Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:27])[C:18]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[N+:15]([O-:6])[CH:16]=[C:17]([Cl:27])[C:18]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1
Reactant: Clc1cncc(Cl)c1COC1CCCCO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc(Cl)c(COC2CCCCO2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Chloroperoxybenzoic acid (mCPBA, 1.32 g, 7.66 mmol) was added to a stirred solution of 3,5-Dichloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine (200 mg, 0.766 mmol) in DCM (5 mL). After stirring for 3 h at RT the solvent was removed in vacuo and the residue was partitioned between DCM (50 mL) and 2 N NaOH solution (50 mL). After extraction of the organic layer with water (50 mL) the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 278.0 [M+H+].
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C@@H:30]2[CH2:34][CH2:33][CH2:32][NH:31]2)[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20]4[C@H:27]([CH3:28])[CH2:26][C@@H:25]([OH:29])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1.[CH:35](N(C(C)C)CC)([CH3:37])[CH3:36].CC(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C@@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[CH:35]([CH3:37])[CH3:36])[C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[C:20]4[C@H:27]([CH3:28])[CH2:26][C@@H:25]([OH:29])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:17][CH2:18]2)=[O:12])=[CH:6][CH:5]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCCN4)CC3)c21
Reactant: CCN(C(C)C)C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(C)=O
Product: CC(C)N1CCC[C@H]1[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone di-hydrochloride (0.074 g, 0.1399 mmol) was dissolved in 1,2-dichloroethane (0.50 mL) and treated with diisopropylethylamine (0.04874 mL, 0.2798 mmol), propan-2-one (0.03082 mL, 0.4197 mmol) and sodium triacetoxyborohydride (0.1483 g, 0.6996 mmol). The mixture was stirred at 40° C. for 18 hours. The reaction was quenched with 3N HCl and stirred for 30 minutes. The reaction was neutralized to a pH of about 8 to about 8.5 with slow addition of saturated NaHCO3. The reaction was diluted with methylene chloride and separated. The aqueous layer was washed with methylene chloride (2×), and the combined organics were dried over Na2SO4 and concentrated in vacuo. The material was subjected to chromatography on SiO2 eluting with 5% MeOH/1% NR4OH/methylene chloride. The recovered free base (51.2 mg) was dissolved in dioxane (1 mL) and treated with 4N HCl in dioxane (1.5 mL). After stirring for 5 minutes, the mixture was concentrated in vacuo. The mixture was re-dissolved and re-concentrated in vacuo three times from MeOH. The mixture was re-dissolved in MeOH (0.5 mL+0.25 mL wash) and added dropwise to stirred Et2O (30 mL). The resultant solid was stirred for 30 minutes. The solid was then filtered, washed with Et2O and dried under a blanket of nitrogen. (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-1-isopropylpyrrolidin-2-yl)ethanone dihydrochloride was recovered as a solid (0.026 g, 59%). MS (ESI+) [M+H] 498.2/500.1. 1H NMR (CD3OD, 400 MHz) δ 8.56 (s, 1H), 7.44 (dd, 4H), 5.29 (t, J=8.1 Hz, 1H), 4.56 (d, J=10.3, 1H), 4.44-4.35 (m, 1H), 4.29-4.06 (m, 3H), 3.87-3.75 (m, 3H), 3.72-3.62 (m, 1H), 3.60-3.35 (m, 5H), 2.31-2.25 (m, 1H), 2.23-2.08 (m, 2H), 2.07-1.95 (m, 1H), 1.90-1.78 (m, 1H), 1.78-1.68 (m, 1H), 1.39 (d, 3H), 1.32 (d, 3H), 1.18 (d, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:13][CH2:14][OH:15]>O>[OH:15][CH2:14][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1ccc(OCCO)cc1

