by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.05% formic acid). 41 mg of the target compound were obtained (75% of theory).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][C:13]=1[O:21][CH3:22])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][CH3:31]>>[CH2:30]([N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[CH2:24][NH:23][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])=[C:13]([O:21][CH3:22])[CH:14]=1)[CH3:31]
Reactant: COc1cc(C(=O)O)ccc1OC/C=C(\C)CCC=C(C)C
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)c(OC)c1
Yield: 79 %

Procedure:
In a manner identical to Example 15, 4-geranyloxy-3-methoxybenzoic acid(1.52 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.63 g(79%) of the aimed compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][C@H:36]([CH3:45])[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][C@H:36]([CH3:45])[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](N)CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: C[C@H](CC(=O)OC(C)(C)C)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1,1-dimethylethyl (3R)-3-aminobutanoate using methods similar to Example 563 to provide an orange solid: ES+ MS: 581 (M+H+).
Reaction SMILES: [CH2:1]([N:8]([CH2:37][C@H:38]([OH:60])[CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:43]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:42]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:36]=[CH:35][C:18]([C:19]([NH:21][C@H:22]([C:30]([O:32]CC)=[O:31])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([N:8]([CH2:37][C@H:38]([OH:60])[CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:43]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:42]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:36]=[CH:35][C:18]([C:19]([NH:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)N[C@@H](Cc4ccccc4)C(=O)O)cc3)CC2)ccc1OCc1ccccc1

Procedure:
A mixture of 0.35 g of ethyl trans-N-(4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)-amino]cyclohexyl}benzoyl)-L-phenylalaninate (0.42 mmol) and of 1.7 ml of a molar aqueous sodium hydroxide solution in ethanol (9.3 ml) is heated at 45° C. for 3 h. The solvents are subsequently evaporated under reduced pressure and water is added. A molar aqueous hydrochloric acid solution is subsequently added to pH=1. The title product is obtained in the form of a white solid (0.2 g, 59%) after filtration and drying under vacuum [M+H+]=807.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:9]([C@@H:10]2[CH2:14][CH2:13][N:12]([CH3:15])[C@H:11]2[CH2:16][OH:17])=[C:8]([O:18][CH3:19])[CH:7]=[C:6]([O:20][CH3:21])[C:5]=1[C:22](=[O:24])[CH3:23].[Cl:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28](OC)=O.Cl>CN(C=O)C.CO>[Cl:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]1[O:3][C:4]2[C:5]([C:22](=[O:24])[CH:23]=1)=[C:6]([O:20][CH3:21])[CH:7]=[C:8]([O:18][CH3:19])[C:9]=2[C@@H:10]1[CH2:14][CH2:13][N:12]([CH3:15])[C@H:11]1[CH2:16][OH:17]
Reactant: COC(=O)c1ccccc1Cl
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (50%, 2.17 g, 45.3 mmol) was added in portions to a solution of compound of example 6 (2.8 g, 9 mmol) in dry DMF (30 mL) at 0° C., under nitrogen atmosphere and with stirring. After 10 min., methyl 2-chlorobenzoate (5.09 g, 29.9 mmol) was added. The reaction mixture was stirred at 25° C. for 2 h. Methanol was added carefully below 20° C. The reaction mixture was poured over crushed ice (300 g), acidified with 1:1 HCl (pH 2) and extracted using EtOAc (2×100 mL). The aqueous layer was basified using a saturated Na2CO3 (pH 10) and extracted using CHCl3 (3×200 mL). The organic layer was dried (anhydrous Na2SO4) and concentrated. To the residue, conc. HCl (25 mL) was added and stirred at room temperature for 2 h. The reaction mixture was poured over crushed ice (300 g) and made basic using a saturated aqueous Na2CO3 solution. The mixture was extracted using CHCl3 (3×200 mL). The organic extract was washed with water, dried (anhydrous Na2SO4) and concentrated to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH2:25]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:39][CH2:38][CH:37]2[C:40]([O-])=[O:41])[CH2:32][CH2:31]1)=[O:29])[CH3:26].[Li+]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=3)[CH2:11][N:10]2[C:40]([CH:37]2[CH2:38][CH2:39][N:36]2[CH:33]2[CH2:32][CH2:31][N:30]([C:28]([O:27][CH2:25][CH3:26])=[O:29])[CH2:35][CH2:34]2)=[O:41])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](Sc3cccc(C(F)(F)F)c3)CN2)CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](Sc3cccc(C(F)(F)F)c3)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-(3-(trifluoromethyl)phenylthio)pyrrolidine-2-carboxamide 12E and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-2-(1-cyanocyclopropylcarbamoyl)-4-(3-(trifluoromethyl)phenylthio)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (58%). MS ISP (m/e): 594.4 (100) [(M+H)]+.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([SH:17])=[C:5]([C:18]([F:21])([F:20])[F:19])[N:4]=1.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].BrBr.O>C(O)(=O)C>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([S:33][S:17][C:6]2[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:3]([CH:2]([F:1])[F:22])=[N:4][C:5]=2[C:18]([F:21])([F:20])[F:19])=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(S)c1CC(C)C
Agent: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(SSc2ccc(C(C)(C)C)cc2)c1CC(C)C
Reaction time: 1 h

