Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@@H:12]2[CH2:17][O:16][C@@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:20][CH2:21][CH3:22]>C(O)(=O)C.CO>[CH2:21]([C:22]1[N:11]([C@@H:12]2[CH2:17][O:16][C@@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)[C:3]2=[C:4]3[S:10][CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]2[N:1]=1)[CH3:20]
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CO)OC1
Reactant: CCC
Solvent: CO
Solvent: CC(=O)O
Product: CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)OC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a solution of {(2R,5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]tetrahydro-2H-pyran-2-yl}methanol (115 mg, 0.412 mmol) in acetic acid (1.1 mL) was added propane, 1,1,1-triethoxy- (265 μL, 1.32 mmol). The resulting mixture was stirred at 120° C. for 30 min. After cooling to room temperature, the mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product as white solid (74.8 mg, 57%). LCMS calculated for C16H20N3O2S (M+H)+: m/z=318.1. Found: 318.1.
Reaction SMILES: [Cl-].C[Al+]C.[N+:5]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[CH:13]2)([O-:7])=[O:6].[C:17](Cl)(=[O:19])[CH3:18].[Cl-].[NH4+]>CCCCCC.ClCCl>[C:17]([C:13]1[C:12]2[C:16](=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=[CH:10][CH:11]=2)[NH:15][CH:14]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1cccc2cc[nH]c12
Agent: C[Al+]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(=O)c1c[nH]c2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 1.0M solution (11 ml) of dimethylaluminum chloride (11 mmol) in hexane was added to 50 ml of a solution of 1.2 g (7.5 mmol) of 7-nitro-1H-indole in dichloromethane at 0° C. in a nitrogen atmosphere, followed by the addition of 2.1 ml (29.5 mmol) of acetyl chloride at 0° C. The obtained mixture was stirred at room temperature for 4 hours, followed by the addition of a saturated aqueous solution of ammonium chloride. The precipitate thus formed was recovered by filtration and washed with hot ethanol sufficiently. The washings and the filtrate were combined and concentrated. Water was added to the residue and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and distilled in a vacuum to remove the solvent. The residue was purified by silica gel column chromatography to give 3-acetyl-7-nitro-1H-indole. This product was dissolved in 100 ml of methanol and hydrogenated in the presence of palladium-carbon at ordinary temperature under normal pressure. After the removal of the catalyst by filtration, the filtrate was concentrated to dryness to give 790 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[CH:13]=[CH:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.C([Li])CCC.CN(C)[CH:27]=[O:28]>O1CCCC1>[CH3:12][O:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH:13]=[CH:14][C:15]1[S:16][C:17]([CH:27]=[O:28])=[CH:18][CH:19]=1
Reactant: CN(C)C=O
Reactant: COc1cc(OC)c(C=Cc2cccs2)c(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(OC)c(C=Cc2ccc(C=O)s2)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
In a stream of argon, in 10 ml of tetrahydrofuran was dissolved 500 mg (1.80 mmol) of 2-[2-(2,4,6-trimethoxyphenyl) vinyl]thiophene, and 1.27 ml of n-butyllithium (1.6 M solution in hexane) (2.03 mmol) was added dropwise thereto under cooling. The mixture was stirred for 1 hour. To this mixture, 0.16 ml (2.00 mmol) of N,N-dimethylformamide was added dropwise and reacted. After reacted at gradually increasing temperature, the reaction mixture was stirred at room temperature for 12 hours. The mixture was poured into 50 ml of ice water and subjected to 3 times of extraction with 200 ml of chloroform. The extract was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography to give 380 mg (yield: 69%) of 5-[2-(2,4,6-trimethoxyphenyl)vinyl]thiophene-2-carbaldehyde as a light yellow crystal.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:12][C@H:11]([OH:13])[CH:10]=[CH:9]1.C(N(CC)CC)C.[C:21](OC=C)(=[O:23])[CH3:22].C(Cl)(Cl)Cl>COC(C)(C)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:12][C@H:11]([O:13][C:21](=[O:23])[CH3:22])[CH:10]=[CH:9]1
Reactant: O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Reactant: C=COC(C)=O
Solvent: COC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 44.9 %

Procedure:
Cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enol (1.091 g, 5.92 mmol, prepared in example 6) is dissolved in tert-butyl methyl ether (8.6 mL, anhydrous). To the solution is added triethylamine (0.59 mL, 4.2 mmol), pancreatin (3.2 g, available from Sigma Chemical Company), and vinyl acetate (2.7 mL, 29 mmol). The reaction is allowed to stir for 7 hours at room temperature. The reaction is then filtered through diatomaceous earth and the filtrate is concentrated under vacuum. The products are separated by chromatography on silica gel (10% to 20% ethyl acetate/hexane) to provide (-)-acetic acid cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enyl ester (B, 601 mg, 45% yield, 91% ee), [α]D =-19.8°, (c=1.00, chloroform) as a yellow oil and (-)-cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enol (A, 560 mg, 50% yield, 94% ee), [α]D =-9.9°, (c=1.06, chloroform) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.C(Cl)CCl.[CH:16](O)=[O:17]>C(Cl)Cl>[O:11]=[C:8]1[CH2:7][C:6]2[C:10](=[C:2]([NH:1][CH:16]=[O:17])[CH:3]=[CH:4][CH:5]=2)[NH:9]1
