Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)[N:5]=[C:4]([NH:17][C:18]2[CH:26]=[C:25]3[C:21]([C:22](=[O:27])[NH:23][NH:24]3)=[CH:20][CH:19]=2)[N:3]=1.Cl.[CH3:29][O-:30].[Na+]>CO>[CH:14]1([C:12]2[CH:13]=[C:9]([NH:8][C:6]3[N:7]=[C:2]([O:30][CH3:29])[N:3]=[C:4]([NH:17][C:18]4[CH:26]=[C:25]5[C:21]([C:22](=[O:27])[NH:23][NH:24]5)=[CH:20][CH:19]=4)[N:5]=3)[NH:10][N:11]=2)[CH2:16][CH2:15]1
Reactant: C[O-]
Reactant: O=c1[nH][nH]c2cc(Nc3nc(Cl)nc(Nc4cc(C5CC5)n[nH]4)n3)ccc12
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc(Nc2ccc3c(=O)[nH][nH]c3c2)nc(Nc2cc(C3CC3)n[nH]2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.8 %

Procedure:
(6-[4-Chloro-6-(5-cyclopropyl-2H-pyrazol-3-ylamino)-[1,3,5]triazin-2-ylamino]-1,2-dihydro-indazol-3-one (70 mg, 0.14 mmol) was dissolved in 6 ml of 0.5 M solution of sodium methoxide in methanol and stirred at room temperature for 3 hours. The reaction was neutralized to pH 6-7 with 0.5 N hydrogen chloride. The cloudy solution was concentrated in vacuo. The resulting yellow solid was suspended in water, filtered, then purified by prep HPLC to afford 7.5 mg of the desired product as a white solid (10.8% yield). H-NMR (DMSO-d6, 500 mHz) δ 10.96 (s br, 1H), 9.76 (s br, 1H), 7.90 (s br, 1H), 7.44 (d, 1H), 7.18 (m, 1H), 6.02 (s br, 1H) 3.85 (s, 3H), 1.80 (s br, 1H), 0.84 (m, 2H), 0.61 (s br, 2H). MS (ES+): m/e=380.1 (M+H), 378.1 (M-H); LC/Method A/3.543 min, 90.0% purity by area %.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][OH:5].[H-].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[C:13](Cl)=[N:14][CH:15]=1.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:5][C:13]1[C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]([Br:9])=[CH:15][N:14]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 117.8 %

Procedure:
Hydroxy-acetic acid methyl ester (46 mg, 0.50 mmol) was dissolved in 2 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, and sodium hydride (40 mg, 1.0 mmol) was added thereto at room temperature. After stirring for 30 minutes, 5-bromo-2-chloro-3-nitro-pyridine (100 mg, 0.42 mmol) dissolved in 1 ml of anhydrous tetrahydrofuran was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction by adding water, the mixture was extracted with dichloromethane, and the organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of n-hexane:ethyl acetate=9:1. The fractions containing the product were collected and evaporated to obtain (5-bromo-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester as yellow solid (144 mg, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([S:18][CH2:19][CH2:20][NH2:21])[CH2:14]1.C(N(CC)CC)C.ClC(OCC)=O.[O:35]=[C:36]1[CH2:41][S:40][C:39]2[CH:42]=[CH:43][C:44]([C:46](O)=[O:47])=[N:45][C:38]=2[NH:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([S:18][CH2:19][CH2:20][NH:21][C:46]([C:44]2[CH:43]=[CH:42][C:39]3[S:40][CH2:41][C:36](=[O:35])[NH:37][C:38]=3[N:45]=2)=[O:47])[CH2:14]1
Reactant: COc1ccc2nccc(N3CCC(SCCN)C3)c2n1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2nccc(N3CCC(SCCNC(=O)c4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 1 h
Yield: 38.9 %

