Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[C:7]([C:12]([OH:14])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[C:7]([C:12]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([Cl:29])=[CH:31][CH:32]=3)=[O:14])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cnc2cc(Cl)ccc2c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(Cl)ccc2c1O
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
7-Chloro-4-hydroxy-3-quinolinecarboxylic acid (500 mg) (Org. Syn. Coll. 3:272-275 (1955)) is dissolved in N,N-dimethylformamide (20 mL) and to the mixture is added 1,1'-carbonyl diimidazole (399 mg). The mixture is heated at 50° C. for 20 h and then allowed to cool to rt. The mixture is treated with water (200 mL) and then after 5 min, 4-chlorobenzylamine (300 mL) is added. The mixture is allowed to stir at rt for 2 days and then is poured into water (50 mL) and the resulting white precipitate is filtered. The crude product is recrystallized (acetic acid, water) to afford 481 mg of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].CCN(CC)CC.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.ClCCl>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([NH:32][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Reactant: NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)c1cn2ncc(C#N)c(NC3CCCCC3)c2c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
To a solution of compound 1D (20 mg, 0.076 mmol) in acetonitrile (1 mL) were added Et3N (32 μL, 0.228 mmol) and cyclohexylamine (10 μL, 0.084 mmol) and the reaction mixture was stirred at 25° C. After 24 h, an additional 10 μL of cyclohexylamine was added and the reaction mixture was stirred for an additional 1.5 h after which time it was poured onto NaHCO3 (sat. aq., 20 mL) and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic layers were washed with water (20 mL), dried over MgSO4, filtered and concentrated in vacuo to yield 18 mg (75%) of compound 1E as a yellow solid, which was used without further purification. HPLC: 100% at 4.60 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 327.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:21][CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+]>Cl.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:21][CH2:20][CH2:19][C:14](=[O:15])[CH2:13][CH2:12]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CCN2CCCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CCN2CCCC(=O)CC2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A mixture of intermediate (6) (0.098 mol) in HCl (3 N, 300 ml) and THF (300 ml) was stirred at 60° C. for 1 hour. The mixture was basified with solid K2CO3 and extracted with ethyl acetate. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 22.6 g of hexahydro-1-[2-(4-methoxyphenyl)ethyl]-4H-azepin-4-one (intermediate 7).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([O:42]C)[CH:41]=1)[CH2:6][N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:19][CH2:18]3)=[CH:12][CH:13]=2)[C:8]1=[O:38].B(Br)(Br)Br>ClCCl>[OH:42][C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([OH:2])[CH:41]=1)[CH2:6][N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH:25]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:21][CH2:22]3)=[CH:12][CH:13]=2)[C:8]1=[O:38]
Reactant: COc1cc(CN2CCc3ccc(N4CCN(CCC(c5ccccc5)c5ccccc5)CC4)cc3C2=O)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1c2cc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)ccc2CCN1Cc1cc(O)cc(O)c1
Yield: 49.1 %

Procedure:
In the same manner as in Example 131, the title compound (28 mg) was prepared from the compound (60 mg) obtained in Example 130 and a 1.0 M aqueous dichloromethane solution (0.6 ml) of boron tribromide.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[N:10][C:11]=1[CH3:12])=[O:5])C.[OH-].[K+].Cl>C(OCCO)C.O>[CH3:12][C:11]1[C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:23])[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:10]=1
Reactant: CCOC(=O)c1c(C)nc(-c2cccc(C(F)(F)F)c2)nc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCCO
Solvent: O
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)nc(C)c1C(=O)O
Temperature: 150 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of 5.21 g (16.1 mmol) of 4,6-dimethyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester in 165 ml of 2-ethoxyethanol/H2O (9:1) was added 2.62 g=40.2 mmol of potassium hydroxide (86%); then, the reaction mixture was heated up to reflux in an oil bath of 150° C. After 4 hours, it was poured into crashed ice, acidified with HCl (25% in water) and extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 4.29 g (90%) of the crude title compound as off-white solid. MS: 295.3 ([M−H]−).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[F:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:22][CH2:23]2)=[CH:3][C:2]([C:37]2[CH:38]=[C:33]([F:32])[C:34]([OH:49])=[C:35]([F:48])[CH:36]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(F)c(O)c(F)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(F)c4)cc23)CC1
Yield: 86.2 %

