Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.C(N(CC)CC)C.[N:44]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([C:50]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[O:51])[CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)N1CCOCC1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (38.1 mg, 0.074 mmol) in DCM (736 μL) at 0° C. was added triethylamine (30.8 μL, 0.221 mmol), followed by morpholine-4-carbonyl chloride (17.2 μL, 0.147 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 30 min. The reaction mixture was concentrated under reduced pressure and purified directly by HPLC Method B, with the exception that a Phenomenex Gemini® C18, 5 μm, ID 30×75 mm column was used, using a 50% to 75% ACN gradient to give the title compound, as a TFA salt, as a yellow solid (11.9 mg, 25.6%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.31 (d, J=6.6 Hz, 6H), 1.96 (m, 2H), 2.13 (m, 2H), 2.81 (t, J=5.8 Hz, 2H), 3.10 (m, 2H), 3.33 (m, 4H), 3.45 (m, 2H), 3.59 (t, J=5.9 Hz, 2H), 3.70 (m, 4H), 4.13 (m, 1H), 4.37 (s, 2H), 4.50 (tt, J=7.2, 3.5 Hz, 1H), 6.88 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+517.5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[C:5]#[N:6].N1C=CC=CC=1.[Cl:18][CH2:19][O:20][C:21](Cl)=[O:22]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[C:8]([Br:11])[C:9]=1[O:10][C:21](=[O:22])[O:20][CH2:19][Cl:18]
Reactant: O=C(Cl)OCCl
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1cc(Br)c(OC(=O)OCCl)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.7 %

Procedure:
To a suspension of 3,5-dibromo-4-hydroxybenzonitrile (10.0 g, 36.1 mmol) in 180 mL of chloroform was added pyridine (2.92 ml, 36.1 mmol). Chloromethylchloroformate (5.2 mL 60 mmol) was then added over 5 min. The mixture was allowed to stir at room temperature for 12 h. The reaction was then washed with 1% HCl aq, water, and brine. The organic layer was then dried over sodium sulfate, filtered, and evaporated to afford a white solid (12.5 g) in 94% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 5.87 (d, 2H), 7.90 (s, 2H). 13C-NMR (300 MHz, CDCl3) δ (ppm): 73.58, 113.87, 115.68, 119.01, 136.40, 149.53, 149.71. Mp=83-85° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1)#[N:17].CCOCC>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(N=C=S)cc1
Reactant: Nc1ncccc1OCc1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: N#Cc1ccc(NC(=S)Nc2ncccc2OCc2ccccc2)cc1

Procedure:
A stirring mixture of 2-amino-3-benzyloxy pyridine (5.68 g, 0.0284 mol) and 4cyanophenyl isothiocyanate (5 g, 0.0312 mol) in toluene (20 ml) was heated under reflux for 2 h. After allowing to cool, the solution was treated with ether, and the resulting solid filtered off, washed and dried. Yield 9.4 g (92%), m.p. 163°-165 ° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:24])=[O:25]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(=O)(=O)c1ccccc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1NS(=O)(=O)c1ccccc1
Yield: 83 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(2-(phenylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (70 mg, 0.16 mmol, 1.0 eq.) and 1.6 mL aqueous solution of sodium hydroxide (2 M, 3.3 mmol, 20 eq.) in tetrahydrofuran (4 mL) was stirred at reflux for 3 h. Thin layer chromatography indicated that the starting material was consumed completely. The tetrahydrofuran was removed under reduced pressure and the residue was acidified to pH 5-6 with 1 M hydrochloric acid. Then a lot of white precipitates were formed and collected by filtration to afford 58 mg of 3,3-dimethyl-2-(2-(phenylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid; yield: 83%. MS (ESI+APCI) M+1=437.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([CH3:18])=[CH:16][N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([CH3:18])=[CH:16][N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Cc1cnc(N)s1
Product: Cc1cnc(NC(=O)c2cc(Br)ccc2O)s1
Yield: 12.9 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-5-methylthiazole as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:16][CH:15]=1>CN(C=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:16][CH:15]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(C)S(=O)(=O)Nc1ccc(N)cc1
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)Nc1ccc(NC(=O)c2ccccc2N)cc1
Temperature: 115 °C
Yield: 23.2 %

