Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])([O-])=O>CO>[NH2:2][C:5]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(S(C)(=O)=O)cc1N
Reaction time: 3 h
Yield: 20.4 %

Procedure:
Concentrated hydrochloric acid (90 ml) was added to a stirred suspension of methyl 2-nitro-4-methylsulphonylbenzoate (25 g) in methanol at -5° C. (ice/salt bath). The cooling bath was then removed and iron dust (17.5 g) was added portionwise over a period of 20 minutes. The resulting exotherm was controlled using a cooling bath so that the temperature did not exceed 50° C. After 15 minutes of cooling, the bath was removed and the reaction mixture was allowed to reach room temperature. Stirring was continued for a further 3 hours. The mixture was poured onto ice and then neutralised with sodium carbonate. Dichloromethane was added and the suspension was filtered. The filtrate was extracted with further dichloromethane and the combined organic extracts were dried (magnesium sulphate), filtered and evaporated to yield a crude product which was purified by recrystallisation from ethyl acetate/hexane to give methyl 2-amino4methylsulphonylbenzoate (4.5 g) as yellow needles, m.p. 98.3-98.5° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:14]=[C:15]([CH3:17])[CH:16]=[C:4]2[N:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][C:15]1[CH:16]=[C:4]2[N:3]=[C:2]([C:23]3[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=3)[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][N:5]2[N:14]=1
Reactant: Cc1cc2nc(Cl)c(-c3ccccc3)cn2n1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: Cc1cc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Temperature: 100 °C

Procedure:
To a mixture of 1.35 g of 5-chloro-2-methyl-6-phenylpyrazolo[1,5-a]pyrimidine and 1.04 g 4-formylphenylboronic acid in 20 ml 1,2-dimethoxyethane are added 10.8 ml of a 10% w/w sodium carbonate solution and 120 mg dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II). The resulting mixture is heated to 100° C. by microwave irradiation under an inert gas atmosphere for 75 min. The work up is performed by diluting the reaction mixture with water and dichloromethane, separating the phases and extraction of the aqueous phase with dichloromethane. The combined organic layers are dried over sodium sulphate and evaporated. The crude product is purified by chromatography on silica gel (dichloromethane/methanol) to yield the desired product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([N:7]1[C:26]2[C:14](=[CH:15][C:16]3[C:17]([CH2:28][CH3:29])([CH3:27])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:24]=3[CH:25]=2)[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6].[C:30](Cl)(=[O:32])[CH3:31]>ClCCl>[C:30]([C:21]1[CH:20]=[CH:19][C:18]2[C:17]([CH2:28][CH3:29])([CH3:27])[C:16]3[CH:15]=[C:14]4[C:13]5[C:8]([N:7]([CH2:5][CH3:6])[C:26]4=[CH:25][C:24]=3[C:23]=2[CH:22]=1)=[CH:9][CH:10]=[CH:11][CH:12]=5)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: CCn1c2ccccc2c2cc3c(cc21)-c1ccccc1C3(C)CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCn1c2ccccc2c2cc3c(cc21)-c1cc(C(C)=O)ccc1C3(C)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminum chloride (3.43 g, 25.6 mmol) was slowly added into a dichloromethane solution (80 mL) in which were dissolved 6,12-diethyl-12-methyl-6,12-dihydro-6-aza-indeno[1,2-b]fluorene (5.95 g, 20.0 mmol) and acetyl chloride (1.83 mL, 25.7 mmol) at 0° C. under nitrogen atmosphere. After stirring at room temperature overnight, the reaction mixture was poured into ice-water. The product was extracted twice with dichloromethane. The combined organic layer was washed with brine, and dried over MgSO4. The dichloromethane was removed under high vacuum and the product thus obtained was used for the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH2:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:9]=[CH:8][CH:7]=2)([CH3:3])[CH3:2].C([Li])CCC.[CH3:24][Si:25](Cl)([CH3:42])[CH:26]1[C:34]2[C:29](=[C:30]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[CH3:41].[Cl-].[NH4+]>[Cu](C#N)C#N.CCCCCC.C(OCC)C>[CH3:24][Si:25]([CH3:42])([CH:5]1[C:6]2[C:11](=[C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:4]1[CH:1]([CH3:3])[CH3:2])[CH:26]1[C:34]2[C:29](=[C:30]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[CH3:41]
Reactant: CC(C)C1=Cc2c(cccc2-c2ccccc2)C1
Reactant: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)Cl
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)C1C(C(C)C)=Cc2c(-c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.7 %

