Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]1[C:16]([C:17]2[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:15]([F:24])[C:14]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:13]1)(=[O:11])=[O:10])#[N:2].C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.C(O)C>[ClH:41].[F:24][C:15]1[C:14]([CH2:25][NH:26][CH3:27])=[CH:13][N:12]([S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])(=[O:11])=[O:10])[C:16]=1[C:17]1[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccccc2C#N)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cn(S(=O)(=O)c2ccccc2C#N)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
tert-Butyl {[1-[(2-cyanophenyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (238 mg) was dissolved in ethyl acetate (1 mL) and ethanol (1 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol=3:1 to give the title compound as colorless crystals (yield 186 mg, 90%).
Reaction SMILES: OC1C=CC(C(=C2CCOCC2)C2C=CC(/[CH:15]=[CH:16]/[C:17]([O:19][C:20](C)(C)[CH3:21])=[O:18])=CC=2)=CC=1.Br[C:31]1[CH:36]=[CH:35][C:34]([C:37](=[C:45]2[CH2:50][C:49]([CH3:52])([CH3:51])[O:48][C:47]([CH3:54])([CH3:53])[CH2:46]2)[C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=[CH:33][CH:32]=1.C(OCC)(=O)C=C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[OH:44][C:41]1[CH:42]=[CH:43][C:38]([C:37](=[C:45]2[CH2:46][C:47]([CH3:53])([CH3:54])[O:48][C:49]([CH3:51])([CH3:52])[CH2:50]2)[C:34]2[CH:33]=[CH:32][C:31](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:36][CH:35]=2)=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCOCC2)c2ccc(O)cc2)cc1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)O1
Agent: [Pd+2]
Agent: C=CC(=O)OCC
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1
Yield: 69 %

Procedure:
Following the procedure described for compound 47, 4-[(4-bromophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenol (53) (0.152 g, 0.379 mmole), ethyl acrylate (0.125 mL, 1.15 mmole), P(o-tolyl)3 (0.0126 g, 0.041 mmole), Et3N (0.160 mL, 1.15 mmole), Pd(OAc)2 (0.0044 g, 0.020 mmole) and DMF (1.5 mL) afforded 0.110 g (69%) of compound 54 as a white solid. 1H NMR (CDCl3): δ 7.65 (d, J=16.0 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.03 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.4 Hz, 2H), 6.40 (d, J=16.0 Hz, 1H), 4.84 (s, 1H), 4.25 (q, J=7.1 Hz, 2H), 2.25 (s, 2H), 2.24 (s, 2H), 1.34 (t, J=7.1 Hz, 3H), 1.23 (s, 6H), 1.22 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14](O)[CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCN(CC)CCC(O)c1ccc(C2CCCCC2)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)CC=Cc1ccc(C2CCCCC2)c(Cl)c1
Yield: 86.3 %

Procedure:
81 g of the compound produced in step (b) were dissolved in 500 ml of toluene and, to the solution so produced, was added a solution of 76 g of p-toluenesulphonic acid in the minimum quantity of water. The mixture was heated under reflux for about 20 hours, continuously removing the water formed. At the end of this time, the solution was cooled and poured into 2 liters of water, to which ammonia was added until the solution became alkaline. The organic phase was then separated, washed with water and dried with sodium sulphate. 66 g (yield 86%) of 3-chloro-4-cyclohexyl-1-(3-diethylamino-propen-1-yl)-benzene (hereinafter referred to as compound 933 CB) were obtained in the form of a light brown oil. This was dissolved in ether and reacted with a sufficient quantity of hydrochloric acid dissolved in the same solvent to produce 67 g of the hydrochloride having a melting point of 161° C.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>>[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[N:17]1[CH2:18][CH2:19][N:20]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:21][CH2:22]1
Reactant: c1csc(N2CCNCC2)n1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc2sc(CN3CCN(c4nccs4)CC3)nc2c1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-(1,3-thiazol-2-yl)piperazine (219 mg, 1.3 mmol), and DIEA (340 μL, 2.1 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.71 (m, 4H) 3.46 (m, 4H) 4.06 (s, 2H) 6.86 (d, J=3.73 Hz, 1H) 7.17 (d, J=3.73 Hz, 1H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.33 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H). (ESI) m/z 318 (M+H)+.
Reaction SMILES: [C:1]([CH:3]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)#[N:2].[BH4-].[Na+].II>O1CCCC1>[NH2:2][CH2:1][CH:3]([C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:16]=1
Reactant: N#CC(c1ccc(OCc2ccccc2)cc1)C1(O)CCCCC1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCC(c1ccc(OCc2ccccc2)cc1)C1(O)CCCCC1
Temperature: 2.5 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
1-[Cyano(p-benzyloxyphenyl)methyl]cyclohexanol (50 g) was dissolved in tetrahydrofuran (300 ml) and sodium borohydride (30 g) was added at room temperature. Reaction mixture was cooled to 0-5° C. and charged with iodine solution drop wise (60 g) in 2.5 h. The reaction mass was stirred for 16 h at 25-30° C., filtered and washed with tetrahydrofuran (50 ml). The filtrate was cooled, DM water (500 ml) was added drop wise at 0-5° C. and tetrahydrofuran was distilled under reduced pressure at 40-45° C. to give residue. The residue was extracted with ethylacetate (250 ml×3), dried, concentrated, cooled and filtered to give 40 g (79.2%) of the 1-[2-amino-1-(4-benzyloxyphenyl)ethyl]-cyclohexanol.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1
Reactant: NS(=O)(=O)c1nc2ccc([N+](=O)[O-])cc2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2nc(S(N)(=O)=O)sc2c1
Yield: 87.2 %

