Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[N+:9]([O-])([OH:11])=[O:10].[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:6][C:5]([F:8])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(F)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.6 %

Procedure:
To a solution of 2-amino-5-fluoropyridine (8.6 g, 77 mmol) in conc. sulfuric acid (40 ml) was added dropwise (30 min) fuming nitric acid (3.25 ml, 77 mmol) at a temperature of +3° C. The reaction mixture was stirred at room temperature for 1 h and at +55° C. for 1 h. The mixture was poured onto ice and neutralized with 10 M sodium hydroxide and was extracted with methylene chloride. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified twice by column chromatography on silica gel, using (i) methanol:methylene chloride (1:20) and (ii) diethyl ether:petroleum ether (1:1) as eluent to give the title compound (0.44 g, 3.6%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][O:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:41]5[CH:40]=[CH:39][CH:38]=[C:37]([O:36][CH3:35])[CH:42]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1cccc(B(O)O)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(OC)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-methoxyphenylboronic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:12]2[CH:13]=[C:8]([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:9]=[C:10]([NH2:15])[N:11]=2)=[CH:25][CH:24]=1
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2OCC(F)(F)F)n1
Reactant: Nc1ccc(Br)cc1
Product: Nc1nc(Nc2ccc(Br)cc2)cc(-c2cc(Br)ccc2OCC(F)(F)F)n1
Yield: 34 %

Procedure:
Following the method described in Example 26, 4-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-phenyl]-6-chloro-pyrimidin-2-ylamine and 4-bromo-phenylamine provided the title compound (34% yield). 1H NMR (acetone-d6) δ 4.76 (q, 2H, J=8.5 Hz, CH2), 5.95 (bs, 2H, NH2), 6.72 (s, 1H, Ar), 7.21 (d, 1H, J=8.8 Hz, Ar), 7.44 (d, 2H, J=8.9 Hz, Ar), 7.58 (dd, 1H, J=8.8 Hz, J=2.4 Hz, Ar), 7.75-7.78 (m, 2H, Ar), 8.07 (d, 1H, J=2.4 Hz, Ar), 8.62 (br s, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][N:14]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][C:16]([C:23]2[S:24][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:26][CH:27]=2)=[N:15]1>>[CH3:13][N:14]1[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][C:16]([C:23]2[S:24][C:25]([S:28]([NH:1][C:2]3[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=3)(=[O:30])=[O:29])=[CH:26][CH:27]=2)=[N:15]1
Reactant: Cn1nc(-c2ccc(S(=O)(=O)Cl)s2)cc1C(F)(F)F
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(-c3cc(C(F)(F)F)n(C)n3)s2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-thiophene-5-sulfonyl chloride as described in the synthetic METHOD B giving a yellow solid with a purity of 93%. MS (electrospray, [M+H]+) m/z 481.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:12]([N:14]([CH3:21])[S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Zn](CC)[CH2:23][CH3:24].O>C1COCC1.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>[CH2:23]([C:2]1[CH:3]=[C:4]([C@H:12]([N:14]([CH3:21])[S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH3:24]
Reactant: C[C@H](c1cc(Br)cc(C(F)(F)F)c1)N(C)[S@@](=O)C(C)(C)C
Reactant: CC[Zn]CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc([C@@H](C)N(C)[S@@](=O)C(C)(C)C)cc(C(F)(F)F)c1
Temperature: 6 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
A mixture of (S)-N-((R)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethyl)-N,2-dimethyl propane-2-sulfinamide (1 g, 2.6 mmol), Pd(PPh3)2Cl2 (182 mg, 0.26 mmol) and Et2Zn (640 mg, 5.2 mmol) in THF (10 mL) under N2 atmosphere was stirred at 6° C. for 16 h. The reaction was poured into water (15 mL) and then extracted with EtOAc (2×30 mL). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=10/1 to 1/1) to give the title compound (700 mg, yield: 80.3%); m/z (ES+): 336 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:23])[O:13][C:14](=O)[C:15]=2[C:16]2[N:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)=[CH:3]1.C[N:25](C=O)C>N>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:23])[NH:25][C:14](=[O:13])[C:15]=2[C:16]2[N:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)=[CH:3]1
Reactant: CN(C)C=O
Reactant: Cn1cccc1C1=C(c2cn(C)c3ccccc23)C(=O)OC1=O
Agent: N
Product: Cn1cccc1C1=C(c2cn(C)c3ccccc23)C(=O)NC1=O

