Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:11]3[CH:12]=[C:13]([O:16][C@@H:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C@@H:20]([NH2:27])[CH2:19][CH2:18]4)[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: N[C@H]1CC[C@H](Oc2ccc3nnc(N4CCCCC4)n3c2)c2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)cc1
Yield: 20 %

Procedure:
A mixture of Intermediate 55a (120 mg, 0.33 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 147 mg, 0.36 mmol), DIPEA (86.0 μL, 110.50 mmol) and 1,4-dioxane (2.5 mL) were heated to 60° C. for 18 h. After cooling the solvent was evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give a pale yellow foam. This was lyophilised to provide the title compound as an off-white solid (28 mg, 20%). LCMS (Method 5) Rt 4.76 min, m/z 619 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.61 (2H, m), 1.72 (5H, m), 2.02-2.17 (3H, m), 2.35 (3H, s), 3.13 (4H, m), 4.90 (1H, m), 5.58 (1H, m), 6.31 (1H, s), 6.99 (1H, d, J 7.8), 7.19 (1H, dd, J 9.7, 2.2), 7.26-7.43 (8H, m), 7.58-7.64 (2H, m), 7.98 (1H, s).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([C:18]3([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[CH2:21][CH2:20][CH2:19]3)=[O:17])[CH2:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+].O>CO>[F:34][C:2]([F:1])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH:16]([C:18]3([C:22]4[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=4)[CH2:21][CH2:20][CH2:19]3)[OH:17])[CH2:10]2)=[CH:32][CH:33]=1
Reactant: O=C(CN1CCCC(COc2ccc(C(F)(F)F)cc2)C1)C1(c2ccc(C(F)(F)F)cc2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(CN1CCCC(COc2ccc(C(F)(F)F)cc2)C1)C1(c2ccc(C(F)(F)F)cc2)CCC1
Yield: 69.7 %

Procedure:
2-[3-(4-Trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-1-[1-(4-trifluoromethyl-phenyl)-cyclobutyl]-ethanone (30 mg) was dissolved in 3 mL of dry methanol and solid sodium borohydride (10 equiv.) was added in portions. Water (10 mL) was added and the mixture was extracted with ether and the ether extracts were concentrated in vacuo and purified on silica gel to give the desired 2-[3-(4-Trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-1-[1-(4-trifluoromethyl-phenyl)-cyclobutyl]-ethanol (21 mg, 67%). Data for this mixture of diastereomeric amino alcohols: MS 502 (M+1); 1H NMR (300 MHz, CDCl3): δ 7.5-7.6 (m, 4H), 7.29-7.35 (m, 2H), 6.89-6.96 (overlapping doublets, total 2H), 3.8-4.0 (m, 4H, 1 of which is exchanged upon exposure to D2O), 1.1-3.1 g (various overlapping multiplets totaling 17H); 13C NMR (75 MHz, CDCl3): δ 207 peak in starting ketone is absent. Most peaks are doubled (adjacent equal intensity peaks) due to diastereoisomerism: δ 161.7, 151.0, 128.6 & 128.5, 128.0 & 127.8, 127.15 & 127.10, 126.45, 124.91 & 124.87, 123.30, 122.86, 114.63, 71.2 & 71.1, 59.7 & 59.5, 58.99 & 58.97, 55.96, 49.31 & 49.28, 36.8 & 36.6, 31.0, 29.5 & 29.4, 27.33 & 27.26, 25.24 & 25.03, 16.42.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]3[CH:27]=[C:26]([CH2:28]Cl)[CH:25]=[N:24][C:18]=3[N:19]([CH2:22][CH3:23])[C:20]=2[N:21]=1>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]3[CH:27]=[C:26]([CH2:28][S:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:25]=[N:24][C:18]=3[N:19]([CH2:22][CH3:23])[C:20]=2[N:21]=1
Reactant: Sc1ccccc1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1c2ncc(CSc3ccccc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reaction time: 18 h
Yield: 61.3 %

