Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([O:18][CH3:19])=[C:11](Cl)[CH:12]=[CH:13]2)=[C:8]([CH2:20][CH3:21])[CH:7]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:29]([NH:36][CH2:37][CH2:38][CH:39]1[CH2:43][CH2:42][NH:41][CH2:40]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([O:18][CH3:19])=[C:11]([N:41]3[CH2:42][CH2:43][CH:39]([CH2:38][CH2:37][NH:36][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:40]3)[CH:12]=[CH:13]2)=[C:8]([CH2:20][CH3:21])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC1CCNC1
Reactant: CCOC(=O)c1cc(CC)c2c(OC)c(Cl)ccn2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CC)c2c(OC)c(N3CCC(CCNC(=O)OC(C)(C)C)C3)ccn2c1=O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
Ethyl-8-chloro-1-ethyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate (Precursor A) (0.151 g) and triethylamine (0.5 ml) are dissolved in acetonitrile (6 ml). To this solution 3-(N-boc-aminoethyl)pyrrolidine (Precursor D) (0.215 g) is added and the solution stirred at 40° C. for 18 hours. The solvent is evaporated and the residue dissolved in dichloromethane, washed with 1N hydrochloric acid and dried over sodium sulfate. The desired product is obtained by evaporation of the solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:26]1([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2F)[CH:32]=[O:33])[CH2:28][CH2:27]1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:36]3[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][C:29]=3[CH:26]3[CH2:27][CH2:28]3)=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(F)c(C2CC2)c1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C2CC2)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
N-(4-Chlorophenethyl)-4-hydroxybenzamide (504 mg, 1.83 mmol) was diluted with DMSO (8 mL) and K2CO3 (379 mg, 2.74 mmol) and 3-cyclopropyl-4-fluorobenzaldehyde (300 mg, 1.83 mmol) were added. The reaction was stirred 85° C. overnight. The reaction was cooled to ambient temperature, diluted with ethyl acetate and washed with twice with 10% sodium carbonate, water and brine, and concentrated. The crude material was purified by silica gel chromatography eluting with hexanes:ethyl acetate (3:1) to provide N-(4-chlorophenethyl)-4-(2-cyclopropyl-4-formylphenoxy)benzamide (160 mg, 20.9% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([C:15](OC)=[O:16])#[C:10][C:11]([O:13][CH3:14])=[O:12]>CO>[CH3:14][O:13][C:11]([C:10]1[CH:9]=[C:15]([OH:16])[C:6]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:8][CH:7]=2)[N:5]=1)=[O:12]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1cccc(Cl)c1
Solvent: CO
Product: COC(=O)c1cc(O)c2ccc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a stirred solution of 3-chloroaniline (40.8 g, 320 mmol) in MeOH (500 mL) at rt was added dimethyl acetylene dicarboxylate (50 g, 352 mmol). After addition, the reaction was kept at reflux for 2 h, then cooled to rt. After evaporating methanol in vacuo, the resulting crude adduct was dissolved in Ph2O (160 mL), and was added dropwise to a hot solution of Ph2O (800 mL) in a three-neck flask at 250° C. The reaction mixture was kept at 250° C. for an additional 30 min, and was cooled to rt. The reaction mixture was diluted with hexane, and the product precipitated. The crude mixture was collected by filtration (washed with hexane and ether). This mixture (78 g) was re-dissolved in pyridine (468 mL) (Note: the other solvent for re-crystallization is acetic acid, and the ratio of crude product to acetic acid is 1:6 based on weight), and kept at reflux for about 30 min. After cooling to rt, the desired product was collected by filtration (washed with ether). The solid was air dried overnight to give 35 g (46%) of 7-chloro-4-hydroxy-2-quinolinecarboxylic acid methyl ester. LC-MS: 237 (M++1). 1H NMR (DMSO-d6): 63.98 (s, 3H), 6.6 (s, 1), 7.38 (d, 1H), 7.96 (s, 1H), 8.04 (d, 1), 12.1 (s, 1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[C:13]([F:19])[CH:12]=1.ClC1C=CC(C(C2C=CC(OC)=CC=2)O)=CC=1>>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[CH3:9])[OH:16])=[C:13]([F:19])[CH:12]=1
Reactant: Cc1cc(F)ccc1Br
Reactant: O=Cc1ccc(Cl)cc1F
Agent: COc1ccc(C(O)c2ccc(Cl)cc2)cc1
Product: Cc1cc(F)ccc1C(O)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared starting from 5.00 g (26.45 mmol) of 2-bromo-5-fluorotoluene and 5.03 g (31.74 mmol) of 4-chloro-2-fluorobenzaldehyde in analogy to the synthesis of the compound from Example 175A. A difference was that the crude product was purified twice by preparative HPLC. 4.84 g (65% of theory) of the title compound were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][C:17]([C:13]3[O:12][CH:16]=[CH:15][CH:14]=3)=[N:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=Cc1ccco1
Solvent: CCO
Product: O=[N+]([O-])c1ccc2oc(-c3ccco3)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.9 %

