Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([OH:16])=[CH:9][CH:10]=3)[C:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:16][C:8]1[CH:9]=[CH:10][C:11]2[O:12][C:13]3[C:4](=[CH:3][C:2]([C:26]4[CH:27]=[N:22][CH:23]=[N:24][CH:25]=4)=[CH:15][CH:14]=3)[C:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:6]=2[CH:7]=1
Reactant: NC1=NC2(CO1)c1cc(O)ccc1Oc1ccc(Br)cc12
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: NC1=NC2(CO1)c1cc(O)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 25 °C

Procedure:
A 150-mL pressure vessel was charged with 2′-bromo-7′-hydroxyspiro[1,3-oxazole-4,9′-xanthen]-2-amine (845 mg, 2434 μmol) in THF (24 mL), pyrimidin-5-ylboronic acid (754 mg, 6085 μmol), tetrakis(triphenylphosphine)palladium(0) (281 mg, 243 μmol), and potassium carbonate (10.1 mL of a 1.2 M aqueous solution, 12.1 mmol). The vessel was sealed and placed in a 100° C. oil bath at for 4 h. The reaction mixture was cooled to RT and partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (50 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The crude material was purified by chromatography on silica gel (eluting with 30-100% of a 90:10:1 DCM/MeOH/NH4OH solution in DCM) to give 2′-hydroxy-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]([NH:7][C:8]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]#[C:23][Si](C)(C)C)=[CH:21][C:16]=2[C:15]2[C:14](=[O:28])[NH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:3]([CH3:6])([CH3:5])[CH3:4].[OH-].[K+]>CO.O>[C:22]([C:20]1[CH:19]=[CH:18][C:17]2[C:8]([NH:7][CH:2]([CH3:1])[C:3]([CH3:4])([CH3:6])[CH3:5])=[N:9][C:10]3[CH:11]=[CH:12][NH:13][C:14](=[O:28])[C:15]=3[C:16]=2[CH:21]=1)#[CH:23]
Reactant: CC(Nc1nc2cc[nH]c(=O)c2c2cc(C#C[Si](C)(C)C)ccc12)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#Cc1ccc2c(NC(C)C(C)(C)C)nc3cc[nH]c(=O)c3c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 6-[(1,2,2-trimethylpropyl)amino]-9-[(trimethylsilyl)ethynyl]benzo[c]-1,6-naphthyridin-1(2H)-one (20 mg, 0.05 mmol) in MeOH (3.0 mL) was added KOH (6.0 mg, 0.09 mmol). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate, filtered, concentrated to afford 9-ethynyl-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (300 MHz, CDCl3) δ 10.15 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.62 (d, J=10.1 Hz, 1H), 7.31 (s, 1H), 6.62 (s, 1H), 3.23 (s, 1H), 1.25 (m, 3H), 1.04 (s, 9H). LRMS calculated for C20H21N3O [M+H]+, 320; found 320.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:29][C:30]#[N:31].O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[CH2:29][C:30]#[N:31])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCCCNc2ccc(Cl)cc2)cc1
Reactant: N#CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCCN(CC#N)c2ccc(Cl)cc2)cc1
Temperature: 90 °C
Reaction time: 168 h
Yield: 74.3 %

Procedure:
Methyl 4-[3-[N-(4-chlorophenyl)amino]propoxy]benzoate (1.2 g) was dissolved in DMF (10 ml), and under heating with stirring at 90° C., sodium bicarbonate (7.6 g) and chloroacetonitrile (6.63 g) were added thereto in 8-10 portions respectively over a period of 7 days. The reaction mixture was cooled, and water and ethyl acetate were added thereto and the mixture was separated into layers. The organic layer was washed with aqueous sodium chloride solution, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with chloroform to give the oily desired product (1.00 g).
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[OH-].[K+].C(N)(=O)C1CC=CNC=1.[CH3:25][O:26]S([O-])(=O)=O.CC1C=CC=C2C=1N=C1C(C=CC=C1)=[NH+]2.[C:46]([OH:55])(=[O:54])[C:47]1[C:48](=C[CH:51]=[CH:52][CH:53]=1)[OH:49]>>[OH:49][C:48]1[C:25]([OH:26])=[CH:51][CH:52]=[CH:53][C:47]=1[C:46]([OH:55])=[O:54]
Reactant: O=C(O)c1ccccc1O
Reactant: COS(=O)(=O)[O-]
Agent: Cc1cccc2[nH+]c3ccccc3nc12
Agent: NC(=O)C1=CNC=CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: O=C(O)c1cccc(O)c1O
Reaction time: 3 h
Yield: 5963 %