Procedure:
To a mixture of 100 mg of compound 7 and 48.6 mg of 4-t-butylbenzenethiol in 5 ml of acetic acid was added 23 mg of bromine. The reaction mixture was stirred for 1 h, poured into water and extracted with ether. The ether extract was washed with saturated sodium bicarbonate, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (9:1 Hexane: EtOAc) on silica gel to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:28](Cl)=[N:27][C:26]([Cl:30])=[CH:25][N:24]=1)(=[O:21])=[O:20]>>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:28]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:27][C:26]([Cl:30])=[CH:25][N:24]=1)(=[O:21])=[O:20]
Reactant: COc1ccc(CO)cc1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Product: COc1ccc(COc2nc(Cl)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)cc1

Procedure:
Prepared by the method of Example 31 using 4-methoxybenzylalcohol (0.3 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.5 g). Yield 0.4 g.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>CC(O)C>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][N:3]=[C:2]2[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1)([O-:14])=[O:13]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc2c(Nc3cccc(C(F)(F)F)c3)ncnc12
Yield: 88.9 %

Procedure:
A solution of 4-chloro-8-nitroquinazoline (300 mg, 1.43 mmol) and 3-(trifluoromethyl)aniline (461 mg, 2.86 mmol) in iPrOH (1.5 mL) was heated in a sealed tube at 120° C. for 2 h. Then the reaction mixture was concentrated and purified by triturating in Et2O to afford 425 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 10.52 (br s, 1H), 8.88 (d, J=7.8 Hz, 1H), 8.75 (s, 1H), 8.42 (d, J=7.2 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J=6.9 Hz, 1H), 7.87-7.81 (t, J=8.4 Hz, 1H), 7.71-7.65 (t, J=7.8 Hz, 1H), 7.56-7.30 (d, J=7.8 Hz, 1H); MS (m/z): 335.19 (M+H)+.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[C:4](N)[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].N([O-])=[O:18].[Na+].F[B-](F)(F)F.[H+]>S(=O)(=O)(O)O.O>[CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[C:4]([OH:18])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12]
Reactant: Nc1ccc2c3c(cccc13)C(=O)OC2=O
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Agent: [H+]
Solvent: O
Product: O=C1OC(=O)c2ccc(O)c3cccc1c23
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of 1.0 g (4.7 mmol) of 4-amino-1,8-naphthalic anhydride in 5 mL concentrated sulfuric acid at 0° C. to 5° C. was added 1.0 g (14.5 mmol) of sodium nitrite, and then 0.5 mL of water. The reaction was stirred for 30 minutes at 0° C. to 5° C., followed by addition of 5 mL (38 mmol) of 48% aqueous fluoroboric acid, with stirring for 30 minutes. The mixture was poured into ice water. The precipitate was isolated, suspended in a solution of 10 mL concentrated sulfuric acid in 50 mL water, refluxed in 3 hours, and again poured onto ice. The precipitate was isolated, washed with water, and dried to yield 620 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9](=[C:10]([C:21]4[CH:26]=CC=[CH:23][CH:22]=4)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.C(C1C=CC=C2C=1NC(=O)C2=O)(CC)C.C(OCC(=O)CC1C=CC(Cl)=CC=1)(=O)C>>[CH:21]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[C:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=1)[C:16]([OH:17])=[C:15]2[C:18]([OH:20])=[O:19])([CH2:22][CH3:23])[CH3:26]
Reactant: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c(-c3ccccc3)cccc12
Agent: CC(=O)OCC(=O)Cc1ccc(Cl)cc1
Agent: CCC(C)c1cccc2c1NC(=O)C2=O
Product: CCC(C)c1cccc2c(C(=O)O)c(O)c(Cc3ccc(Cl)cc3)nc12

