Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]2[NH:22][C:21](=[O:23])[CH2:20][O:19][C:18]([CH3:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:36]=[C:37]=O)(=O)=O>>[C:1]([O:5][C:6]([N:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]3[NH:22][C:21](=[O:23])[CH2:20][O:19][C:18]([CH3:30])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:17]=3[CH:31]=2)=[CH:10][CH:11]=[C:12]1[C:37]#[N:36])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(c1ccccc1)OCC(=O)N2
Reactant: O=C=NS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(c1ccccc1)OCC(=O)N2

Procedure:
tert-Butyl-2-cyano-5-(5-methyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-1-carboxylate was prepared from tert-butyl-2-(5-methyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-1-carboxylate and chlorosulfonyl isocyanate according to the cyanation procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.02 (s, 1H), 7.42-7.38 (m, 2H), 7.32-7.10 (m, 7H), 6.49 (d, J=3.80 Hz, 1H), 4.20 (d, J=14.63 Hz, 1H), 3.99, (d, J=14.41 Hz, 1H), 1.87 (s, 3H), 1.39 (s, 9H); MS (ES) m/z 442 ([M−H]−, 100%).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([N:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:13][CH2:14][CH3:15]>O>[CH2:11]([N:16]1[C:17]2[CH:18]=[CH:19][C:20]([CH:3]=[O:4])=[CH:21][C:22]=2[C:23]2[C:28]1=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCn1c2ccccc2c2ccccc21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCCCCn1c2ccccc2c2cc(C=O)ccc21
Reaction time: 1.5 h

Procedure:
Dimethylformamide (100 mL) is stirred and cooled in an ice bath while phosphorus oxychloride (35 mL, 58 g, 0.38 mol) is gradually added. 9-Pentylcarbazole (52 g, 0.22 mol) is introduced and the resulting mixture is heated on a steam bath with stirring for 1.5 hours. The entire mixture is cooled and added to water (200 mL) and the crude product is filtered off at the pump, washed with water (200 mL). The crude product is recrystallized to form 9-pentyl-3-carbazolecarboxaldehyde.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:16])[CH3:3].[CH2:17]([O:19][N:20]=[CH:21][CH3:22])[CH3:18].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH2:17]([O:19][N:20]1[CH:21]([CH3:22])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:16])[CH3:18]
Reactant: CC=NOCC
Reactant: C=C(C)C1CCCCCCCCCCC1=O
Agent: CCON1C(=O)CCCCCCCCCC/C=C(\C)CC1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCON1C(=O)CCCCCCCCCCC=C(C)CC1C

Procedure:
Following the general procedure as described in Example 23, 2-(prop-1-en-2-yl)cyclododecanone (2.00 g, 9.02 mmol), acetaldehyde O-ethyl oxime (1.18 g, 13.53 mmol), and SnCl4 (2.35 g, 9.02 mmol) in 1,2-dichloroethane (90 ml) were reacted to give the title product as a colorless liquid (2.45 g, 88% yield). Mixture of E/Z isomers in a ratio of 2:1.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH3:5])[CH3:4].COCCOC[C:13]1[C:26]2[NH:27][N:28]=[C:24]3[C:25]=2[C:16]([C:17](=[O:29])[C:18]2[C:23]3=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:15]([OH:30])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:4][CH:3]([CH3:5])[CH2:2][CH2:1][O:30][C:15]1[CH:14]=[CH:13][C:26]2[NH:27][N:28]=[C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17](=[O:29])[C:16]=1[C:25]=23
Reactant: COCCOCc1cc(O)c2c3c(n[nH]c13)-c1ccccc1C2=O
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCOc1ccc2[nH]nc3c2c1C(=O)c1ccccc1-3
Temperature: 80 °C

Procedure:
Isopentyl bromide is added to a mixture of 3-(2-methoxyethoxymethyl)5-hydroxyanthra[1,9cd]pyrazol-6(2H)-one and potassium carbonate in dimethylformamide at room temperature. After stirring the mixture for sixteen hours, water is added, and the mixture was extracted with ethyl acetate (×2). The combined organic layer is washed with aqueous sodium bicarbonate, water, 1N hydrochloric acid, and brine, dried and evaporated. The reside is taken in 6N hydrochloric acid and heated at 80° C. for 4 hours. After cooling, the mixture is extracted with ethyl acetate (×2), and the combined organic layer is washed with brine, dried, and evaporated. The residue is purified by column chromatography to afford the title compound as yellow solid.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]1([CH:10]2[CH2:15][CH2:14][O:13][C:12](=[O:16])[CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[OH:13][CH2:14][CH2:15][CH:10]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:11][C:12]([NH:2][NH2:3])=[O:16]
Reactant: NN
Reactant: O=C1CC(c2ccccc2)CCO1
Solvent: O
Solvent: CCO
Product: NNC(=O)CC(CCO)c1ccccc1
Temperature: 25 °C