Procedure:
17 l of a 0.006M solution of citric acid are poured into a reactor and pH is brought to 4.5 by means of caustic potash, whereafter 17 g of cellulose modified with 1,4-dihydronicotinamide with the content of 0.2 mmol/g of dihydronicotinamide groups and 0.03 g of 9-methylphenazinium methylsulphate are added thereto and allowed to stand for 3 hours. Then 1.1 g of salicylic acid is added and the mixture is vigorously stirred for additional 3 hours. Cellulose modified 1,4-dihydronicotinamide is filtered off, the solution is evaporated to 100 ml and extracted with chloroform. The resulting extract is evaporated to 50 ml and cooled. The formed precipitate is crystallized with a mixture consisting of water and ethanol in the ratio of 1:1 to give 0.9 g of 2,3-dihydroxybenzoic acid (82% as calculated for the starting compound) having its melting point of 203°-204° C. Composition, in %, is as follows:
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[C:17]#[N:18])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[NH2:14][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([C:17]#[N:18])[CH:9]=1)[NH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13]2
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(C#N)c2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc2cc(N)cc(C#N)c2[nH]1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a solution of crude product 2-tert-butyl-5-nitro-1H-indole-7-carbonitrile (0.87 g, 3.6 mmol) in MeOH (10 mL) was added NiCl2.6H2O (1.8 g, 7.2 mmol) at −5° C. The reaction mixture was stirred for 30 min, then NaBH4 (0.48 g, 14.32 mmol) was added to the reaction mixture at 0° C. After 5 min, the reaction mixture was quenched with water, filtered and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain the crude product, which was purified by column chromatography (5-20% EtOAc in petroleum ether) to obtain 5-amino-2-tert-butyl-1H-indol-7-carbonitrile (470 mg, 32% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.06 (d, J=2.4 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.14 (d, J=2.4 Hz, 1H), 3.57 (br s, 2H), 1.38 (s, 9H). MS (ESI) m/z: 214 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]3)=[O:15])[C:10]([CH3:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/B(O)O)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:2]2[CH:3]=[C:4]([N:8]3[C:12]([CH3:13])=[C:11]([C:14]([N:16]4[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]4)=[O:15])[C:10]([CH3:26])=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Reactant: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(Br)c3)c2C)C1
Product: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(/C=C/c4ccc(Cl)cc4)c3)c2C)C1
Yield: 67 %

Procedure:
In analogy to the procedure described in Example 14C], [1-(3-bromo-phenyl)-3,5-dimethyl-1H-pyrazol-4-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone (Example 28A]) and trans-2-(4-chlorophenyl)vinylboronic acid gave the title compound in 67% yield as light brown foam. MS: 477.3 (MH+, 1 Cl).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH3:11])[CH:3]=1.[NH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[C:19]([Br:30])[C:18]=2[CH:31]=1>C(O)C>[Br:30][C:19]1[C:18]2[CH:31]=[C:14]([CH2:13][NH:12][C:2]3[N:7]4[N:8]=[CH:9][CH:10]=[C:6]4[N:5]=[C:4]([CH3:11])[CH:3]=3)[CH:15]=[CH:16][C:17]=2[O:21][C:20]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[N:29]
Reactant: Cc1cc(Cl)n2nccc2n1
Reactant: N#Cc1ccccc1-c1oc2ccc(CN)cc2c1Br
Solvent: CCO
Product: Cc1cc(NCc2ccc3oc(-c4ccccc4C#N)c(Br)c3c2)n2nccc2n1
Temperature: 25 °C

