Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5].CCN(C(C)C)C(C)C.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>C(Cl)Cl>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)=[O:26])=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: O=C(Cl)c1cccs1
Reactant: N#Cc1cc(Br)ccc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Br)ccc1NC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
To a solution of 2-amino-5-bromobenzonitrile (1 g, 5.1 mmol) in 20 mL of DCM, DIPEA (27.9 mmol, 5.5 eq.) was added followed by thiophene-2-carbonyl chloride (25.4 mmol, 5.0 eq.). The reaction was stirred at room temperature overnight. The organic solution of the crude reaction mixture was extracted twice with aqueous HCl (0.1 M), twice with aqueous sodium hydroxide (0.1 M), and once with a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20% EtOAc in hexane eluant) to afford 120 mg of N-(4-bromo-2-cyanophenyl)thiophene-2-carboxamide. MS (EI) for C12H7BrN2OS: 307 (M+H). Step 2: N-[4-Bromo-2-(1H-tetrazol-5-yl)phenyl]thiophene-2-carboxamide: To a mixture of the nitrile N-(4-bromo-2-cyanophenyl)thiophene-2-carboxamide (120 mg, 0.4 mmol), sodium azide (0.5 mmol, 1.3 eq.), and triethylamine hydrochloride (0.5 mmol, 1.3 eq.) in a sealed tube, 1 mL of toluene was added. The tube was tightly capped and the reaction was stirred and heated to 10° C. overnight. The mixture was cooled to room temperature, diluted with another 5 mL of toluene, transferred to a separatory funnel and washed 3×10 mL with water. The aqueous layer was collected and acidified to a pH of 4 with concentrated HCl. The solid was collected by filtration, washed with acetonitrile, and dried under vacuum to afford 18 mg of desired product. 1H-NMR (400 MHz, d6-DMSO): δ 11.60 (s, 1H), 8.44 (d, 1H), 8.23 (d, 1H), 7.99-7.95 (m, 21), 7.82 (dd, 1H), 7.33 (t, 1H). MS (EI) for C12H8BrN5OS: 350 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:31])[N:15]([CH2:17][C:18]4[C:19]([C:28]([OH:30])=O)=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:40])=O>C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:31])[N:15]([CH2:17][C:18]4[C:19]([C:28]([Cl:40])=[O:30])=[N:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=C(Cl)c1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 3-((7-(4-chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)methyl)-6-(trifluoromethyl)picolinic acid (71 mg, 0.133 mmol) in anhydrous ClCH2CH2Cl (1 mL) at room temperature was added dropwise thionyl chloride (2 mL). The mixture was then stirred at 80° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was evaporated with toluene (5 mL×2), and dried in high vacuum to afford the title compound (72 mg) as a yellow foam, which was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1.C(OOC(=O)C1C=CC=CC=1)(=[O:22])C1C=CC=CC=1.C1C(=O)N(Br)C(=O)C1.C([O-])([O-])=O.[Na+].[Na+].Cl>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([CH:14]=[O:22])=[CH:4][C:5]2[C:9]([CH3:10])([CH3:11])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1
Reactant: Cc1cc2c(cc1F)B(O)OC2(C)C
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(O)c2cc(F)c(C=O)cc21
Temperature: 25 °C
Yield: 908.7 %

Procedure:
To a solution of 6-fluoro-3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (388 mg, 2 mmol) in CCl4 (60 mL) at rt was added benzoyl peroxide (48.4 mg, 0.2 mmol) followed by NBS (783 mg, 4.4 mmol). The reaction mixture was heated under reflux for 16 h, cooled to rt and treated with Na2CO3. The aqueous layer was acidified with 3 N HCl to pH of 3 and extracted with DCM (60 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give 6-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde (378 mg, 91%) as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ 10.369 (s, 1H), 7.687 (d, J=5.5 Hz, 1H), 7.409 (d, J=8.0 Hz, 1H), 2.715 (s, 3H), 1.484 (s, 6H) ppm.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[CH2:1]([N:8]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1c(NCc2ccccc2)cccc1NS(C)(=O)=O
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(F)cc1