Procedure:
Following general procedure F, tert-butyl cis-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (54 mg, 0.110 mmol) was reacted with 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (34 mg, 0.132 mmol) to afford the desired product (51 mg, 86%) as a light yellow solid: ESI MS m/z 538 [C30H33F2N3O4+H]+.
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[C:7]([C:13]([O:15]CC)=[O:14])[S:8][C:9]=2[S:11][CH3:12])[CH2:5][CH2:4][C:3]=1[CH:18]=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[OH-].[Na+]>C(O)C.O.Cl.C(OCC)(=O)C>[CH3:12][S:11][C:9]1[S:8][C:7]([C:13]([OH:15])=[O:14])=[C:6]2[CH2:5][CH2:4][C:3]3[CH:18]=[C:7]([C:6]4[CH:10]=[CH:2][CH:3]=[CH:4][CH:5]=4)[S:8][C:2]=3[C:10]=12
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(C=O)=C2Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CSc1sc(C(=O)O)c2c1-c1sc(-c3ccccc3)cc1CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-chloro-5-formyl-6,7-dihydro-3-methylthiobenzo[c]thiophene-1-carboxylate (1.32 g), methyl α-mercaptophenyl acetate (0.76 g) and potassium carbonate (0.69 g) were added to N,N-dimethylformamide (15 ml). The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured over water, and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:5, v/v) to yield yellow powder. The powder was dissolved in ethanol (10 ml), to which an aqueous sodium hydroxide (0.10 g) in water (2 ml) was added. The obtained solution was stirred at 60° C. for 7 hours. To the reaction solution was added concentrated hydrochloric acid (1 drop). After the mixture was poured over water, it was extracted-with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol to yield 4,5-dihydro-8-methylthio-2-phenylbenzo[2,1-c:3,4-b′]dithiophene-6-carboxylic acid, which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 215-217° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:11]=1[NH2:12]>ClCCl>[Br:1][C:15]1[C:14]([F:17])=[CH:13][C:11]([NH2:12])=[C:10]([F:9])[CH:16]=1
Reactant: Nc1cc(F)ccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1cc(F)c(Br)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-Bromosuccinimide (28.50 g, 0.160 mol) is added in small quantities over 1.5 hours to a stirred, cooled (-10° to 0° C.) solution of 2,5-difluoroaniline (20.00 g, 0.155 mol) in dry dichloromethane under dry nitrogen. This mixture is stirred at 0° C. for 2 hours (glc analysis revealing a complete reaction), and the red solution then washed with a large amount of water (×2) and dried (MgSO4). The solvent is removed in vacuo to afford a red solid with a yield of 32.19 g (100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[CH:4]([CH:8]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20](O)=[O:21])=[O:14])[CH2:9][CH2:10][CH2:11][CH3:12])[O:3]1.CC[N:26](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[CH:4]([CH:8]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20]([NH2:26])=[O:21])=[O:14])[CH2:9][CH2:10][CH2:11][CH3:12])[O:3]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCCC(C(=O)N1CCC[C@H]1C(=O)O)C1OC(C)(C)OC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCCCC(C(=O)N1CCC[C@H]1C(N)=O)C1OC(C)(C)OC1=O
Reaction time: 2 h

