Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])N(CCO)N=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[C:22](=[O:29])[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: NNc1ccccc1
Product: COc1ccc(C2=NN(c3ccccc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C (see starting compounds) and phenylhydrazine as described for compound 35. Crystallized from diethyl ether. M.p. 134°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][CH:10]=[CH:11][N:12]=1.[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19].C[O-].[Na+].Cl>COC(C)(C)C.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13](=[O:15])[CH2:14][C:18](=[O:19])[C:17]([F:24])([F:23])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][CH:10]=[CH:11][N:12]=1
Reactant: CC(=O)c1ccc(-c2ncco2)c(Cl)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CO
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-c2ncco2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 113.1 %

Procedure:
To a solution of 1-[3-chloro-4-(1,3-oxazol-2-yl)phenyl]-1-ethanone (1.89 g, 8.572 mmol) in t-butyl methyl ether (100 mL) were added ethyl trifluoroacetate (1.1 mL, 9.38 mmol) and 28% wt sodium methoxide in MeOH (2.6 ml) at 0° C. and stirred at room temperature for 4 hours. Water (100 mL) was added to the mixture, the mixture was neutralized with 2N HCl, extracted with ethyl acetate (100 mL×2) and dried over MgSO4. Removal of the solvent, gave a title compound (3.08 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Si]([O:47][CH2:48][C:49]1[S:53][C:52]([C:54](=[N:56]O)[NH2:55])=[C:51]([CH2:58][CH3:59])[CH:50]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[CH2:58]([C:51]1[CH:50]=[C:49]([CH2:48][OH:47])[S:53][C:52]=1[C:54]1[N:56]=[C:5]([C:4]2[CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([F:1])[CH:3]=2)[O:7][N:55]=1)[CH3:59]
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO
Reactant: O=C(O)c1ccc(Oc2ccccc2)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3)c(F)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 12 (12a) using 3-fluoro-4-phenoxybenzoic acid (0.12 g, 0.50 mmol) that was obtained in Example 11 (11e), 1-hydroxybenzotriazole (72 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10 g, 0.53 mmol), 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N′-hydroxythiophene-2-carboximidamide (0.15 g, 0.48 mmol) that was obtained in Example 10 (10d), and a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.96 ml, 0.96 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3) as the eluent to afford the title compound (0.16 g) in a yield of 85% as a pale yellowish crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH2:8][C@@H:7]1[CH3:35])=[O:5])[CH3:2].N1C=CC=CC=1.Cl[C:43]([O:45][CH3:46])=[O:44]>ClCCl.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([N:19]([CH2:20][C:21]2[CH:22]=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=2)[C:43]([O:45][CH3:46])=[O:44])[CH2:8][C@@H:7]1[CH3:35])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc3c(cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C)CCC3
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)N1c2cc3c(cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C)CCC3
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
cis-4-(3,5-Bis-trifluoromethyl-benzylamino)-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic acid ethyl ester (Example 4) (1.30 g, 2.55 mmol) was dissolved in anhydrous dichloromethane (100 mL), and pyridine (2.05 mL, 25.5 mmol) was added. The mixture was cooled to 0° C., and methyl chloroformate (1.97 mL, 25.5 mmol) was slowly added over 20 min. The reaction was stirred at 0° C. for 1 h, then at room temperature for 18 h. The reaction mixture was then diluted with chloroform, and washed twice with 1N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 10% ethyl acetate/hexanes as eluent afforded the title compound (1.00 g). MS m/z 558 (M+); 1H NMR (CDCl3) δ1.1(d, 3H), 2.9 (m, 4H), 3.8 (s, 3H), 6.8 (s, 1H), 7.3 (s, 1H).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([C:60](=[O:62])[NH2:61])=[C:53]([O:58][CH3:59])[CH:54]=4)[O:49][C:48]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([C:60]([NH2:61])=[O:62])=[C:53]([O:58][CH3:59])[CH:54]=4)[O:49][C:48]=3[C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: COc1cc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2cc1C(N)=O
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1cc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2cc1C(N)=O
Yield: 93 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(7-carbamoyl-6-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a pale yellow solid (17 mg, 93%). 1H NMR (400 MHz, DMSO-d6): δ 7.99 (s, 1H), 7.91-7.88 (br s, 1H), 7.85-7.81 (br s, 1H), 7.59 (s, 1H), 7.45-7.31 (m, 7H), 7.16-7.11 (m, 2H), 3.98 (s, 3H), 2.41-2.33 (m, 2H), 2.13-2.04 (m, 2H), 2.04-1.94 (m, 1H), 1.70-1.60 (m, 1H). LCMS (Method E): RT=2.99 min, [M+H]+=441.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1.C(N(CC)CC)C.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].O>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][C:4]1[S:5][CH:6]=[C:2]([C:16]#[C:15][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1
Reactant: Cc1nc(Br)cs1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc(C#C[Si](C)(C)C)cs1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A flask was charged with 4-bromo-2-methylthiazole (400 mg, 2.247 mmol) and triethylamine (8 mL) and sparged with nitrogen for 15 min. To this was added ethynyltrimethylsilane (0.381 mL, 2.70 mmol) and purged 15 min longer. To this was added copper(I) iodide (21.39 mg, 0.112 mmol), and Pd(PPh3)2Cl2 (79 mg, 0.112 mmol). The reaction stirred at room temperature for 72 h. The reaction was diluted with ethyl acetate (16 mL) and poured into water. The black heterogeneous emulsion was filtered through a plug of celite and the layers separated. The organics were washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (5%-->6% EtOAc/Hex) gave 307 mg (70%) as a light amber oil. 1H-NMR (CDCl3, 500 MHz) δ 7.34 (s, 1H), 2.72 (s, 3H), 0.27 (s, 9H). 13C-NMR (CDCl3, 126 MHz) δ 165.6, 137.0, 123.0, 98.4, 94.6, 19.3, −0.1.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1.[CH3:20]O>>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:20])=[O:14])=[C:8]([C:16]([F:17])([F:18])[F:19])[CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Cl)cc1C(F)(F)F
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Cl)cc1C(F)(F)F