Procedure:
The product from Example 8A and 4-fluorobenzaldehyde were processed as described in Example 1C to provide the title compound. 1H NMR (300 MHz, CDCl3) δ7.07-7.32 (m, 9H), 7.00-6.85 (m, 3H), 6.10 (s, 1H), 4.03 (s, 2H), 4.02 (s, 2H), 2.95 (s, 3H), 2.33 (s, 3H); MS (ESI+) m/z 399 (M+H)+; Analysis calculated for C22H23FN2O2S 0.75 TFA: C, 58.26; H, 4.95; N, 5.79. Found: C, 58.26; H, 5.17; N, 5.63.
Reaction SMILES: I[C:2]1[CH:6]=[C:5]([CH:7]2[CH:12]3[CH:8]2[CH2:9][CH2:10][CH:11]3[OH:13])[N:4]([CH:14]([CH3:16])[CH3:15])[N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[C:28]([NH2:31])=[N:29][CH:30]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:31][C:28]1[N:29]=[CH:30][C:25]([C:2]2[CH:6]=[C:5]([CH:7]3[CH:12]4[CH:8]3[CH2:9][CH2:10][CH:11]4[OH:13])[N:4]([CH:14]([CH3:16])[CH3:15])[N:3]=2)=[CH:26][C:27]=1[C:32]([F:35])([F:33])[F:34]
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: CC(C)n1nc(I)cc1C1C2CCC(O)C21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1nc(-c2cnc(N)c(C(F)(F)F)c2)cc1C1C2CCC(O)C21
Temperature: 110 °C

Procedure:
A solution of (±)-6-(3-iodo-1-isopropyl-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-2-ol (30 mg, 90.3 μmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (39 mg, 0.14 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (6 mg, 0.009 mmol) and cesium carbonate (59 mg, 0.18 mmol) in 1,4-dioxane (0.5 mL) and water (0.1 mL) was purged with nitrogen. The reaction mixture was heated to 110° C. by microwave irradiation for 20 min. The mixture was concentrated, and the resulting residue was diluted with ethyl acetate (2 mL), and the solution was filtered. The filtrate was concentrated. Purification by preparation HPLC followed by chiral SFC separation afforded the title compounds:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH3:13])[C:9]=1[C:10]([OH:12])=O)=[O:4].Cl.Cl.[CH3:16][N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:26][CH2:27][NH2:28]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH3:13])[C:9]=1[C:10](=[O:12])[NH:28][CH2:27][CH2:26][C:18]1[N:17]([CH3:16])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=1)=[O:4]
Reactant: COC(=O)c1ncn(C)c1C(=O)O
Reactant: Cn1c(CCN)nc2ccccc21
Agent: Cl
Product: COC(=O)c1ncn(C)c1C(=O)NCCc1nc2ccccc2n1C

Procedure:
The product was obtained starting from 1-methyl-1H-imidazole-4,5-dicarboxylic acid 4-methyl ester (200 mg, 1.09 mmol) and 2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethanamine dihydrochloride (296 mg, 1.19 mmol) according to the method described in example 8, step 3 as pink foam (156 mg, 457 μmol, 42.1%). MS: M=342.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=O)[N:7]([CH3:13])[C:6]=2[CH:14]=1.C(O)C.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[O:10][CH:9]([CH3:11])[CH2:8][N:7]([CH3:13])[C:6]=2[CH:14]=1
Reactant: COC(=O)c1cc(Cl)cc2c1OC(C)C(=O)N2C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1CN(C)c2cc(Cl)cc(C(=O)O)c2O1
Yield: 93.6 %

