Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[C:4](=[O:18])[N:5]([CH3:17])[CH2:6][CH2:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1.[C:19](OC)([O:23]C)([O:21][CH3:22])[CH3:20].C(O)(=O)C(C)(C)C>COCCOCCOC>[CH3:22][O:21][C:19]([CH2:20][C:8]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH2:7][CH2:6][N:5]([CH3:17])[C:4](=[O:18])[C:3]1=[CH2:2])=[O:23]
Reactant: COc1cccc(C2=C(CO)C(=O)N(C)CC2)c1
Reactant: COC(C)(OC)OC
Agent: CC(C)(C)C(=O)O
Solvent: COCCOCCOC
Product: C=C1C(=O)N(C)CCC1(CC(=O)OC)c1cccc(OC)c1

Procedure:
The allylic alcohol 27 of Example 9 (1.22 g, 4.96 mmol), trimethyl orthoacetate (5.52 g, 46 mmol), and pivalic acid (26 mg, 0.50 mmol) were placed in diglyme (25 mL) and refluxed at 155°-160° C. (internal) with fractionation to remove CH3OH. After 18 h the solvents were evaporated and the residue distilled [bp 175°-185° C. (0.15 mm)] to return 1.21 g (80%) of methyl ester 28. Upon standing the ester crystallized: mp 85°-86° C.; NMR δ7.30 (m, 1H), 6.66 (m, 4H), 6.65 (s, 1H), 5.57 (s, 1H), 3.76 (s, 3H), 3.47 (s, 3H), 3.17 (m, 3H), 2.87 (s, 4H), 2.53 (m, 2H); IR 1733, 1653, 1595 cm-1 ; mass spectrum m/e (rel intensity) 303 (38), 230 (100). Anal. Calcd for C17H21NO4 : C, 67.3; H, 7.0; N, 4.6. Found: C, 67.2; H, 7.0; N, 4.6.
Reaction SMILES: [F:1][C:2]([F:12])([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)[C:3]([F:6])([F:5])[F:4].[CH2:13]=[O:14]>CC(C)=O>[F:12][C:2]([F:1])([C:7]1[N:11]=[CH:10][N:9]([CH2:13][OH:14])[N:8]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: C=O
Reactant: FC(F)(F)C(F)(F)c1nc[nH]n1
Solvent: CC(C)=O
Product: OCn1cnc(C(F)(F)C(F)(F)F)n1
Temperature: 150 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
The mixture of 1.45 g of 3-(pentafluoroethyl)-1H-1,2,4-triazole and 0.46 g of paraformaldehyde was stirred at 150° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added. The mixture was filtered. The filtrate was concentrated. Hexane was added to the residue, as a result, a crystal was formed. The crystal was collected to obtain 1.52 g of 3-(pentafluoroethyl)-1H-1,2,4-triazole 1-ylmethanol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C-:32]#[N:33].O>CS(C)=O>[C:32]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[N:33]
Reactant: BrCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Reactant: [C-]#N
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
1-(7-Bromoheptyl)-2,4,5-triphenylimidazole (7 g) in dry dimethylsulphoxide (15m1) was added over 20 minutes to a mixture of sodinto cyanide (0.87 g) in dimethyl-sulphoxide (25 ml ). The reaction was stirred at 40° C. for 1 hour. The cooled reaction mixture was poured into water (800 ml) and extracted with diethyl ether (4×100 ml). The extracts were combined, washed with water, dried over anhydrous magnesinm sulphate and evaporated to dryness in vacuo. Recrystallisation from dichloro-methane/hexane gave 1-(7-cyanoheptyl)-2,4,5-triphenylimidazole (3.7 g,60%) as a white solid, m.p. 93°-94°; Found: C, 82.35; H, 6.90; N, 9.96%; C29H29N3 1% CH2Cl2 requires C, 82.43; H, 6.91; N, 9.91%.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Li]CCCC.[CH3:12][C:13]1([CH3:25])[C:22]2[C:17](=[CH:18][C:19]([Br:23])=[CH:20][CH:21]=2)[C:16](=O)[CH2:15][CH2:14]1>C1COCC1.CCOCC.C(OC(=O)C)C>[CH3:1][C:2]1[S:3][C:4]([C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=3)[C:13]([CH3:25])([CH3:12])[CH2:14][CH:15]=2)=[CH:5][CH:6]=1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: Cc1cccs1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 62.3 %