Procedure:
In a 200-ml two-necked flask were charged 7.38 g (31.5 mmol) of 2-i-propyl-4-phenylindene, 55.3 mg (0.618 mmol) of copper cyanide and 100 ml of dry diethyl ether. To the mixture was added at -78° C., 22.0 ml of 1.62 M hexane solution of n-butyllithium (35.2 mmol) and the mixture was stirred at room temperature for 2 hours. Subsequently, 8.46 g (28.3 mmol) of dimethyl(2-methyl-4-phenylindenyl)silyl chloride was added at -78° C. and the mixture was stirred at room temperature for 12 hours. After it was poured into aqueous ammonium chloride, the reaction mixture was extracted with diethyl ether. The organic layer was washed with saturated saline and dried over sodium sulfate. The sodium sulfate was removed by filtration and the organic solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: n-hexane, methylene chloride) to obtain 10.93 g (22.0 mmol, yield: 77.7%) of a pale yellow liquid. The product was confirmed to be a mixture of two isomers by 1H-NMR.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH:18]([NH:27]S(C(C)(C)C)=O)/[CH:19]=[N:20]/S(C(C)(C)C)=O)=[CH:11][CH:10]=2)[CH2:4][O:3]1.[CH2:35]([Mg]Cl)[CH2:36][CH3:37].C([Mg])CC>C1COCC1.C(OCC)C>[NH2:27][CH:18]([CH:19]([NH2:20])[CH2:35][CH2:36][CH3:37])[CH2:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C@@H:5]([OH:6])[CH2:4][OH:3])=[CH:14][CH:13]=1
Reactant: CCC[Mg]Cl
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCC(/C=N/S(=O)C(C)(C)C)NS(=O)C(C)(C)C)cc2)O1
Agent: CCC[Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC(N)C(N)CCCc1ccc(OC[C@@H](O)CO)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid (4-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-1-{[(E)-2-methyl-propane-2-sulfinylimino]-methyl}-butyl)-amide (907 mg, 1.7 mmol) in THF (20 ml) at 0° C. n-propylmagnesium chloride (1.76 ml of a 2M solution in diethyl ether, 3.52 mmol). The solution is stirred at 0° C. for 30 minutes then at room temperature for 3 hours. A further portion of n-propylmagnesium (1.76 ml of a 2M solution in diethyl ether, 3.52 mmol) is added and the mixture is stirred at room temperature overnight. The resulting mixture is quenched with sat. aq. NH4Cl solution (50 ml) and extracted with EtOAc (2×50 ml). The organic phase is dried (MgSO4) and concentrated in vacuo. The residue is dissolved in EtOAc (10 ml) and treated with 4M HCl/dioxan (10 ml). After 10 minutes, the solution is concentrated in vacuo and the residue diluted with DCM (100 ml). This is treated with sat. aq. NaHCO3 solution (100 ml) and the organic phase is removed and dried (MgSO4). The DCM solution is applied to a SCX-2 cartridge (10 g) and this is eluted with DCM and MeOH. The product is released with 2M NH3 in MeOH, and the methanolic ammonia fraction concentrated to give (S)-3-[4-(4,5-Diamino-octyl)-phenoxy]-propane-1,2-diol as a mixture of diastereomers as a gum; [M+H]+ 515.38
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH2:30][C:31]4[CH:36]=CC=C[CH:32]=4)=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[C:39](OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N)=CN=C3CC2)=O)=CC=1)=N)([CH3:42])([CH3:41])[CH3:40].C(=O)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([N:29]([CH2:40][CH:39]([CH3:42])[CH3:41])[CH2:30][CH:31]([CH3:36])[CH3:32])=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCc4ccccc4)c(=O)n32)cc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)C=O
Agent: [Na+]
Product: CC(C)CN(CC(C)C)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Yield: 79.5 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 1k, intermediate 1j (97.1 mg, 0.228 mmol), isobutyraldehyde (32.8 mg, 0.455 mmol) and NaBH(OAc)3 (135.1 mg, 0.638 mmol) yielded 87.4 mg (79.5%) of intermediate 9a. MS (ESI) 539.2 (M+H+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[CH2:25]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:26][CH2:27][CH2:28][CH3:29]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CCCCCNCCCCC
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Solvent: CC(=O)CC(C)C
Product: CCCCCN(CCCCC)CCOc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
Using 1.9 g N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138), 5.6 ml of dipentylamine, and 50 ml of methylisobutylketone, a reaction similar to that conducted in Example 142 was carried out. As a result, 2.97 g of N-(trans-4-methylcyclohexyl)-4-(2-dipentylaminoethoxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([Br:15])=[CH:13][C:12]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][O:26][CH2:27][O:28][CH3:29])=[CH:20][CH:19]=2)O)=[C:11]([CH3:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:30])[C:12]([CH2:16][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][O:26][CH2:27][O:28][CH3:29])=[CH:22][CH:23]=2)=[CH:13][C:14]=1[Br:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOCCc1ccc(C(O)c2cc(Br)c(OCc3ccccc3)cc2C)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COCOCCc1ccc(Cc2cc(Br)c(OCc3ccccc3)cc2C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
Then to a chloroform solution (1 L) of [4-(benzyloxy)-5-bromo-2-methylphenyl][4-[2-(methoxymethoxy)ethyl]phenyl]methanol (102 g) cooled in ice were added Et3SiH (46.7 mL, 0.293 mol) and BF3.Et2O (29.7 mL, 0.243 mol), and the mixture was stirred for 15 minutes at the same temperature. To the reaction solution cooled in ice was added a saturated sodium bicarbonate aqueous solution and warmed to room temperature. The resulting mixture was extracted with ethyl acetate, washed with brine, and then the organic layer was dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with NH type silica gel column chromatography (hexane:ethyl acetate=19:1 to 9:1) to obtain the title compound (60 g, 68%) as a pale yellow oily compound.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[S:6][CH2:7][C:8]1[CH2:9][S:10][C@@H:11]2[CH:18]([NH:19][C:20](=[O:37])[CH:21]([OH:36])[C:22]3[N:23]=[C:24]([NH:27]C(OC(CC)(C)C)=O)[S:25][CH:26]=3)[C:17](=[O:38])[N:12]2[C:13]=1[C:14]([OH:16])=[O:15].C(O)=O.C(O)(=O)C>C(=O)(O)[O-].[Na+].C([O-])(=O)C>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[S:6][CH2:7][C:8]1[CH2:9][S:10][C@@H:11]2[CH:18]([NH:19][C:20](=[O:37])[CH:21]([OH:36])[C:22]3[N:23]=[C:24]([NH2:27])[S:25][CH:26]=3)[C:17](=[O:38])[N:12]2[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: CCC(C)(C)OC(=O)Nc1nc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Agent: CC(=O)[O-]
Agent: CCC(C)(C)OC(=O)N=c1[nH]c(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Agent: O=C([O-])O
Solvent: O=CO
Solvent: CC(=O)O
Product: Nc1nc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (2.1 g.) and 98 to 100% formic acid (40 ml.) was stirred for 2.5 hours at room temperature. After the reaction, the reaction mixture was concentrated under reduced pressure. The residue was pulverized in acetonitrile, collected by filtration and then washed with ether to produce brown powder (1.3 g.). The powder was dissolved in 5% sodium bicarbonate aqueous solution (20 ml.) and then adjusted to pH 6 with acetic acid. The mixture was subjected to neutral almina column chromatography by using pH 5.0 acetate buffer as an eluent. The eluates containing object compound (230 ml.) were collected, adjusted to pH 2.8 to 3.0 with 10% hydrochloric acid, washed with ethyl acetate, and then remaining ethyl acetate was distilled off from the eluates under reduced pressure. The resulting aqueous layer was subjected to column chromatography (Amberlite XAD-4 prepared by Rohm & Haas Co.), and the column was washed with water and then eluted with 20% methanol (80 ml.), 50% methanol (80 ml.) and 70% methanol (300 ml.) in turn. The eluates containing the object compound were collected and then methanol was distilled off under reduced pressure. The remaining aqueous solution was lyophillized to give pale brown powder of 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2(2-amino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (0.40 g.), mp. 151° to 180° C. (dec.).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.CC(C)([O-])C.[K+].Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.O>CN(C)C=O>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:5]=1
Reactant: Clc1ncccn1
Reactant: COC(OC)c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)c1cccc(Oc2ncccn2)c1
Temperature: 60 °C