Procedure:
A mixture of 6-nitrobenzothiazole-2-sulfonamide (3.0 g, 0.011 mol), 95% ethanol (290 ml), and 10% Pd on carbon (3.0 g) was hydrogenated at an initial pressure of 50 psig for 36 hours during which time the theoretical amount of hydrogen was consumed. The reduction mixture was vacuum filtered through a pad of Celite contained in a Buchner funnel and the volatiles removed under reduced pressure. The resulting product was purified by dissolving in aqueous 10% sodium carbonate (25 ml), filtering and adjusting the pH of the filtrate to 6 with glacial acetic acid. The precipitated product was collected by vacuum filtration in a Buchner funnel and dried under reduced pressure at 78° C. in an Abderhalden to give 2.2 g (82.9% yield) of 6-aminobenzothiazole-2-sulfonamide: m.p. 221°-222° C., Anal. (C7H7N3O2S2) CHN.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([CH3:10])[CH:4]=1.CN(C)CC.[C:16](OC(=O)C)(=[O:18])[CH3:17]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:16](=[O:18])[CH3:17])=[C:5]([CH3:10])[CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)c(C)c1
Agent: CCN(C)C
Solvent: C1CCOC1
Product: COc1ccc(NC(C)=O)c(C)c1
Temperature: 0 °C
Yield: 74.4 %

Procedure:
41.1 g (0.3 mol) of 4-methoxy-2-methylphenylamine and 37 g (0.5 mol) of dimethylethylamine were dissolved in 50 ml of tetrahydrofuran, and 35.7 g (0.35 mol) of acetic anhydride were added while stirring. The solution heated to boiling during this. It was stirred at room temperature for 1 hour and cooled to 0° C. The resulting precipitate was filtered off with suction and washed several times with a little cold tetrahydrofuran and dried. 40 g (75%) of colorless crystals of the desired product were obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][C@@H:14]([OH:17])[C@H:9]1[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:18]I>CN(C=O)C>[C:1]([N:8]1[CH2:16][CH2:15][C@@H:14]([O:17][CH3:18])[C@H:9]1[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CI
Reactant: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1[C@H](OC)CCN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
To a solution of 500 mg (2.05 mmol) of N-BOC-3(R)-hydroxy-(L)-proline, methyl ester and 1.7 g (12.2 mmol) of MeI in 10 mL of DMF was added 473 mg (2.05 mmol) of Ag2O. The mixture was stirred for 18 h and was then filtered through a pad of celite and concentrated. The crude residue was dissolved in EtOAc and washed with 1M HCl (2×10 mL), saturated NaHCO3 (2×10 mL), brine (1×10 mL), dried anhydrous MgSO4, and concentrated to give 500 mg of N-BOC-3(R)-methoxy-(L)-proline, methyl ester as a light yellow oil which was used without further purification.
Reaction SMILES: [O:1]1[CH2:29][C@:2]1([CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Cl[C:32]1[NH:33][CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[N:36]=1.C([O-])(=O)C.[Na+].C(OC(C)(C)C)(=O)C.[OH-].[Na+]>C(OCC)(=O)C.O.CO>[CH3:30][C@@:2]1([CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([N:11]3[CH2:16][CH2:15][CH:14]([O:17][C:18]4[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:28])[F:27])=[CH:22][CH:23]=4)[CH2:13][CH2:12]3)=[CH:9][CH:10]=2)[O:1][C:32]2=[N:36][C:35]([N+:37]([O-:39])=[O:38])=[CH:34][N:33]2[CH2:29]1
Reactant: C[C@]1(COc2ccc(N3CCC(Oc4ccc(OC(F)(F)F)cc4)CC3)cc2)CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)(C)C
Product: C[C@]1(COc2ccc(N3CCC(Oc4ccc(OC(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 73.7 %