Procedure:
To a cold (−78° C.) solution of 2-methylthiophene (800 mg, 8.1 mmol) in THF (10 mL) was added n-BuLi (1.6M solution in hexane, 5 mL). The mixture was stirred for 1.5 hours and transferred to a cold (−78° C.) flask containing 3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone (Compound A, 1.63 g, 6.5 mmol), in THF (15 mL). The mixture was gradually warmed to 0° C. The reaction mixture was diluted with ether:ethylacetate (1:1, 80 mL), washed with water (10 mL), brine (10 mL). dried with MgSO4 and the solvent was removed by evaporation. The crude material was dissolved in dichloroethane (20 mL) and pTSA (40 mg) was added. The mixture was stirred at ambient temperature for 16 hours and at 50° C. for 4 hours. . The reaction mixture was diluted with ether (150 mL), washed with aqueous 10% NaHCO3 (10 mL), brine (10 mL) and dried with MgSO4. Purification by chromatography on silica gel gave 1.35 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20](=[N:26]O)[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[O:12][N:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1
Reactant: O=C(O)Cc1ccc(F)cc1F
Reactant: CCOC(=O)C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CCOC(=O)c1noc(Cc2ccc(F)cc2F)n1
Yield: 36.7 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(2,4-difluorophenyl)acetic acid (0.651 g; 3.78 mmol) and oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (6 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.372 g (37%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.CCN(C(C)C)C(C)C.C([Mg]Cl)(C)C.[Cl:22][C:23]1[CH:54]=[CH:53][C:26]([C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[N:37][CH:38]=2)[N:35]([CH3:39])[C:34](=[O:40])[CH:33]=[C:32]3[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[C:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH:42]=2)=[O:28])=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:22][C:23]1[CH:54]=[CH:53][C:26]([C:27]([OH:28])([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=2)[C:29]2[CH:30]=[C:31]3[C:36](=[N:37][CH:38]=2)[N:35]([CH3:39])[C:34](=[O:40])[CH:33]=[C:32]3[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[C:48][Si:49]([CH3:50])([CH3:52])[CH3:51])[CH:42]=2)=[CH:25][CH:24]=1
Reactant: Cn1cncc1Br
Reactant: Cn1c(=O)cc(-c2cccc(C#C[Si](C)(C)C)c2)c2cc(C(=O)c3ccc(Cl)cc3)cnc21
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1cnc2c(c1)c(-c1cccc(C#C[Si](C)(C)C)c1)cc(=O)n2C
Reaction time: 1.5 h
Yield: 35.8 %

