Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][NH:6][CH:7]=[O:8])[CH3:2].CN1C=CN=C1.[C:16](Cl)(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(N(CCCC)CCCC)CCC>[Ti](Cl)(Cl)(Cl)Cl.O.C(Cl)Cl>[CH:7]([NH:6][CH:5]([C:16](=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:4]([O:3][CH2:1][CH3:2])=[O:9])=[O:8]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)CNC=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: CCCCCCCCCCCCCCCC(=O)C(NC=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 0.1 %

Procedure:
A methylene chloride solution (100 ml) of N-formylglycine ethyl ester (1.31 g, 10 mmol) and N-methylimidazole (985.4 mg, 12 mmol) was cooled to −45° C., and a methylene chloride solution (10 ml) of palmitoyl chloride (2.85 mg, 10 mmol) was added thereto in nitrogen atmosphere. After the mixture was stirred for 20 minutes at the same temperature, a methylene chloride solution (10 ml) of titanium tetrachloride (6.78 mg, 35 mmol) and a methylene chloride solution (10 ml) of tributylamine (7.42 g, 40 mmol) were added thereto. The resulting mixture was stirred for 3 hours at −45° C. After 100 ml of water was added thereto, and the mixture was heated to room temperature, and the organic layer was separated. Further, the water layer was extracted twice with methylene chloride. The organic layers were combined and dried with magnesium sulfate. After the solvent was removed in reduced pressure, the obtained crude product was purified by silica gel chromatography (Kieselgel 60 manufactured by Merck, solely ethyl acetate) to obtain the title compound (3.15 mg, yield: 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23][CH3:24])=[O:22])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:25].[CH3:26][O:27][C:28]1[CH:40]=[CH:39][C:31]2[N:32]=[C:33](S(C)(=O)=O)[S:34][C:30]=2[CH:29]=1.Cl.[CH2:42](O)[CH2:43][CH2:44]C>>[F:25][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23][CH2:24][CH2:42][CH2:43][CH3:44])=[O:22])=[O:15])=[CH:12][CH:13]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:33]1[S:34][C:30]2[CH:29]=[C:28]([O:27][CH3:26])[CH:40]=[CH:39][C:31]=2[N:32]=1
Reactant: COc1ccc2nc(S(C)(=O)=O)sc2c1
Reactant: CCCCO
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(N)c(F)c2)cc1
Agent: Cl
Product: CCCCOC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC)cc4s3)c(F)c2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Methyl (1R,2R)-2-[(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)carbonyl]cyclo-pentanecarboxylate (462 mg, 1.35 mmol) was dissolved in n-butanol (15 mL), and 6-methoxy-2-(methylsulfonyl)-1,3-benzothiazole (162 mg, 0.8 mmol) and 4 M aqueous HCl (1.5 mL) were added. The mixture was heated at 90° C. for 5 h. An additional portion of 6-methoxy-2-(methylsulfonyl)-1,3-benzothiazole (162 mg, 0.8 mmol) was added, and the mixture was stirred overnight at 90° C. Solvent was then removed by rotary evaporation, and the residue was purified by flash chromatography (Biotage Flash 40 M, 3:1 hexane/EtOAc) to afford butyl (1R,2R)-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylate (480 mg, 65%). LC-MS ret. time 4.36 min, m/z 547.3 (MH+); 1H NMR (300 MHz, CDCl3) δ 0.85 (t, 3H), 1.25–1.35 (m, 2H), 1.40–1.58 (m, 2H), 1.74–1.84 (m, 3H), 1.91–1.96 (m, 1H), 2.11-2.20 (m, 2H), 3.40–3.46 (m, 1H), 3.84 (s, 3H), 4.03 (t, 2H), 6.81–6.87 (m, 1H), 6.98 (dd, 1H), 7.18 (d, 1H), 7.40–7.52 (m, 2H), 7.64 (d, 2H), 8.14 (d, 2H), 8.42 (t, 1H).
Reaction SMILES: ClC1N=C(Cl)C2CCN(CC3C=CC(OC)=CC=3)C=2N=1.[CH:21]([C:33]([O:35]CC)=O)([C:28]([O:30]CC)=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH2:38][C:39]([NH2:41])=[O:40]>>[OH:40][C:39]1[N:41]=[C:28]([OH:30])[C:21]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:33]([OH:35])[N:38]=1
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Reactant: NC(N)=O
Agent: COc1ccc(CN2CCc3c(Cl)nc(Cl)nc32)cc1
Product: CCOC(=O)Cc1c(O)nc(O)nc1O
Yield: 52.4 %