Procedure:
Hydrazine monohydrate (1.6 mL) was added to a solution of 4-phenyl-tetrahydropyran-2-one (573 mg; CAS No. 61949-75-5) in ethanol (3 mL) at room temperature, and the reaction solution was heated under reflux for three hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-methanol system) to obtain 492 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[C@H:18]([CH2:19][CH2:20][C:21](=[O:25])[CH:22]=2)[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C:12](=[O:27])[CH2:11][CH2:10]1.O>C(#N)C.[Cu](Br)Br>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C:12](=[O:27])[CH2:11][CH2:10]1
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCBr)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: Br[Cu]Br
Solvent: CC#N
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCBr)[C@H]3[C@@H]1CCC2=O
Reaction time: 8 h
Yield: 73.7 %

Procedure:
17.0 g of copper(II) bromide is added to 27.8 g of 7α-(5-bromopentyl)-11β-fluoro-estr-4-ene-3,17-dione in 190 ml of acetonitrile at 80° C. After 8 hours, the reaction mixture is stirred into water, extracted three times with ethyl acetate, washed twice with ammonium chloride, with sodium bicarbonate and common salt, dried and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 20.4 g of 7α-(5-bromopentyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)trien-17-one is obtained as colorless crystals with a melting point of 178° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[S:5][CH:6]=1.Br[CH2:14][CH:15]([C:17]1[CH:25]=[C:21]([C:22]([NH2:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1)[OH:16].C(N(CC)CC)C>CCOCC>[OH:16][CH:15]([C:17]1[CH:25]=[C:21]([C:22]([NH2:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1)[CH2:14][N:10]1[CH2:11][CH2:12][N:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH2:8][CH2:9]1
Reactant: Cc1csc(N2CCNCC2)n1
Reactant: NC(=O)c1cc(C(O)CBr)ccc1O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1csc(N2CCN(CC(O)c3ccc(O)c(C(N)=O)c3)CC2)n1
Reaction time: 2 h

Procedure:
18.9 g of 1-(4-methyl-2-thiazolyl)-piperazine and 26 g of 5-(2-bromo-1-hydroxyethyl)-salicylamide (obtainable by acylation of salicyamide with bromoacetyl bromide/AlCl3 to give 5-bromoacetyl-salicylamide and subsequent reaction with NaBH4) are dissolved in 400 ml of ether, 15 ml of triethylamine are added, the mixture is boiled for 2 h and subjected to the usual working-up, and 5-[1-hydroxy-2-(4-(4-methyl-2-thiazolyl)-piperazino)-ethyl]salicylamide ("A"), m.p. 182°, is obtained. Dihydrochloride m.p. 244°-245°.
Reaction SMILES: [CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=O)[CH3:23])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:33][N:34](C(OC(C)(C)C)=O)[NH2:35].C(O)=O>C(O)(=O)C>[CH:1]1([N:4]([CH:30]2[CH2:31][CH2:32]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:21]=[C:22]([CH3:23])[N:34]([CH3:33])[N:35]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(C)=O)SC)nc21
Solvent: CC(=O)O
Solvent: O=CO
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3cc(C)n(C)n3)nc21
Temperature: 35 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
A mixture of (Z)—N,N-dicyclopropyl-6-ethyl-1-methyl-4-(1-(methylthio)-3-oxobut-1-enylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 72B, 70 mg, 0.155 mmol) and tert-butyl 1-methylhydrazinecarboxylate (0.046 mL, 0.309 mmol) in acetic acid (1 mL) wan stirred at 35° C. for 4 h (monitored by LC/MS until no starting material left). Formic acid (0.5 mL) was added and stirred at 60° C. for 6 h. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 2-10% methanol/dichloromethane). The impure product was further purified by preparative HPLC to give N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (45 mg, 63.9% yield) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(N)cc(C(F)(F)F)c1
Yield: 95 %