Procedure:
To a solution of 5-bromo-1-methylimidazole (0.68 g, 4.26 mmol) in dry DCM (15 mL), DIPEA (0.77 mL, 4.47 mmol) and iPrMgCl (2.13 mL, 4.26 mmol, 2.0 M solution in THF) was added at 10° C. The reaction mixture was stirred for 1.5 h and a solution of compound J (0.5 g, 1.06 mmol) in DCM was added to it. The reaction mixture was refluxed for 2 h and quenched with saturated NH4Cl solution. The product was extracted with DCM (30 mL). The organic layer was dried, filtered and concentrated to give crude c. Purification of the crude product provided 210 mg (36%) of compound K.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:32])=[C:18]([C@:20]23[CH2:28][O:27][C@H:26]([CH2:29][F:30])[C@H:25]2[CH2:24][S:23][C:22]([NH2:31])=[N:21]3)[CH:19]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[NH4+]>CCOC(C)=O.O>[NH2:31][C:22]1[S:23][CH2:24][C@@H:25]2[C@@H:26]([CH2:29][F:30])[O:27][CH2:28][C@:20]2([C:18]2[CH:19]=[C:14]([NH:13][C:9]([C:6]3[CH:5]=[N:4][C:3]([CH:2]([F:1])[F:12])=[CH:8][N:7]=3)=[O:11])[CH:15]=[CH:16][C:17]=2[F:32])[N:21]=1
Reactant: NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](CF)[C@H]2CS1
Reactant: O=C(O)c1cnc(C(F)F)cn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(C(F)F)cn4)ccc3F)CO[C@H](CF)[C@H]2CS1
Temperature: 42.5 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
5-(Difluoromethyl)pyrazine-2-carboxylic acid (30.0 g, 1.05 equiv) and (4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (49.2 g, 1.00 equiv.) were charged to a reactor and EtOAc (443 mL) was added to the mixture to give a suspension. A solution of ®T3P (105 g, 1.10 equiv, 50 wt % in EtOAc) (Archimica, Germany) was added at ambient temperature while controlling the internal temperature below 30° C. The reaction mixture was stirred at 40-45° C.>3 hours and monitored by HPLC. The reaction mixture was cooled to ambient temperature and water (98 mL) was charged. After 10-15 minutes charged 28% ammonium hydroxide (137 mL) while controlling the temperature below 30° C. Additional EtOAc (172 mL) was added and the reaction mixture was stirred for 30 minutes at ambient temperature. The aqueous phase was separated and back-extracted with EtOAc (246 mL). The organic phases were combined and washed with 15% aq. NaCl (98 mL) and water (98 mL). The organic layer was filtered over Celite (0.5 Wt) and concentrated under vacuum to obtain a beige solid (quantitative crude yield) which was recrystallized from 1-propanol to afford N-(3-((4aS,5S,7aS)-2-amino-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-(difluoromethyl)pyrazine-2-carboxamide as a tan solid (54.2 g).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[CH:29][C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[C:14]([NH:16][CH2:17][C:18]2[CH:28]=[CH:27][C:21]([C:22](OCC)=[O:23])=[CH:20][CH:19]=2)=[O:15])=[CH:9][CH:8]=1.O>CO.C(O)(=O)C>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[CH:29][C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[C:14]([NH:16][CH2:17][C:18]2[CH:28]=[CH:27][C:21]([C:22]([NH:2][OH:3])=[O:23])=[CH:20][CH:19]=2)=[O:15])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(CNC(=O)C(=Cc2cc(OC)c(OC)c(OC)c2)c2ccc(F)cc2)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C=C(C(=O)NCc2ccc(C(=O)NO)cc2)c2ccc(F)cc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
Hydroxylamine hydrochloride (1.25 g, 18 mmol) in methanol (3 mL) was mixed with KOH (1.0 g, 18 mmol) in methanol (6 mL) at 0° C. and the reaction mixture was sonicated for 5 minutes. A white precipitate was formed which was filtered. The filtrate was immediately added to the ethyl 4-((2-(4-fluorophenyl)-3-(3,4,5-trimethoxyphenyl)acrylamido)methyl)benzoate (0.4 g, 1 mmol) followed by the addition of KOH (0.084 g, 1.5 mmol) and the mixture was stirred at room temperature for 1 hour. Around 20 mL of water was added to the reaction mixture and it was neutralized to pH 7 by addition of dilute acetic acid. Upon standing, a colorless precipitate was formed, it was filtered, dried and triturated with dichloromethane/hexanes (1:1, 20 mL), to afford the required compound as a pure colorless solid (0.254 g, 38% yield). 1H NMR (DMSO-d6) δ (ppm): 3.49 (61-1, s, —OCH3), 3.60 (3H, s, —OCH3), 4.36 (2H, d, —CH2), 6.32 (2H, s, Ar—H), 7.29-7.39 (6H, d, Ar—H), 7.48 (1H, s, ═CH), 7.69 (2H, d, Ar—H), 7.96 (1H, t, —NH), 8.99 (1H, s, —OH), 11.16 (1H, s, —NH); MS m/z: 497.1 (M++1).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[CH3:25])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][N:27]1[CH:31]=[C:30]([C:2]2[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:15][C:14]=4[CH3:25])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH:29]=[N:28]1
Reactant: Cc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(-c3cnn(C)c3)c2n1
Temperature: 100 °C
Yield: 51.9 %