Procedure:
Thionyl chloride (9.5 mL) was added dropwise to a solution of 4-chloro-2-(trifluoromethyl)phenylacetic acid (CAS #601513-31-9, 10.5 g) in methanol (50 mL) under ice-cooling. Then, the reaction solution was heated under reflux for three hours. The reaction solution was concentrated under reduced pressure. A saturated sodium bicarbonate solution and ethyl acetate were added to the resulting residue, and the organic layer was separated. The resulting organic layer was sequentially washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 10.96 g of the title compound. 1H-NMR (CDCl3) δ (ppm): 3.71 (s, 3H), 3.80 (s, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.50 (dd, J=8.4, 2.0 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH2:1]([CH:5]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:6](=[O:8])[CH3:7])[CH2:2][CH2:3][CH3:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:1]([CH:5]([CH2:9][CH2:10][CH:11]([CH3:12])[CH3:13])[CH:6]([OH:8])[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CCC(C)C)C(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(CCC(C)C)C(C)O
Temperature: -15 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
3-butyl-6-methylheptan-2-one (5.00 g, 27.1 mmol) was dissolved in dry THF (70 ml). The solution was cooled to −15° C., and a suspension of LiAlH4 (3.5M, 2.7 ml, 9.45 mmol) was added over 15 minutes under stirring. After one hour at −15° C., a complete conversion was observed. The grey suspension was warmed to 0° C., and hydrolyzed by slow and successive addition of: water (0.36 g), 15% aqueous NaOH (0.36 g) and water (1.08 g). After warming to room temperature, the white precipitate was filtered, and the solvent removed under vacuum. The crude product was distilled bulb-to-bulb (Kugelrohr, oven 50° C., 0.2 mbar) (yield: 74.5%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][CH:9]([OH:12])[CH2:10][NH2:11])[CH:2]=[CH2:3].O=[C:18]([CH3:31])[CH2:19][O:20][C:21]1[CH:29]=[C:25]([C:26]([NH2:28])=[O:27])[C:24]([OH:30])=[CH:23][CH:22]=1.O>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:1]([O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][CH:9]([OH:12])[CH2:10][NH:11][CH:18]([CH3:31])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([C:26](=[O:27])[NH2:28])[CH:29]=1)[CH:2]=[CH2:3]
Reactant: CC(=O)COc1ccc(O)c(C(N)=O)c1
Reactant: C=CCOc1ccccc1OCC(O)CN
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=CCOc1ccccc1OCC(O)CNC(C)COc1ccc(O)c(C(N)=O)c1
Reaction time: 8 h