Procedure:
According to General Protocol I, 2,4-dichloro-7-(4-methoxybenzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was prepared from triethyl ethane-1,1,2-tricarboxylate (10 g, 41 mmol) and urea (2.44 g, 41 mmol), and isolated as a pale-yellow solid (4.6 g, yield 35%).
Reaction SMILES: [C:1]([S-:4])(=[S:3])[CH3:2].[Na+].Cl[CH:7]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[CH:17][CH:16]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[C:1]([S:4][CH:7]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[CH:17][CH:16]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[S:3])[CH3:2]
Reactant: CCOC(=O)C(Cl)CCc1ccc(-c2ccccc2Cl)cc1
Reactant: CC(=S)[S-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccc(-c2ccccc2Cl)cc1)SC(C)=S

Procedure:
A mixture of 0.2 moles of sodium dithioacetate and 0.12 moles of ethyl α-chloro-γ-(2'-chloro-4-biphenylyl)butyrate in 300 ml. of absolute ethanol is stirred at room temperature for 15 hours. The reaction mixture is filtered, washed with absolute ethanol and evaporated to dryness in vacuo. The residue is treated with ether, filtered and evaporated to obtain ethyl α-thioacetylthio-γ-(2'-chloro-4-biphenylyl)butyrate.
Reaction SMILES: NC[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH2:9]([N:11](CC)CC)C.Cl.[N:17]1([CH2:23][CH2:24][C:25]2[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]3=[C:27]([C:34](Cl)=[O:35])[N:26]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(Cl)Cl>[N:4]1[CH:3]=[CH:8][CH:7]=[C:6]([CH2:9][NH:11][C:34]([C:27]2[N:26]=[C:25]([CH2:24][CH2:23][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=23)=[O:35])[CH:5]=1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Reactant: CCN(CC)CC
Reactant: NCc1ccccn1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCc1cccnc1)c1nc(CCN2CCOCC2)n2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
To a solution of 2-(aminomethyl)pyridine (0.052 g, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (52 mg, 32%). 1H NMR (DMSO-d6) δ 8.50 (2H), 8.35 (1H), 8.05 (1H), 7.54 (1H), 7.32 (1H), 7.25 (1H), 78.08 (1H), 6.85 (1H), 4.59 (2H), 3.57 (4H), 3.20 (2H), 2.80 (2H), 2.43 (4H); m/z (M+H)=366.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=2[O:2][CH3:1])=[O:20])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(N)c(OC)c1
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(OC)c1
Yield: 83.2 %

Procedure:
Using 2,4-dimethoxyaniline (2.53 g, 16.0 mmol) and 4-nitrobenzoic acid (2.50 g, 14.8 mmol), the procedure of Reference Example 16 was repeated to obtain 3.72 g (91.3%) of the title compound in the form of yellow needle crystals.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=2[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:4]=1)=O.[NH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]1.C([BH3-])#N.[Na+]>CO.CC(O)=O>[C:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][CH:25]([CH2:24][NH:23][CH2:1][C:3]2[C:11]3[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=3[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:4]=2)[CH2:26]1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)c1ccnc2c1c(C=O)cn2C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccnc2c1c(CNCC1CCN(C(=O)OC(C)(C)C)C1)cn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of 1-tert-butyl 4-methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (91 mg, 0.3 mmol) in MeOH (2 mL) was added AcOH (5 drops) and tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (90 mg, 0.45 mmol). After stirring for 60 min at rt, the reaction mixture was cooled to 0° C. Sodium cyanoborohydride (57 mg, 0.9 mmol) was added, and the reaction mixture was stirred for an additional 3 h at rt. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers washed with saturated NaHCO3 and with brine, dried over Na2SO4, and concentrated in vacuo to give 125 mg of crude 1-tert-butyl 4-methyl 3-(((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate as a colorless oil which was used without further purification. [M+H] found 489.40.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][B:6]1[O:10][C:9]([CH3:12])([CH3:11])[C:8]([CH3:14])([CH3:13])[O:7]1.[I-:15].[Na+]>CC(C)=O>[I:15][CH2:2][CH2:3][CH2:4][CH2:5][B:6]1[O:10][C:9]([CH3:12])([CH3:11])[C:8]([CH3:14])([CH3:13])[O:7]1
Reactant: CC1(C)OB(CCCCBr)OC1(C)C
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)OB(CCCCI)OC1(C)C
Temperature: 25 °C
Yield: 98.1 %