Procedure:
To a solution of 8-chloro-N-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Preparation 113, 12 mg, 0.034 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was added 1-methylpyrazole-4-boronic acid pinacol ester (14 mg, 0.068 mmol), cesium carbonate (17 mg, 0.051 mmol) and Pd(PPh3)4 (2 mg, 1.71 umol). The reaction mixture was heated to 100° C. under microwave irradiation for 30 minutes. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-15% MeOH in EtOAc to give the title compound (7 mg, 52%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][N:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[BH3-]C#N.[Na+].[O:26]1[CH2:29][C:28](=O)[CH2:27]1>[Cl-].[Zn+2].[Cl-].CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][N:14]([CH:16]3[CH2:21][CH2:20][N:19]([CH:28]4[CH2:29][O:26][CH2:27]4)[CH2:18][CH2:17]3)[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2cn(C3CCNCC3)cn2)c1=O
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(Br)cc(Nc2cn(C3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 50 °C
Reaction time: 5 h
Yield: 31.1 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 243e (2.2 g, 6.3 mmol), NaBH3CN (995 mg, 15.8 mmol), oxetan-3-one (907 mg, 12.6 mmol), zinc chloride (2.1 g, 15.8 mmol), and methanol (60 mL). The reaction mixture was stirred at 50° C. for 5 hrs and concentrated under reduced pressure. To the residue was added water and the resulting mixture was extracted with dichloromethane three times. The combined organic layer was then concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 1% triethylamine in methanol. The fractions containing the desired product were concentrated under reduced pressure. Dichloromethane was added to the residue and the resulting suspension was filtered. The filtrate was concentrated under reduced pressure afford 243f as a yellow solid (800 mg, 62%). MS-ESI: [M+H]+ 408.2
Reaction SMILES: [OH-].[Na+].C(O[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:11][CH:12]=1)=[O:7])C.Cl.[CH3:24][C:25]1[CH:26]=[C:27]([NH2:43])[CH:28]=[N:29][C:30]=1[C:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH2:33][CH:32]=1>O1CCCC1.ClCCl.O.C(N(CC)CC)C>[CH3:24][C:25]1[CH:26]=[C:27]([NH:43][C:6]([C:8]2[N:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[S:11][CH:12]=2)=[O:7])[CH:28]=[N:29][C:30]=1[C:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH2:33][CH:32]=1
Reactant: Cc1cc(N)cnc1C1=CCC(N2CCOCC2)CC1
Reactant: CCOC(=O)c1csc(-c2ccc(C(F)(F)F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(NC(=O)c2csc(-c3ccc(C(F)(F)F)cc3)n2)cnc1C1=CCC(N2CCOCC2)CC1
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 61 %

Procedure:
1N Aqueous solution of sodium hydroxide (2 ml) was added at room temperature to a solution of 2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxylic acid ethyl ester (300 mg) described in Reference Example 178 in tetrahydrofuran (2 ml) and stirred at 50° C. for 4.5 hours. After the reaction, 1N aqueous solution of hydrochloric acid (2 ml) was added, the solvent was evaporated and the residue was azeotropically distilled twice with toluene. N,N-Dimethylformamide (catalytic amounts) and thionyl chloride (2 ml) were added to the resulting residue at room temperature, stirred at 80° C. for an hour, and an excess amount of thinly chloride was evaporated. The resulting reaction solution was dissolved in dichloromethane (5 ml), triethylamine (416 μl) and 5-methyl-6-[4-(morpholin-4-yl)cyclohex-1-en-1-yl]pyridine-3-amine (327 mg) were added and stirred at room temperature for 20 minutes. After the reaction, water was added, extracted with chloroform and the solvent was evaporated. The resulting residue was purified with a basic silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (321 mg) as a white solid.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][O:3][CH2:2]1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:9]([O:16][C:5]([CH2:4][O:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: O=C1COCC(=O)O1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)COCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
Diglycolic anhydride (4.11 g, 31.9 mmol) was dissolved in methylene chloride and benzyl alcohol (3.3 g, 31.9 mmol) was added, followed by triethylamine (3.22 g, 31.9 mmol). The reaction mixture was stirred at room temperature for 4 hours. Toluene (20 mL) was added, volatiles were evaporated and the residue was dried on vacuum pump overnight to afford 7.17 g of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ4.17 (s, 2H), 4.26 (s, 2H), 5.18 (s, 2H), 7.21-7.42 (m, 5H).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[C:15]([OH:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[OH-].[Na+].Cl[CH:22]([F:24])[F:23]>O>[F:23][CH:22]([F:24])[O:16][C:15]1[C:7]([F:6])=[C:8]([CH:12]=[C:13]([F:18])[C:14]=1[F:17])[C:9]([OH:11])=[O:10]
Reactant: FC(F)Cl
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Reaction time: 0.5 h

