Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([O-:3])=[O:2].C([O:11][CH:12](O)[C:13]([F:16])([F:15])[F:14])C.C(=O)([O-])[O-].[K+].[K+]>CC(=O)OCC>[N+:1]([CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[CH:12]([OH:11])[C:13]([F:16])([F:15])[F:14])([O-:3])=[O:2]
Reactant: CCCCC[N+](=O)[O-]
Reactant: CCOC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCCC(C(O)C(F)(F)F)[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a stirred solution of 1-nitropentane (1.0 g, 8.5 mmol) and trifluoroacetaldehyde ethyl hemiacetal (1.2 mL, 8.5 mL) was added potassium carbonate (K2CO3) (0.06 g, 0.43 mmol). The reaction mixture was heated at 60° C. under Ar for 3 h. The mixture was cooled to R.T., then taken up in EA (50 mL). The organic layer was washed with 1N HCl (2×10 mL), sat. NaCl (2×10 mL), dried (MgSO4), filtered and concentrated to give (2SR)-(3SR)-3-nitro-1,1,1-trifluoro-2-heptanol as a crude oil (1.7 g, 93%): 1H NMR (CDCl3, 300 MHz) δ 0.91 (t, 3 H, J=7.2 Hz), 1.24-1.43 (m, 4 H), 2.04-2.11 (m, 2 H), 4.08-4.77 (m, 3 H) ppm.
Reaction SMILES: O.Cl.[F:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([O:11][CH3:12])[CH:5]=1.Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl>ClC1C=CC=CC=1>[F:3][C:4]1[CH:10]=[CH:9][C:7]([N:8]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: COc1cc(F)ccc1N
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc(F)ccc1N1CCNCC1
Temperature: 20 °C
Yield: 25 %

Procedure:
9 ml of chlorobenzene and H2O were distilled from a solution of 1.14 g of p-TosOH (6.03×10−3 moles) in 200 ml of chlorobenzene. The solution was cooled to 20° C. and then 1.19 g of 4-fluor-2-methoxyaniline hydrochloride (6.7×10−3 moles) and 1.31 g of bis (2-chloroethyl)amine hydrochloride (7.36×10−3 moles) were added. The reaction was held under reflux for 72 hours after which the solvent was removed and the residue was extracted with 5 ml of NaOH 2N and 30 ml of toluene. The organic phase was washed with H2O, was dried with Na2SO4 and the toluene was removed. The product was purified by silica column using dichloromethane/MeOH (9:1) as mobile phase. An oil was obtained. Yield: 25%.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:39][C:40]1[CH:41]=[CH:42][C:43]([OH:49])=[C:44](B(O)O)[CH:45]=1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:42]5[CH:41]=[C:40]([F:39])[CH:45]=[CH:44][C:43]=5[OH:49])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Reactant: OB(O)c1cc(F)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(F)ccc5O)c4)nn23)CC1
Temperature: 90 °C
Yield: 75.1 %

Procedure:
To (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.24 g, 0.41 mmol, 1 equiv), (5-fluoro-2-hydroxyphenyl)boronic acid (96 mg, 0.62 mmol, 1.5 equiv), and Pd(PPh3)4 (47 mg, 0.041 mmol, 0.1 equiv) was added DMF (4.1 mL that had been degassed by sparging with nitrogen for 10 min) Na2CO3 (0.41 mL of a 2 M aqueous solution, 0.82 mmol, 2 equiv) was added and the reaction was heated to 90° C. for 3 h. Upon cooling to ambient temperature, the reaction was diluted with EtOAc and washed with water. The EtOAc layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-60% acetone in hexane) to provide the product as a yellow foam (0.19 g, 75%). 1H NMR (400 MHz, CDCl3) δ 8.13-8.08 (m, 1H), 8.05-8.00 (m, 1H), 7.67-7.48 (m, 3H), 7.09-6.94 (m, 4H), 6.07-5.92 (m, 1H), 5.45-5.36 (m, 1H), 5.22-5.07 (m, 2H), 4.04-3.97 (m, 2H), 3.81-3.77 (m, 3H), 3.77-3.74 (m, 4H), 2.74-2.65 (m, 3H), 2.08-1.94 (m, 3H), 1.80-1.68 (m, 1H), 1.36 (s, 3H), 1.24 (s, 9H). LCMS (M+1)=617.35.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH3:14][CH2:15][CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH3:14][CH2:15][CH2:16][CH:17]([NH:21][C:11]([C:3]1[C:2]([CH3:1])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)=[O:13])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(N)CCC
Reactant: Cc1cc2c(cc1C(=O)O)OCO2
Product: CCCC(CCC)NC(=O)c1cc2c(cc1C)OCO2