Procedure:
The hydrochloride salt of [2-({1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-pyrrolidinyl}thio)ethyl]amine (from Example 7b) (300 mg, 0.88 mmol) was dissolved in DCM (5 mL) with triethylamine (0.31 mL, 2.2 mmol) and cooled in an ice bath. The cooled solution was treated with ethyl chloroformate (0.15 mL, 1.59 mmol) and triethyl amine (0.79 mL, 5.3 mmol) and stirred for 1 h. 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (222 mg, 1.06 mmol) was added. After stirring at 25° C. for 12 h, the reaction mixture was diluted with chloroform and poured into saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined organic layers were washed with brine, dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 0-10% MeOH in CDCl3 (1% NH4OH) to afford the title compound as a white solid (170 mg, 39%): LC/MS m/z 497 (M+H)+; 1H NMR (CDCl3, 400 MHz) δ 8.33 (d, J=4.4 Hz, 1H), 8.29 (br, 1H), 8.2 (d, J=9.0 Hz, 1H), 8.02-8.06 (m, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.47 (d, J=4.4 Hz, 1H), 4.47-4.49 (m, 1H), 3.95-4.15 (m, 6H), 3.75-3.81 (m, 2H), 3.64-3.70 (m, 2H), 3.13-3.17 (m, 1H), 2.92-2.94 (m, 2H), 2.47-2.52 (m, 1H), 2.11-2.19 (m, 1H).
Reaction SMILES: [OH:1]O.C(N1[C@H](C)C[N:9]([C@H:13](C2C=C(C=CC=2)C#N)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16](O)[CH:15]=2)[C@@H](C)C1)C=C.[OH-].[Na+].Cl>C(O)C>[C:13]([NH2:9])(=[O:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OO
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C#N)c2)C[C@H]1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccccc1
Temperature: 60 °C

Procedure:
Hydrogen peroxide (0.5 mL of a 30% by weight solution) was added to a mixture of the benzonitrile (0.50 g, 1.4 mmol), 0.7 mL of 10 N aqueous sodium hydroxide and 3 mL of ethanol. The reaction was exothermic with gas evolution and formation of a white precipitate. After a few minutes, the mixture was carefully heated under a reflux condenser in an oil bath at 60° C. for three hours. After cooling to room temperature, 6 N aqueous hydrochloric acid was added to adjust the pH to 8. The mixture was evaporated to dryness under vacuum, and the residue was extracted between ethyl acetate and pH 8 buffer solution. The organic layer was washed with pH 8 buffer and brine, dried over sodium sulfate, and the solvent was evaporated to give 0.42 g (79%) of (±)-3-((αR*)-α-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzamide as a bright yellow solid.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13](=[O:20])[NH:12][C:11]1=[O:21])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[C:13](=[O:20])[NH:12][C:11]1=[O:21]
Reactant: CC(C)(C)[Si](C)(C)OCCCn1cc(C(F)(F)F)c(=O)[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c(=O)n(CCCO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
A solution of 1-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-5-trifluoromethyl-1H-pyrimidine-2, 4-dione (Prep 19, 0.86 g, 2.4 mmol) in DCM (10 mL) was cooled at 0° C. and then TFA (2.8 mL, 36 mmol) was added. The mixture was stirred for 1 hour at room temperature and then the solvent was evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (7-3) to afford the title compound (0.33 g, 57% yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1>ClCCl>[C:12]([Si:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:11])[CH3:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: Oc1ccc(I)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
4-Iodophenol (1.0 g, 4.55 mmol) was dissolved in dichloromethane (5 mL). tert-Butyldimethylsilyl chloride (0.685 g, 4.55 mmol) and imidazole (0.309 g, 4.55 mmol) were added. The reaction was stirred overnight at room temperature. The reaction mixture was partitioned between water (30 mL) and dichloromethane (30 mL). The organic layer was removed and the aqueous layer was extracted with dichloromethane (30 mL). The organic layers were combined, dried and concentrated, and the residue was purified by chromatography (0-10% EtOAc/hexanes) to give the title compound as a light yellow oil (1.45 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10]([CH2:13][C:14](O)=O)(=[O:12])=[O:11])=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18].N1CCCCC1.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:29]=1C=O>N1C=CC=CC=1>[CH3:26][O:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:29]=1/[CH:14]=[CH:13]/[S:10]([CH2:9][C:6]1[CH:5]=[C:4]([N+:17]([O-:19])=[O:18])[C:3]([O:2][CH3:1])=[N:8][CH:7]=1)(=[O:12])=[O:11]
Reactant: COc1cccc(OC)c1C=O
Reactant: COc1ncc(CS(=O)(=O)CC(=O)O)cc1[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1cccc(OC)c1/C=C/S(=O)(=O)Cc1cnc(OC)c([N+](=O)[O-])c1