Procedure:
A solution of 168 mg of 3-hydroxybenzaldehyde dimethyl acetal in 2 ml of anhydrous dimethylformamide was stirred under nitrogen and 220 mg of potassium tert.butoxide were added. The mixture was heated at 60° C. for 1 hour, then cooled to room temperature and 114 mg of 2-chloropyrimidine were added in portions. The mixture was heated at 150° C. for 20 hours. After cooling 20 ml of water were added and the product was extracted with ethyl acetate. The extracts were washed with 10 ml of 1M sodium hydroxide solution and 5 ml of brine and then dried over anhydrous magnesium sulphate. After filtration and evaporation of the filtrate the residual brown gum was purified by column chromatography on silica gel using ethyl acetate/hexane (1:1) for the elution to give 3-(2-pyrimidinyloxy)-benzaldehyde dimethyl acetal as a syrup.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[N:4][C:5]2[N:6]([N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=2)[C:7]=1O.O=P(Cl)(Cl)[Cl:21]>ClCCl>[Cl:21][C:7]1[N:6]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:5]2[N:4]=[C:3]([CH3:18])[C:2]=1[F:1]
Reactant: Cc1nc2cc(-c3ccccc3)nn2c(O)c1F
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1nc2cc(-c3ccccc3)nn2c(Cl)c1F
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-ol x133 (25 mmol, 1 eq, 6.2 g) in POCl3 (150 ml) is heated at 125° C. overnight. After cooling to room temperature, the solution is diluted in dichloromethane and quenched on ice (temperature must be kept under 25° C.). After separation of the organic layer, the aqueous phase is extracted twice with dichloromethane. The cumulated organic layers are dried over MgSO4, filtered, evaporated under reduced pressure and the residue purified by chromatography on silicagel (CH2Cl2) to afford 6.6 g of 7-chloro-6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x136.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:35][C:36]([CH3:38])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][N:21]([CH:36]([CH3:38])[CH3:35])[CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CN(C(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluoro-2-methylphenyl)octahydropyrano[3,4-c]pyrrole (29.6 mg, 0.06 mmol), acetone (0.044 mL, 0.60 mmol) and NaB(OAc)3H (69 mg, 0.33 mmol) in DCM was added 1 drop of HOAc and was stirred at rt for 16 hr. The mixture was diluted with DCM and was washed with NaHCO3. The organic phase was dried with Na2SO4, filtered and concentrated. The crude was purified by reverse phase HPLC to afford the title compound. MS: (MH)+534.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([CH3:12])=[CH:4][S:3]1(=[O:14])=[O:13].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>ClCCCl.C(Cl)Cl>[Br:15][C:4]1[S:3](=[O:13])(=[O:14])[N:2]([CH3:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]=1[CH3:12]
Reactant: CC1=CS(=O)(=O)N(C)c2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CC1=C(Br)S(=O)(=O)N(C)c2ccccc21
Reaction time: 48 h