Reactant: Nc1cccc2c1NC(=O)C2
Reactant: O=CO
Solvent: ClCCl
Solvent: ClCCCl
Product: O=CNc1cccc2c1NC(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a suspension of 7-aminooxindole (32 mg, 0.22 mmol) in CH2Cl2 (1 mL) was added EDC (83 mg, 0.43 mmol) and formic acid (12 mg, 0.26 mmol). The reaction mixture was stirred at rt for 2 h and then filtered. The filter cake was washed with diethyl ether to give the title compound as a grey solid (27 mg, 71%). 1H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 7.20 (d, 1H, J=8 Hz), 7.15 (d, 1H, J=8 Hz), 7.02 (t, 1H, J=8 Hz), 3.59 (s, 2H); MS ESI [M+H]+, calcd for [C9H8N2O2+H]+ 177.07. found m/z 177.0.
Reaction SMILES: [Br-:1].C([NH:7][CH2:8][CH2:9][N+:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH2:21][CH3:22])[CH:16]=2)[CH:11]=1)(OCC)=O>Br>[BrH:1].[Br-:1].[NH2:7][CH2:8][CH2:9][N+:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH2:21][CH3:22])[CH:16]=2)[CH:11]=1
Reactant: CCOC(=O)NCC[n+]1ccc2cc(OCC)ccc2c1
Agent: Br
Agent: [Br-]
Product: CCOc1ccc2c[n+](CCN)ccc2c1

Procedure:
6-Ethoxyisoquinoline (0.5 g.) and ethyl (2-bromoethyl) carbamate (0.7 g.) in acetonitrile (20 ml) were heated under reflux for 50 hrs. The solvent was removed in vacuo and the residue triturated with ethyl acetate to give 2-(2-carbethoxyaminoethyl)-6-ethoxyisoquinolinium bromide (1.0 g.). The crude bromide was heated under reflux in 24% aqueous hydrobromic acid (16 ml) for 2 hrs. The solvent was removed in vacuo and the residue was crystallised from ethanol and had m.p. 238°-240° (dec.).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:11]1.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:36][C:35]([CH3:38])([CH3:37])[C:34]([NH:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[O:27])[CH2:11]1)=[O:39]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
212 μl of triethylamine (1.52 mmol) and 18.6 mg of DMAP (0.152 mmol) were added to a solution of the compound from Example 57A (200 mg, 0.508 mmol) in dichloromethane (12 ml), and 94 μl of pivaloyl chloride (0.76 mmol) were then added at 0° C. The reaction mixture was warmed to RT and stirred overnight. The reaction solution was washed with aqueous 1 N hydrochloric acid and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (RP18 column; acetonitrile/water gradient). Yield: 154 mg (68% of theory)
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O>O1CCOCC1>[CH:10]1([NH:16][C:2]2[N:4]=[C:5]([NH:16][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[N:7]=[C:8]([NH:16][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[N:1]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCCCC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: C1COCCO1
Product: C1CCC(Nc2nc(NC3CCCCC3)nc(NC3CCCCC3)n2)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 91.8 %

Procedure:
18.5 g (0.1 mol.) of cyanuric chloride were dissolved in 400 mL of 1,4-dioxane. The mixture solution was warmed to 50° C. While stirring, the warmed solution was dropwise added with 60.2 g (0.6 mol.) of cyclohexylamine over two hours in such a manner that the reaction temperature did not raise over 50° C. While continuing further stirring, the temperature was raised to 85° C. and 60.2 g (0.61 mol.) of cyclohexylamine by keeping the temperature. Thereafter, the temperature was again raised and the reaction was carried out at the reaction temperature of 95° C. for six hours. 230 g of water were added to the reaction solution so that the temperature did not fall less than 90° C. and then, cooled. to the room temperature while stirring. Product was separated, from the reaction solution through filtration and washed with each 150 mL of water four times. The filtered product was dried at 70° C. for six hours under vacuum to obtain 34.2 g of 2,4,6-tris(cyclohexylamino)-1,3,5-triazine (yield: 225° C.)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])(=[O:25])=[O:24]
Reactant: N#CCCCCCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCCCCCCCC#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 15 g. of 12-hydroxydodecanonitrile and 14 ml. of triethylamine in 320 ml. of methylene chloride is stirred at 0° C. while 5.7 ml. of methanesulfonylchloride is added dropwise. The mixture is stirred at 0° C. for 1 hour, diluted with methylene chloride and extracted with water; cold, dilute hydrochloric acid; saturated aqueous sodium bicarbonate; and brine. The solution is dried over anhydrous magnesium sulfate and eaporated to yield 12-(methanesulfonyloxy)dodecanonitrile as a yellow oil.
