Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[NH2:14][CH:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:20]2)[CH3:16].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:14][CH:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:20]2)[CH3:16])=[O:8]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Reactant: COC(=O)N1CCc2cc(C(C)N)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)N1CCc2cc(C(C)NC(=O)C=Cc3ccc(F)cc3F)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2,4-difluorocinnamic acid (0.5 mmol), (±)-5-(1-aminoethyl)-2,3-dihydro-indole-1-carboxylic acid, methyl ester, Preparation 20 (132 mg, 0.6 mmole), EDC hydrochloride (192 mg, 1.0 mmole), DMAP (61 mg, 0.5 mmole), and triethylamine (202 mg, 2 mmole) in CH2Cl2 (8 mL) was stirred at room temperature for 16 hours. Water was added, the aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The crude product was purified by flash column chromatography on silica eluting with EtOAc/hexane (7:3) to give the title compound (125 mg) as a solid.
Reaction SMILES: CCN(CC)CC.[CH2:8]1[CH2:14][O:13][CH2:12][CH2:11][NH:10][CH2:9]1.Cl.[O:16]1[C:20]2([CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[O:16]1[C:20]2([CH2:25][CH2:24][CH:23]([N:10]3[CH2:9][CH2:8][CH2:14][O:13][CH2:12][CH2:11]3)[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: C1CNCCOC1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: C1COCCN(C2CCC3(CC2)OCCO3)C1
Reaction time: 0.17 h
Yield: 101.9 %

Procedure:
Et3N (96.9 mL, 0.695 mol) was added in one portion to a stirred suspension of homomorpholine hydrochloride (79.76 g, 0.579 mol) and 1,4-dioxaspiro[4.5]decan-8-one (90.5 g, 0.579 mol) in 1,2-dichloroethane (1.81 L). Then glacial acetic acid (34.8 mL, 0.607 mol) was added in one portion followed by solid NaBH(OAc)3 (154 g, 0.727 mol) in one portion as well. This was accompanied by 5° C. increase in the temperature of the reaction mixture. After 2 h 45 min the reaction was quenched by addition of 10% aqueous NaOH (800 mL). The mixture was stirred for 10 min. The organic layer was separated, washed with brine (100 mL), dried (MgSO4) and concentrated to afford an oil (142.36 g) with some suspended solid, which was filtered off (3.00 g). The aqueous part of the reaction mixture was combined with the brine washings and extracted with EtOAc (4×500 mL). Combined extracts were washed with brine (100 mL), dried (MgSO4) and concentrated to afford additional portion of oil (16.82 g). The two oily products were combined and distilled in vacuum to give 8 (101.07 g, 72%) as colorless liquid, b.p. 122° C./8.9·10−3 mbar. 1H NMR (400 MHz, CDCl3) δ 1.48-1.64 (m, 4H), 1.70-1.88 (m, 6H), 2.50-2.63 (m, 1H), 2.71-2.81 (m, 4H), 3.66-3.72 (m, 2H), 3.78 (t, J=6.0 Hz, 2H), 3.93 (s, 4H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[O:12][C:13]([F:16])([F:15])[F:14])[NH2:8])(=[O:4])=[O:3].Cl.C1(C)C=CC=CC=1.Cl[C:26](OC(Cl)(Cl)Cl)=[O:27]>C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:8]=[C:26]=[O:27])[CH:9]=[CH:10][C:11]=1[O:12][C:13]([F:14])([F:15])[F:16])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc(N)ccc1OC(F)(F)F
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cc(N=C=O)ccc1OC(F)(F)F
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 3-methylsulfonyl-4-trifluoromethoxyaniline (2.0 mmol, 500 mg) dissolved in ethyl acetate (6 ml) was added 3N HCl in ethyl acetate (5 ml) followed by concentration in vacuo. The residue was treated with toluene (3×5 mL) and each time concentrated in vacuo. To the residue was added toluene (10 mL) and trichloromethyl chloroformate (6 mmol, 0.73 mL), and under a N2-atmosphere the suspension was gently refluxed for 2 hours at 120° C. Additional trichloromethyl chloroformate (6 mmol, 0.73 mL) was added and refluxing was continued overnight. The reaction mixture was concentrated in vacuo to afford 3-methylsulfonyl-4-trifluoromethoxyphenyl isocyanate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:29]([CH3:34])[C:30](OC)=[O:31])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH3:35][NH2:36]>>[CH3:35][NH:36][C:30](=[O:31])[C@H:29]([O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2)[CH3:34]
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: CN
Product: CNC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Yield: 86 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.55 mmol) was reacted with methylamine to give the title compound as a beige solid (213 mg, 86%); NMR Spectrum 1.65 (d, 3H), 2.67 (d, 3H), 5.16 (q, 1H), 5.77 (s, 2H), 6.96 (d, 1H), 7.00 (d, 1H), 7.29 (m, 1H), 7.36 (d, 1H), 7.72 (m, 4H), 8.17 (s, 1H), 8.38 (m, 1H), 8.53 (m, 3H), 10.68 (br s, 1H); Mass spectrum MH+ 454.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:2]12>CN1CCCC1=O.CN1C(=O)N(C)CC1.[Cl-].[Li+]>[C:2]1(=[O:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCCCCC2OC2CCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCN(C)C1=O
Solvent: CN1CCCC1=O
Product: O=C1CCCCCCCCCCC1
Yield: 94 %