Procedure:
A solution of methyl 3-nitro-5-(trifluoromethyl)benzoate (Reference Example 27, 24.6 g, 98.9 mmol) in ethanol (1500 mL) was sparged in a Parr bottle with nitrogen for 10 min. After this time, 10 wt % Pd/C (5.0 g, 5.0 mmol) was added and the reaction mixture was subjected to 40 psi of hydrogen on Parr shaker at room temperature for 1 h. After this time, the reaction mixture was filtered through a pad of celite and concentrated under reduced pressure to provide Methyl 3-amino-5-(trifluoromethyl)benzoate (20.6 g, 95%) as a light purple oil.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:16](=[O:28])[N:17]([CH2:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=3)[N:18]=2)[C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)O1.ClCCl.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[CH:6]=[C:5]([CH3:15])[N:4]3[C:16](=[O:28])[N:17]([CH2:19][C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=4)[N:18]=[C:3]3[C:2]=2[C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2nn(Cc3ccc(C#N)cn3)c(=O)n12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(Cl)cc2)c(-c2ccncc2)c2nn(Cc3ccc(C#N)cn3)c(=O)n12
Temperature: 100 °C
Yield: 62.2 %

Procedure:
In a pressure tube, to a stirring solution of 6-((8-bromo-7-(4-chlorophenyl)-5-methyl-3-oxo-[1,2,4]triazolo[4,3-a]pyridine-2(3H)-yl)methyl)nicotinonitrile (54 mg, 0.11 mmol) in THF (2 mL) at room temperature under argon was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (45 mg, 0.22 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex with dichloromethane (9 mg, 0.011 mmol) and powdered K3PO4 (60 mg, 0.28 mmol). The resulting suspension was stirred and heated at 100° C. under argon for 7 h. The reaction mixture was filtered through filter paper and the filtrate was concentrated under vacuum to a dark brown solid. The crude product thus obtained was purified by reverse phase preparative HPLC (without TFA) to obtain 31 mg of the title compound as a yellow solid. HPLC/MS: retention time=2.482 min, [M+H]+=453.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:9]1([S:15][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(I)c1
Reactant: Sc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Brc1cccc(Sc2ccccc2)c1
Yield: 90.5 %

Procedure:
The general procedure in example 39 was followed. 3-bromoiodobenzene (283 mg, 1.0 mmol), thiophenol (103 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 μL) were used to obtain the 3-bromophenyl phenyl sulfide (240 mg, 91% yield) as colorless liquid. Column chromatography solvent (hexane). Rf=0.6 (hexane). 1H NMR (CDCl3, 300 MHz) δ 7.11-7.22 (m, 2 H), 7.28-7.40 (m, 7 H). 13C NMR (CDCl3, 75 MHz) δ 139.2, 134.1, 132.5, 132.4, 130.6, 129.8, 129.7, 128.6, 128.2, 123.2. MS (EI) m/z (relative intensity) 266 (40), 264 (40).
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[N+:11]=2[O-:27])=[CH:6][CH:5]=1)([O-])=O.[S-2].[Na+].[Na+].O>C(O)C>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH:17]=[CH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]=[CH:8][C:7]3[CH:28]=[CH:29][C:4]([NH2:1])=[CH:5][CH:6]=3)[N+:11]=2[O-:27])=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2cccc(C=Cc3ccc([N+](=O)[O-])cc3)[n+]2[O-])cc1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: Nc1ccc(C=Cc2cccc(C=Cc3ccc(N)cc3)[n+]2[O-])cc1
Yield: 88.7 %