Reaction SMILES: FS([O-])(=O)=[O:3].[CH3:6][N+:7]1[S:8][C:9]([Cl:14])=[C:10]([Cl:13])[C:11]=1Cl>C([O-])(=O)C.[Na+]>[Cl:13][C:10]1[C:11](=[O:3])[N:7]([CH3:6])[S:8][C:9]=1[Cl:14]
Reactant: O=S(=O)([O-])F
Reactant: C[n+]1sc(Cl)c(Cl)c1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cn1sc(Cl)c(Cl)c1=O
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
2-Methyl-3,4,5-trichloroisothiazolium fluorosulfonate (16.9 g, 0.058 mol) was added in portions to 150 ml of a saturated sodium acetate solution. After stirring for 30 min. the solid was collected, washed with water, and recrystallized from ethanol to yield 7.5 g (70%) of 4,5-dichloro-2-methyl-4-isothiazolin-3-one, mp 119°-120°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Cl[CH2:11][C:12]1[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1.ClCC1C=CC(OC)=CC=1>>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([CH2:11][S:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:13]=[C:14]([O:22][CH3:23])[C:15]=1[O:20][CH3:21]
Reactant: COc1ccc(S)cc1
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: COc1ccc(CCl)cc1
Product: COc1ccc(SCc2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
The desired product was prepared by substituting 4-methoxybenzenethiol and 5-(chloromethyl)-1,2,3-trimethoxybenzene for Example 85A and 1-(chloromethyl)-4-methoxybenzene, respectively, in Example 85B.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[C:10]([CH3:17])=[N:9]2)[CH:7]=1.[N:20]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([N:28]3[CH2:29][CH2:30][CH:25]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:26][CH2:27]3)=[O:16])[C:10]([CH3:17])=[N:9]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-n1nc(C)c(C(=O)O)c1C
Reactant: C1CCN(C2CCNCC2)C1
Product: COc1ccc(Cl)cc1-n1nc(C)c(C(=O)N2CCC(N3CCCC3)CC2)c1C
Yield: 99 %

Procedure:
In analogy to the procedure described in Example 18], 1-(5-chloro-2-methoxy-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the title compound in 99% yield as light yellow foam. MS: 417.0 (MH+, 1 Cl).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([C:18]4[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1.C(OC[CH:43]1[CH2:45][O:44]1)C1C=CC=CC=1.C(N(CC)CC)C.C[OH:54]>CN1CCCC1=O.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]>[C:25]([NH:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][C@H:15]([C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)[O:16][CH2:17][C@:8]2([C:6]2[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=2[F:33])[C:45]([O:44][CH3:43])=[O:54])[N:9]=1)(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CO
Reactant: c1ccc(COCC2CO2)cc1
Reactant: Cn1cc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(Br)ccc3F)CO2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(F)c([C@]23CO[C@@H](c4cnn(C)c4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a mixture of N-[rel-(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide [(+/−)—C46, which may be prepared in the same manner as C46, by using the chemistry described in Preparation 1 followed by Examples 10 and 12, but employing racemic 2-[(benzyloxy)methyl]oxirane as starting material] (1.0 g, 1.9 mmol) and triethylamine (580 mg, 5.73 mmol) in methanol (20 mL) and 1-methylpyrrolidin-2-one (10 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (140 mg, 0.19 mmol) in one portion at room temperature. The reaction mixture was stirred under carbon monoxide (2.5 MPa) at 120° C. for 18 hours, whereupon it was concentrated in vacuo to remove methanol, and partitioned between water (500 mL) and ethyl acetate (500 mL). The organic layer was washed with saturated aqueous sodium chloride solution (2×400 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Eluent: ethyl acetate) afforded the product as a red solid. Yield: 570 mg, 1.12 mmol, 59%. LCMS m/z 509.1 [M+H+].