Procedure:
Prepared in a similar manner to example 4 using 6-methylbenzo[d][1,3]dioxole-5-carboxylic acid and heptan-4-amine. MS (M+H, 278.67).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][N:16]3[C:19](=[O:21])[CH3:20])=[CH:11][CH:10]=2)O1.Br[C:24]1[S:25][C:26]([Cl:34])=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O1CCOCC1>[C:19]([N:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([C:24]3[S:25][C:26]([Cl:34])=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=3)[CH:18]=2)[CH2:13][CH2:14][CH2:15]1)(=[O:21])[CH3:20]
Reactant: CCOC(=O)c1nc(Br)sc1Cl
Reactant: CC(=O)N1CCCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCC3)sc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
To 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (1G) (1.24 g, 4.12 mmol), ethyl 2-bromo-5-chlorothiazole-4-carboxylate (1I) (1.12 g, 4.12 mmol), lithium chloride (0.52 g, 12.4 mmol), tetrakis(triphenylphosphine)palladium (0.476 g, 0.412 mmol), and cesium carbonate (4.03 g, 12.4 mmol) was added 1,4-dioxane (30 mL) and water (10 mL). Nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction mixture was heated to 100° C. and stirred overnight. The reaction mixture was cooled to rt, diluted with EtOAc, filtered through Celite, and concentrated under reduced pressure. To the crude residue was added EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc and the combined organic extracts were washed sequentially with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 80% EtOAc in hexanes to provide 0.505 g (34%) of the desired product ethyl 2-(1-acetyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-chlorothiazole-4-carboxylate (1J): LC/MS (APCI): m/z 365.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)=[CH:9][N:10]=2)[N:7]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[S:18][C:14]=4[CH:13]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cc3cnc4ccc(Cl)nn34)cc2s1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cc3cnc4ccc(Cl)nn34)cc2s1
Temperature: 140 °C
Reaction time: 48 h
Yield: 47.4 %

Procedure:
A mixture of 6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.0 g, 2.7 mmol), (1R,2R)-2-aminocyclohexanol (0.93 g, 8.1 mmol) and DIEA (697 mg, 5.4 mmol) in NMP (40 mL) was stirred for 2 d at 140° C. The mixture was cooled to rt and water (150 mL) was added. The mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 10:1 DCM/MeOH to afford (1R,2R)-2-((6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a brown solid (530 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ 8.20 (d, J=9.6 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.63 (s, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.32 (d, J=9.9 Hz, 1H), 7.27 (d, J=1.8 Hz, 1H), 7.12 (dd, J=1.5, 8.4 Hz, 1H), 4.73 (d, J=5.1 Hz, 1H), 4.29 (s, 2H), 3.52-3.49 (m, 1H), 3.39-3.36 (m, 1H), 2.05-2.01 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m, 2H), 1.30-1.16 (m, 4H). LCMS (ESI) m/z 414 (M+H)+.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:26]=2)=[O:22])[CH2:17][CH2:16]1)=O)(C)(C)C>CO.CCOCC>[ClH:1].[C:34]1([CH2:33][CH2:32][O:31][C:27]2[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=2)[CH2:24][O:23][C:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[O:22])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2cccc(OCCc3ccccc3)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CO
Product: O=C(OCc1cccc(OCCc2ccccc2)c1)N1CCNCC1
Reaction time: 3 h
Yield: 93 %

Procedure:
4M HCl in 1,4-dioxane (2.3 mL, 9.2 mmol) was added to a solution of piperazine-1,4-dicarboxylic acid 3-(2-phenylethoxy)benzyl ester tert-butyl ester (0.10 g, 0.23 mmol) in methanol (2 mL) and ether (2 mL) and the solution was left to stand with occasional swirling at room temperature for 3 h. The solution was concentrated in vacuo and the residue was triturated with ether to yield the title compound (0.08 g, 93%) as a white solid. 1H-NMR (400 MHz, d6-DMSO): 3.03 (2H, t, J=6.8 Hz), 3.08 (4H, m), 3.61 (4H, m), 4.19 (2H, t, J=7.0 Hz), 5.06 (2H, s), 6.88–6.94 (3H, m), 7.20–7.33 (6H, m) and 9.19 (2H, br s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:22][CH:23]([F:25])[F:24])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:24][CH:23]([F:25])[O:22][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:32]1[C:27]([F:26])=[N:28][CH:29]=[CH:30][CH:31]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(OC(F)F)cc12
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(OC(F)F)cc12
Temperature: 100 °C
Yield: 72.1 %