Procedure:
Isatoic anhydride (0.690 g, 4.20 mmol) was added to a solution of N-(4-aminophenyl)propane-2-sulfonamide (0.910 g, 4.20 mmol) in DMF (15 mL) and heated at 115° C. overnight. The mixture was concentrated in vacuo and purified by flash chromatography on silica gel, eluting with 6% MeOH in CH2Cl2. Further purification was effected by reverse phase chromatography, eluting with 10% to 90% CH3CN in H2O with 0.1% TFA. The desired fractions were collected, basified, and extracted with EtOAc to afford 2-amino-N-(4-(1-methylethylsulfonamido)phenyl)benzamide (0.325 g, 23%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[C:8]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:10][C:3]=2[CH:2]=1.[CH3:14][N:15]([CH3:29])[C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:51].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>ClCCCl.C1COCC1.C(O)C.CC(=O)CC.C(O)(=O)C>[ClH:51].[ClH:51].[CH3:14][N:15]([CH3:29])[C:16]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18][CH:19]([NH:13][CH2:12][CH2:11][C:8]2[C:4]3[C:3](=[CH:2][CH:1]=[C:6]([OH:7])[CH:5]=3)[NH:10][CH:9]=2)[CH2:20][CH2:21]1
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(NCCc2c[nH]c3ccc(O)cc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Serotonin (405 mg) was dissolved in 1,2-dichloroethane/THF (5 ml/20 ml), and 4-dimethylamino-4-phenylcyclohexanone (500 mg), glacial acetic acid (131 μl) and red-hot sodium sulfate (2 g) were added thereto. After one hour's stirring at RT, sodium triacetoxyborohydride (759 mg) was added and stirring was carried out for a further two days. For working up, the mixture was concentrated, the residue was suspended in diethyl ether (15 ml), water (10 ml) and 2M HCl (1 ml), further diethyl ether (20 ml) was added, and the organic phase was coarsely separated off. The aqueous phase was first brought to pH 9 with 1M NaOH and extracted with ethyl acetate (3×5 ml), then adjusted to pH 11 and again extracted with ethyl acetate (5×10 ml). The organic extracts were dried and concentrated and the residue was purified by flash chromatography (eluant: MeOH/NEt3 99.5:0.5). 267 mg of the nonpolar diastereomer (m.p. 90-100° C.) were isolated and, dissolved in ethanol/2-butanone (3 ml/15 ml), were converted with 3.3M ethanolic HCl (642 μl) into the corresponding dihydrochloride (white solid; 304 mg; m.p. 215-217° C.).
Reaction SMILES: N1C=CN=C1.[CH2:6]=[CH:7][CH2:8][CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>O>[CH:14]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[O:13][CH:9]([CH2:10][CH:11]=[CH2:12])[CH2:8][CH:7]=[CH2:6])([CH3:16])[CH3:15]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C=CCC(O)CC=C
Agent: c1c[nH]cn1
Solvent: O
Product: C=CCC(CC=C)O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 0 °C
Yield: 46 %