Procedure:
A solution of 800 mg of 3-(1-methyl-3-indolyl)-4-(1-methyl-2-pyrrolyl)furan-2,5-dione in 6 ml of DMF and 50 ml of 33% aqueous ammonia was heated to 130° C. for 3 hours. The precipitate was filtered off and dried to yield 400 mg of 3-(1-methyl-3-indolyl)-4-(1-methyl-2-pyrrolyl)-1H-pyrrole-2,5-dione, m.p. 248°-250° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C@@H:17]2[CH3:16])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)nc2cc(F)cc(F)c2c1Cl
Temperature: 120 °C

Procedure:
The 2,4-dichloro-5,7-difluoro-3-methylquinoline (150 mg, 0.60 mmol) was slurried in N-methylpyrrolidinone (1.0 mL) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (110 mg, 0.54 mmol) and cesium carbonate (360 mg, 1.10 mmol) were added and the reaction mixture was heated at 120° C. for 2.5 h in the microwave. The reaction mixture was then diluted with water (15 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined layers were combined and washed with water (1×100 mL) and brine (1×30 mL). The organic layer was dried over magnesium sulfate and the residue was purified by medium pressure chromatography (silica gel, 0 to 15% EtOAc:hexanes) to give (S)-tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-3-methylpiperazine-1-carboxylate. Mass Spectrum (ESI) m/e=412.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[O:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[O:11]1[C:15]2([CH2:20][CH2:19][N:18]([C:2]3[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[CH:4][N:3]=3)[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: NC(=O)c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: NC(=O)c1ccnc(N2CCC3(CC2)OCCO3)n1
Yield: 97.6 %

Procedure:
5 g (0.0318 mol) of 2-chloropyrimidine-4-carboxamide, 4.55 g (0.0318 mol) of 1,4-dioxa-8-azaspiro[4.5]decane and 6.6 g (0.0477 mol) of potassium carbonate are introduced into 100 ml of 2-butanone. The mixture is heated and stirred at reflux temperature for 6 hours. The mixture is filtered and the filtrate is concentrated under reduced pressure. 8.2 g of product are obtained which are recrystallised from 2-propanol. 4.1 g of product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(N)ccc1OC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(C)(=O)=O)ccc1OC
Yield: 88.7 %

Procedure:
To a solution of methyl 2-methoxy-5-aminobenzoate (300 mg) and dry pyridine (3 ml), methanesulfonyl chloride (210 mg) is added dropwise with ice cooling and stirring, and the resultant mixture is stirred at room temperature for 1 hour. The reaction mixture is acidified with 6 N hydrochloric acid and shaken with methylene chloride. The organic layer is washed with water, dried over sodium sulfate, and evaporated under reduced pressure to remove the methylene chloride. The residue is chromatographed on a column of silica gel, which is eluted with methylene chloride-2% methanol/methylene chloride, and the eluate is evaporated to remove the solvent. The residue is recrystallized from ethyl acetate/isopropyl ether to give methyl 2-methoxy-5-methanesulfonamidobenzoate (381 mg) as colorless prisms melting at 84° to 86° C.
Reaction SMILES: N(C1C=CC2[O:8]CCOC=2C=1)=C=S.[F:14][C:15]1[CH:20]=[CH:19][C:18](C(=O)C)=[C:17]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=1.ClC1C=C(C(OO)=O)C=CC=1>ClCCl>[F:14][C:15]1[CH:20]=[CH:19][C:18]([OH:8])=[C:17]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=1
Reactant: CC(=O)c1ccc(F)cc1OCc1ccccc1
Reactant: S=C=Nc1ccc2c(c1)OCCO2
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Oc1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 93 %

Procedure:
A mixture of 11 parts of 1-[4-fluoro-2-(phenylmethoxy)phenyl]ethanone, 8.48 parts of 3-chlorobenzenecarboperoxoic acid and 260 parts of dichloromethane was stirred for 5 days at room temperature. The precipitate was filtered off and the filtrate was stirred in a saturate thiosulfurate solution for 15 minutes. The organic layer was separated and stirred in a saturate hydrogen carbonate solution for 15 minutes. The organic layer was separated, washed with water, dried, filtered and evaporated. The solid residue was stirred in 240 parts of methanol. 5.3 Parts of sodium methoxide were added portionwise. After complete addition, the whole was stirred for 1 hour at room temperature. After evaporation in vacuo at 50° C., the residue was stirred in water and acidified with a hydrochloric acid solution 3N. Trichloromethane was added, the organic layer was separated, washed twice with water, dried, filtered and evaporated, yielding 10 parts (93%) of 4-fluoro-2-(phenylmethoxy)phenol as a residue (intermediate 77).
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]>CO>[CH3:1][O:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][Br:5]
Reactant: O=C(O)CCCCCBr
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)CCCCCBr
Temperature: 25 °C
Yield: 351.9 %