Procedure:
While under a nitrogen atmosphere, a solution of 2-(4-bromobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (46.2 g, 0.176 mol, 1.0 equiv) and sodium iodide (52.8 g, 0.35 mol, 2 equiv) in acetone (176 mL, 1.0 M) was heated to 50° C. for 4 h. After cooling to room temperature the solution was concentrated under reduced pressure. The resulting residue was diluted with heptane (200 mL) and filtered through a short pad of silica gel (300 g) wetted with heptane. After eluting with a solution of 10% ethyl acetate in heptane (500 mL) the filtrate was concentrated to give 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a colorless oil (53.5 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 3.18 (t, J=7.2 Hz, 2H), 1.90-1.78 (m, 2H), 1.58-1.44 (m, 2H), 1.24 (s, 12H), 0.79 (t, J=7.5 Hz, 2H); ESI-LCMS m/z calcd for C10H20BIO2: expected 310.1. found 311.1 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:6]([CH2:14][CH3:15])[S:7](=[O:13])(=[O:12])[N:8]=[C:9]([CH3:11])[N:10]=1>O1CCCC1>[CH2:14]([N:6]1[C:5]([O:2][CH3:1])=[N:10][C:9]([CH3:11])=[N:8][S:7]1(=[O:13])=[O:12])[CH3:15]
Reactant: C[O-]
Reactant: CCN1C(Cl)=NC(C)=NS1(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1C(OC)=NC(C)=NS1(=O)=O

Procedure:
19.8 parts of 30 percent strength sodium methylate were added to a solution of 20.95 parts of 3-chloro-2-ethyl-5-methyl-2H-1,2,4,6-thiatriazine-1,1-dioxide in 120 parts of tetrahydrofuran at 20°-25° C. in the course of 10 minutes, while stirring. The reaction mixture was stirred for three hours at 25° C. and then concentrated, the residue was taken up in ethyl acetate, and the solution was extracted twice with dilute sodium carbonate solution. The organic phase was separated off, dried and chromatographed over silica gel. The solution was then concentrated under reduced pressure, giving 14.5 parts of 2-ethyl-5-methyl-3-methoxy-2H-1,2,4,6-thiatriazine-1,1-dioxide of melting point 50°-53° 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][C:11]=2[O:16][CH3:17])=[CH:6][CH:5]=[CH:4][N:3]=1.S(OC(CC#C)C(=O)C)([C:21]1[CH:27]=[CH:26][C:24](C)=[CH:23][CH:22]=1)(=O)=O>C(O)C>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]2[N:3]([C:21]([CH2:22][C:23]#[CH:24])=[C:27]([CH3:26])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccccc1COc1cccnc1N
Reactant: C#CCC(OS(=O)(=O)c1ccc(C)cc1)C(C)=O
Solvent: CCO
Product: C#CCc1c(C)nc2c(OCc3ccccc3OC)cccn12
Yield: 32 %

Procedure:
A solution of 2-amino-3-(2-methoxybenzyloxy)pyridine (3.50 g) and 3-tosyloxy-5-hexyn-2-one (4.86 g) in ethanol (30 ml) was stirred and refluxed for 24 hours and then evaporated in vacuo. To the residue was added an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The oily residue was purified by column chromatography on silica gel (50 g) using chloroform as an eluent to give a solid, which was recrystallized from a mixture of ethyl acetate and n-hexane to give 8-(2-methoxybenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (1.49 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH2:4][NH2:5].[NH2:14][C:15](N)=[O:16].Cl>O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:3]=1[CH2:4][NH:5][C:15]([NH2:14])=[O:16]
Reactant: NC(N)=O
Reactant: NCc1c(F)cccc1C(F)(F)F
Agent: Cl
Solvent: O
Product: NC(=O)NCc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To 2-fluoro-6-(trifluoromethyl)benzylamine 4a (51.5 g, 0.267 mmol) in a flask, urea (64 g, 1.07 mmol), HCl (conc., 30.9 mmol, 0.374 mmol) and water (111 mL) were added. The mixture was refluxed for 6 hours. The mixture was cooled to ambient temperature, further cooled with ice and filtered to give a yellow solid. Recrystallization with 400 mL of EtOAc gave 4b as a white solid (46.2 g, 0.196 mmol). MS (CI) m/z 237.0 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:7]2[C:12]([C:13]3[N:18]=[CH:17][N:16]=[C:15]([O:19][C:20]4[C:25]5[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:24]=5[CH:23]=[CH:22][CH:21]=4)[CH:14]=3)=[CH:11][CH:10]=[C:9]([C:33]([F:36])([F:35])[F:34])[N:8]=2)[CH2:2]1.[CH3:37][C:38]([CH3:40])=O>>[CH:38]([N:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:7]2[C:12]([C:13]3[N:18]=[CH:17][N:16]=[C:15]([O:19][C:20]4[C:25]5[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:24]=5[CH:23]=[CH:22][CH:21]=4)[CH:14]=3)=[CH:11][CH:10]=[C:9]([C:33]([F:36])([F:34])[F:35])[N:8]=2)[CH2:2]1)([CH3:40])[CH3:37]
Reactant: CC(C)=O
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4NC4CCNC4)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4NC4CCN(C(C)C)C4)ncn3)cccc2s1