Procedure:
There was supplied 1.35 g of imidazole manufactured by Wako Pure Chemical Industries, Ltd. to a 50 mL-Schlenk tube, and thereto, 10 mL of anhydrous N,N-dimethylformaide manufactured by Wako Pure Chemical Industries, Ltd., and 1.2 mL of 1,6-heptadien-4-ol manufactured by Aldrich Chemical Company were added. The obtained mixture was cooled down to 0° C. To the mixture, 1.93 mL of triisopropylsilyl chloride manufactured by Tokyo Chemical Industry Co., Ltd. was added, and the resultant mixture was stirred for 85 hours at a room temperature. Then, an excess amount of water was added thereto, thereby terminating the reaction. A product contained in the reaction mixture was extracted with hexane, and the obtained organic extract was dried over anhydrous sodium sulfate manufactured by Nacalai Tesque, Inc. The dried hexane solution was distilled in vacuo, thereby obtaining 1.1 g (yield: 46%) of 4-(triisopropylsiloxy)-1,6-heptadiene at 93° C. under 21 mmHg as clear colorless oil.
Reaction SMILES: O(Cl)Cl.[Zr:4].Cl.[Si:6]([O-:10])([O-:9])([O-:8])[O-:7].[Na+].[Na+].[Na+].[Na+].[P:15](=[O:19])([OH:18])([OH:17])[OH:16]>O>[Si:6]([O-:10])([O-:9])([O-:8])[O-:7].[P:15]([OH:19])([OH:18])([OH:17])=[O:16].[Zr+4:4]
Reactant: [Zr]
Agent: Cl
Agent: ClOCl
Agent: O=P(O)(O)O
Solvent: O
Product: [Zr+4]
Reaction time: 0.5 h

Procedure:
Three hundred and twenty-two (322) g of zirconium oxychloride is dissolved in 3 liter of water, and to this solution is added 200 g of concentrated hydrochloric acid. To the resulting acidic solution are added the aqueous solution prepared by dissolving 552 g of sodium silicate (Na2SiO3) in 10 liter of water as well as the aqueous solution consisting of 100 g of 98% phosphoric acid and 3 liter of water, and, after stirred for about 30 minutes, precipitates of zirconium phosphate silicate formed in the solution are separated. The subsequent procedures are conducted in the same manner as in the above (1) to prepare particles of the desired compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:29]=[CH:28][C:16]([CH2:17][NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:29]=[CH:28][C:16]([CH2:17][N:18]([CH2:30][C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCCCc1ccc(C#Cc2ccc(CNCCc3ccc(Cl)cc3)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(CCc3ccc(Cl)cc3)Cc3ccc(C(=O)OC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.7 %

Procedure:
To a solution of {4-[(4-butylphenyl)ethynyl]benzyl}[2-(4-chlorophenyl)ethyl]amine (2.85 g, 7.1 mmol) and methyl 4-formylbenzoate (1.16 g, 7.1 mmol) in DCE (24 mL) was added at once sodium triacetoxyborohydride (2.25 g, 10.6 mmol) and the resulting reaction mixture was stirred 12 hrs at rt. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure to give the crude product. Purification by chromatography on silicagel (EtOAc/c-hex (5/95)) gave 2.8 g (73%) of the title compound as a white solid. HPLC, Rt: 5.0 min (purity: 99.9%). 1H NMR (CDCl3) δ: 7.98 (d, J=8.3 Hz, 2H), 7.51-7.43. (m, 4H), 7.36 (d, J=8.3 Hz, 2H), 7.29-7.15 (m, 6H), 7.00 (d, J=8.3 Hz, 2H), 3.94 (s, 3H), 3.68 (s, 2H), 3.64 (s, 2H), 2.83-2.59 (m, 6H), 1.69-1.55 (m, 2H), 1.44-1.30 (m, 2H), 0.95 (J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([N:4]([CH:15]1[CH2:24][CH2:23][C:18]2(OCC[O:19]2)[CH2:17][CH2:16]1)[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH3:3].Cl>C(#N)C>[O:19]=[C:18]1[CH2:23][CH2:24][CH:15]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:14])[O:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:16][CH2:17]1
Reactant: CCCN(C(=O)OCc1ccccc1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: CCCN(C(=O)OCc1ccccc1)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzyl propyl(1,4-dioxaspiro[4.5]decan-8-yl)carbamate (350 mg, 1.1 mmol) was dissolved in acetonitrile, treated with 6N HCl, and stirred at room temperature for 18 h. reaction mixture was concentrated in vacuo, treated with saturated NaHCO3 to pH 6. The solvents were removed under vacuum and the residue treated with saturated NaCl (2 mL) and extracted with 4:1 EtOAc/iPrOH (×4). The organic fractions were combined, filtered and evaporated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10](=O)[NH:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10](=[S:29])[NH:9]2)[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(c2cc(Br)ccc2F)NC(=O)COCC1(F)F
Solvent: C1CCOC1
Product: CC1(c2cc(Br)ccc2F)NC(=S)COCC1(F)F