Procedure:
A mixture of 11.2 g of 1-(2-allyloxyphenoxy)-3-aminopropan-2-ol and 10.5 g of 5-(2-oxopropoxy)salicylamide is boiled using a water separator in 200 ml of toluene with the addition of a few drops of acetic acid. After the splitting off of water has ceased (after about 2-3 hours), the solution is concentrated by evaporation, the dark red residue is dissolved in 300 ml of ethanol and a total of 5.7 g of sodium borohydride is added in portions whilst stirring. The temperature increases during this operation to 36°. The reaction mixture is stirred for a further 2 hours at 20°-30°, and left to stand overnight. Whilst cooling with ice, it is then brought to pH 3-4 with approximately 6N hydrochloric acid, filtered and concentrated by evaporation. The residue is divided between 100 ml of water and 100 ml of ethyl acetate, the aqueous phase is separated off, rendered alkaline with concentrated ammonia and extracted with 200 ml of ethyl acetate. Working up of the organic phase yields crude oily 1-(2-allyloxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]propan-2-ol as an enantiomer mixture. By slow crystallisation from isopropanol the two pure enantiomer pairs having melting points of 123°-125° and 98°-102° respectively are obtained.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:5][N:4]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][OH:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][O:29][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:5][N:4]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1
Reactant: OCc1cccc(Cl)c1
Product: Clc1ccc(-c2nc(OCc3cccc(Cl)c3)ncc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylthio-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with 3-chlorobenzyl alcohol according to the procedure described in Example 59 to afford 2-(3-chlorobenzyloxy)-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=475 (M++1); Rt=4.92 min; 1H-NMR 400 MHz (CDCl3): δ 5.58 (s, 2H), 7.15 (d, J=9 Hz, 1H), 7.25-7.38 (m, 7H), 7.40-7.50 (m, 2H), 7.58 (s, 1H), 8.48 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14]2)[CH3:5])[CH:2]=[CH2:3].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28](Cl)=[S:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][N:4]([CH2:1][CH:2]=[CH2:3])[CH3:5])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[S:29])=[CH:23][CH:22]=1
Reactant: S=C(Cl)Oc1ccc(Cl)cc1
Reactant: C=CCN(C)CCCCOc1ccc2c(c1)CCN2
Product: C=CCN(C)CCCCOc1ccc2c(c1)CCN2C(=S)Oc1ccc(Cl)cc1

Procedure:
In analogy to example 7.8, Allyl-[4-(2,3-dihydro-1H-indol-5-yloxy)-butyl]-methyl-amine and chloro-thioformic acid (4-chloro-phenyl)ester were converted to yield 5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)ester as light grey waxy solid, MS: 431 (MH+, 1Cl).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[NH2:5][C:6]1[N:11]=[C:10]([CH3:12])[C:9]([Br:13])=[CH:8][CH:7]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[Br:13][C:9]1[CH:8]=[C:7]([N+:1]([O-:4])=[O:2])[C:6]([NH2:5])=[N:11][C:10]=1[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1nc(N)ccc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(N)c([N+](=O)[O-])cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Nitric acid (2.9 ml) was added dropwise to a solution of 6-amino-3-bromo-2-methylpyridine (7.2 g) in concentrated sulfuric acid (39 ml) under ice-cooling over 30 minutes, and the mixture was stirred at the same temperature for one hour. After further stirring at room temperature for one hour, the reaction solution was poured into ice water. A 50% aqueous sodium hydroxide solution was added, and the resulting precipitate was collected by filtration, washed with distilled water and then dried under reduced pressure to give the title compound (9.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]2=[O:18].P(Cl)(Cl)([Cl:21])=O.CCN(C(C)C)C(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:21])[N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]2=[O:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2c(Br)cccc2c(=O)n1CC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c2cccc(Br)c2nc(Cl)n1CC(F)(F)F
Yield: 76.5 %