Procedure:
A mixture of 4-hydroxybenzaldehyde (45.5 g), sodium hydroxide (15 g) and 2-chloroethanol (30 g, 25 ml) was heated at reflux in water (200 ml) for 7 hours. The mixture was cooled and extracted with dichloromethane (200 ml). The dichloromethane solution was washed with sodium hydroxide solution (2M, 2×150 ml), brine (150 ml), dried (MgSO4) and evaporated to afford the title compound as an oil.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][C:48]=1[CH3:53])(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=4)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=3)[CH:10]=2)=[N:49][C:48]=1[CH3:53])(=[O:45])=[O:46])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Reactant: Cc1nc(Cl)sc1S(=O)(=O)NC(C)(C)C
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)sc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 25.1 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (Example G.12) (0.570 g, 0.88 mmol), 2-chloro-4-methyl-thiazole-5-sulfonic acid tert-butylamide (Example H.5) (0.266 g, 0.99 mmol), tetrakis(triphenyl-phosphine)palladium (0.061 g, 0.046 mmol) in toluene (6 mL) was heated under reflux conditions for 16 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (130 mg, 25%). MS (ISP) 590.4 [(M+H)+]; mp 260° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]([C:12]([F:11])([F:21])[F:20])[O:1]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)cc1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2ccc(F)cc2OC1C(F)(F)F
Temperature: 90 °C
Yield: 60.3 %

Procedure:
A mixture of 2-hydroxy-4-fluorobenzaldehyde (log, 71.4 mmol), ethyl 4,4,4-trifluorocrotonate (15 mL, 100 mmol), and anhydrous potassium carbonate (14.8 g, 107.1 mmol) in 40 ml dry dimethylformamide was heated to 90° C. for five hours. LC-MS indicated that the reaction was done. After cooling to room temperature, to the reaction was added 500 mL of ethyl acetate. The organic phase was washed with brine (×3), and was then dried over anhydrous magnesium sulfate. After removing the solvent, the residue was purified on silica gel column with 1:18 EtOAc/hexane. It gave 12.5 g (60%) product as a light yellow oil. 1H NMR (CDCl3/300 MHz) 7.73(s, 1H), 7.30-7.22(m, 1H), 6.79-6.73(m, 2H), 5.76(q, J=6.9 Hz, 1H), 4.38(m, 2H), 1.37(t, J=7.2 Hz, 3H). 13C(CDCl3/300 MH) 167.2, 164.0, 163.9, 155.0(d, J=13.0 Hz), 136.3(d, J=1.28 Hz), 131.0(d, J=10.4 Hz), 123.5(q, J=287.5 Hz), 115.9(dd, J=2.4, 7.3 Hz), 110.2(d, J=22.5 Hz), 104.4(d, J=26.0 Hz), 71.0(q, J=33.2 Hz), 61.7(d, J=10.4 Hz), 14.4. 19F(CDCl3/300 MHz) −79.0(d, J=6.5 Hz), −104.8(m). LC-MS(ES+) 291.0(M+1, 100), HRMS (EI+) m/z calcd for (C13H10F4O3) 290.0566(M+), found 290.0586.
Reaction SMILES: [C:1]1([NH:7][C:8](=O)[CH2:9][CH:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCOCC1>[C:1]1([NH:7][C:8](=[S:35])[CH2:9][CH:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(CC(Sc1ccccc1)Sc1ccccc1)Nc1ccccc1
Solvent: C1COCCO1
Product: S=C(CC(Sc1ccccc1)Sc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To N-phenyl-3,3-bis(phenylthio)propionamide (0.90 g) were added Lawesson's reagent (2.0 g) and 1,4-dioxane (20 mL), and the mixture was heated to reflux for 1.5 hours. The reaction mixture was left to cool to room temperature, and then concentrated under reduced pressure. The residue was isolated and purified by medium pressure preparative liquid chromatography (YAMAZEN SI-40B, hexane:ethyl acetate=3:1) to obtain N-phenyl-3,3-bis(phenylthio)thiopropionamide (0.69 g) as an orange oil.