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:13](O)([CH3:16])([CH3:15])[CH3:14].CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of 4-acetylbenzoic acid (3.9 g) in anhydrous methylene chloride (120 ml) are added 4-dimethylaminopyridine (1.5 g), t-butyl alcohol (4.6 ml), N-methylmorpholine (3.4 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.0 g) under ice cooling. The mixture is stirred under ice cooling for six hours and under water cooling overnight. The reaction mixture is concentrated under reduced pressure, water is added to the concentrate, and the whole is extracted with ether. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 3.13 g (59%) of t-butyl 4-acetylbenzoate as crystals.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].C([O-])(=O)C.[Na+].[C:16](OCC)(OCC)(OCC)[O:17][CH2:18][CH3:19]>C(O)C>[CH2:18]([O:17][C:16]1[O:10][C:4]2[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=2[N:2]=1)[CH3:19]
Reactant: Nc1ccc(O)cc1O
Reactant: CCOC(OCC)(OCC)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2ccc(O)cc2o1
Yield: 60 %

Procedure:
A mixture of equivalent amounts of 4-aminoresorcinol hydrochloride and anhydrous sodium acetate in anhydrous ethanol was stirred for 16 hours at room temperature with a slight excess of tetraethyl orthocarbonate to give 2-ethoxy-6-hydroxybenzoxazole in 60% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[O:7])[C:5]2=[CH:15][C:16]=1[Cl:17]>CO.[BH4-].[K+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:15][C:16]=1[Cl:17])[C:6](=[O:7])[N:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH:9]2[OH:10]
Reactant: CC(C)CN1C(=O)c2cc(Cl)c(Cl)cc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: CC(C)CN1C(=O)c2cc(Cl)c(Cl)cc2C1O
Temperature: 20 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
5,6-Dichloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 3.78 g of 4,5-dichloro-N-isobutylphthalimide in 75 cm3 of methanol and 0.75 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and is then cooled to a temperature in the region of 0° C. and distilled water is added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40° C., followed by addition of 100 cm3 of ethyl acetate. After separation of the phases by settling, the aqueous phase is extracted twice with 75 cm3 of ethyl acetate. The organic extracts are combined, washed with 150 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 3.42 g of 5,6-dichloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1one are thus obtained in the form of an off-white solid. (Rf=0.69, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:52])[CH2:18][C:17]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[C:27]4[CH:30]=[C:31]([CH2:33][CH3:34])[S:32][C:26]=4[N:25]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]5[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=5)=[CH:38][C:37]=4[F:50])[C:24]3=[O:51])[CH:21]=[CH:22][C:16]=2[O:15]1>O>[CH3:52][C:14]1([CH3:13])[CH2:18][C:17]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[C:27]4[CH:30]=[C:31]([CH2:33][CH3:34])[S:32][C:26]=4[N:25]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=5[C:48]5[NH:3][C:4](=[O:7])[O:5][N:49]=5)=[CH:38][C:37]=4[F:50])[C:24]3=[O:51])[CH:21]=[CH:22][C:16]=2[O:15]1
Reactant: CCc1cc2c(=O)n(-c3ccc4c(c3)CC(C)(C)O4)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc2c(=O)n(-c3ccc4c(c3)CC(C)(C)O4)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3F)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.6 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.54 g) was added, and the mixture was stirred at 90° C. for 16 hr. To the reaction mixture was added water, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure. The solid was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.43 g, 72%).
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:24])=[C:20]([F:33])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14](C)(C)C)=[O:12])[CH2:7][CH2:6]1.Cl.ClC(OC)=O.CCN(CC)CC>CO.O1CCOCC1>[F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:24])=[C:20]([F:33])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1
Reactant: Cc1ccc(NC(=O)Nc2c(F)ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2F)cn1
Agent: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)N1CCN(Cc2ccc(F)c(NC(=O)Nc3ccc(C)nc3)c2F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.3 %

Procedure:
To a solution of tert-butyl 4-(2,4-difluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate (790 mg, 1.71 mmol, 1.0 equiv) in MeOH (5 mL) was added by syringe HCl (71 (4.0 M in dioxane, 4.5 mL, 17 mmol, 10 equiv) After 30 minutes, the reaction mixture was concentrated in vacuo. The resulting solid was then suspended in DCM (20 mL) and methyl chloroformate (158 μL, 2.05 mmol, 1.2 equiv) and Et3N (716 μL, 5.13 mmol, 3.0 equiv) were added by syringe. The reaction mixture was allowed to stir at room temperature for 1.5 h and then quenched by the addition of aq. satd. NaHCO3. The organic layer was separated, dried over sodium sulfate and purified by preparative thin layer chromatography (10% MeOH/DCM) to provide methyl 4-(2,4-difluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate (275 mg, 38%). LCMS m/z (APCI)=420.2 (M+H).