Procedure:
N-(4-(6-(2-(Pyrrolidin-3-ylamino)-6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide, Example 3(c), (30 mg, 0.06 mmol) was reacted with acetone (1 mL, 136 mmol, Aldrich) under the conditions of Example 3(d) to give the title compound as a yellow solid. MS (ESI, pos. ion.) m/z: 558 (M+1). Mp: 140-141° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([S:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([S:18]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:35])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)CSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
tert-Butyl {[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]thio}acetate (0.34 g, 1.00 mmol) was dissolved in chloroform (20 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.23 g, 1.00 mmol) in chloroform (10 ml) was added thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.30 g, 75%) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[CH:23]([OH:28])[CH2:24][CH2:25][CH2:26][CH3:27].C1CCN2C(=NCCC2)CC1.[Cl-].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCC(O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC(=O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 60.7 %

Procedure:
Under an argon atmosphere, 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-1-pentanol (compound 10) (45.7 mg) was dissolved in methylene chloride (2 ml) to prepare a solution. 1,8-Diazabicyclo[5.4.0]-7-undecene (37 mg) was then added to the solution, and the mixture was cooled to 0° C. N-Tert-butylbenzenesulfineimidoyl chloride (43 mg) was dissolved in methylene chloride to prepare a solution, the solution was added thereto, and the mixture was stirred at 0° C. for 40 min. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (27.6 mg, yield 61%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)=[CH:9][CH:8]=1.CN(C)[CH:22]=[O:23]>O1CCCC1>[CH3:18][C:16]1([CH3:19])[CH2:15][O:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH:22]=[O:23])=[CH:8][CH:9]=2)=[N:17]1
Reactant: CC1(C)COC(c2ccc(Br)cc2)=N1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccc(C=O)cc2)=N1
Temperature: 25 °C

Procedure:
n-Butyl lithium (9.44 ml, 2.5N solution in hexanes) was added to a solution of 2-(4-bromophenyl)-4,5-dihydro-4,4-dimethyl-oxazole [A. I. Meyers et al., J.O.C., 1974, 39, 2787] (5 g) in tetrahydrofuran (80 ml) at −78° C. The reddish solution was stirred at −78° C. for 15 minutes before dimethylformamide (2.3 g) was added dropwise. The resulting deep red solution was allowed to warm to room temperature, quenched with ammonium chloride solution and extracted into ether. The combined extracts were washed with brine, dried (sodium sulphate) and evaporated to dryness in vacuo. The residue was purified by column chromatography (30% ethyl acetate/hexane) to afford the title compound as a colourless liquid, 3.01 g.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=1[NH:10][C:11]([NH:13]C(=O)C1C=CC=CC=1)=[S:12])#[N:2].[OH-].[Na+]>CCO>[NH2:2][C:1]1[C:3]2[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=2[NH:10][C:11](=[S:12])[N:13]=1
Reactant: Cc1sc(NC(=S)NC(=O)c2ccccc2)c(C#N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc2[nH]c(=S)nc(N)c2c1C
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A solution of N-(3-cyano-4,5-dimethylthiophen-2-ylcarbamothioyl)benzamide (example 1a) (1.90 g, 6.03 mmol) and NaOH (2 N, 8.3 mL) in EtOH (25 mL) was stirred at 100° C. under nitrogen for half an hour. After cooling to room temperature, the clear reaction solution was filtered and the filtrate was carefully neutralized with 10% AcOH with vigorous stirring at 0° C. The resultant precipitate was collected by filtration, washed with warm water and then 20% EtOH in water to give the final product 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-thione (1.11 g, 87%) as an off-white solid. M.p.: >260° C. 1H NMR (400 MHz, DMSO-d6) δ 2.25 (s, 3H), 2.26 (s, 3H). MS 212 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](O)=[O:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36](=[O:37])[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=4)[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1ccccn1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccccn2)c1