Procedure:
To 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-carboxypyrrolidin-1-ylcarbonyl)pentane C-2 in DMF was added an amine R14NH2, DIEA and HATU and the solution stirred for 2 h. Aqueous workup followed by silica gel chromatography afforded 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-aminocarbonylpyrrolidin-1-ylcarbonyl)pentane C-3.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[CH:11]=[CH:12][C:7]=2[N:6]=[N:5]1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.C(NC(C)C)(C)C.Cl.[CH3:30][NH:31][O:32][CH3:33]>C(Cl)Cl.CN(C=O)C>[CH3:33][O:32][N:31]([CH3:30])[C:13]([C:10]1[CH:11]=[CH:12][C:7]2[N:6]=[N:5][N:4]([CH:1]([CH3:2])[CH3:3])[C:8]=2[CH:9]=1)=[O:15]
Reactant: CC(C)n1nnc2ccc(C(=O)O)cc21
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2nnn(C(C)C)c2c1
Reaction time: 72 h
Yield: 95.5 %

Procedure:
To a stirred mixture of 3-isopropyl-3H-benzotriazole-5-carboxylic acid (9 g) in 150 mL of methylene chloride and 0.15 mL of DMF was added 5.0 mL of oxalyl chloride. The solution was stirred overnight before 27 mL of N,N-diisopropylamine and 5.6 g of N,O-dimethylhydroxylamine hydrochloride was added. The mixture was stirred for 3 days before mixture was washed with a solution of sodium dihydrogenphosphate, aqueous bicarbonate, dilute hydrochloric acid, brine, dried (sodium sulfate), filtered, and the filtrate was concentrated to a dark oil. This oil was purified by flash chromatography (eluting with 3:2 ethyl acetate/hexanes) to afford 10.4 g of 3-isopropyl-3H-benzotriazole-5-carboxylic acid methoxy-methyl-amide as brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:24][C:25](=O)[NH:26][C:27]1[N:28]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)[N:29]=[C:30]([C:32]2([CH3:35])[CH2:34][CH2:33]2)[CH:31]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:25]([NH:26][C:27]3[N:28]([C:36]4[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=4)[N:29]=[C:30]([C:32]4([CH3:35])[CH2:33][CH2:34]4)[CH:31]=3)=[O:24])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Reactant: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1
Temperature: 25 °C

Procedure:
Heat a solution of 4-(5-amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (Preparation 4, 1.05 equiv, 0.5845 g), [5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloroethyl ester (Preparation 39, 1.0 equiv, 0.8054 g) and diisopropylethylamine (2 equiv, 0.7 mL) in DMSO (0.25 M, 8 mL) to 60° C. for 6 hours. Cool the resulting mixture to ambient temperature, and add water (20 mL). Extract with EtOAc (2×25 mL), then wash the combined organic phases with water (10 mL) and saturated aq. sodium chloride solution (10 mL). Dry over MgSO4, then subject residue to silica gel chromatography eluting with a gradient 2 M ammonia-methanol in dichloromethane. LCMS(ES+): m/z=532.3 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([CH:8]1[CH:12]=[CH:11]OC1=O)=[O:7])([O-:3])=[O:2].[ClH:18]>>[Cl:18][CH2:11][CH2:12][CH2:8][C:6]([C:5]1[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=1[N+:1]([O-:3])=[O:2])=[O:7]
Reactant: O=C1OC=CC1C(=O)c1ccccc1[N+](=O)[O-]
Reactant: Cl
Product: O=C(CCCCl)c1ccccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 95 %

Procedure:
A mixture of dihydro-3-(o-nitrobenzoyl-2(3H)-furanone (2.0 g, 8.5 mmole) in 10 g of 37% HCl solution is stirred at 70° C. until reaction is complete by TLC, cooled to room temperature and extracted with toluene. The organic extracts are combined and concentrated in vacuo to give the title product as a golden oil, 1.84 g (95% yield), 99% pure by HPLC analysis, identified by 1HNMR.
Reaction SMILES: [O-2].[Sr+2:2].[N+]([O-])([O-])=O.[Sr+2].[N+]([O-])([O-])=O.[C:12]([OH:17])(=[O:16])[C:13]([CH3:15])=[CH2:14]>C1COCC1.N1C=CC=CC=1>[C:12]([O-:17])(=[O:16])[C:13]([CH3:15])=[CH2:14].[Sr+2:2].[C:12]([O-:17])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [O-2]
Agent: [Sr+2]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C(C)C(=O)[O-]
Reaction time: 12 h