Procedure:
8-Bromo-2-chloro-3-(2,2,2-trifluoroethyl)quinazolin-4(3H)-one (501c) as an off-white solid (1.22 g, 76%) was prepared according to the procedures described for 720 using 8-bromo-3-(2,2,2-trifluoroethyl)quinazoline-2,4(1H,3H)-dione (1.51 g, 4.67 mmol, 501b), phosphorus oxychloride (2.1 mL, 23.37 mmol, Sigma Aldrich), and DIEA (3.3 mL, 18.70 mmol, Sigma Aldrich). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (1H, dd, J=7.82, 1.37 Hz) 8.16 (1H, dd, J=7.82, 1.37 Hz) 7.53 (1H, t, J=7.92 Hz) 5.11 (2H, q, J=8.74 Hz). m/z (ESI, +ve) 342.8/344.8 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13]([OH:31])=[C:14]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:15](=[O:20])[O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.Br.O>C(O)(=O)C>[OH:31][C:13]1[C:12]2[C:17](=[C:18]([CH3:19])[C:9]([OH:8])=[CH:10][CH:11]=2)[O:16][C:15](=[O:20])[C:14]=1[C:21](=[O:30])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1
Reactant: Cc1c(OCc2ccccc2)ccc2c(O)c(C(=O)Nc3cccc(F)c3)c(=O)oc12
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(O)ccc2c(O)c(C(=O)Nc3cccc(F)c3)c(=O)oc12
Temperature: 100 °C
Yield: 27.4 %

Procedure:
To a solution of the compound of Step A (471 mg, 1.12 mmol) in acetic acid (10 ml) was added hydrobromic acid (48%, 5 ml). The mixture was refluxed at 100° C. for 18 hours. After cooling to room temperature, the reaction mixture was poured into water and a precipitate formed. After filtration, the solid was washed with water and then crystallized from dioxane-methanol. The title product was obtained as a white crystalline solid, mp 287°-289° C., (94.9 mg, 0.307 mmol, yield 27.4%). Analysis: Calculated for C17H12NO5F: C, 62.01 ; H, 3.65; N, 4.26. Found: C, 6204; H, 3.65; N, 4.34. 1H NMR (DMSO-d6): 7.74 (d, J=8.70 Hz, 1H), 7.65 (d, J=11.3 Hz, 1H), 7.43 (m, 1H), 7.40 (m, 1H), 7.04 (m, 1H), 6.98 (d, J=8.70 Hz, 1H), 2.26 (s, 3H).
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[Li+].[I:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:15]#[N:16].O.Cl>O1CCCC1>[I:11][C:12]1[CH:13]=[C:14]([C:15](=[NH:5])[NH2:16])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1ccc(C#N)cc1I
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=N)N)cc1I
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 25.3 %