Procedure:
15.4 g of 4-nitro-2-aminophenol is dissolved in 250 ml of ethanol and to this solution 9.6 g of furaldehyde is added to room temperature. The reaction is allowed to stir at room temperature for 0.25 hr and the precipitated crystals are collected. The resulting Schiff Base is then dissolved in 250 ml of glacial acetic acid, treated with 44 g of lead tetraacetate and then refluxed for 2 hr. The mixture is then diluted with 250 ml of water and the precipitated product is collected and washed with water. Recrystallization from 150 ml of CH2Cl2 yields 10.1 g of 5-nitro-2-(2-furyl)benzoxazole, mp 175°-177°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[NH:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].Cl[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([S:30][CH3:31])[N:25]=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[N:9]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([S:30][CH3:31])[N:25]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c(-c2cccc(C(F)(F)F)c2)n1
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccnc(SC)n2)c(-c2cccc(C(F)(F)F)c2)n1
Temperature: 140 °C
Yield: 74.6 %

Procedure:
To a solution of 2-(3-trifluoromethylphenyl)-1H-imidazole4-carboxylic acid ethyl ester (6.0 g, 0.0211 mol) in dimethyl formamide (60 mL) was added a 60% dispersion of sodium hydride in mineral oil (1.01 g, 0.0253 mol) and stirring was continued until noticeable H2 evolution stopped. 4-Chloro-2-methylthiopyrimidine (3.73 g, 0.0232 mol) was added dropwise and the reaction heated to 120° C. for 2 h and 140° C. overnight. The reaction was cooled and partitioned between H2O (300 mL) and ethyl acetate (300 mL). A small (30 mL) portion of 10% citric acid solution was added before the layers were shaken and separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated to an oil which was chromatographed on silica using 15-35% ethyl acetate in hexanes to yield 6.43 g (75%) of the title compound as an oil.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].C(Cl)Cl.[CH:8]([CH:10]1[CH2:14][S:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]1[C:21]([O:23][CH3:24])=[O:22])=[O:9].[Cl-].[NH4+]>CO>[OH:9][CH:8]([CH:10]1[CH2:14][S:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]1[C:21]([O:23][CH3:24])=[O:22])[CH:1]=[CH2:2]
Reactant: COC(=O)N1C(C=O)CSC1c1ccccc1
Reactant: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: C=CC(O)C1CSC(c2ccccc2)N1C(=O)OC
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a mixture of 310 ml. (0.440 mole) of vinylmagnesium chloride (from Ventron Corp., 1.42 molar in tetrahydrofuran) and 250 ml. of methylene chloride, which had been previously prepared and kept at -74°C., a solution of 14.2 g. (0.0565 mol) of 4-formyl-3-carbomethoxy-2-phenylthiazolidine dissolved in 50 ml. of methylene chloride was added over a period of 7-10 minutes, while the temperature of the reaction was kept at -60° to -70°C. After addition, the reaction mixture was stirred for 30 minutes at the same temperature while 30 ml. of methanol were slowly added, followed by addition of 150 ml. of saturated ammonium chloride. When the addition was finished, the mixture was allowed to reach room temperature and extracted with 3 × 300 ml. of methylene chloride. The combined organic phases were washed with 2 × 200 ml. of water, dried with sodium sulfate, and evaporated to give 13.7 g. (87% yield) of crude 4-(1-hydroxyprop-2-en-1-yl)-3-carbomethoxy-2-phenylthiazolidine which was obtained as thick oil. This contains a small amount of starting material which, for future separation purposes, is convenient to convert into its corresponding alcohol. To this end, the crude product, dissolved in 100 ml. of tetrahydrofuran was slowly added to a solution of 0.9 g. (0.0503 mol) of sodium borohydride in 75 ml. of water and 75 ml. of tetrahydrofuran. After addition, the resulting yellow emulsion was stirred for 2 hours at room temperature. 55 ml. of 1N hydrochloric acid were then slowly added, the tetrahydrofuran removed in vacuo and the residue extracted with 3 × 100 ml. of ethyl acetate. The combined organic phases were washed with 100 ml. of 5% sodium bicarbonate solution and finally with 2 × 100 ml. of water. Drying with magnesium sulfate and evaporating the solvent gave 13.0 g. of the desired product, which can be used as such for the further transformations or it can be further purified by chromatography on silica gel, using benzene/ethyl acetate (1:1) as eluent. 4.1 g. (corresponding to a yield of 26% from a starting material) of very pure product was obtained as pale yellow thick oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Br:13].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Br:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:14])=[O:23]
Reactant: Cc1ccccc1N=C=O
Reactant: COC(=O)Cc1ccc(N)c(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(Br)c1
Reaction time: 21 h
Yield: 71.8 %