Procedure:
A mixture of 5.1 g of methyl 6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazine-8-carboxylate, 20 ml of ethanol and 50 ml of 4% aqueous potassium hydroxide solution is refluxed with heating for 5 hours. The resultant solution is cooled and 350 ml of water is added thereto followed by filtration. The filtrate is made acid with concentrated hydrochloric acid. The precipitated crystals are collected by filtration, washed with water and dried, and then recrystallized from ethanol to give 4.28 g of 6-chloro-3,4-dihydro-2,4-dimethyl-2H-1,4-benzoxazine-8-carboxylic acid, melting at 191°14 193° C.
Reaction SMILES: C([CH2:5][C:6]([O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH2:19][CH2:20][C:21](=[O:37])[C:22]2[S:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)=[CH:14][C:13]=1[CH3:38])([CH3:10])[C:7]([O-:9])=[O:8])(C)(C)C.FC(F)(F)C(O)=O>>[CH3:38][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][C:21](=[O:37])[C:22]2[S:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[CH:16]=[C:17]([CH3:18])[C:12]=1[O:11][C:6]([CH3:10])([CH3:5])[C:7]([OH:9])=[O:8]
Reactant: Cc1cc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc(C)c1OC(C)(CC(C)(C)C)C(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc(C)c1OC(C)(C)C(=O)O

Procedure:
2-(2,6-Dimethyl-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoic acid is prepared from tert-butyl-(2,6-dimethyl-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate according to general procedure E using 10 equivalents of trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([O:32]C)=[O:31])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]2[C:16]([C:17]([CH2:27][CH3:28])=[CH:18][C:19](=[O:26])[O:20]2)=[CH:15][CH:14]=1.[OH-].[K+].Cl>CO.O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([OH:32])=[O:31])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]2[C:16]([C:17]([CH2:27][CH3:28])=[CH:18][C:19](=[O:26])[O:20]2)=[CH:15][CH:14]=1
Reactant: CCCc1c(OCCCSc2ccc(CC(=O)OC)cc2Cl)ccc2c(CC)cc(=O)oc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1c(OCCCSc2ccc(CC(=O)O)cc2Cl)ccc2c(CC)cc(=O)oc12
Temperature: 40 °C

Procedure:
To a solution of methyl 3-chloro-4-(3-(4-ethyl-8-propyl-7-coumarinoxy)propylthio)phenylacetate (Example 1; 82 mg, 0.1677 mmol) in 1.2 mL methanol:water (1:1) was added a 0.5M solution of potassium hydroxide in methanol. The mixture was heated to 40° C. for two hours at which time the mixture was acidified to pH=3 with 1M aqueous hydrochloric acid. The aqueous solution was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate, filtered, and the crude residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexane/1% acetic acid) which provided the title compound.
Reaction SMILES: C=C.C(O)(=O)C.[CH2:7]=[CH:8][CH2:9][CH3:10].[F:11][C:12]([F:17])([F:16])[C:13]([OH:15])=[O:14]>C(OCC)(=O)C>[F:11][C:12]([F:17])([F:16])[C:13]([O:15][CH:8]([CH2:9][CH3:10])[CH3:7])=[O:14]
Reactant: C=CCC
Reactant: O=C(O)C(F)(F)F
Agent: C=C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCC(C)OC(=O)C(F)(F)F