Reaction SMILES: Cl.Cl.C([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[NH:19][C:20]1[CH:25]=[C:24]([NH:26][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:30]=2)=[O:28])[CH:23]=[CH:22][C:21]=1[CH3:41])(=O)C.N>>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[NH:19][C:20]1[CH:25]=[C:24]([NH:26][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[CH:30]=2)=[O:28])[CH:23]=[CH:22][C:21]=1[CH3:41]
Reactant: COc1cc2ncnc(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)c2cc1OC(C)=O
Agent: Cl
Agent: N
Product: COc1cc2ncnc(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)c2cc1O
Temperature: 50 °C
Yield: 78.3 %

Procedure:
A mixture of 6-acetoxy-7-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline dihydrochloride (150 mg) and methanolic ammonia (2 ml) was stirred and heated to 50° C. for 48 hours. The mixture was allowed to cool to ambient temperature and the resultant solid was isolated and washed with diethyl ether (10 ml). There was thus obtained the title compound (95 mg, 78%); NMR: 2.12 (s, 3H), 3.51 (m, 4H), 3.7 (m, 4H), 3.97 (s, 3H), 7.09 (m, 1H), 7.12 (s, 1H), 7.23 (m, 2H), 7.57 (m, 1H), 7.69 (s, 1H), 7.72 (m, 1H), 8.23 (s, 1H), 8.26 (m, 1H), 9.17 (s, 1H), 10.28 (s, 1H); m/s: M+H+ 487.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N+]([C:21]1C=CC=CC=1)([O-])=O.[OH-].[K+].COS(=O)(=O)OC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C.O>[CH3:21][NH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: O=[N+]([O-])c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CC(=O)O
Product: CNc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 30 °C
Yield: 99.5 %

Procedure:
A mixture of 1-aminoanthraquinone (purity 99.6%, 22.4 g), nitrobenzene (224 g), 96% potassium hydroxide (11.7 g), tetra-n-butyl ammonium bromide (1.7 g) and dimethylsulfuric acid (25 g) was stirred, while being maintained at 30° C. for 24 hours. Then, after water (150 g) was added, the solution was stirred for one hour while being maintained at 50° C. The aqueous phase had pH of 10 or higher. After acetic acid (0.5 g) was added for neutralization until pH of the aqueous phase was 7, nitrobenzene was recovered. The solution was cooled down to 50° C., and filtered. The solid material was washed and dried, to obtain 1-methylaminoanthraquinone (23.7 g, purity: 99.5%, yield 99.5%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11].[NH3:12].[OH-].[Na+]>O>[NH2:12][C:2]1([CH3:1])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11]
Reactant: CC1Cc2ccccc2C1=O
Reactant: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(N)Cc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 20 h

Procedure:
According to the procedure of Farnum et. al (Synthesis 1972, 191-192.), water (1.35 L) is stirred at 80° C. and de-gassed by periodic evacuating and flushing with nitrogen (3×). K3FeCN6 (202 g, 615 mmol) and 2-methyl-indan-1-one (20 g, 137 mmol) are added. The mixture is stirred rapidly under nitrogen at 80° C. while aqueous concentrated ammonia solution (105 mL) is added over 30 minutes. Stirring is continued at 80° C. for 20 hours. When cool, the solution is made alkaline by addition of sodium hydroxide (2 g) and extracted with ethyl acetate (2×200 mL). The organic extract is concentrated to a volume of 200 ml and the product is extracted into aqueous HCl (200 mL, 1M). The acidic aqueous phase is separated, basified with sodium hydroxide, and extracted with ethyl acetate (2×100 mL). The organic layer is separated, dried (Na2SO4) and the solvent removed to give an orange oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[C:32]1[C:36]([C:37](Cl)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[C:32]1[C:36]([C:37]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCO)CC2)c1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)OCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxybutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 572.2 (M+H)+.
Reaction SMILES: [Na+].[F:2][C:3]([F:19])([S:15]([O-:18])(=[O:17])=[O:16])[CH2:4][O:5][CH2:6][CH:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.FC(F)(F)S([O-])(=O)=O.[C:28]1([SH+:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(C)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([SH+:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([F:2])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[F:19][C:3]([F:2])([S:15]([O-:18])(=[O:17])=[O:16])[CH2:4][O:5][CH2:6][CH:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[SH+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)COCC(O)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Product: F[SH+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
As shown in the following reaction scheme (2-2), the 1,1-difluoro-2-(2-hydroxy-2-phenylethoxy)ethanesulfonic acid sodium salt produced in Step 1 was allowed to react with diphenyl methylphenyl sulfonium trifluoromethane sulfonate in the same manner as in Step 2 of Synthesis Example 1, and thus 1,1-difluoro-2-(2-hydroxy-2-phenyl-ethoxy)-ethanesulfonic acid diphenyl fluorophenyl sulfonium salt was obtained. Its structure was confirmed by 1H-NMR.