Procedure:
390 mg of 1,4-dimethyl-1H-benzo[c][1,2]thiazin-2,2-dioxide in 20 ml 1,2-dichloroethane are combined with 332 mg of N-bromosuccinimide and 50 mg of 2,2′-azodiisobutyronitrile. The yellow solution is refluxed for a total of 10 h and then left to stand for another two days at ambient temperature. The reaction mixture is distributed between water and methylene chloride, the organic phase is washed with water, dried over magnesium sulphate and evaporated down. A yellowish resin is left which is purified through a silica gel column with petroleum ether/ethyl acetate (5:1 to 4:1) as eluant. A mixture of 4-bromo-methyl-1-methyl-1H-benzo[c][1,2]thiazin-2,2-dioxide and 3-bromo-1,4-dimethyl-1H-benzo[c][1,2]thiazin-2,2-dioxide is obtained, which is further reacted as it is.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.C([Li])CCC.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(OC(NC1C2C(=CC=CC=2)C(O)=CC=1)=O)(C)(C)C.Cl.Cl[CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C1COCC1>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH2:55][CH2:56][N:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)=[CH:5][CH:4]=1
Reactant: ClCCN1CCOCC1
Reactant: Nc1ccc(O)c2ccccc12
Agent: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: Nc1ccc(OCCN2CCOCC2)c2ccccc12

Procedure:
4-Amino-1-naphthol hydrochloride (40) can be neutralized with a base, such as n-butyl lithium, in a non-protic solvent, such as THF, and reacted with di-tert-butyl dicarbonate ((BOC)2O) at temperatures between −78 −25° C. The product, 4-tert-butyloxycarbonylamino-1-naphthol (41) can be alkylated with 4-(2-chloroethyl)morpholine hydrochloride in a non-protic solvent, such as acetonitrile, with a base, such as powdered potassium carbonate, at temperatures between 60-80° C. Purification of the product 4-tert-butyloxycarbonylamino-1-(2-(morpholin-4-yl)ethoxy)naphthalene (42) can be accomplished by silica gel chromatography. Removal of the BOC-protecting group can be accomplished with HCl in a non-protic solvent, such as dioxane, to furnish 1-amino-4-(2-(morpholin-4-yl)ethoxy)naphthalene (39) as the hydrochloride salt.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>[Cu]I.C(OCC)(=O)C.CS(C)=O>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([NH:19][C:2]3[CH:10]=[C:9]([CH2:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:8]=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])=[CH:28][CH:27]=2)[CH:23]=[N:24]1
Reactant: O=C(O)c1ccc(CCc2ccccc2)cc1I
Reactant: Nc1ccc2[nH]ncc2c1
Agent: [Cu]I
Agent: Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CCc2ccccc2)cc1Nc1ccc2[nH]ncc2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 9.9 %

Procedure:
To 2-iodo-4-phenethylbenzoic acid 40 mg were added 5-aminoindazole 23 mg, copper(I) iodide 2.2 mg, proline 2.6 mg, potassium carbonate 19 mg and dimethyl sulfoxide 0.40 mL at room temperature, and it was stirred at 70° C. for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with water and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; chloroform:methanol=100:1] to give 2-((1H-indazol-5-yl)amino)-4-phenethylbenzoic acid 4.0 mg of a white solid.