Procedure:
In addition, the esterification of olefins with carboxylic acids and subsequent ester hydrolysis of the alkyl esters formed to the corresponding alcohol with recovery of the acid is known. For instance, U.S. Pat. No. 4,384,148 describes the reaction of ethene with acetic acid to give ethyl acetate in an autoclave. The subsequent hydrolysis of the ethyl acetate removed by distillation with water in a molar ratio of 1:5 in an autoclave affords a mixture comprising ethyl acetate, ethanol and diethyl ether. GB 2 238 539 discloses the two-stage hydration of 1-butene by reaction with trifluoroacetic acid to give 2-butyl trifluoroacetate in the presence of a highly acidic ion exchange resin and subsequent hydrolysis of the ester to give 2-butanol.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].Cl[C:8]1[S:12][C:11]([CH2:13][O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([CH2:22][CH2:23][C:24](OCC)=[O:25])=[CH:17][C:16]=2[F:29])=[C:10]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][CH:31]=2)[CH:9]=1>>[CH2:36]([C:33]1[CH:34]=[CH:35][C:30]([C:10]2[CH:9]=[CH:8][S:12][C:11]=2[CH2:13][O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][C:16]=2[F:29])=[CH:31][CH:32]=1)[CH3:37]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2sc(Cl)cc2-c2ccc(CC)cc2)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(-c2ccsc2COc2c(F)cc(CCCO)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 223 by LAH reduction of ethyl 3-(4-[[5-chloro-3-(4-ethylphenyl)thiophen-2-yl]methoxy]-3,5-difluoro phenyl)propanoate to give the desired product as off-white oil. 1H NMR (300 MHz, CD3OD) δ 7.36-7.42 (m, 3H), 7.21 (d, J=7.8 Hz, 2H), 7.08 (d, J=8.1 Hz, 1H), 6.70-6.80 (m, 2H), 5.13 (s, 2H), 3.51 (t, J=7.2 Hz, 2H), 2.525-2.69 (m, 4H), 1.72-1.81 (m, 2H), 1.23 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H22F2O2S, 201.1 [M-C9H9F2O2]. found 201.1.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[N:3]=1.FC(F)(F)C(O)=O.[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[N:20]1.C(N(CC)CC)C.O>CN(C)C=O>[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][N:34]([C:2]3[S:6][N:5]=[C:4]([C:7]4[S:8][CH:9]=[CH:10][CH:11]=4)[N:3]=3)[CH2:33][CH2:32]2)=[O:30])=[N:20]1
Reactant: Clc1nc(-c2cccs2)ns1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3cccs3)ns2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To a solution of 5-chloro-3-(2-thienyl)-1,2,4-thiadiazole (119 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to water, and the precipitated solid was separated by filtration, which was recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran to give 128 mg (55.9%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[OH:7][C:8]([CH3:20])([CH3:19])[CH2:9][O:10][C:11]1([CH3:18])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(=O)([O-])O.[Na+]>[CH3:20][C:8]([OH:7])([CH3:19])[CH2:9][O:10][C:11]1([CH3:18])[CH2:16][CH2:15][CH:14]([NH:1][C:2]2[N:6]=[CH:5][NH:4][N:3]=2)[CH2:13][CH2:12]1
Reactant: Nc1nc[nH]n1
Reactant: CC(C)(O)COC1(C)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(O)COC1(C)CCC(Nc2nc[nH]n2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.6 %

Procedure:
To a solution of 3-amino-1H-1,2,4-triazole (441 mg) and 4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexanone (1.05 g) in acetic acid (10 mL) was added sodium triacetoxyborohydride (1.67 g), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=0/100→10/90 (volume ratio)] to give colorless amorphous 2-methyl-1-{[1-methyl-4-(1H-1,2,4-triazol-3-ylamino)cyclohexyl]oxy}propan-2-ol (810 mg, 54%) as a diastereomixture.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9](Cl)=[N:10][CH:11]=1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:28])[CH:4]([C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)[CH2:5][C:6]1[C:7]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:8][C:9]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:10][CH:11]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
A mixture of 2-(3,5-bis-trifluoromethyl-phenyl)-3-(2,4-dichloro-pyrimidin-5-yl)-propionic acid methyl ester (0.35 g, 0.78 mmol) (from Example 8b supra) and aniline (2.0 mL) (Aldrich) was heated at 120° C. for 1 hour. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was then triturated with ethyl acetate-hexanes. The resulting solid was collected by filtration and washed with diethyl ether to give crude 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-propionic acid methyl ester as an off-white solid which was used in the next step without further purification. (Yield 0.47 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([F:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:4]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][N:31]=1>C(Cl)Cl.CN(C=O)C>[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:1][CH2:2][C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][C:8]([F:14])=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[CH:4]=2)=[O:35])=[CH:32][N:31]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a mixture of 3-(aminomethyl)-7-fluoro-1-(2-fluorophenyl)quinolin-4(1H)-one (intermediate H) (470 mg, 1.64 mmol), triethylamine (0.229 mL, 1.64 mmol), and 35 mL of a CH2Cl2-DMF mixture was added 6-chloronicotinoyl chloride (298 mg, 1.64 mmol). The resulting mixture was stirred at room temperature for 1 hr. After this time, the reaction was complete, giving 6-chloro-N-[7-fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-yl-methyl]-nicotinamide (500 mg, 72%). MS calcd. for C22H14ClF2N3O2 [(M+H)+] 426.1, obsd. 426.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:6]=1[C:7]#[N:8].[C:18](OC)(=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21].Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:8][C:7]1[C:6]2[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)=[C:4]([CH3:17])[S:3][C:2]=2[NH:1][C:18](=[O:24])[C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COc1cccc(-c2c(C)sc(N)c2C#N)c1
Reactant: COC(=O)CC(=O)OC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1c(N)c2c(-c3cccc(OC)c3)c(C)sc2[nH]c1=O
Temperature: 25 °C
Yield: 41 %