Reaction SMILES: [H-].[Na+].C([O:5][CH2:6][CH3:7])=O.[CH3:8][C:9]1(C)[CH2:25][C:13]2=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[S:15][C:16]([S:17][CH3:18])=[C:12]2[C:11](=[O:26])[CH2:10]1.CO>C1COCC1>[CH3:8][C:9]1([CH3:10])[CH2:25][C:13]2=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[S:15][C:16]([S:17][CH3:18])=[C:12]2[C:11](=[O:26])[C:7]1=[CH:6][OH:5]
Reactant: CSc1sc(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CSc1sc(-c2ccccn2)c2c1C(=O)C(=CO)C(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
To a solution of sodium hydride (108 mg of a 60% dispersion in mineral oil, 2.7 mmol) and ethyl formate (0.55 mL, 6.8 mmol) at 0C in THF (5 mL) was added a solution of 6,6-dimethyl-3-methylthio-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (205 mg, 0.68 mmol) in THF (5 mL). The mixture was stirred at room temperature for 2 h then more sodium hydride (50 mg of a 60% dispersion in mineral oil, 1.3 mmol) and ethyl formate (0.55 mL, 6.8 mmol) were added. The mixture was stirred for a further 2 h before MeOH (0.2 mL) was added and the mixture evaporated in vacuo. The residue was dissolved in water (20 mL) and the undissolved solid filtered off. The mixture was acidified to pH 1 using 1M HCl then neutralised with Na2CO3. The mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic layer separated and dried (MgSO4). The solvent was evaporated and the residue triturated with ether to afford the title compound (90 mg, 40%) as a yellow solid. 1H NMR (250 MHz, CDCl3) δ1.21 (6H, s), 2.70 (3H, s), 2.93 (2H, s), 7.16-7.22 (1H, m), 7.4.3 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=10.4 Hz), 7.74 (1H, d of t, J=7.7 and 1.8 Hz), 8.62-8.65 (1H, m), 14.68 (1H, d, J=10.4 Hz). MS (ES+) 332 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:15])[N:10]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[N:9]=[CH:8]2>CO.[Pd]>[NH2:33][C:31]1[CH:30]=[CH:29][C:3]([O:4][C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][C:13]=2[C:14]([NH:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:15])[N:10]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[N:9]=[CH:8]3)=[C:2]([F:1])[CH:32]=1
Reactant: O=C(NC1CCOCC1)c1cc2c(cnn2C2CCCCO2)cc1Oc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2cc3cnn(C4CCCCO4)c3cc2C(=O)NC2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
To a solution of 5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-indazole-6-carboxamide (0.49 g, 1.0 mmol) in MeOH (50 mL) is added Pd/C (100 mg, 10% wt) under N2. The resulting mixture is degassed by evacuation and backfilled with nitrogen. Then the reaction mixture is stirred at RT under H2 atmosphere overnight. The solid is removed by filtration and the filtrate is concentrated to give a crude product (0.42 g, 91.4% yield). MS (m/z): 455.1 (M+H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(OCC(O)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])C1C=CC=CC=1.[I:26][CH2:27][CH2:28]O.C(OCC)=C>C1COCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:23]([O:22][CH:20]([O:21][CH2:28][CH2:27][I:26])[CH3:19])[CH3:24]
Reactant: CCOC(=O)CC(O)COCc1ccccc1
Reactant: OCCI
Agent: C=COCC
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)OCCI
Temperature: -20 °C
Yield: 159.1 %

Procedure:
Ethyl 4-benzyloxyacetoacetate (42.1 g) synthesized according to the method describe in U.S. Pat. No. 5,399,722 was dissolved in methanol (300 mL) and sodium borohydride (3.03 g) was added at a temperature of from 5° C. to 10° C. The mixture was stirred for 1 hr and water (300 mL) was added. The solvent was mostly evaporated, and the organic layer extracted twice with MTBE (300 mL) was washed twice with 2% sodium hydrogen carbonate (100 mL) and washed twice with saturated brine (150 mL), dried over anhydrous magnesium sulfate and filtrated. MTBE was evaporated to give ethyl (±)-4-benzyloxy-3-hydroxybutanoate (38.8 g). To a solution of lithium diisopropylamide 