Procedure:
To a solution of thiophenol (0.16 mL, 1.6 mmol) in N,N-dimethylformamide (15 mL) was treated with sodium hydride (60% wt, 62 mg, 1.6 mmol). After stirring 15 minutes the 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.50 g, 1.5 mmol) was added and the mixture was stirred for 18 hours more. The excess thiolate was quenched with methanol and the mixture was diluted with aqueous sodium bicarbonate and extracted with dichloromethane. The organics were dried over sodium sulfate, filtered, concentrated and the residue was purified by flash chromatography (hexanes/ethyl acetate) and recrystallization from hexanes/ethyl acetate to give the title compound (0.378 g, 62%), m.p. 92°-93° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]=[C:6]1[O:10][C:8](=[O:9])[CH2:7]1>O1CCCC1>[CH:1]1([NH:4][C:8](=[O:9])[CH2:7][C:6](=[O:10])[CH3:5])[CH2:3][CH2:2]1
Reactant: C=C1CC(=O)O1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81578.9 %

Procedure:
26 ml (0.38 mmol) cyclopropylamine was added dropwise to a solution of 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 43.83 g (0.31 mol, 87% yield) of a white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[CH:15][CH:16]=1)#[N:5]
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(Oc2ccccc2C#N)c1
Temperature: 160 °C

Procedure:
4.23 g (35 mmol) of 2-fluorobenzonitrile, 6.3 g (35 mmol) of ethyl 3-hydroxyphenylacetate and 4.84 g of potassium carbonate (anhydrous) are dissolved in 40 ml of dimethylformamide and heated with stirring to a temperature of 160° C. Ethyl 3-(2-cyanophenoxy)-phenylacetate is formed takes place [sic]. The mixture is stirred for three hours while maintaining the temperature. The cooled reaction solution is treated with 150 ml of water and extracted with methyl t-butyl ether. The organic phase is separated off, washed with water and NaCl solution and dried. After distilling off the solvent, the product is obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[C@H:25]1([NH2:32])[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1.C(N(CC)CC)C>CS(C)=O>[NH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:32][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]4[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:26][CH2:27]1
Reactant: C[C@@H]1CC(CNc2cccc(-c3cc(F)ncc3Cl)n2)C[C@H](C)O1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CC(CNc2cccc(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)n2)C[C@H](C)O1
Temperature: 110 °C

Procedure:
The mixture of 5′-chloro-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2′-fluoro-2,4′-bipyridin-6-amine L (30 mg, 0.08 mmol), trans-1,4-cyclohexanediamine (49 mg, 0.43 mmol) and triethylamine (26 mg, 0.25 mmol) in 1.5 ml DMSO was heated in a reaction vesel at 110° C. in an oil bath for 16 h. Formation of desired product was confirmed by LC/MS. The reaction mixture solution was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. Crude compound was purified by HPLC to give desired product as TFA salt. LCMS (m/z): 444.2/446.2 (MH+), retention time=0.54 min.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:26]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:27]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C(=O)C1CCCCC1)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.72 mmol), cyclohexanecarbonyl chloride (0.22 g, 1.5 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 2 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was successively washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (1:1, v/v). The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.20 g, 71%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.C>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([S:19]([NH2:22])(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: NS(=O)(=O)c1cccc(C#CCCOCCCCCCBr)c1
Product: NS(=O)(=O)c1cccc(CCCCOCCCCCCBr)c1
Temperature: 20 °C
Reaction time: 6 h
Yield: 78.8 %