Procedure:
A solution of 2-((6-methoxy-5-nitropyridin-3-yl)methylsulfonyl)acetic acid (0.29 g, 1 mmol) in dry pyridine (20 mL) was treated with piperidine (2 mL), followed by 2,6-dimethoxybenzaldehyde (0.17 g, 1 mmol). The mixture was refluxed for 6 h, and evaporated to dryness. The residue was purified by column chromatography using a mixture of EtOAc/PE (1:2, v/v) to yield the titled compound. HR-MS (ESI+) m/z 394.8362; C17H18N2O7S requires 394.0835.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:11]([O:10][C:8]([NH:6][CH2:5][CH2:4][CH2:3][Br:2])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCCCBr)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a stirred suspension of 3-bromopropylamine hydrobromide (2 g, 9.14 mM) in 40 mL dry THF was added, via hypodermic syringe, benzyl chloroformate (1.64 g, 9.60 mM) at room temperature. After cooling to 0° C., diisopropylethylamine (1.6 mL, 9.20 mM) was added dropwise via syringe and the reaction mixture was allowed to stir at 0° C. for 1 hour. The crude reaction mixture was filtered over a pad of Celite and solvents were evaporated. The residue was flash chromatographed on silica gel, eluting with 10-20-30% EtOAc/hexane to afford 1.56 g desired product as a liquid, homogeneous by TLC in 80:20 hexane-EtOAc;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][NH2:11]>C1COCC1>[CH3:10][NH:11][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: N#Cc1ccnc(Cl)n1
Solvent: C1CCOC1
Product: CNc1nccc(C#N)n1
Reaction time: 8 h

Procedure:
2-Chloro-4-pyrimidinecarbonitrile (14.1 g, 101 mmol, prepared according to the procedure of Daves et. al J. Het. Chem. 1964, 1, 130-132) in 100 ml THF was cooled to 0° C. Reaction progress was monitored as aliquots of methylamine solution (in THF, 2.0 M, Aldrich) were added dropwise over the course of 1 h (58 ml+15 ml+15 ml). The mixture was stirred overnight. Additional methylamine solution (15 ml) was added very slowly, and the reaction was stirred 10 min. After concentration, the residue was extracted with EtOAc (400 ml) and saturated aqueous NaHCO3 (15 ml), and the organic layer was washed with 100 ml brine. The combined aqueous layers were extracted with EtOAc again (200 ml), and this organic layer was washed with brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The orange solid was packed into a filtration apparatus, and submerged in just enough MeOH to cover the material (15 ml). Orange liquid was allowed to drain by gravity, then under high vacuum. The solid was washed in the same manner with t-BuOMe (15 ml). 2-Methylamino-pyrimidine-4-carbonitrile was obtained as peach-colored “fly-away” crystals. MS: 135.0 (M+1); Calc'd. for C6H6N4—134.14.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([C@H:22]([CH2:34][CH:35]=O)[CH2:23][N:24]([CH3:33])[C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:18]=[CH:19][C:20]=1[Cl:21].ClCCl.CO>O>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([C@H:22]([CH2:34][CH2:35][N:11]2[CH2:12][CH2:13][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)[CH2:9][CH2:10]2)[CH2:23][N:24]([CH3:33])[C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Oc1cccc(C2CCNCC2)c1
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CN(C[C@@H](CCN1CCC(c2cccc(O)c2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: Cl

Procedure:
Using a procedure similar to that described in Example 1 (alternative preparation), except using 4-(3-hydroxyphenyl)piperidine and (S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide, the title compound was prepared. Chromatography with dichloromethane:methanol followed by conversion to the hydrochloride salt gave a white solid; mp 178°-182° C.; MS: 511; NMR (CD3OD): 1.8-2.3 (m, 6), 2.8 (s, 3), 2.8-3.3 (m, 6), 3.4-3.9 (m, 4), 6.6-6.7 (m, 3), 7.0 (d, J=7, 1), 7.1-7.2 (m, 3), 7.3-7.6 (m, 6); [α]D =-40.3°, c=0.645 (methanol). Analysis for C29H2Cl2N2O2 ·1.0 HCl·0.5 H2O: Calculated: C, 62.54; H, 6.15; N, 5.03; Found: C, 62.19; H, 6.10; N, 5.0.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH:7]([F:9])[F:8])[C:5]([CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=1[F:19].C(=O)([O-])[O-].[K+].[K+].Cl[N:27]1[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[NH:28]1>CN(C)C=O>[Cl:1][C:2]1[N:6]([CH:7]([F:8])[F:9])[C:5]([CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[C:15]([O:17][N:27]2[N:28]=[C:29]([O:35][CH3:36])[CH:30]=[C:31]([O:33][CH3:34])[NH:32]2)[C:14]([Cl:18])=[CH:13][C:12]=1[F:19]
Reactant: Cc1nc(-c2cc(O)c(Cl)cc2F)c(Cl)n1C(F)F
Reactant: COC1=CC(OC)=NN(Cl)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC1=CC(OC)=NN(Oc2cc(-c3nc(C)n(C(F)F)c3Cl)c(F)cc2Cl)N1
Temperature: 110 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
5-Chloro-4-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-difluoromethyl-2-methylimidazole (prepared according to the procedure as described in EP 590,834) (0.31 g, 1 mMol) was dissolved in N,N-dimethylformamide (5 ml). Potassium carbonate (0.17 g, 1.2 mMol) and 2-chloro-4,6-dimethoxytriazine (0.21 g, 1.2 mMol) were added and the suspension stirred at 110° C. for 2 hours under an atmosphere of nitrogen. The mixture was processed and the residue chromatographed on silica gel eluting with methylene chloride:methanol, 98:2, to give the title compound (0.25 g, 55%). 1H NMR (CDCl3, TMS): 2.61 (3H, br s), 4.00 (6H, s), 7.17 (1H, t, J=58.1 Hz), 7.29 (1H, d, J=9.3 Hz), 7.53 (1H, d, J=6.6 Hz).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]([O:20][C:21](=[O:23])[NH2:22])[CH2:15][C:16]([N:18]=[O:19])=[O:17].C(Cl)(Cl)Cl.C(O)(=O)C>O>[Br:1][C:13]1[S:9][C:10]([CH:14]([O:20][C:21](=[O:23])[NH2:22])[CH2:15][C:16]([N:18]=[O:19])=[O:17])=[CH:11][CH:12]=1
Reactant: NC(=O)OC(CC(=O)N=O)c1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)OC(CC(=O)N=O)c1ccc(Br)s1
Reaction time: 24 h
Yield: 75.4 %