1.5 M cyclohexane solution (190 mL) in THF (200 mL) was added a solution of ethyl (±)-4-benzyloxy-3-hydroxybutanoate (29.4 g) in THF (50 mL) at a temperature of from −78° C. to −60° C. and the temperature was raised to −20° C. Separately, 2-iodoethanol (34.4 g) and ethyl vinyl ether (23.1 g) were mixed in the presence of p-toluenesulfonic acid monohydrate (20 mg) to give 2-(1-ethoxyethoxy)ethyl iodide (47.9 g) and 39.3 g thereof was added dropwise at a temperature near −20° C. to 0° C. The mixture was stirred overnight at room temperature. The reaction mixture was poured into a 1N aqueous hydrochloric acid (450 mL), and the mixture was extracted twice with MTBE (200 mL) and washed with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated and methanol (300 mL) and p-toluenesulfonic acid monohydrate (5.3 g) were added to the residue. The mixture was stirred at room temperature for 6 hr. Triethylamine (2.0 g) was added to the reaction mixture and the solvent was mostly evaporated. The residue was extracted with ethyl acetate (300 mL). The organic layer was washed with water (150 mL) and saturated aqueous sodium hydrogen carbonate solution (150 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated. Diisopropyl ether (120 mL) was added to the residue and the mixture was recrystallized to give the title compound (5.65 g) (yellow fine crystals). The peak of syn-form (1′R*,2R*-body) was not detected in NMR and HPLC under the following conditions.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=2)=[C:6]([O:19][CH3:20])[C:5]([O:21][CH:22]([F:24])[F:23])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:39]2[CH:47]=[CH:46][CH:45]=[C:44]3[C:40]=2[CH2:41][CH2:42][C:43]3=[O:48])O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:23][CH:22]([F:24])[O:21][C:5]1[C:6]([O:19][CH3:20])=[C:7]([C:2]([C:39]2[CH:47]=[CH:46][CH:45]=[C:44]3[C:40]=2[CH2:41][CH2:42][C:43]3=[O:48])=[CH:3][CH:4]=1)[O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=1
Reactant: COc1c(OC(F)F)ccc(Br)c1OCc1ccc(C(N)=O)cc1
Reactant: CC1(C)OB(c2cccc3c2CCC3=O)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1OCc1ccc(C(N)=O)cc1
Temperature: 80 °C
Yield: 26.7 %

Procedure:
A stirring solution of 4-((6-bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)benzamide (500 mg, 1.24 mmol) in dimethylformamide (10 mL) was purged with argon for 1 h, to this cesium carbonate (1.2 g, 3.73 mmol), tetrakis(triphenylphosphine) palladium(0) (72 mg, 0.06 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (641 mg, 2.48 mmol) was added and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-80% ethyl acetate in pet ether) to afford title compound as a solid (150 mg, 26.7%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.C(Cl)Cl.[NH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[C@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:38]1[CH:43]=[CH:42][N:41]2[N:44]=[CH:45][C:46]([CH:47]=O)=[C:40]2[N:39]=1>[Cl-].[Na+].O>[F:32][C:29]1[CH:28]=[C:27]2[C:26](=[CH:31][CH:30]=1)[O:25][CH2:24][CH2:23][NH:22][CH2:47][C:46]1=[C:40]3[N:39]=[C:38]([CH:43]=[CH:42][N:41]3[N:44]=[CH:45]1)[N:34]1[C@@H:33]2[CH2:37][CH2:36][CH2:35]1
Reactant: NCCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Fc1ccc2c(c1)[C@H]1CCCN1c1ccn3ncc(c3n1)CNCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
Tetramethylammonium triacetoxyborohydride (46.7 mg, 0.629 mmol) was added to a DCM (50 mL) solution of (R)-5-(2-(2-(2-aminoethoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (155 mg, 0.420 mmol), and the reaction was stirred at ambient temperature overnight. The reaction mixture was then diluted with brine and extracted with several portions of DCM in a phase separator tube, and the combined organic extracts were concentrated and purified by reverse-phase column chromatography, eluting with 0-90% acetonitrile-H2O, to obtain the title product (32 mg, 21.6% yield). MS (apci) m/z=354.2 (M+H).