Procedure:
(R)-1-[4-(2,3-epoxy-2-methylpropoxy)phenyl]-4-[4-(trifluoromethoxy)phenoxy]piperidine (10.0 g, 23.6 mmol, optical purity of 94.3% ee), 2-chloro-4-nitroimidazole (4.0 g, 27.2 mmol), sodium acetate (0.4 g, 4.9 mmol), and t-butyl acetate (10 ml) were mixed and stirred at 100° C. for 3.5 hours. Methanol (70 ml) was added to the reaction mixture, and then a 25% sodium hydroxide aqueous solution (6.3 g, 39.4 mmol) was added thereto dropwise while cooling with ice. The resulting mixture was stirred at 0° C. for 1.5 hours, and further stirred at approximately room temperature for 40 minutes. Water (15 ml) and ethyl acetate (5 ml) were added thereto, and the mixture was stirred at 45 to 55° C. for 1 hour. The mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The precipitated crystals were subsequently washed with methanol (30 ml) and water (40 ml). Methanol (100 ml) was added to the resulting crystals, followed by stirring under reflux for 30 minutes. The mixture was cooled to room temperature. The crystals were then collected by filtration and washed with methanol (30 ml). The resulting crystals were dried under reduced pressure, obtaining 9.3 g of the objective product (yield: 73%).
Reaction SMILES: [O:1]([C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][S:20](O)(=[O:22])=[O:21]>>[Cl:19][S:20]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:9]=2)=[CH:7][CH:6]=1)(=[O:22])=[O:21]
Reactant: CCOC(=O)c1ccc(Oc2ccccc2)nc1
Reactant: O=S(=O)(O)Cl
Product: CCOC(=O)c1ccc(Oc2ccc(S(=O)(=O)Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To chlorosulfonic acid (20 mL) was dropped ethyl 6-phenoxynicotinate (5.6 g) on ice bath, and the reaction mixture was stirred for 15 minutes at room temperature, and 3 hours at 60° C. To reaction mixture was added ice, and extracted with tert-butyl methyl ether. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (7.5 g) having the following physical data.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[N:7]=1)=O)C.C1(C)C=CC=CC=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1.[H-].C([Al+]CC(C)C)C(C)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH:9]=[CH:10][C:6]([CH2:4][OH:3])=[N:7]2)=[N:12][CH:13]=1
Reactant: CCOC(=O)c1ccn(-c2ccc(F)cn2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1ccn(-c2ccc(F)cn2)n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl-1-(5-fluoropyridin-2-yl)-1H-pyrazole-3-carboxylate obtained in Reference Example 27 (10.0 g, 42.5 mmol) in THF (50 mL), diisobutylaluminium hydride (a 1.01 mol/L toluene solution, 105.2 mL, 106.3 mmol) was added under cooling at −78° C., and after dropwise addition the resulting mixture was heated to 0° C. and stirred for 2 hours. An aqueous solution of potassium sodium tartrate (Rochelle salt) was added to the reaction mixture under ice-cooling, followed by extraction with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over MgSO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure to obtain the title compound (8.0 g) (colorless solid).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[CH:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[O:53]1[CH2:58][CH2:57][CH:56]([CH2:59][CH:60]=[O:61])[CH2:55][CH2:54]1>O1CCCC1>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([CH:60]([OH:61])[CH2:59][CH:56]3[CH2:57][CH2:58][O:53][CH2:54][CH2:55]3)[N:14]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[N:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CCC1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)Nc1cnc2c(c1)cc(C(O)CC1CCOCC1)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 32.9 %