Procedure:
20 ml of dimethylformamide, followed by 4.97 g (0.026 mole) of 2.4,5-trifluoro-3-hydroxybenzoic acid [(XXIII), X=X'=F], were added in portions, whilst ice-cooling, to a solution of 2.18 g (0.052 mole) of sodium hydroxide in 5 ml of water. Thereafter the solution was stirred for 30 minutes, whilst ice-cooling. The reaction mixture was then transferred to a 200 ml stainless steel autoclave, and 100 ml of dimethylformamide containing 24.0 g (0.277 mole) of chlorodifluoromethane were added to it. The mixture was then stirred at between 100° and 110° C. for 5 hours under pressure. At the end of this time, the reaction mixture was poured into water and extracted with chloroform. The chloroform extracts were washed with water and dried over anhydrous sodium sulfate; the solvent was then removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel using a 9:1 by volume mixture of ethyl acetate and ethanol as the eluent, to afford 2.00 g of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid as a colorless powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.Br[C:32]1[C:33]([C:39]#[N:40])=[N:34][N:35]([CH3:38])[C:36]=1[CH3:37].C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.ClCCl.C(O)CC>[CH3:37][C:36]1[N:35]([CH3:38])[N:34]=[C:33]2[C:32]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:21]=[C:39]2[NH2:40]
Reactant: Cc1c(Br)c(C#N)nn1C
Reactant: Nc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCCO
Solvent: ClCCl
Solvent: O
Product: Cc1c2c(nn1C)c(N)nc1ccccc12
Temperature: 100 °C
Yield: 20 %

Procedure:
Triphenylphosphine (0.10 g, 0.45 mmol), 2-aminophenylboronic acid hydrochloride (3.89 g, 22.0 mmol), and 4-bromo-1,5-dimethyl-1H-pyrazole-3-carbonitrile (prepared as described in Parts A-C of Example 5, 3.00 g, 15.0 mmol) were placed in a flask. After 1-propanol was added (22 mL), the flask was placed under vacuum and back-filled with nitrogen three times. Palladium (II) acetate (30 mg, 0.15 mmol) was added, followed by aqueous sodium carbonate (22.5 mL of 2 M) and water (4.4 mL). The reaction was heated overnight under a nitrogen atmosphere at 100° C. Additional 2-aminophenylboronic acid hydrochloride (1.0 g), palladium (II) acetate (approximately 10 mg), aqueous sodium carbonate (10 mL of 2 M), and water (5 mL) were added. The reaction was heated at 100° C. for 8 hours, then was allowed to cool to ambient temperature. The reaction mixture was partioned between dichloromethane and water. The organic layer was concentrated under reduced pressure and the crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-30% CMA in chloroform). The appropriate fractions were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane and concentrated under reduced pressure, which resulted in the formation of a solid. Hexanes were added to the solid, which was isolated by filtration and crystallized from acetonitrile to yield 0.637 g of 1,2-dimethyl-2H-pyrazolo[3,4-c]quinolin-4-amine as white needles, mp>250° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[Br:14][C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:12]=1[OH:13])[CH:8]=[O:9]
Reactant: CC(C)(C)c1cc(C=O)ccc1O
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=O)cc(Br)c1O
Reaction time: 3 h

Procedure:
To 3-tert-butyl-4-hydroxybenzaldehyde (3 gm) in acetic acid (30 ml) was added dropwise bromine (1.5 ml). The mixture was stirred at 25° for 3 hours and the solvent removed in vacuo. Recrystallisation of the residue from aqueous ethanol gave 3-bromo-5-tert-butyl-4-hydroxybenzaldehyde (3.2 gm) m.p. 126°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][N:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1.O>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([CH2:7][OH:8])=[CH:9][CH:10]=1
Reactant: COc1ccc(C=O)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CO)cn1
Yield: 82.2 %

Procedure:
According to Scheme 16 Method A: A solution of 6-methoxynicotinaldehyde (1 eq, 2.19 mmol, 0.30 g) and LiAlH4 (0.5 eq, 1.05 mmol, 0.04 g) in THF (10 mL) was stirred for 30 min. at 0° C. and overnight at room temperature. After the addition of AcOEt, the reaction mixture was diluted with water. The organic layer washed with saturated NH4Cl solution, dried over Na2SO4, filtered and evaporated. The resulting crude residue was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 80/20 to afford (6-methoxypyridin-3-yl)methanol (1.80 mmol, 0.26 g, 90%) as a pale oil.