Procedure:
To a solution of acetyl chloride (1.0 mL, 14 mmol) in methanol (150 mL) at 0° C. was added a solution of 6-bromohexanoic acid (10.0 g, 51 mmol) in methanol (50 mL). The mixture was heated at reflux for 2 hours, then allowed to cool down to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and washed consecutively with saturated aqueous sodium hydrogen carbonate (2×50 mL), distilled water (50 mL), and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the title compound (10.3 g, 96%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:7])=[N:4][NH:5][CH:6]=1.[CH2:8]=[O:9]>CO>[OH:9][CH2:8][N:5]1[CH:6]=[C:2]([Cl:1])[C:3]([CH3:7])=[N:4]1
Reactant: Cc1n[nH]cc1Cl
Reactant: C=O
Solvent: CO
Product: Cc1nn(CO)cc1Cl
Yield: 95 %

Procedure:
116 g (1.0 mol) of 4-chloro-3-methylpyrazole in 50 ml of methanol were dissolved in 100 g (1.0 mol) of formalin solution (30%) at room temperature. Water and methanol were then evaporated. The title compound remained as a white solid (yield 95%).
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[C:7]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1.CC(C)=O>CN(C)C=O>[O:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]1[O:28][CH2:27][CH2:26][N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[CH:5]=[CH:4][N:3]=[CH:2]3)[CH2:14][CH2:15]1
Reactant: BrCCOC1CCCCO1
Reactant: c1cc(NC2CCNCC2)c2ccncc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: c1cc(NC2CCN(CCOC3CCCCO3)CC2)c2ccncc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of the compound of Example 20 (70 mg) and potassium carbonate (142 mg, Kokusan Chemical) in N,N-dimethylformamide (1.5 ml) was added with 2-(2-bromoethoxy)tetrahydro-2H-pyran (254 μl, Aldrich) and stirred at room temperature for 48 hours. The reaction mixture was added with acetone (10 ml), and insoluble matters were separated by filtration. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=6:1) to obtain the title compound (40 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1C=CC=CC=1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[CH:20]([C:19]1[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1)[O:12][CH2:11][CH2:10]2
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CCO)cc1Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Br)CCOC2c1ccc([N+](=O)[O-])cc1
Yield: 67 %

Procedure:
Hydrogen chloride gas that is dried for 5 hours is introduced into a suspension of 7.50 g (32.4 mmol) of 2-(3-bromo-4-methoxy-phenyl)-ethanol, 4.90 g (32.4 mmol) of 4-nitro-benzaldehyde and 4.39 g (32.4 mmol) of freshly melted zinc chloride in anhydrous benzene (96 ml). The reaction mixture is then diluted with ethyl acetate and washed neutral with water. After drying and concentration by evaporation, the solid residue is recrystallized from ethyl acetate (25 ml). 7.91 g (67%) of 6-bromo-7-methoxy-l-(4-nitrophenyl)-isochroman, melting point 144-147° C., is obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[H-].[Na+].[CH3:42]I>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]([O:39][CH3:42])([CH3:37])[CH3:38])=[CH:32][CH:33]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 29 %

Procedure:
To a solution of 4′-({2-ethyl-1-[4-(2-hydroxy-2-methylpropoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.33 g) in N,N-dimethylformamide (5 mL) was added sodium hydride (0.05 g, 60%), and the mixture was stirred for 15 min. Then methyl iodide (0.08 mL) was added, and the mixture was further stirred for 2 hr. Small pieces of ice were added to the reaction mixture, and the mixture was stirred for 15 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.10 g, 29%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](OC)=[O:9])=[N:6][CH:7]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(Br)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 5-bromopyridine-2-carboxylate (2.00 g, 9.27 mmol) was dissolved in ethanol (20.0 mL). Sodium borohydride (1.05 g, 27.8 mmol) was added at 0° C., and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated under reduced pressure, quenched with 1 N hydrochloric acid, neutralized with solid potassium carbonate and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporated to give 1.57 g (90% of th.) of the title compound.
Reaction SMILES: C[O-].[Na+].[CH:4]([O:6][CH3:7])=[O:5].[Br:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][C:24](OC)=[O:25])[CH:12]=[CH:11][CH:10]=1.O>C1(C)C=CC=CC=1>[Br:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[C:23](=[CH:24]\[OH:25])/[C:4]([O:6][CH3:7])=[O:5])[CH:12]=[CH:11][CH:10]=1
Reactant: COC=O
Reactant: COC(=O)Cc1ccccc1COc1cccc(Br)n1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)/C(=C/O)c1ccccc1COc1cccc(Br)n1
Yield: 97.9 %