Procedure:
N-bromosuccinimide (1.79 g) was added in portions to a solution of (±)-(2-(2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide (2.2 g 9.5 mmol) in 40 ml of a 1:1 mixture of chloroform and acetic acid. The resulting suspension was stirred for 24 hours. The reaction mixture was then diluted with an equal volume of water and the separated organic layer was recovered, and sequentially washed with potassium hydroxide solution and water. The extracts were dried over sodium sulfate, filtered, concentrated and purified by recrystallization from dichloromethane to yield the title compound as a white solid (2.2 g). M.p. 160-161° (from dichloromethane).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[N:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][OH:25])=[CH:21][CH:20]=1>CN1C(=O)CCC1.O>[Cl:17][C:13]1[CH:12]=[C:11]([C:4]2[N:3]=[C:2]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][OH:25])=[CH:21][CH:20]=3)[CH:7]=[C:6]([CH:8]3[CH2:10][CH2:9]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Clc1cccc(-c2nc(Cl)cc(C3CC3)n2)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: OCCc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)cc1
Temperature: 120 °C
Yield: 72.6 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6-cyclopropylpyrimidine (0.100 g, 0.38 mmol) and 4-aminophenethyl alcohol (0.103 g, 0.75 mmol) in NMP (3 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 1 h. The reaction mixture was cooled, diluted with water (20 mL) affording a solid. The solid was isolated by filtration and purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 1:1) as eluent to afford the title compound (0.101 g, 73%) as a white solid. MW=365.86. M.p. 124-126° C. 1H NMR (DMSO-d6, 500 MHz) δ 9.46 (s, 1H), 8.27-8.21 (m, 2H), 7.62-7.51 (m, 4H), 7.21 (d, J=8.5 Hz, 2H), 6.62 (s, 1H), 4.61 (br s, 1H), 3.60 (t, J=7.0 Hz, 2H), 2.70 (t, J=7.0 Hz, 2H), 2.06-1.99 (m, 1H), 1.11-1.06 (m, 2H), 1.02-0.95 (m, 2H); ESI MS m/z 366 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]#[C:12][CH2:13][CH2:14][OH:15]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: COc1ccc(C#CCCO)c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CCCCO)c(OC)c1
Yield: 89.7 %