Procedure:
Lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 9.9 mL, 9.9 mmol) was added dropwise over 2 minutes to a cooled (10° C.) solution of 3-iodo-4-methylbenzonitrile (preparation 51a, 2.00 g, 8.2 mmol) in tetrahydrofuran (10 mL). After 1.5 hours, the mixture was cooled to 0° C. and water (20 mL) was slowly added. The pH was adjusted to 1 with 3M aqueous hydrochloric acid and then the mixture was stirred for 30 minutes. The aqueous layer was extracted with diethyl ether and ethyl acetate and then made basic with sodium hydroxide pellets which resulted in the separation of an oil. The mixture was extracted with ethyl acetate and the organic layer was dried and evaporated under reduced pressure. The residue was triturated with diethyl ether to give the title compound (0.54 g, 25%) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:34]([NH2:36])[CH3:35])[CH:20]=[N:21][C:22]=1[O:23][C:24]1[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:36]([CH:34]([C:19]3[CH:20]=[N:21][C:22]([O:23][C:24]4[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[C:17]([CH3:16])[CH:18]=3)[CH3:35])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1Oc1ccc(C(F)(F)F)nc1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1Oc1ccc(C(F)(F)F)nc1
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (160 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.73 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethanamine hydrochloride (290 mg, 0.86 mmol, Amine-41, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13]CC#N)=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:24]([OH:27])(=[O:26])[CH3:25].S(=O)(=O)(O)O>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:25][C:24]([OH:27])=[O:26])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(c2ccccc2)Cc2cc(OCC#N)c(Cl)c(Cl)c2C1=O
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C

Procedure:
A mixture of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetonitrile (3.0 g.), Example 19, Step A, acetic acid (20 ml.), water (5 ml.) and concentrated sulfuric acid (5 ml.) is refluxed for 2 hours then poured into ice-water (100 ml.) affording 2.5 g. of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 168°-169° C. after recrystallization from acetic acid.
Reaction SMILES: C([O:6][C:7]1[CH:12]([C:13]([O:15][CH3:16])=[O:14])[CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:10][C:9](=[O:25])[CH:8]=1)(=O)CCC>CN(C)C1C=CN=CC=1.ClCCl>[C:7]([C:8]1[C:9](=[O:25])[CH2:10][CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:12]([C:13]([O:15][CH3:16])=[O:14])[C:7]=1[OH:6])(=[O:6])[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(=O)OC1=CC(=O)CC(CCCCC(=O)OC)C1C(=O)OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)C1=C(O)C(C(=O)OC)C(CCCCC(=O)OC)CC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
81 parts by weight of 3-butyryloxy-4-methoxycarbonyl-5-(4-methoxycarbonylbutyl)-cyclohex-2-en-1-one and 8 parts by weight of 4-dimethylaminopyridine were dissolved in anhydrous dichloromethane, and the solution was stirred for 48 hours at room temperature. The solution was washed with 10 wt % strength hydrochloric acid and water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to give 2-butyryl-3-hydroxy-4-methoxycarbonyl-5-(4-methoxycarbonylbutyl)-cyclohex-2-en-1-one as an oil (compound no. 4).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>CS(C)=O>[Cl:13][C:4]1[CH:3]=[C:2]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Solvent: CS(C)=O
Product: CCOC(=O)c1cnc(Cl)cc1NCc1ccc(OC)cc1
Yield: 89.6 %

Procedure:
Stir a mixture of ethyl 4,6-dichloronicotinate (16 g, 73.1 mmol), (4-methoxybenzyl)amine (10 g, 73.1 mmol), and TEA (15.2 g, 146 mmol) in DMSO (150 mL) at RT overnight. Add EtOAc, wash with water (2×), then brine (1×), dry the organics over MgSO4 and concentrate to afford the title compound (21 g, 90%). 1H NMR (300 MHz, CDCl3): δ 8.62 (s, 1H), 8.39 (s, 1H), 7.16 (d, J=8.7 Hz, 2H), 6.85-6.80 (m, 2H), 6.49 (s, 1H), 4.33-4.25 (m, 4H), 3.77 (s, 3H), 1.31 (t, J=6.9 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH2:24]([NH:27][C:28]1[CH2:32][O:31][C:30](=[O:33])[N:29]=1)[C:25]#[CH:26].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:32]2/[C:28]([NH:27][CH2:24][C:25]#[CH:26])=[N:29][C:30](=[O:33])[O:31]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: C#CCNC1=NC(=O)OC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)O/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 1 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (339 mg) and 4-(prop-2-yn-1-ylamino)-1,3-oxazol-2(5H)-one (152 mg) in 2-propanol (3 mL) was added piperidinium acetate (160 mg) at room temperature. The reaction mixture was stirred at 90° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane to give the title compound (4.40 mg)