Procedure:
To a solution of 5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-one (2.0 g, 5.93 mmol) in THF (25 mL) was added Lawesson's reagent (2.87 g, 7.1 mmol) at rt and heated to reflux temperature for 16 h. Reaction mixture was concentrated under reduced pressure and directly purified by column chromatography on silica gel using 4% ethyl acetate in Hexane to furnish title compound as colorless gum. Yield=1.0 g (50%). LCMS: RtH8=1.75 [M+H]+=354.8, 355.7,
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[O:20])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]>CO.O>[CH2:21]([C:5]1([CH2:4][C:3]([OH:23])=[O:2])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[O:20])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19])[CH3:22]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=O
Solvent: O
Solvent: CO
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3=O
Yield: 93.6 %

Procedure:
A solution of the product produced in step B (1.25 g, 3.9 mmol), K2 CO3 (3.5 g, 25.3 mmol) and 60 ml MeOH/H2O 1:1 was refluxed for 3 h. The methanol was evaporated, and the aqueous residue acidified to pH 1 using 6N HCl. The aqueous phase was extracted with EtOAc. The organic phase was washed with water, dried (MgSO4), and evaporated to produce a crude glass which was recrystallized from EtOAc-hexane to afford 1.1 g of the title compound as a solid, m. p. 198°-201° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>N1C=CC=CC=1>[CH:32]1([C:35]([NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=2[CH3:18])[N:5]=3)=[O:36])[CH2:34][CH2:33]1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(N)sc2n1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}-3-(trifluoromethyl)benzamide (200 mg, 0.450 mmol) in pyridine (5 mL) was added cyclopropanecarbonyl chloride (77.5 μL, 1.12 mmol), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was evaporated under reduced pressure, and a mixture of the obtained residue, methanol (3 mL) and 0.5N aqueous sodium hydroxide solution (3 mL) was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was precipitated with tetrahydrofuran to give the title compound (130 mg, 56%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[O:9][C:8](=O)[NH:7][C:6](=[O:12])[C:5]=2[CH2:4][CH2:3]1.[OH-].[NH4+:20]>>[CH3:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[NH:20][C:8](=[O:9])[NH:7][C:6](=[O:12])[C:5]=2[CH2:4][CH2:3]1
Reactant: [NH4+]
Reactant: CC1(c2ccccc2)CCc2c1oc(=O)[nH]c2=O
Agent: [OH-]
Product: CC1(c2ccccc2)CCc2c1[nH]c(=O)[nH]c2=O
Temperature: 80 °C
Yield: 70 %

Procedure:
To solid 7-methyl-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (420 mg, 1.727 mmol) was added concentrated Ammonium Hydroxide (4706 μL, 121 mmol) in a sealed tube. The tube was heated for 4 h at 80° C. Cooled to rt. Removed the solvent under a stream of N2. Loaded the residue onto Silica gel and eluted with an EtOAc/Hexane gradient to afford 7-methyl-7-phenyl-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (293 mg, 1.209 mmol, 70.0% yield). LC-MS (M+H)+=243.1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].O.Cl>CO>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(C=O)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1cc(F)c(CO)cc1F
Reaction time: 0.75 h

Procedure:
2,5-Difluoro-4-formylbenzonitrile (3.60 g, 0.0215 mol; see step (ii) above) was dissolved in 50 mL of methanol and cooled on an ice bath. Sodium borohydride (0.815 g, 0.0215 mol) was added in portions with stirring and the reaction was left for 45 min. Water (300 mL) was added and thereafter carefully 2M HCl was added until an acidic pH was attained. The mixture was extracted three times with diethyl ether, and the combined ethereal phase washed with water, dried (Na2SO4) and evaporated. The crude product crystallised soon and could be used without further purification. Yield: 3.1 g (85%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[OH:23]>>[OH:23][C:17]1[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[S:3][C:2]=1[Br:1])=[O:9]
Reactant: Cc1cc(C(=O)O)c(Br)s1
Reactant: Cc1cccc(N)c1O
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)Nc2cccc(C)c2O)c(Br)s1