Procedure:
3-{4-[(6-Bromohexyl)oxy]but-1-ynyl}benzenesulfonamide (627 g) in IMS (1900 ml) was stirred with activated charcoal (314 g) at room temperature for 2 h and then filtered through a short pad of Celite. The filter pad was washed with IMS (4300 ml) and the filtrate transferred to a hydrogenation vessel. 5% Platinum on Charcoal (520.1 g, ˜50% water) was added and the reaction mixture was then stirred under an atmosphere of hydrogen (0.2 bar) at 20° C. for 6 h. The mixture was then filtered through a short pad of Celite and concentrated under reduced pressure to give the title compound (499 g) as a solid, LC RT=5.66, δ (DMSO-d6) 7.65 (1H, s), 7.64 (1H, d, J 9.2 Hz), 7.47 (1H, m), 7.42 (1H, m), 7.31 (2H, s), 3.50 (2H, t, J 6.9 Hz), 3.34 (4H, m), 2.66 (2H, t, J 7.5 Hz), 1.78 (2H, m), 1.62 (2H, m), 1.49 (4H, m), 1.37 (2H, m), 1.30 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:9][S:10][C:6]=2[C:5]([Cl:15])=[C:4]([OH:16])[CH:3]=1.OS(O)(=O)=O.[CH3:22]O>>[CH3:22][O:13][C:12](=[O:14])[CH2:11][C:8]1[C:7]2[C:2]([Cl:1])=[CH:3][C:4]([OH:16])=[C:5]([Cl:15])[C:6]=2[S:10][CH:9]=1
Reactant: O=C(O)Cc1csc2c(Cl)c(O)cc(Cl)c12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1csc2c(Cl)c(O)cc(Cl)c12
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
A mixture of methyl(4,7-dichloro-6-methoxy-1-benzothiophen-3-yl)acetate (300.9 mg), DMF (dry) (9.0 mL) and sodium 2-methyl-2-propanethiolate (442 mg) was stirred at 160° C. for 20 min. The mixture was quenched with water and 1N HCl and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo to give (4,7-dichloro-6-hydroxy-1-benzothiophen-3-yl)acetic acid (327 mg) as a crude mixture. A crude mixture of (4,7-dichloro-6-hydroxy-1-benzothiophen-3-yl)acetic acid (369 mg) was dissolved in MeOH (10 mL). To the solution was added conc. H2SO4 (0.100 mL). The mixture was stirred at 80° C. for 40 min. The mixture was concentrated. The residue was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The solid was washed with hexane to give the title compound (345 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C@@H:14]([CH3:17])[CH2:15][OH:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:18]=O.[BH4-].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:18])[C@@H:14]([CH3:17])[CH2:15][OH:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN[C@@H](C)CO)cc1OC
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CCN(C)[C@@H](C)CO)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.1 %

Procedure:
To a solution of 6.25 g of (0.026 mole) (S)-2-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-1-propanol in 50 ml of MeOH under argon was added 3.9 ml (0.052 mole) of 37% aqueous formaldehyde and 4.7 g of sodiumborohydride pellets added one at a time. The solution was stirred at RT for 24 hr. an additional 1.0 ml of 37% aqueous formaldehyde and 1.0 g of sodium borohydride were added and the solution stirred for an additional 2.5 hr. Enough glacial acetic acid was added to react with the sodium borohydride. The reaction was made basic by addition of 3N sodium hydroxide. The methanol was evaporated in vacuo and the residue was extracted three times with ether. The organics were washed with brine an dried (K2CO3). Evaporation of the solvent in vacuo gave 5.74 g of (S)-2-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-1-propanol as an oil (87% yield).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCCl>[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Reactant: COc1ccc(OCCCN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(OCCCNCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Reaction time: 8 h

Procedure:
3-tert-Butyldimethylsilyloxybenzaldehyde (1.5 g, 6.34 mmol) was dissolved in 1,2-dichloroethane (10.0 mL). Subsequently, 3-(4-methoxyphenoxy)propylamine (1.5 g, 8.25 mmol) was added thereto, and the resultant mixture was stirred for 20 minutes. At room temperature, sodium triacetoxyborohydride (1.75 g, 8.25 mmol) and acetic acid (495 mg, 8.25 mmol) were added thereto, and the mixture was stirred overnight. A saturated aqueous sodium hydrogencarbonate solution was added thereto. The reaction mixture was extracted with chloroform, and the organic layer was washed with brine. The resultant mixture was subjected to drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=50/1), whereby the target compound was obtained (1.9 g, 78%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH3:23])([CH3:22])[C:15](=[O:21])[N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>ClCCl.C(OCC)C>[ClH:24].[CH3:23][C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)([CH3:22])[C:15]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)C(=O)N2CCCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C(=O)N1CCCC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.745 g) in dichloromethane (10 mL) was added 2M hydrogen chloride in diethyl ether (4 mL) and the mixture stirred at room temperature for 12 hours. The solvent was evaporated to give 2-methyl-2-piperazin-1-yl-1-pyrrolidin-1-yl-propan-1-one hydrochloride salt as a beige solid. Reductive amination with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde using the standard method in the presence of triethylamine gave the title compound as a white solid (0.355 g).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1.[C:24](=[O:26])=[O:25].Cl>C1COCC1>[Cl:16][C:17]1[C:22]([C:24]([OH:26])=[O:25])=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1
Reactant: O=C=O
Reactant: Clc1cncc(Cl)n1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ncc(Cl)nc1Cl
Reaction time: 0.5 h