Procedure:
0.103 Gram (1×10-3 mole) of strontium oxide (prepared by the thermal decomposition of strontium (II) nitrate) was taken in a 100 ml round bottom flask. A solution of 0.280 g of methacrylic acid (3.2×10-3 mole) in 1.1 g of THF was added to it. The sytem was kept for stirring for 12 hrs. The slurry so obtained is soluble in pyridine on sonication.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1>C(O)(=O)C>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH:1][C:2]2[NH:11][C:10](=[O:12])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:14]=1
Reactant: O=Cc1cccnc1
Reactant: Cc1nc2ccccc2c(=O)[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]c(C=Cc2cccnc2)nc2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 2-methylquinazolin-4-one (6.1 g) and 3-pyridinecarbaldehyde (4.1 g) in acetic acid (80 mL) was heated to reflux for 20 hours. After cooling to room temperature, the precipitate was collected by filtration, washed with methanol and dried to obtain the title compound as an acetic acid salt (10.5 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][C:8]([Br:15])=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:6]=1)=[O:4].[OH-].[Li+]>O1CCCC1.O>[Br:15][C:8]1[N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
To a solution of 7.7 g 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester in 50 ml tetrahydrofuran was added at 0° C. 20 ml of a 1M solution of lithium hydroxide in water. The cooling bath was removed and the mixture was stirred at ambient temperature for 20 min. The orange reaction mixture was partitioned between heptane and water. The phases were separated the aqueous phase was mixed with ethyl acetate and 10% aqueous citric acid whereby the yellow orange color almost disappeared. The phases were separated and the organic phase was washed with brine dried over sodium sulfate, evaporated and dried under high vacuum to yield 5.54 g of the title compound as yellow solid. This material was recrystallized from ethyl acetate/heptane before use. MS (M−H) at 381.1 and 379.1.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[Br:13]Br>C(Cl)(Cl)(Cl)Cl.[Fe]>[CH3:1][C:2]([CH3:12])([C:6]1[CH:11]=[CH:10][C:9]([Br:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C(=O)O)c1ccccc1
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C(=O)O)c1ccc(Br)cc1
Temperature: 35 °C

Procedure:
Dry dimethylphenylacetic acid, 152 g, 0.926 mole, was added to a flask equipped with a reflux condenser, magnetic stirrer and oil bath. A solution of bromine, 50 mL, 0.97 mole, in dry carbon tetrachloride (172 mL) was then added along with iron metal "filings," 0.23 g. The mixture was gently refluxed for 16 hours and cooled to ca. 35° C. whereupon material began to crystallize out of solution. Enough carbon tetrachloride (ca. 300 mL) was then added to redissolve the crystals and the solution was washed with ca. 500 mL of dilute aqueous H2SO4, followed by 500 mL of water. The washed CCl4 solution was extracted with 10% aqueous NaOH. The combined basic extracts were washed with petroleum ether or pentane to remove CCl4 and then neutralized at 0° C. with aqueous H2SO4 (50%). The precipitated crude acid was collected on a filtering funnel, washed with cold water and vacuum dried at 40° C. The crude yield was 220 g (98%), mp=106°-116° C. Four recrystallizations from methanol-water (50/50 vol) gave a final mp of 122°-124° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:33]([OH:35])[CH3:34]>>[CH2:33]([O:35][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=1)[CH3:34]
Reactant: CCO
Reactant: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1nc(C)cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)n1
Temperature: 160 °C
Yield: 41 %