Procedure:
To a solution of 2-amino-5-methyl-4-[3-(methyloxy)phenyl]-3-thiophene carbonitrile (Description 3) (2.80 g, 11.46 mmol) in toluene (75 mL) was added dimethyl malonate (1.31 mL, 11.46 mmol) and SnCl4 (2.68 mL, 22.92 mmol). The reaction mixture was then refluxed under nitrogen for ca. 2 h. The reaction mixture was then cooled to RT and concentrated in vacuo. The residue was partitioned between water and ethyl acetate (ca. 150 mL each) and the organic layer separated and washed with water (ca. 100 mL). The combined aqueous layer was re-extracted with ethyl acetate (ca. 100 mL). All organic layers were combined and passed through a phase separator and the mixture concentrated in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-60% ethyl acetate in DCM followed by 0-20% MeOH in DCM, to afford the title compound (1.62 g). LCMS (A) m/z: 343 [M−1]−, Rt 1.18 min (acidic).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[N:10]=[C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[S:12][CH:13]=1)=[O:8])C.Cl>O1CCCC1.O>[C:18]([O:17][C:15]([NH:14][C:11]1[S:12][CH:13]=[C:9]([C:7]([OH:8])=[O:6])[N:10]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(C(=O)O)cs1
Yield: 93.6 %

Procedure:
Lithium hydroxide monohydrate (20.16 g, 0.48 mol) was added to a stirred solution of 2-tert-butoxycarbonylamino-thiazole-4-carboxylic acid ethyl ester (52.35 g, 0.192 mol) in a mixture of tetrahydrofuran (800 mL) and water (200 mL). The mixture was stirred over night. 1 N Aqueous hydrochloric acid (480 mL) was added and the reaction mixture concentrated in vacuo to remove tetrahydrofuran. The mixture was then diluted with water and filtered. The solid was washed with water, ether and dried overnight to give 2-tert-butoxycarbonylamino-thiazole-4-carboxylic acid (43.9 g, 94%).
Reaction SMILES: [Br-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[CH3:26][O:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O>C1COCC1.O>[CH3:2][O:3][CH:4]=[CH:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:28]=1[O:27][CH3:26]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(C=O)c1OC
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC=Cc1cccc(OC)c1OC
Reaction time: 0.25 h
Yield: 83 %

Procedure:
THF (15 mL) was added to a mixture of methoxymethyltriphenylphosphonium bromide and sodium amide (mfd. by Aldrich Chemical Co.; 3.0 g, 6.9 mmol) at room temperature and stirred for 15 minutes. To the resulting orange-colored suspension was added a solution of 2,3-dimethoxybenzaldehyde (997 mg, 6.00 mmol) in THF (5 mL), and stirred for 3 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by the use of a silica gel column (silica gel 50 mL; hexane/ethyl acetate=1/0 to 15/1) to obtain 2-(2,3-dimethoxyphenyl)ethenyl methyl ether (808 mg, 83%) as a yellow oil.