Procedure:
To a THF solution of 2,2,6,6-tetramethylpiperidine was added n-butyllithium under ice cooling and was further added a THF solution of 2,6-dichloropyrazine at −78° C. After 30 minutes of stirring, dry ice was added to the reaction mixture and, after 30 minutes of stirring, 1 M hydrochloric acid was added thereto. Thereafter, purification in the usual way afforded 3,5-dichloropyrazine-2-carboxylic acid (pale yellow solid). FAB-MS: 191 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][NH:6][C:7]([C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH3:10])=O.B.O1CCCC1.CO>O1CCCC1>[C:15]([O:14][C:13](=[O:19])[NH:12][C:9]([CH3:11])([CH3:10])[CH2:7][NH:6][CH2:5][C:4]1[CH:20]=[CH:21][C:22]([Cl:23])=[C:2]([Cl:1])[CH:3]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)NCc1ccc(Cl)c(Cl)c1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(CNCc1ccc(Cl)c(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The crude crystals (1.0 g) of tert-butyl [1-(3,4-dichlorobenzylcarbamoyl)-1-methylethyl]carbamate obtained in the previous step was dissolved in tetrahydrofuran (5 ml) and cooled to 0° C. under an argon atmosphere. A borane-tetrahydrofuran complex (1.0 M/tetrahydrofuran solution) (15 ml) was added dropwise at the same temperature, removed from an ice-bath and stirred at room temperature for 2 hr. A borane-tetrahydrofuran complex (1.0 M/tetrahydrofuran solution) (5 ml) was added every 30 minutes twice in total. To the obtained reaction mixture was added methanol (10 ml) under ice-cooling, and the solvent was evaporated. The obtained residue was dissolved in tetrahydrofuran (10 ml) and 1N aqueous sodium hydroxide solution (4 ml) and the mixture was stirred at 90° C. for 1 hr. The obtained reaction mixture was extracted twice with toluene, and the combined organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica-gel column chromatography (hexane:ethyl acetate=l:l) to give tert-butyl[2-(3,4-dichlorobenzylamino)-1,1-dimethylethyl]carbamate (290 mg).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1>O>[CH:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([CH:9]([CH3:10])[CH3:11])[CH:6]([OH:8])[CH2:7]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Solvent: O
Product: CC1CCC(C(C)C)C(O)C1

Procedure:
In a control experiment, l-menthol (12 g) is stirred with water (876 g) for 2 h, initially at 47° C., then at ambient temperature, but no homogeneous mixture results. Menthol is isolated by filtration. Gas chromatography analysis shows that the clear aqueous solution contains 0.06% menthol.
Reaction SMILES: [CH2:1]([N:5]([CH2:36][CH2:37][CH2:38][CH3:39])[C:6]([C:8]1[N:9]=[C:10]([C:23]2[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][C:24]=2[C:25]([OH:27])=O)[N:11]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[Si:40]([O:47][CH2:48][C@@H:49]1[CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51][NH:50]1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>>[Si:40]([O:47][CH2:48][C@@H:49]1[CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51][N:50]1[C:25]([C:24]1[CH:28]=[C:29]([CH:30]=[CH:31][C:23]=1[C:10]1[N:11]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:36][CH2:37][CH2:38][CH3:39])[N:9]=1)[C:32]([O:34][CH3:35])=[O:33])=[O:27])([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1Cc2ccccc2CN1
Reactant: CCCCN(CCCC)C(=O)c1cn(CCCN2CCN(C)CC2)c(-c2ccc(C(=O)OC)cc2C(=O)O)n1
Product: CCCCN(CCCC)C(=O)c1cn(CCCN2CCN(C)CC2)c(-c2ccc(C(=O)OC)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)n1
Yield: 93.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 271H, 2-(4-(dibutylcarbamoyl)-1-(3-(4-methylpiperazin-1-yl)propyl)-1H-imidazol-2-yl)-5-(methoxycarbonyl)benzoic acid (110 mg, 0.2 mmol) and (S)-3-((tert-butyldimethylsilyloxy)methyl)-1,2,3,4-tetrahydroisoquinoline (73 mg, 0.26 mmol) were converted to the title compound (150 mg, 93%). MS(ESI+) m/z 802.4 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:14]([CH3:15])=[CH:13][C:8]2[NH:9][C:10]([SH:12])=[N:11][C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2].[OH-].[Na+].Cl.[CH3:19][O:20][C:21]1[C:22]([CH2:29]Cl)=[N:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>O.CO>[C:1]([C:5]1[C:14]([CH3:15])=[CH:13][C:8]2[NH:9][C:10]([S:12][CH2:29][C:22]3[C:21]([O:20][CH3:19])=[C:26]([O:27][CH3:28])[CH:25]=[CH:24][N:23]=3)=[N:11][C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COc1ccnc(CCl)c1OC
Reactant: COC(=O)c1cc2nc(S)[nH]c2cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2nc(SCc3nccc(OC)c3OC)[nH]c2cc1C
Reaction time: 1 h
Yield: 92 %