Procedure:
A solution of 1.7 g (10.1 mmol) 7-chloro-5-methylpyrazolo[1,5-a]pyrimidine (prepared according to Y. Makisumi, Chem. Pharm. Bull. 1962, 10, 620) and 3.27 g (10.0 mmol) 5-(aminomethyl)-3-bromo-2-(2-cyanophenyl)benzofuran (prepared according to WO 92/09600) in 50 ml dry ethanol was heated with reflux for 5 h. The title compound precipitated upon cooling to room temperature, was filtered with suction, and recrystallized from ethanol to give colorless crystals. yield: 3.5 g (76%), m.p. 210°-215° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([O:19]CC)=O)[CH2:11][CH2:10]1.O.[NH2:23][NH2:24]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([NH:23][NH2:24])=[O:19])[CH2:11][CH2:10]1
Reactant: NN
Reactant: CCOC(=O)CCN1CCN(c2ccccc2OC)CC1
Solvent: O
Solvent: CCO
Product: COc1ccccc1N1CCN(CCC(=O)NN)CC1
Yield: 86.1 %

Procedure:
A solution of ethyl 3-[4-(2-methoxyphenyl)piperazino]propanoate D1 (8.30 g, 28.38 mmol) and hydrazine monohydrate (8.52 g, 8.3 mL, 170.03 mmol) in ethanol (80 mL) was refluxed for 18 hrs. The solvent was evaporated under reduced pressure, the resulting solid was slurred in 50% acetone in hexane, filtered and dried to afford 6.80 g (87%) 3-[4-(2-methoxyphenyl)piperazino]propanohydrazide D2 as a white solid.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1OC)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7].[C:23]1(OC)C(=CC=CC=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].CC1C=CC(C(Cl)=O)=CC=1>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[C:6]([C:5]1[CH:4]=[CH:3][C:20]([CH3:23])=[CH:19][CH:18]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Reactant: COc1ccccc1OC
Agent: Cc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2ccc(C)cc2)cc1OC

Procedure:
The title compound was prepared analogously to 3,4,3',4'-tetramethoxybenzophenone using veratrole (3.9 mL, 28 mmol), aluminum chloride (4.1 g, 31 mmol) and 4-methylbenzoyl chloride (4.6 mL, 29 mmol) with a reaction time of 6 hours at room temperature. The crude mixture was purified by flash column chromatography (silica gel, 2% ethyl acetate/methylene chloride) to afford 4.22 g (59%) of the product as a white solid: mp 121.5-122° C.; 1H NMR (CDCl3) δ 7.70-7.67 (d, J=8 Hz, 2 H), 7.48-7.26 (m, 4 H), 6.91-6.88 (d, J=8.3 Hz, 1 H), 6.96 (s, 3 H), 3.94 (s, 3 H), 2.44 (s, 3 H); 13C NMR (CDCl3) δ 195.1, 152.6, 148.8, 142.4, 135.3, 130.3, 129.8, 128.7, 125.0, 112.0, 109.6, 55.9, 55.8, 21.4; Anal. Calcd for C16H16O3. Theoretical: C, 74.98; H, 6.29. Found: C, 74.84; H, 6.43.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:7]=2)[CH2:3][CH2:2]1.Br[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[N:29]([CH2:35][CH:36]1[CH2:38][CH2:37]1)[CH:28]=[C:27]2[CH:39]=[O:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30](=[O:34])[N:29]([CH2:35][CH:36]3[CH2:38][CH2:37]3)[CH:28]=[C:27]4[CH:39]=[O:40])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=Cc1cn(CC2CC2)c(=O)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Temperature: 80 °C

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.47 g) [prepared as described in US2005020590], the product of step ii) (0.4 g), tetrakis(triphenylphosphine)palladium(0) (0.15 g) and potassium carbonate (0.54 g) in DMF (10 mL) were heated at 80° C. for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organics were dried over magnesium sulphate and evaporated. The residue was purified (SiO2, eluting with 1:1 ethyl acetate: isohexane) to give the sub-title compound (0.2 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([O:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[CH:3]=1.[NH2:20][NH2:21]>O1CCOCC1>[NH:20]([C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([O:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[CH:3]=1)[NH2:21]
Reactant: CC(C)(O)COc1cc(Cl)nc(N2CCOCC2)n1
Reactant: NN
Solvent: C1COCCO1
Product: CC(C)(O)COc1cc(NN)nc(N2CCOCC2)n1