Procedure:
Prepared as described in Example 83 using (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 28 mg, 0.07 mmol) and picolinic acid (9 mg, 0.07 mmol). Yield 14 mg (39%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:14]1[C:15](O)=[CH:16][C:17]3[O:21][CH2:20][CH2:19][C:18]=3[CH:22]=1)([CH2:12][OH:13])[C:5](=[O:11])[NH:6]2.C(P(CCCC)CCCC)CCC.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:12][O:13][C:15]3[CH:16]=[C:17]4[C:18](=[CH:22][C:14]1=3)[CH2:19][CH2:20][O:21]4)[C:5](=[O:11])[NH:6]2
Reactant: O=C1Nc2cccc(Br)c2C1(CO)c1cc2c(cc1O)OCC2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Product: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Reaction time: 2 h
Yield: 37.2 %

Procedure:
To a solution of 4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (1.80 g, 4.80 mmol) in anhydrous ethyl acetate (50 mL) was added tributylphosphine (1.26 g, 1.54 mL, 6.24 mmol) at 0° C. under nitrogen. A solution of di-tert-butyl azodicarboxylate (1.44 g, 6.24 mmol) in anhydrous ethyl acetate (15.0 mL) was added over 10 min. The reaction solution was stirred for 2 h, and then quenched with saturated ammonium chloride solution (30.0 mL). After the aqueous layer was separated, the organic layer was washed with 10% aqueous HCl solution (2×25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate-hexane (70%) to obtain a solid which was triturated with diethyl ether to give the title compound (0.64 g, 37%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.18-7.13 (m, 1H), 7.08 (d, 1H), 6.90 (d, 1H), 6.47 (s, 1H), 6.30 (s, 1H), 4.80 (ABq, 2H), 4.46 (t, 2H), 2.92 (t, 2H); 13C NMR (75 MHz, DMSO-d6) δ 178.7, 162.2, 161.7, 144.5, 131.1, 131.0, 126.1, 119.8, 119.2, 119.1, 118.3, 109.7, 92.4, 77.6, 72.5, 59.2, 28.8; MS (ES−) m/z 358.4 (M−1), 356.3 (M−1).
Reaction SMILES: C([O:5][C:6]([C:8]1[NH:17][C:16]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:11](=[O:25])[C:10]=2[C:9]=1[CH3:26])=O)(C)(C)C.FC(F)(F)C(O)=O.C(OC(OCC)OCC)C>>[CH2:23]([N:20]([CH2:21][CH3:22])[CH2:19][CH2:18][N:12]1[CH2:13][CH2:14][CH2:15][C:16]2[NH:17][C:8]([CH:6]=[O:5])=[C:9]([CH3:26])[C:10]=2[C:11]1=[O:25])[CH3:24]
Reactant: CCN(CC)CCN1CCCc2[nH]c(C(=O)OC(C)(C)C)c(C)c2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(OCC)OCC
Product: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Temperature: 40 °C
Yield: 81.6 %

Procedure:
5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxylic acid tert-butyl ester 1i (0.413 g, 1.14 mmol) was dissolved in trifluoroacetic acid (1.5 ml, 20 mmol) under stirring, heated to 40° C. for 5 minutes in an oil bath under an argon atmosphere, and cooled down to −5° C. in an ice-salt bath under stirring, and added with triethoxy methane (0.34 ml, 1.7 mmol) and stirred for 2 minutes. Then the ice-salt bath was removed, and the reaction mixture was allowed to warm up to room temperature and stirred for another about 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with 3 ml of ice water and 10 ml of dichloromethane, adjusted to pH 11 with aqueous sodium hydroxide solution (2 mol/L) and extracted with dichloromethane (10 ml×3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain yellow oil. The residue was purified by silica gel column chromatography to obtain the title compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j (0.271 g, yield 55%) as a light brown oil.