Procedure:
This compound was synthesized by the procedure described above for Compound 2, reacting 7-sec-butylisatin (1.00 g, 4.92 mmol) with 3-(4-chlorophenyl)-2-oxopropyl acetate (1.39 g, 6.15 mmol). The crude acid was purified as described above for Compound 3 and, after hydrochloric acid treatment of an acetonitrile/water solution of the triethylammonium salt, extracted into ethyl acetate (3×), washed with brine, dried over anhydrous magnesium sulfate, filtered, evaporated and lyophilized. It was then purified (preparative HPLC, eluting with acetonitrile/water/triethylamine), and converted back to the free acid and extracted and evaporated once more as described above. A final lyophilization step gave product Compound 10 as a fluffy, bright yellow solid (72 mg, 3.9% yield): 1H NMR (400 MHz, DMSO-D6) δ 0.74 (t, J=7.3 Hz, 3H) 1.22 (d, J=6.8 Hz, 3H) 1.61 (m, 2H) 3.91 (m, 1H) 4.32 (dd, 2H) 7.34 (m, 4H) 7.39 (d, J=6.1 Hz, 1H) 7.51 (dd, J=8.6, 7.3 Hz, 1H) 8.25 (dd, J=8.3, 1.3 Hz, 1H); HRMS (ESI/FTMS) calcd for C21H21ClNO3 (MH+) 370.1205, found 370.1204. Anal. Calcd for C21H20ClNO3: C, 68.20; H, 5.45; N, 3.79. Found: C, 67.97; H, 5.47; N, 3.53.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:10][CH:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[C:8]#[N:9]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Br)C#N
Yield: 87.7 %

Procedure:
Pivaloylacetonitrile (1.00 g, 7.99 mmol) was dissolved in carbon tetrachloride (15 mL). N-Bromosuccinimide (1.42 g, 7.99 mmol) was added, and the mixture was refluxed for 15 minutes. After cooling, the insoluble matter was filtered off, and the residue obtained by evaporation of the filtrate under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (1.43 g, 87.9%) as a yellowish brown oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][C:13](=[N:17][O:18][CH2:19][CH3:20])[C:14]=2[C:15]=1[OH:16])=[O:5])C.Cl>[OH-].[Na+].C(O)C>[CH2:19]([O:18][N:17]=[C:13]1[CH2:12][CH2:11][CH2:10][C:9]2[N:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:15]([OH:16])[C:14]1=2)[CH3:20]
Reactant: CCON=C1CCCc2ncc(C(=O)OCC)c(O)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C1CCCc2ncc(C(=O)O)c(O)c21
Temperature: 90 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
5-Ethoxyimino-4-hydroxy-5,6,7,8-tetrahydroquinoline-3-carboxylic acid ethyl ester (2.0 g) was dissolved in a mixture of 20 ml of 1 N sodium hydroxide and 10 ml of ethyl alcohol. The resulting reaction mixture was stirred at 90° C. for 2 hours. Under cooling with ice, the reaction mixture was adjusted to pH 4 with dilute hydrochloric acid. The crystals so precipitated were separated by filtration to obtain a yield of 0.95 g of the desired compound. This compound melted (and decomposed) at 225°-228° C. (uncorrected values). Its infrared absorption spectrum (KBr tablet) had absorption peaks at 3440, 2910, 1690, 1640, 1400, 1060, and 825 cm-1, and its n.m.r. spectrum (CF3COOH, 60MC, TMS) had signals at δ values of 1.57 (3H, t, J=7.5 Hz), 2.0-2.6 (2H, m), 3.0-3.5 (4H, m), 4.59 (2H, q, J=7.5 Hz), and 8.94 (1H, s).
Reaction SMILES: [N:1]1([S:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[C:18]4[N:19]([CH2:25][CH2:26][N:27]=4)[C:20]([NH2:24])=[N:21][C:22]=3[CH:23]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:35](O)=[O:36])=[CH:31][N:30]=1>>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:35]([NH:24][C:20]2[N:19]3[CH2:25][CH2:26][N:27]=[C:18]3[C:17]3[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][S:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)(=[O:8])=[O:9])=[CH:23][C:22]=3[N:21]=2)=[O:36])=[CH:31][N:30]=1
Reactant: NC1=Nc2cc(OCCCS(=O)(=O)N3CCOCC3)ccc2C2=NCCN12
Reactant: Nc1ncc(C(=O)O)cn1
Product: Nc1ncc(C(=O)NC2=Nc3cc(OCCCS(=O)(=O)N4CCOCC4)ccc3C3=NCCN23)cn1

Procedure:
The procedure used for the preparation of Example 28, Step 2 was used to prepare the title compound from 8-[3-(morpholin-4-ylsulfonyl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Example 28, Step 1) and 2-aminopyrimidine-5-carboxylic acid. Yield 150 mg (45%). TLC Rf=0.47 in 10% MeOH/CH2Cl2, HPLC MS RT=0.76 min, MH+=515.4; 1H NMR (DMSO-d6) δ: 2.24 (2H, m), 3.21 (4H, m), 3.29 (2H, m), 3.67 (4H, m), 4.20 (2H, t), 4.30 (2H, t), 4.53 (2H, t), 7.20 (1H, d), 7.70 (1H, br s), 7.97 (1H, s), 8.13 (1H, d), 9.02 (2H, s).