Procedure:
1-(6-chloro-2-morpholin-4-yl-pyrimidin-4-yloxy)-2-methyl-propan-2-ol (2.58 g) was dissolved in dioxane (50 mL) and hydrazine (3 mL) was added. The solution was heated to reflux for one hour, at which point the solvent was evaporated. The solid was dissolved in dichloromethane (200 mL) and washed with 10% sodium carbonate (10 mL). The organic layer was dried over magnesium sulfate and evaporated to give 1-(6-hydrazino-2-morpholin-4-yl-pyrimidin-4-yloxy)-2-methyl-propan-2-ol, which was used without purification in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[H-].[Na+].Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: O=C1Nc2cccc(Br)c2C1=O
Reactant: BrCc1ccccn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccccn2)c2cccc(Br)c21
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of 4-bromoisatin (8.94 g, 39.5 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added sodium hydride (3.34 g, 86.9 mmol, 60% dispersion in mineral oil) in portions at 0° C. The brown reaction mixture was stirred for 30 min followed by the addition of a solution of 2-(bromomethyl)pyridine hydrobromide (10.0 g, 39.5 mmol) neutralized with sodium hydride (1.52 g, 39.5 mmol, 60% dispersion in mineral oil) in N,N-dimethylformamide at 0° C. The reaction mixture was stirred for 16 h and quenched with water (100 mL). The reaction mixture was extracted with diethyl ether (3×100 mL) and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers was washed with water (5×200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with ether to afford the title compound (10.6 g, 85%) as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, 1H), 7.67 (t, 1H), 7.30 (t, 2H), 7.25-7.19 (m, 2H), 6.94 (d, 1H), 5.04 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 180.5, 157.3, 154.2, 152.3, 149.5, 138.4, 137.5, 128.6, 123.3, 122.3, 121.5, 116.4, 110.3, 45.8.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18])[CH3:13]>>[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:10]=[C:9]([NH:11][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][CH2:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:18])[CH3:13]
Reactant: Nc1ccc(C(=O)O)c(N)c1
Reactant: CCOc1ccccc1C(=O)Cl
Product: CCOc1ccccc1C(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccccc2OCC)c1

Procedure:
By the procedure similar to that described in Example 1, 2,4-diaminobenzoic acid was condensed with 2-ethoxybenzoylchloride to obtain 2,4-bis(2'-ethoxybenzamido)-benzoic acid having a melting point between 225° - 226°C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:7]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:25])=[C:17](F)[C:18]=3[O:20][CH:21]([F:23])[F:22])[C:13](=[O:26])[C:12]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:11]2[S:32]([CH3:35])(=[O:34])=[O:33])[CH2:9][CH2:8]1.NC([C@@H]1CCN(C2C(OC)=C3C(C(=O)C(C(OCC)=O)=C(S(C)(=O)=O)N3C3CC3)=CC=2F)C1)(C)C>>[CH:7]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:25])=[C:17]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)[C:18]=3[O:20][CH:21]([F:23])[F:22])[C:13](=[O:26])[C:12]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:11]2[S:32]([CH3:35])(=[O:33])=[O:34])[CH2:9][CH2:8]1
Reactant: CCOC(=O)c1c(S(C)(=O)=O)n(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Reactant: C1CNCCN1
Agent: CCOC(=O)c1c(S(C)(=O)=O)n(C2CC2)c2c(OC)c(N3CC[C@@H](C(C)(C)N)C3)c(F)cc2c1=O
Product: CCOC(=O)c1c(S(C)(=O)=O)n(C2CC2)c2c(OC(F)F)c(N3CCNCC3)c(F)cc2c1=O

Procedure:
The title compound is prepared from piperazine and ethyl 1-cyclopropyl-8-(difluoromethoxy)-6,7-difluoro-2-(methylsulfonyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate using a procedure analogous to that describing the preparation of (R)-ethyl 7-(3-(2-aminopropan-2-yl)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-2-(methylsulfonyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate. (See US 2008071086, and Hashimoto, et al., 2007) 1H NMR (CDCl3): δ 0.30-0.33 (m, 1H), 0.84-0.88 (m, 1H), 0.99-1.04 (m, 1H), 1.20-1.25 (m, 1H), 1.38 (t, J=7.2 Hz, 3H), 2.95-3.21 (m, 6H), 3.44 (s, 3H), 3.51-3.58 (m, 2H), 4.13-4.18 (m, 1H), 4.36-4.48 (m, 2H), 6.54 (dd, J=76.0 Hz, 73.0 Hz, 1H), 7.72 (d, J=12.0 Hz, 1H). 19F NMR (CDCl3): δ −120.4 (s, 1F), −82.1 (s, 2F). LCMS: m/z calcd for C21H24F3N3O6S ([M]+) 503. found ([M+H]+) 504.
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]/[C:19](=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[NH4+].[Cl-]>CO>[Si:3]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]/[CH:19]([OH:28])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])([C:6]([CH3:7])([CH3:9])[CH3:8])([CH3:5])[CH3:4]
Reactant: COC(=O)CCCCC(=O)/C=C/c1ccccc1O[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)CCCCC(O)/C=C/c1ccccc1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C