Procedure:
In the same manner as in Starting Material Synthesis Example 67 and using 2-bromo-5-methyl-3-thiophenecarboxylic acid, thionyl chloride and 2-amino-6-methylphenol, N-(2-hydroxy-3-methylphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide is obtained.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]([C:12]2[CH:13]=[N:14][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[CH:16][CH:17]=2)O)=[CH:2]1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.O>[F:28][C:26]([F:27])([F:29])[C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][O:18][C:15]1[N:14]=[CH:13][C:12]([CH2:10][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[CH:17][CH:16]=1
Reactant: OC(c1ccc(OCc2cccc(C(F)(F)F)c2)nc1)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: FC(F)(F)c1cccc(COc2ccc(Cc3c[nH]c4ncccc34)cn2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(1H-Pyrrolo[2,3-b]pyridin-3-yl)-[6-(3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-methanol 74 was dissolved in 9:1 trifluoroacetic acid: triethylsilane. The reaction was stirred at room temperature for 15 hours. The reaction was diluted with water and extracted with ethyl acetate and concentrated. The crude material was purified by reverse phase HPLC to provide 3-[6-(3-Trifluoromethyl-benzyloxy)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine P-0057. MS (ESI) [M+H+]+=384.3.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[C:13]([Cl:19])=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[C:9](=[O:20])[NH:8][C:7]1=[O:21]>C1COCC1>[Cl:19][C:13]1[C:12]([C:10]2[C:9](=[O:20])[NH:8][C:7](=[O:21])[N:6]([CH2:5][CH2:4][CH:3]=[O:2])[CH:11]=2)=[CH:17][C:16]([F:18])=[CH:15][N:14]=1
Reactant: COC(CCn1cc(-c2cc(F)cnc2Cl)c(=O)[nH]c1=O)OC
Solvent: C1CCOC1
Product: O=CCCn1cc(-c2cc(F)cnc2Cl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
1-(3,3-Dimethoxy-propyl)-5-(2-chloro-5-fluoro-pyridin-3-yl)-1H-pyrimidine-2,4-dione (Prep72, 100 mg, 0.29 mmol) was dissolved in THF (3 ml) and 2N HClaq (0.5 ml) was added. The solution was stirred at room temperature for 1 hour. THF was evaporated under vacuum and the aqueous residue was lyophilized to give 90 mg of a yellow solid that was used in the next step without further purification (93% yield).
Reaction SMILES: Br.Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[CH3:15][C:16]1[CH:36]=[CH:35][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:24]=2)=[O:21])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[NH2:14][C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:17]3[C:16]([CH3:15])=[CH:36][CH:35]=[C:19]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:24]=4)=[O:21])[CH:18]=3)=[CH:4][CH:5]=2)[N:10]=1
Reactant: Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Agent: Br
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1-c1ccc(-c2csc(N)n2)cc1

Procedure:
Example 1 was prepared using 4-(4-bromophenyl)-2-thiazolamine monohydrobromide and 4-methyl-N-[3-(4-morpholinyl)phenyl]-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (Intermediate 5).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C:8]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[C:10]([O:11][CH3:12])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[CH:7]([C:8]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[C:10]([O:11][CH3:12])[CH:9]=1)[Br:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CC(=O)OC(C)(C)C)cc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(Br)C(=O)OC(C)(C)C)cc1OC

Procedure:
Heat 58.2 g of homoveratric acid tert.-butyl ester and 43.3 g of N-bromosuccinimide under reflux for 2 hours in 1.3 liters of carbon tetrachloride under irradiation with a 500-watt immersion lamp. After cooling, filter out the succinimide and concentrate the filtrate. Dissolve the resulting concentrate in 250 ml of diethyl ether and extract the produced solution by shaking it with water. Free the ether solution from the solvent under a vacuum to obtain 50 g (66% of theory) of the title compound as a non-distillable oil.