Procedure:
To a solution of 75 (4.2 g, 0.022 mol) in ethanol (approx. 200 mL) was added palladium (5% wet on activated carbon, 1 g). Then the mixture was hydrogenated at 40 psi overnight at room temperature. The mixture was filtered through a pad of silica gel and the solvent was evaporated to give 76 (4.15 g, 97%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.59 (m, 4H), 2.55 (m, 2H), 3.79 (s, 6H), 6.43 (m, 2H), 7.00 (m, 1H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:28][C:29]([F:32])([F:31])[F:30])[S:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:20])=[O:19])=[C:12]([F:33])[CH:11]=1.IC>O1CCCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:28][C:29]([F:30])([F:31])[F:32])[S:18]([CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:1])(=[O:20])=[O:19])=[C:12]([F:33])[CH:11]=1
Reactant: O=S(=O)(Cc1ccccc1)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Reactant: CC(C)NC(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CI
Product: CC(c1ccccc1)S(=O)(=O)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a solution of lithium diisopropylamine (2.0 M in THF/heptane/ethylbenzene) (1.2 mL, 2.5 mmol) at −78° C. was slowly added a solution of N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide (1 g, 2.3 mmol) in tetrahydrofuran (11 mL) and the reaction was stirred at −78° C. for 1 hour. Iodomethane (0.16 mL, 2.5 mmol) was then added and the reaction was warmed to ambient temperature and stirred for 2 hours. The reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc, washed with 1 N aqueous HCl, and brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (0-30% EtOAc in heptane) to give N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)ethanesulfonamide (614 mg, 60% yield). LCMS (m/z) ES+ 471 [M+18]+.
Reaction SMILES: [CH:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[CH2:2].[CH2:8]([Br:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CO>C(OCC)C>[Br-:22].[CH:1]([N+:3]1[CH:7]=[CH:6][N:5]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])[CH:4]=1)=[CH2:2]
Reactant: C=Cn1ccnc1
Reactant: CCCCCCCCCCCCCCBr
Solvent: CCOCC
Solvent: CO
Product: C=C[n+]1ccn(CCCCCCCCCCCCCC)c1
Product: [Br-]
Temperature: 60 °C
Reaction time: 15 h

Procedure:
(From Yuan & Antonietti, DOI: 10.1021/ma102858b.) A solution/suspension comprising 0.1 mol of 1-vinylimidazole, 0.1 mol of n-tetradecyl bromide and 30 mL of methanol were loaded into a 100 mL reactor. The mixture was stirred at 60° C. for 15 h. After cooling the reaction mixture was added dropwise into 1 L of diethyl ether. The white precipitate was filtered off and dried at room temperature to yield a powder.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:8]([S:15]([NH2:18])(=[O:17])=[O:16])=[C:9]([N+:12]([O-])=O)[S:10][CH:11]=1)(=[O:4])=[O:3]>[Pd].O1CCCC1>[NH2:12][C:9]1[S:10][CH:11]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:8]=1[S:15]([NH2:18])(=[O:16])=[O:17]
Reactant: CS(=O)(=O)NCc1csc([N+](=O)[O-])c1S(N)(=O)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CS(=O)(=O)NCc1csc(N)c1S(N)(=O)=O
Reaction time: 17 h

Procedure:
Palladium on carbon (10%, 0.150 g, dry) was added to a solution of 4-(methanesulfonylamino-methyl)-2-nitro-thiophene-3-sulfonic acid amide (0.156 g, 0.495 mmol) in tetrahydrofuran (12 mL) at 25° C. The flask was degassed and backfilled with hydrogen gas via balloon and the mixture was stirred under a positive pressure of hydrogen (2 balloons) for 17 h. The mixture was then filtered through Celite and the Celite was washed with tetrahydrofuran (3×20 mL). The combined filtrate and washings were concentrated in vacuo to afford the crude product, 2-amino-4-(methanesulfonylamino-methyl)-thiophene-3-sulfonic acid amide, as a yellow oil. This material was used in subsequent synthetic transformations without additional purification.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][O:8][CH:7]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:6]1)=[O:4].C1COCC1.[OH-].[Li+]>O>[C:12]([O:11][CH2:10][C@@H:7]1[O:6][C@@H:5]([C:3]([OH:4])=[O:2])[CH2:9][O:8]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@H]1COC(COC(=O)c2ccccc2)O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OC[C@H]1OC[C@H](C(=O)O)O1)c1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of methyl-2-(R, S)-benzoyloxymethyl-1,3-dioxolane-4-(R)-carboxylate, (411 g, 1.54 mmol, 1 eq., 2:1 mixture of cis and trans isomers) in a 1:1 mixture of THF and water, lithium hydroxide (64.8 g, 1.54 moles, 1 eq) was added portionwise over a period of 30 min., keeping the reaction flask temperature below 30° C. After 90 min., THF was removed by vacuum and the aqueous solution was acidified to pH 2.5-3.2, by dropwise addition of 30% (w/w) sulphuric acid. The resulting solution was extracted with dichloromethane (4×400 mL). The combined organic phase was washed with brine, dried over sodium sulphate and concentrated to produce 380 g of a dark oil. The isomers were separated by column chromatography on silica gel, using 2% acetic acid in dichloromethane to produce 220 g of the cis isomer (56.5%) and 116 g of the trans isomer (30%). Each of isomers was independently used for next step.