Procedure:
A mixture of 2-chloro-6-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (40 mg, 0.1 mmol, Step-1 of Example 456, single enantiomer) and cesium carbonate (50 mg, 0.15 mmol) in ethanol (2 mL) is heated by microwave irradiation at 160° C. for 1 hour. After cooled to room temperature, the mixture is concentrated under reduced pressure. The residue is suspended in ethyl acetate and filtered through a short column of amine gel eluting with ethyl acetate. The filtrate is concentrated and then by preparative LC-MS to give 17 mg (41% yield) of the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:7])=[CH:4][CH2:5][NH2:6].[S:8](=[O:12])(=[O:11])([OH:10])[OH:9]>>[S:8]([O:12][C:3]([CH3:7])([CH2:4][CH2:5][NH2:6])[CH3:2])([OH:11])(=[O:10])=[O:9]
Reactant: O=S(=O)(O)O
Reactant: CC(C)=CCN
Agent: Cl
Product: CC(C)(CCN)OS(=O)(=O)O
Temperature: 90 °C
Yield: 85 %

Procedure:
3-Methyl-2-butene-1-amine hydrochloride (2.86 g, 0.02 mmoles) was dissolved in 5% aqueous sulfuric acid (25 ml) and heated to 90° C. for 18 h. The solvent was removed under reduced pressure yielding 4-amino-2-methyl-butan-2-ol sulfate as a yellow oil (4.73 g, 85%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[C:21]([F:28])=[C:22]([CH2:26][OH:27])[CH:23]=[CH:24][CH:25]=1>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[C:21]=1[F:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1cccc(Br)c1F
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1cccc(CO)c1F

Procedure:
Following the general method as outlined in Intermediate 19, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and (3-bromo-2-fluorophenyl)methanol (Intermediate 11), the title compound was obtained as a dark brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:2]1.[C:12]([C@H:16]1[CH2:20]OS(=O)(=O)[O:17]1)([CH3:15])([CH3:14])[CH3:13].C(Cl)(=O)C.C(=O)(O)[O-].[Na+]>C(#N)C.CO>[CH3:13][C:12]([CH3:15])([CH3:14])[C@H:16]([OH:17])[CH2:20][N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:2]1
Reactant: CC(C)(C)[C@H]1COS(=O)(=O)O1
Reactant: c1cncc(-c2cc[nH]n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: CC(=O)Cl
Product: CC(C)(C)[C@H](O)Cn1ccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
To a solution of 0.38 g (2.62 mmol) of 3-(1H-pyrazol-3-yl)pyridine and 0.47 g (2.62 mmol) of (4S)-4-tert-butyl-1,3,2-dioxathiolane 2,2-dioxide in 15 mL of acetonitrile was added 1.3 g of a potassium fluoride/alumina mixture [prepared by mixing 10 g of potassium fluoride, 200 mL of water, and 15 g of activated neutral alumina (Brockmann I, 150 mesh) and concentrating at 55° C.]. The mixture was stirred at ambient temperature for 4 h. Then, a solution of 2 mL of acetyl chloride in 10 mL of methanol was added to the reaction mixture. After 18 h, saturated aqueous sodium bicarbonate was added, the mixture was filtered, and the filter cake was rinsed with methanol. The filtrate was concentrated, and the residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic phase was dried over sodium sulfate and concentrated to provide 0.6 g (94%) of (2S)-3,3-dimethyl-1-[3-(3-pyridinyl)-1H-pyrazol-1-yl]-2-butanol as a yellow solid. 1H-NMR (DMSO-d6): δ 8.97 (s, 1H), 8.45 (d, J=4 Hz, 1H), 8.1 (t, J=8 Hz, 1H), 7.76 (d, J=2 Hz, 1H), 7.38 (dd, J=8 Hz, J=5 Hz, 1H), 4.86 (d, J=6 Hz, 1H), 4.27 (dd, J=13 Hz, J=2 Hz, 1H), 3.90 (dd, J=14 Hz, J=10 Hz, 1H), 3.5–3.4 (m, 1H), 0.90(s, 9H).