Procedure:
At 0° C., 0.146 g (3.86 mmol) of sodium borohydride was added to a solution of 1.436 g (3.86 mmol) of CeCl3.7H2O and 3.67 mmol of methyl (E)-8-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-6-oxo-7-octenoate from Ex. XIIc in 30 ml of methanol. The mixture was stirred at 0° C. and the progress of the reaction was monitored by thin-layer chromatography. Saturated NH4Cl solution was added, the mixture was extracted with ethyl acetate and the combined organic phases were dried over Na2SO4. The product was purified chromatographically (silica gel, cyclohexane/EA 10:2). This gave 1.38 g (91.5%) of a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31]#[CH:32])[CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:32]#[C:31][CH2:30][O:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#CCOc1cccnc1
Product: Cc1nnc2n1-c1sc(C#CCOc3cccnc3)cc1C(c1ccccc1Cl)=NC2

Procedure:
Coupling of 4-(2-chlorophenyl)-2-iodo-9-methyl -6H-thieno[3,2-f][1,2,4] triazolo[4,3-a][1,4]diazepine with 1-(3-pyridinyloxy)-2-propyne [ref. J. Bruhn J., Zsindely, H. Schmid and G. Frater, Helv. Chim. Acta 61, 2542 (1978)] under conditions described in EXAMPLE 37 yielded after the usual chromatographic isolation resinous material containing the title compound which did not crystallize and was therefore characterized spectroscopically only. Nmr (CDCl3): 2.72 ppm (s,3,Me) 4.95 (s,4,CH2 ; C6 -H), 6.8 (s.1,C3 -H) 7.2-7.6 (m,6,aromatic H), 8.26 (m,1,) and 8.36 (broad s,1) pyridine C2 and C6 -H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]3[S:26][C:25]([O:27][CH2:28][CH3:29])=[N:24][CH:23]=3)[S:21][C:14]=12>>[CH2:28]([O:27][C:25]1[S:26][C:22]([C:20]2[S:21][C:14]3[C:15](=[N:16][CH:17]=[CH:18][C:13]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:19]=2)=[CH:23][N:24]=1)[CH3:29]
Reactant: CCOc1ncc(-c2cc3nccc(Cl)c3s2)s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: CCOc1ncc(-c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)s1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 7-chloro-2-(2-ethoxy-thiazol-5-yl)-thieno[3,2-b]pyridine by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ10.95 (s, 1H), 8.62 (s, 1H), 8.23 (d, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.33 (m, 2H), 6.88 (d, 1H), 6.52 (d, 1H), 6.08 (s, 1H), 4.44 (q, 2H), 2.46 (s, 3H), 1.35 (t, 3H); RP18-HPLC RT: 5.83 minutes; API MS: 407 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[C:13]([O:25][CH3:26])=[C:14]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[C:13]([O:25][CH3:26])=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35]
Reactant: CCOC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3cccc(CCC(=O)O)c3OC)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.7 %

Procedure:
To a solution of ethyl 3-(3-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-2-methoxyphenyl)propanoate (450 mg) in methanol (4.0 mL) and THF (8.0 mL) was added 1N aqueous sodium hydroxide solution (8.0 mL), and the mixture was stirred at room temperature 15 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added to the residue to adjust to pH<4. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (275 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:15]N(C=O)C>CO>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:15])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc(Br)n1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cccc(Br)n1

Procedure:
A mixture of 6-bromo-2-pyridinecarboxylic acid (0.3 g, 1.5 mmol), thionyl chloride (0.27 ml, 3.7 mmol) and DMF (catalytic amount) in methanol (10 ml) was heated to reflux for 2 hrs under nitrogen atmosphere. The reaction mixture was concentrated to dryness to provide methyl 6-bromo-2-pyridinecarboxylate.