Procedure:
A microwave vial was charged with (S)-7-bromo-3-(difluoromethoxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.056 g, 0.136 mmol). 2-fluoropyridin-3-ylboronic acid (0.038 g, 0.272 mmol), potassium phosphate (0.087 g, 0.408 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4.81 mg, 6.79 μmol) were added. The vial was flushed with Ar (g), then dioxane (0.509 mL) and water (0.170 mL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 100° C. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (0-10% MeOH/DCM) to afford (S)-3-(difluoromethoxy)-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.042 g, 0.098 mmol) as a light yellow solid. [M+H]+=429.0
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1S(Cl)(=O)=O.CCN(CC)CC.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31].O>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[O:31][CH2:30][CH:29]([OH:32])[CH2:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: OCC(O)COc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)c(OCC(O)COc2ccccn2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
2-Mesitylenesulfonyl chloride (120.8 mg, 0.55 mmol), Bu2SnO (63.1 mg, 0.25 mmol), DMAP (61.9 mg, 0.51 mmol) and Et3N (1 mL) were added to a solution of 3-(pyridin-2-yloxy)propane-1,2-diol (83.7 mg, 0.50 mmol) in toluene (5 mL). The reaction mixture was stirred at room temperature for 2 h. Following the addition of water, the mixture was extracted with CH2Cl2. The organic layers were dried with Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography to give the title product (123.9 mg, 71%).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=CC=CC=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:19]1(=[O:29])[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.Cl>CCOCC.C1C=CC=CC=1>[C:5]1([C:9]2[CH:18]=[C:17]([CH:16]=[CH:11][CH:10]=2)[C:22]([C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[C:19]([OH:24])=[O:29])=[O:23])[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=1
Reactant: Brc1cccc(-c2ccc3ccccc3c2)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C(O)c1ccccc1C(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
Under an argon atmosphere, 132 g of magnesium were dispersed in 500 mL of ether. A solution of 142 g of 2-(3-bromophenyl)naphthalene in 500 mL of ether was added to the dispersion, and then the mixture was stirred at room temperature for 1 hour. A solution of 74 g of phthalic anhydride in 150 mL of benzene was added to the mixture, and then the resultant reaction solution was stirred for 3 hours under reflux. After having been cooled to room temperature, the reaction solution was poured into ice water, and then 1 L of 10% hydrochloric acid was added to the mixture. The organic layer was separated and extracted with an aqueous solution of potassium carbonate. The alkaline extract was acidified, and then the resultant solid was washed with boiling water. The resultant crude product was recrystallized with acetic acid. Thus, 121 g of 2-(3-phenylbenzoyl)benzoic acid were obtained (in 69% yield).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]2[C:5]=1[C:6](=[O:15])[C:7](=[O:14])[NH:8]2.I[CH3:17].Cl>C1COCC1>[CH3:17][N:8]1[C:9]2[C:5](=[C:4]([Cl:3])[CH:12]=[C:11]([Cl:13])[CH:10]=2)[C:6](=[O:15])[C:7]1=[O:14]
Reactant: CI
Reactant: O=C1Nc2cc(Cl)cc(Cl)c2C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)C(=O)c2c(Cl)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of 60% NaH (20.5 mg), 4,6-dichloroisatin (947 mg), and iodomethane (0.328 mL) in THF (20 mL) were stirred overnight at room temperature, poured into 1 N hydrochloric acid, and extracted with ethyl acetate. The extracts were washed with sat. aqueous NaCl, dried over MgSO4, and concentrated. The residue was washed with hexane to give the title compound (849 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13](=[O:15])[CH3:14].[OH-].[K+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl>CS(C)=O.O>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:1]([CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[F:18])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13](=[O:15])[CH3:14]
Reactant: Fc1ccccc1CCl
Reactant: CC(=O)c1c(C)nc2ccccc2c1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1c(C)nc2ccccc2c1N(Cc1ccccc1F)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-amino-2-methyl-3-quinolinyl)-ethanone in dimethylsulfoxide (150 ml) was added to a stirred slurry of pulverized 85% potassium hydroxide (7 g) in dimethylsulfoxide (40 ml). This mixture was stirred at ambient temperature for twenty minutes, and thereafter a solution of o-fluorobenzylchloride (15.2 g) in dimethylsulfoxide (40 ml) was added dropwise. The mixture was stirred for two hours and allowed to stand overnight at room temperature. Thereafter, it was then poured onto ice and diluted with water to form a tacky lump. This was allowed to stand for fifteen minutes, and the aqueous dimethylsulfoxide was decanted. The tacky precipitate was dissolved in dichloromethane, washed with water (3×) and saturated sodium chloride solution, and dried over sodium sulfate. Removal of the sodium sulfate by filtration and the solvent by evaporation gave 26.5 g of viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].C(Cl)(=O)C(Cl)=O.[CH2:20]([NH:22]CC)[CH3:21].C(N(CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH2:20]([NH:22][C:11]([C@H:8]1[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]1)=[O:13])[CH3:21]
Reactant: CCNCC
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)[C@H]1CC[C@H](C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A stirred and cooled (0° C.) solution of trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (0.500 g, 2.69 mmol) in CH2Cl2 (10 mL) was treated dropwise with a solution of oxalyl chloride (2.0 M in CH2Cl2 1.58 mL, 3.15 mmol) and one drop of DMF, under an atmosphere of nitrogen. The reaction was stirred for 20 min at 0° C., allowed to warm to room temperature and stirred for an additional 2 h. The product was placed under high vacuo for 20 min, dissolved in THF (15 mL) and treated with diethylamine (2.0 M solution in THF, 1.37 mL, 2.73 mmol) and triethylamine (380 uL, 2.73 mmol). The reaction was stirred at room temperature for an additional 18 h. Saturated NH4Cl (1 mL) was added and the resultant mixture was partitioned between H2O (20 mL) and EtOAC (20 mL). The aqueous layer was re-extracted with EtOAc (3×20 mL) and the combined extracts were washed with brine (40 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford methyl trans-4-[(ethylamino)carbonyl]cyclohexanecarboxylate as a colorless oil. LCMS=214.2 (M+1)+.
Reaction SMILES: [C:1](=S)=[S:2].[NH2:4][CH2:5][CH2:6][S:7][CH2:8][C:9]1[O:13][C:12]([CH2:14][N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>CC(C)=O>[N:4]([CH2:5][CH2:6][S:7][CH2:8][C:9]1[O:13][C:12]([CH2:14][N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)=[C:1]=[S:2]
Reactant: S=C=S
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc(CSCCN=C=S)o1
Reaction time: 0.25 h
Yield: 39.4 %