Procedure:
To a suspension of (1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-carbamic acid tert-butyl ester (prepared as in Example 107, 3.4 g, 9.1 mmol) in dry tetrahydrofuran (120 mL) at −78° C. was added freshly prepared lithium diisopropylamide [prepared by adding 1.6 M n-butyllithium in n-hexane (17.1 mL, 27.3 mmol) to a 0° C. solution of diisopropylamine (2.76 g, 27.3 mmol) in dry tetrahydrofuran (20 mL)] dropwise. The mixture was stirred at −78° C. for 5 min and then treated with (tetrahydro-pyran-4-yl)-acetaldehyde (2.91 g, 22.75 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 75% ethyl acetate/hexanes) afforded {1-benzenesulfonyl-2-[1-hydroxy-2-(tetrahydro-pyran-4-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-carbamic acid tert-butyl ester (1.5 g, 33%) as a white solid: LC/MS m/e calcd for C25H31N3O6S [M+H]+ 502.61, observed 502.2.
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[O:23][CH2:22][CH2:21][C:20]2=O.O>CCCCCC.O1CCCC1>[S:4]1[CH2:5][CH2:6][CH2:7][S:8][C:3]1=[C:20]1[C:19]2[CH:18]=[C:17]([F:16])[CH:26]=[CH:25][C:24]=2[O:23][CH2:22][CH2:21]1
Reactant: O=C1CCOc2ccc(F)cc21
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Fc1ccc2c(c1)C(=C1SCCCS1)CCO2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
28.8 g of 2-trimethylsilyl-1,3-dithiane were dissolved in 290 ml of peroxide-free tetrahydrofuran and the solution was treated dropwise at -60° C. with 93 ml of a 1.6M solution of n-butyl lithium in hexane. The mixture was left to warm to 0° C. within 3 hours and subsequently again cooled to -60° C. A solution of 24.87 g of 6-fluoro-4-chromanone in 150 ml of tetrahydrofuran was subsequently slowly added dropwise and the mixture was left to warm slowly from -60° C. to room temperature while stirring overnight. The mixture was subsequently poured into 2.5 l of water and extracted with four portions of ethyl acetate. The organic extracts were washed with saturated sodium chloride solution and dried with sodium sulfate The concentrated extract was decolorized with active carbon in a mixture of ether and low-boiling petroleum ether (1:1) and crystallized from the same mixture in the cold. After two recrystallizations, the combined mother liquors were chromatographed on a silica gel 60 column [hexane/ethyl acetate (9:1)]. The product-containing fractions were concentrated and the residue was recrystallized. There was obtained 4-m-dithian-2-ylidene-6-fluoro-2,3-dihydro-4H-1-benzopyran of melting point 47°-49° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[Cl:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Product: O=C(O)c1ccc(OCc2ccccc2)c(Cl)c1
Yield: 55.5 %

Procedure:
Using 3-chloro-4-hydroxybenzoic acid 1/2 hydrate (25 g, 0.14 mole) and benzyl chloride (52.3 g, 0.41 mole), the reaction was carried out in the same manner as described in Synthesis Example 1, (1) to give 20.4 g of 4-benzyloxy-3-chlorobenzoic acid as white crystals having a m.p. of 211°-213° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17](O)[C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:19]=3)=[CH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)=[CH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(C(=O)Nc3ccc(Cl)cc3)nc2)c2cccnc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(Nc1ccc(Cl)cc1)c1ccc(Cc2c[nH]c3ncccc23)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To 5-[Hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridine-2-carboxylic acid (4-chloro-phenyl)-amide (71, 100.0 mg, 0.19 mmol) in acetonitrile (10.0 mL) were added trifluoroacetic acid (0.20 mL, 2.6 mmol) and triethylsilane (0.40 mL, 2.5 mmol). The reaction was stirred at 80° C. for 2 hours. The reaction was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a yellow solid compound (P-0076, 5.5 mg, 8.1%). MS (ESI) [M−H+]−=361.1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1([CH2:17][CH2:18][CH:19]([C:24](OC)=[O:25])[C:20](OC)=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1([CH2:17][CH2:18][CH:19]([CH2:20][OH:21])[CH2:24][OH:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(CCC1(CCOCc2ccccc2)CCCCC1)C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCC(CO)CCC1(CCOCc2ccccc2)CCCCC1
Reaction time: 2 h
Yield: 36.5 %

Procedure:
To a solution of dimethyl 2-[2-[1-(2-benzyloxyethyl)-cyclohexyl]ethyl]malonate (1.03 g) in diethyl ether (40 mL) was added lithium aluminum hydride (207 mg) under ice cooling. After stirring the solution under ice cooling for 2 hours, water (0.2 mL) and a 15% aqueous sodium hydroxide solution (0.2 mL) were successively added to the solution. The solution was stirred at room temperature for 15 minutes, water (0.6 mL) was added thereto, and it was stirred for additional 30 minutes. The solution was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=2:3) to give the title compound (320 mg)
Reaction SMILES: C(O)(=O)C.[N:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C:8](O)=[CH:7][CH:6]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][N:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: Oc1ccnc2cccnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: Clc1ccnc2cccnc12
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1,5-naphthyridin-4-ol acetic acid salt (D-6) (800 mg, 3.0 mmol, 1.0 eq) in phosphoroxychloride (5 mL, 53 mol, 17.6 eq) is stirred at 110° C. for 30 min, cooled to RT and then concentrated in vacuo. The residue is poured into ice-water (50 mL) and neutralized with saturated aqueous NaHCO3 solution to adjust the pH to 8-9 while keeping the temperature below 5° C. The mixture is stirred at RT for 30 min and then extracted with DCM (3×40 mL). The combined organic layers are washed with brine, dried over Na3SO4 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash column chromatography on silica gel (1-2% MeOH-DCM) to afford the product, 4-chloro-1,5-naphthyridine (D-7).