Procedure:
5-Carbomethoxy-6-methyl-2-mercapto-1H-benzimidazole (0.67 g, 0.003 mol) and NaOH (0.12g, 0.003 mol) in H2O (0.6 ml) were dissolved in CH3OH (15 ml). 3,4-dimethoxy-2-chloromethylpyridine hydrochloride, (=0.0036 mol) as a crude material in CH3OH (10 ml) and NaOH (0.144 g, 0.0036 mol) in H2O (0.72 ml) were added. The mixture was heated to reflux and the reflux was continued for 1 hour. CH3OH was evaporated off and the crude material was purified by chromatography on a silica column using CH2Cl2 --CH3OH (98-2) as eluent, giving (1.03 g, 92%) of the pure title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:14][C:13](=O)[CH2:12][N:11]3[C:7](=[N:8][C:9]([CH2:16][O:17][CH3:18])=[N:10]3)[C:6]=2[CH:19]=1.ClC1C=CC2NC(=O)C[N:30]3[C:26](=[N:27][C:28](COC)=[N:29]3)C=2C=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:29]3[CH:28]=[N:27][CH:26]=[N:30]3)[CH2:12][N:11]3[C:7]([C:6]=2[CH:19]=1)=[N:8][C:9]([CH2:16][O:17][CH3:18])=[N:10]3
Reactant: COCc1nc2n(n1)CC(=O)Nc1ccc(Cl)cc1-2
Reactant: COCc1nc2n(n1)CC(=O)Nc1ccc(Br)cc1-2
Product: COCc1nc2n(n1)CC(n1cncn1)=Nc1ccc(Br)cc1-2
Yield: 79 %

Procedure:
As described for example 4e) 9-bromo-2-methoxymethyl-6H-1,3,3a,6-tetraaza-benzo[e]azulen-5-one (12.5 g, 38.7 mmol), instead of 9-chloro-2-methoxymethyl-6H-1,3,3a,6-tetraaza-benzo[e]azulen-5-one, was converted to the title compound (11.4 g, 79%) which was obtained as a light yellow solid. MS: m/e=373.0/375.1 [M+H]+.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)C>Cl.O>[CH:1](=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: Nc1ccccc1
Reactant: O=Cc1ccccc1O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Oc1ccccc1C=Nc1ccccc1
Temperature: 25 °C
Yield: 42.7 %

Procedure:
To a mixture of salicylaldehyde (40 mL, 45.84 g, 375.37 mmol)) and aniline (22 mL, 31.72 g, 374.66 mmol), was added ethanol (90 mL), 8 drops of concentrated hydrochloric acid and water (10 mL). This reaction mixture was refluxed for one hour, allowed to cool to room temperature and left in the refrigerator over the weekend. A large quantity of orange solid was formed after 2 hours in the refrigerator. It was filtered off and washed with ethanol. Recrystallisation from ethanol afforded 31.53 g of product.