Procedure:
Sodium methoxide (0.34 g, 6.0 mmol) and methyl formate (1 ml, 16 mmol) were added portionwise to a stirred solution of methyl 2-(6-bromopyrid-2-yloxymethyl)phenylacetate (0.8 g, 2.3 mmol) in dry toluene (10 ml) under a nitrogen atmosphere at room temperature. After 8 hours at room temperature the mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were washed with water, dried and the ethyl acetate removed to give (E)-methyl 2-[2-(6-bromopyrid-2-yloxymethyl)phenyl]-3-hydroxyacrylate (0.82 g, 80%) as a brown gum which was used in the final stage without further purification; 1H NMR (270 MHz)δ: 3.74(3H,s), 5.28(2H,s), 6.66(1H,d), 7.06(1H,d), 7.15-7.55(6H,m), 11.95(1H,d) ppm.
Reaction SMILES: [OH-].[K+].[CH2:3](I)[CH3:4].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=1>C(O)C>[CH2:3]([S:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=1)[CH3:4]
Reactant: CCI
Reactant: COc1cccc(S)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCSc1cccc(OC)c1
Reaction time: 72 h
Yield: 100.2 %

Procedure:
Solid potassium hydroxide (2.2 g, 39 mmol) and ethyl iodide (3.14 ml, 39 mmol) were added to a solution of 3-methoxybenzenethiol (5.0 g, 35 mmol) in ethanol (35 ml) (Caution—exotherm). The mixture was stirred for 72 h, then partitioned between water and ethyl acetate. The organic phase was dried over MgSO4 and the solvent removed under reduced pressure to give 1-(ethylsulfanyl)-3-methoxybenzene (5.9 g) as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:28][C:29]1(C)[C:33](C)(C)OB(CC=C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:14]([CH2:33][CH:29]=[CH2:28])[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1OS(=O)(=O)C(F)(F)F
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: C=CCc1nc(-c2c(C)nn3ccccc23)sc1C(=O)OC
Yield: 72.2 %

Procedure:
Using methyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (1.5 g, 3.6 mmol) produced in Example 13-B (ii), 4,4,5,5-tetramethyl-2-prop-2-en-1-yl-1,3,2-dioxaborolane (897 mg, 5.3 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (180 mg, 0.22 mmol), cesium carbonate (3.5 g, 11 mmol), 1,2-dimethoxyethane (50 mL) and water (3 mL) as starting materials and in the same manner as in Example 13-B (iii), the title compound (815 mg, 73%) was obtained as a yellow solid.
Reaction SMILES: [Cl:1]C1C=C(OC)C(C(O)=O)=NC=1.[CH3:13][O:14][C:15]1[CH:24]=[N:23][C:22]2[C:21](=O)[N:20]=[CH:19][NH:18][C:17]=2[CH:16]=1>>[Cl:1][C:21]1[C:22]2[N:23]=[CH:24][C:15]([O:14][CH3:13])=[CH:16][C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: COc1cnc2c(=O)nc[nH]c2c1
Reactant: COc1cc(Cl)cnc1C(=O)O
Product: COc1cnc2c(Cl)ncnc2c1

Procedure:
Using an analogous reaction to that described for Intermediate 14, step 3, 7-methoxypyrido[3,2-d]pyrimidin-4(1H)-one was converted to the title compound. LC/MS (ESI+) m/z=196 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[N:3]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:20][CH2:21]3)[N:3]=[C:2]([N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: CCNCC
Reactant: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(Cl)n2)cc1Cl
Product: CCN(CC)c1nc(-c2ccc(F)c(Cl)c2)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1
Temperature: 60 °C

Procedure:
Combine a mixture of 2-chloro-4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine (47 mg, 1 mmol) and diethylamine (2 mL). Heat the mixture in a sealed tube at 60° C. for 16 hours. Cool to room temperature and evaporate. Add 1 M NaOH (1 mL) and extract 2× with EtOAc (2 mL each). Combine the organic layers, dry (Na2SO4), and purify using preparative TLC (9:1 hexanes/EtOAc) to obtain {4-(3-Chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-diethyl-amine as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C)C=O.O>[Si:13]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc2cccc(O)c2n1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2cccc(O[Si](C)(C)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
8-Hydroxyquinaldine (10 g), t-butyldimethylsilyl chloride (10 g) and imidazole (8.6 g) were dissolved in N,N-dimethylformamide (150 ml) and stirred at ambient temperature overnight. Further t-butyldimethylsilyl chloride (4.7 g) was added and the reaction stirred for another 30 minutes. The reaction was diluted with water (600 ml) and extracted with dichloromethane (3×300 ml). The combined organic phases were dried over magnesium sulphate and concentrated in vacuo to afford the title compound as an orange oil (17 g).