Procedure:
To a mixture of methyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-methylphenyl isocyanate (0.287 ml, 2.40 mmol) in THF (2 ml) was added Et3N (33 ml, 0.24 mmol) at room temperature. After 21 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-bromo-4-[N′-(2-methylphenyl)ureido]phenylacetate (650 mg, 72%) as a pale brown powder. 1H-NMR (CDCl3) δ2.34 (s, 3H), 3.53 (s, 2H), 3.68 (s, 3H), 6.18 (br, 1H), 6.96 br, 1H), 7.18-7.33 (m, 4H), 7.29 (d, J=4.4 Hz, 1H), 7.30 (d, J=7.3 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H); MS (ESI) m/z 377 (M+), 379 (M++2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][NH2:28])=[O:26])=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:5])[CH3:2].[CH3:34]OC(OC)OC>>[CH2:1]([O:3][C:4]([C:6]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[O:26][CH:34]=[N:28][N:27]=3)=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(C(=O)NN)cc2)nc1
Reactant: COC(OC)OC
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(-c3nnco3)cc2)nc1
Yield: 97.4 %

Procedure:
A mixture of affording 1-[6-(4-Hydrazinocarbonyl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g, 0.44 mmol), trimethylorthoformate (0.1 mL, 0.91 mmol) and 1 mL of xylenes was refluxed for 24 hours. The mixture was concentrated in vacuo, affording 1-[6-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.2 g) as a colorless syrup. MS (APCl, m/z): 467.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:22])[CH2:20]C)[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:39]([CH3:44])[C:40]([O:42][CH3:43])=[O:41].O>CN(C)C=O>[CH3:43][O:42][C:40](=[O:41])[CH:39]([NH:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:19](=[O:22])[CH3:20])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1)[CH3:44]
Reactant: COC(=O)C(C)Br
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)Nc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccccc3)C[C@@H]2C)cc1
Temperature: 100 °C
Yield: 87 %

Procedure:
(±)-Cis-2-{4-[4-(acetyl-phenyl-amino)-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl]-phenylamino}-propionic acid methyl ester was prepared from (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide. A mixture of (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide (210 mg, 0.53 mmol), potassium carbonate (123 mg, 0.89 mmol), and methyl 2-bromopropionate (70 uL, 0.63 mmol) in dry dimethylformamide (2 mL) was heated at 100° C. for 6 h, then cooled to room temperature and stirred with 20 ml water until all of the salts dissolved. The aqueous layer was separated and was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography, eluting with (97:3 methylene chloride/methanol) to afford the title compound (220 mg, 87%).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[S-:19][C:20]1[CH:25]=[C:24]([C:26]([O-:28])=[O:27])[CH:23]=[CH:22][N:21]=1.[Na+].[Na+].C(=O)(O)[O-].[Na+].Cl>O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: O=C([O-])c1ccnc([S-])c1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3cc(C(=O)O)ccn3)CS[C@H]12
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 52.7 %

Procedure:
To a suspension of 7-aminocephalosporanic acid (9.30 g) and disodium 2-sulfido-4-pyridinecarboxylate (6.80 g) in water (160 ml) was dropwise added sodium bicarbonate (5.73 g) at room temperature. To the resulting mixture was added a saturated aqueous solution of sodium bicarbonate so that the pH was adjusted to 6.8. The resulting mixture was warmed to 65° C. and stirred for 1.5 hours during which period the temperature was allowed to rise from 65° to 75° C. The reaction mixture was cooled and then adjusted to pH 3.6 with 10% hydrochloric acid. The precipitates were collected by filtration, washed successively with water (x2), acetone (x2) and diethyl ether and then dried to give 7-amino-3-(4-carboxypyridin-2-yl)thiomethyl-3-cephem-4-carboxylic acid (6.61 g).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:36][CH2:37][O:38][CH2:39][CH2:40][OH:41]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][OH:41])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Reactant: OCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCOCCO)c2ccc(C#CCO)cc2c1=O
Temperature: 100 °C