Procedure:
More specifically, the synthesizing procedure is as follows. 2,6-dimethylpyridine or a substituted product thereof, is reacted with p-nitrobenzenealdehyde or a substituted product according to a method described, for example, in Journal of Organic Chemistry, vol. 15, P. 1184 (1950) to synthesize 2,6-di(p-nitrostyryl)pyridine (K). 30 g of this nitro compound is reacted wtih 27 g of m-chloroperbenzoic acid in three liter of dichloromethane to obtain 24 g of 2,6-di(p-nitrostyryl)pyridine-N-oxide. 24 g of this pyridine-N-oxide is reacted with 90 g of sodium sulfide in a solution mixed four liter of water with four liter of ethanol to reduce nitro group selectively and form 18 g of 2,6-di(p-aminostyryl)pyridine-N-oxide (M). The N-oxide amino compound is converted into a diazo compound according to a conventional method, and thereby tetrazonium salt is isolated as 15 g of hydroborofluoric salt (N). 5.0 g of the tetrazonium salt (N) and 5.0 g of 2-hydroxy-3-phenylcarbamoylnaphthalene (O) were dissolved in one liter of DMF, to which aqueous sodium acetate solution (7 g/100 ml) was added to perform coupling reaction. After two hours of stirring, the resultant crystals were separated by filtration, and the crystals were rinsed three times respectively with five liter water, three times respectively with five liter THF, then dried, to obtain 4.0 g of the final product, azo compound (P - 1).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.C(N(C(C)C)CC)(C)C.[N:24]1([CH2:30][CH2:31][N:32]([CH2:44][CH2:45][CH3:46])[CH:33]2[CH2:42][C:41]3[CH:40]=[C:39]([OH:43])[CH:38]=[CH:37][C:36]=3[CH2:35][CH2:34]2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[OH:43][C:39]1[CH:40]=[C:41]2[C:36]([CH2:35][CH2:34][CH:33]([N:32]([CH2:44][CH2:45][CH3:46])[CH2:31][CH2:30][N:24]3[CH2:25][CH2:26][N:27]([CH2:3][C:4]4[CH:13]=[CH:12][C:11]([OH:14])=[C:10]5[C:5]=4[CH:6]=[CH:7][CH:8]=[N:9]5)[CH2:28][CH2:29]3)[CH2:42]2)=[CH:37][CH:38]=1
Reactant: CCCN(CCN1CCNCC1)C1CCc2ccc(O)cc2C1
Reactant: Oc1ccc(CCl)c2cccnc12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCN1CCN(Cc2ccc(O)c3ncccc23)CC1)C1CCc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
To a mixture of 5-chloromethyl-8-quinolinol hydrochloride, 11 (0.20 g, 0.86 mmol) and diisopropylethylamine (0.3 mL, 1.73 mmol, 2.2 equiv) in 25 mL CHCl3 at 0° C. was added 9a (0.25 g, 0.78 mmol). The mixture was stirred for 24 h at room temperature. CHCl3 (100 mL) was added and the solution obtained was washed with 10% NaHCO3, brine, and then dried over Na2SO4. The solution was filtered and evaporated to dryness. The residue was made hydrochloride salt and crystallized from ethanol to yield 12a as yellow solid (0.28 g, 57.3%). 1H NMR of HCl salt (400 MHz, DMSO-d6) δ ppm 0.88-0.99 (m, 3H), 1.79-1.81 (bs, 4H), 2.298 (bs, 1H), 2.476-2.48 (m, 2H), 2.74 (s, 2H), 2.96-3.02 (t, 1H, J=12 Hz), 3.122 (bs, 3H), 3.34-3.65 (m, 12H), 6.51-6.56 (m, 2H), 6.86-6.88 (d, 1H, J=8 Hz), 7.50-7.52 (d, 1H, J=8 Hz), 7.997-8.008 (m, 2H); 9.06-9.07 (d, 1H, J=4 Hz); 9.49-9.51 (d, 1H, J=8 Hz). The hydrochloride salt mp 242-242° C. Analysis calculated for (C29H40.6N4O3.3, 4HCl) C, H, N.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([C:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][N+:10]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Cl-].[NH4+]>CO.O1CCCC1.[Zn]>[NH2:10][CH2:9][CH:8]([C:7]1[C:2]([F:1])=[C:3]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:4]=[CH:5][CH:6]=1)[C:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:19][CH:20]=2)[NH:15][CH:14]=1
Reactant: COCCOc1ccc2c(C(C[N+](=O)[O-])c3cccc(NC(=O)OCc4ccccc4)c3F)c[nH]c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1ccc2c(C(CN)c3cccc(NC(=O)OCc4ccccc4)c3F)c[nH]c2c1
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a solution of benzyl 2-fluoro-3-(1-(6-(2-methoxyethoxy)-1H-indol-3-yl)-2-nitroethyl)phenylcarbamate (3.75 g, 7.39 mmol) and ammonium chloride (5.93 g, 111 mmol) in methanol (148 mL) and tetrahydrofuran (148 mL) under nitrogen was added zinc (7.25 g, 111 mmol). After 3 hr, the reaction was filtered through a pad of CELITE®, rinsed with EtOAc and MeOH. The filtrate was concentrated in vacuo. Water (40 mL) was added followed by saturated aq. NaHCO3 (to pH ˜11 by litmus paper) and extracted with EtOAc (4×50 mL). The organic layers were combined, washed with brine (40 mL), dried over MgSO4, and concentrated in vacuo to give the desired product (3.523 g, 6.35 mmol, 86% yield) as a light tan solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:37]=[CH:36][C:13]([CH2:14][N:15]2[CH:19]=[C:18]([C:20]3[CH:21]=[C:22]4[N:27]([C:28]5[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=5[CH3:35])[NH2:31])[CH:26]=[CH:25][N:23]4[N:24]=3)[CH:17]=[N:16]2)=[CH:12][CH:11]=1.[CH3:38][C:39]1[N:40]([C:44]2[CH:45]=[C:46]([CH:50]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:52]=2)[C:47](O)=[O:48])[CH:41]=[CH:42][N:43]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[CH:19]=[C:18]([C:20]3[CH:21]=[C:22]4[N:27]([C:28]5[CH:29]=[C:30]([NH:31][C:47](=[O:48])[C:46]6[CH:50]=[C:51]([C:53]([F:54])([F:55])[F:56])[CH:52]=[C:44]([N:40]7[CH:41]=[CH:42][N:43]=[C:39]7[CH3:38])[CH:45]=6)[CH:32]=[CH:33][C:34]=5[CH3:35])[CH:26]=[CH:25][N:23]4[N:24]=3)[CH:17]=[N:16]2)=[CH:36][CH:37]=1
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(N)ccc5C)ccn4n3)cn2)cc1
Reactant: Cc1nccn1-c1cc(C(=O)O)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cc(-n7ccnc7C)cc(C(F)(F)F)c6)ccc5C)ccn4n3)cn2)cc1