Procedure:
A solution of carbon disulphide (4.2 g) in dry acetone (8 ml) was added dropwise to a solution of 5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine (10.71 g) in dry acetone (30 ml) during 15 minutes at -10° to 0°. To the stirred solution at -15° was added dropwise a solution of mercuric chloride (13.6 g) in dry acetone (20 ml) during 45 minutes. The solution was warmed to 0° and triethylamine (11.5 g) was added dropwise with stirring during 15 minutes. The mixture was refluxed for 45 minutes, the suspension filtered and the filtrate evaporated to dryness. The oily residue was dissolved in ether (150 ml), decolourising charcoal and excess anhydrous sodium sulphate were added and the suspension filtered after 2 hours. The filtrate was evaporated to dryness, the oily residue dissolved in ether and the solution chromatographed (alumina deactivated with water, 72.5 ml/kg/ether). The appropriate eluate was evaporated to give the title compound (5.05 g) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1CO
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
4-Bromo-2-methylbenzoic acid (11.1 g, 51.6 mmol) is dissolved in anhydrous THF (11.2 mL). The solution is cooled to 0-5° C. and a 1 M solution of BH3. THF (103 mL) is added to the mixture. The solution is left stirring 3 h at room temperature. Cold water is then added (20 mL) and the reaction mixture is washed with a saturated solution of NaHCO3 (120 mL). The aqueous phase is extracted with diethyl ether (3×300 mL) and the combined organic phases washed with brine (200 mL), dried with MgSO4 and concentrated in vacuo. The resulting oil is purified by flash-chromatography, eluting with hexane/EtOAc from 95:5 to 70:30, to provide the expected product (4-Bromo-2-methylphenyl)methanol (10.4 g, 100%) as a clear oil.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[O:12][N:11]=[C:10]([CH2:13][OH:14])[CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>ClCCl>[CH3:24][S:25]([O:14][CH2:13][C:10]1[CH2:9][CH:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[O:12][N:11]=1)(=[O:27])=[O:26]
Reactant: OCC1=NOC(CN2CCOCC2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCC1=NOC(CN2CCOCC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [5-(morpholin-4-ylmethyl)-4,5-dihydro-isoxazol-3-yl]methanol (0.38 g) in dichloromethane was added dropwise diisopropylethylamine (0.33 mL) and methanesulfonyl chloride (0.15 mL). The resulting solution was stirred at room temperature for 3 h and treated with water. The layers were separated and the organic layer was dried (Na2SO4) en concentrated in vacuo to afford [5-((morpholin-4-yl)methyl)-4,5-dihydro-isoxazol-3-yl]methanol methanesulfonate, 0.52 g (˜100%). Rf 0.63 (CH2Cl2/MeOH/NH4OH 92/7.5/0.5).