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide (0.37 gm) from Preparation No. 5 in DMF (10 mL) is treated with potassium carbonate (2.75 gm), potassium iodide (1.66 gm) and 2-(2-chloroethoxy)ethanol (1.0 mL). The mixture is tightly capped and heated to 100° C. for 48 hrs. The reaction mixture is allowed to cool to room temperature, poured into water and extracted with dichloromethane. The layers are separated and the aqueous layer is re-extracted with dichloromethane containing a small amount of methanol and finally again with dichloromethane. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 3% to 15% methanol in dichloromethane and then by recrystallization from methanol to afford 82 mg of the title compound as a light yellow solid.
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[CH3:16].[C:17](=[O:19])=[O:18]>C1COCC1>[CH3:16][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:17]([OH:19])=[O:18])[CH:8]=2)[NH:12][N:11]=1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1n[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
A three necked round bottom flask equipped with an internal thermometer and an overhead stir motor was charged with 600 mL of THF and chilled to −78° C. t-BuLi (1.7 M in THF, 200 mL, 0.340 mol) was added to the flask, and the mixture was stirred for 15 minutes. 5-Bromo-3-methyl-1H-indazole (22.4 g, 0.106 mol) in 200 mL THF was then added dropwise via an addition funnel. The rate of addition was closely monitored to make sure that the internal temperature remained below −70° C. The resulting orange solution was stirred for 30 minutes, at which point CO2 was bubbled through the mixture. A white precipitate was observed. After 20 minutes, the ice bath was removed and the temperature was allowed to warm to room temperature. The resulting mixture was stirred for an additional 30 minutes. Water was then added to the mixture (40 mL initially followed by a further 200 mL). The biphasic mixture was partially concentrated under reduced pressure, removing about 75% of the original organic portion. The biphasic solution was then transferred to an addition funnel, and the organic phase was extracted with 100 mL of 2M NaOH. The combined aqueous extracts were washed with ether and then acidified to pH=2.0 with concentrated HCl. A precipitate began to form, and the mixture was cooled to 0° C. to complete the precipitation. The resulting solid was filtered, washed with 1M HCl, and dried under reduced pressure at 160° C. over phosphorus pentoxide, affording 3-methyl-1H-indazole-5-carboxylic acid (18.1 g, 96% yield) as a pink/beige solid. LCMS (API-ES) m/z (%): 177.0 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 2.61 (s, 3H) 3.33 (b, 2H), 7.52 (d, J=6.0 Hz, 1H), 8.05 (d, J=6.0 Hz, 1H), 8.50 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:28]=[C:27]([CH3:29])[C:7]([O:8][C:9]2[C:10]3[NH:26][CH:25]=[CH:24][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[N:14]=2)=[C:6]([CH3:30])[CH:5]=1)(=[O:3])[CH3:2].C1C(=O)N([Cl:38])C(=O)C1>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[C:6]([CH3:30])[C:7]([O:8][C:9]2[C:10]3[NH:26][CH:25]=[C:24]([Cl:38])[C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=3)[N:14]=2)=[C:27]([CH3:29])[CH:28]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3cc[nH]c23)c(C)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC(=O)c1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3c(Cl)c[nH]c23)c(C)c1
Yield: 32.4 %

Procedure:
To a solution of 4-(4-(4-acetyl-2,6-dimethylphenoxy)-5H-pyrrolo[3,2-d]pyrimidin-2-ylamino)benzonitrile (13 mg, 0.03 mmol) in CH2Cl2 (1 mL) was added NCS (4.4 mg, 0.03 mmol) and the mixture refluxed for 16 h. After the completion of the reaction, the solvent was concentrated and purified by preparative TLC eluting with hexanes:ethyl acetate (2:1) to give the product (4.2 mg, 30%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1>>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:2]2[N:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:7]=2)[CH:23]=1
Reactant: OB(O)c1cccnc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccnc3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.2) (0.33 g, 1.0 mmol) and commercially available 3-pyridineboronic acid (0.184 g, 1.5 mmol) according to the general procedure IVb. Obtained as a light yellow solid (0.03 g, 8%). MS (ISP) 370.1 [(M+H)+]; mp 134° C.
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=3)=[CH:16][C:15]=2[NH:30][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:43])[CH3:42])=[N:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O1CCCC1.O>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=3)=[O:29])=[CH:16][C:15]=2[NH:30][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:43])[CH3:42])=[N:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc(Sc3ccc(N)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)nc1
Temperature: 60 °C

Procedure:
To a solution of the product of Example 173B in tetrahydrofuran and water (1:1) was added 1 M NaOH (5 equiv). The solution was heated at 60° C. for 40 minutes, cooled, adjusted to pH 6 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with 4% methanol in dichloromethane to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 2.27 (s, 3 H) 3.14-3.29 (m, 1 H) 5.62 (s, 2 H) 6.64 (d, J=8.09 Hz, 2 H) 6.82 (d, J=8.46 Hz, 1 H) 7.15 (d, J=8.09 Hz, 2 H) 7.64 (d, J=8.46 Hz, 2 H) 7.87 (dd, J=8.27, 1.29 Hz, 1 H) 7.97-8.11 (m, 2 H) 8.19 (s, 1 H) 8.32 (s, 1 H) 8.50-8.61 (m, 1 H) 8.89 (d, J=8.82 Hz, 1 H) 10.12 (s, 1 H) 10.63 (s, 1 H).