Procedure:
60 mg (0.12 mmol) of the compound of Example 8A and 31.6 mg (0.12 mmol) of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid [lit.: WO 2004/005281-A1, Example 91b] were reacted and worked up analogously to the procedure of Example 48A. This gave 61 mg (77% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCCl.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:12][C:13]2[CH:14]=[C:15]([N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])[CH:16]=[CH:17][CH:18]=2)=[N:6][CH:7]=1
Reactant: Nc1cccc(N2CCCC2=O)c1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1CCCN1c1cccc(Nc2ncc(Br)cc2[N+](=O)[O-])c1
Yield: 65.4 %

Procedure:
A suspension of 5-bromo-2-chloro-3-nitropyridine (3.79 g, 16 mmol), 1-(3-aminophenyl)pyrrolidin-2-one (2.56 g, 15 mmol) and potassium carbonate (2.0 g, 15 mmol) in 1,2-dichloroethane (25 ml) was heated at reflux for 60 hours. The reaction was cooled, diluted with dichloromethane (200 ml) and extracted with water. The organic phase was then dried over anhydrous sodium sulphate, filtered and pre-adsorbed on to silica (25 g). Purification by column chromatography eluting with isohexane on a gradient of ethyl acetate (10%-40%) gave 1-[3-(5-bromo-3-nitropyridin-2-ylamino)phenyl]pyrrolidin-2-one as a red solid (3.7 g, 68%).
Reaction SMILES: [CH3:1]N(C)C=O.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1.CI>O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[O:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]([CH3:1])[C:30](=[O:38])[O:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:27][CH:28]=1
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCCC4)cc3)c2cc1OC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(N(C)C(=O)OC4CCCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (7 mg), and cyclohexyl N-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (35 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of methyl iodide (47 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (30 mg, yield 83%).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH2:16][CH3:17])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH2:18]([OH:20])[CH3:19]>C(O)(=O)C>[O:20]=[C:18]1[C:19]2[C:8](=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH2:9][N:1]1[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH2:16][CH3:17])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOc1cc(C(N)CC(=O)O)ccc1OC
Reactant: CCO
Solvent: CC(=O)O
Product: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Yield: 62 %

Procedure:
A stirred mixture of phthalic dicarboxaldehyde (2.68 g, 20.0 mmol) and 3-amino-3-(3-ethoxy4-methoxyphenyl)propionic acid (4.78 g, 20.0 mmol) in glacial acetic acid (50 mL) under nitrogen was heated to reflux for 5 minutes. The reaction mixture was then allowed to cool to room temperature and was concentrated in vacuo to afford a yellow solid. The crude product was recryslallized twice from refluxing ethanol (150 mL). The resulting solid was then dried in vacuo (60° C., <1 mm) to afford 4.4 g (62%) of 3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid as a white solid: mp 193.5°-194° C.; 1H NMR (DMSO-d6) δ 12.40 (br s, 1 H), 7.75-7.40 (m, 4 H), 7.05-6.85 (m, 3 H), 5.71 (m, 1 H), 4.51 (d, J=17.7 Hz, 1 H), 4.11 (d, J=17.7 Hz, 1 H), 3.99 (m, 2 H), 3.73 (s, 3 H), 3.25-3.02 (m, 2 H), 1.30 (t, J=6.9 Hz, 3 H); 13C NMR (DMSO-d6) δ 171.9, 166.9, 148.5, 147.9, 141.7, 132.2, 131.6, 131.4, 127.9, 123.5, 122.9, 119.3, 111.8, 63.7, 55.4, 51.2, 46.3, 36.8, 14.7; Anal. Calcd. for C20H21NO5. Theoretical: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.64; H, 5.97; N, 3.92.