Procedure:
For example, German Patent DE3744094 discloses a technique where an epoxycyclododecane is isomerized by using N-methylpyrrolidone or N,N′-dimethylethyleneurea as a solvent and using lithium chloride as a catalyst and thereby a cyclododecanone is obtained in a yield of 94%.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[C:6](Cl)[C:5]=1[Cl:12].[CH3:13][O:14][CH2:15][CH2:16][OH:17]>>[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[C:6]([O:17][CH2:16][CH2:15][O:14][CH3:13])[C:5]=1[Cl:12]
Reactant: Nc1c(Cl)cnc(Cl)c1Cl
Reactant: COCCO
Agent: [K+]
Agent: [OH-]
Product: COCCOc1ncc(Cl)c(N)c1Cl
Temperature: 118 °C

Procedure:
A solution of 16.5 grams (0.25 mole) of 86 percent potassium hydroxide dissolved in 100 milliliters of 2-methoxyethanol was added to a mixture of 49.5 grams (0.25 mole) of 4-amino-2,3,5-trichloropyridine in 150 milliliters of 2-methoxyethanol. The mixture was heated, with agitation, to 118° C. and held between 118°-120° C. for 31/2 hours. The reaction mixture was cooled to 75° C. and filtered under reduced pressure to remove the insoluble solids. The excess 2-methoxyethanol was evaporated off under reduced pressure and the liquid residue remaining was crystallized from hexane. The 4-amino-3,5-dichloro-2-(2-methoxyethoxy)pyridine product was recovered by filtration under reduced pressure, and obtained in a yield of 57 grams melting at 92°-93.5° C.
Reaction SMILES: C([O:3][C:4](=[O:28])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[C:19]([CH2:21][N:22]([CH:24]3[CH2:26][CH2:25]3)[CH3:23])[CH:18]=[CH:17][C:16]=2[CH3:27])=[CH:9][CH:8]=1)C.[OH-].[K+].Cl>C(O)C.O1CCCC1>[CH:24]1([N:22]([CH2:21][C:19]2[CH:18]=[CH:17][C:16]([CH3:27])=[C:15]([C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7](/[CH:6]=[CH:5]/[C:4]([OH:28])=[O:3])=[CH:12][CH:11]=3)[CH:20]=2)[CH3:23])[CH2:25][CH2:26]1
Reactant: CCOC(=O)/C=C/c1ccc(C#Cc2cc(CN(C)C3CC3)ccc2C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(CN(C)C2CC2)cc1C#Cc1ccc(/C=C/C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A solution of (E)-3-(4-{5-[(cyclopropyl-methyl-amino)-methyl]-2-methyl-phenylethynyl}-phenyl)-acrylic acid ethyl ester (Intermediate 100, 0.14 g, 0.37 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with a 3M solution of potassium hydroxide (1 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230–400 mesh) using 5% methanol in ethyl acetate as the eluent to afford the title product as an amorphous solid (0.071 g, 55%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:58]=[CH:57][C:13]([CH2:14][N:15]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C:23]3[C:24]([NH:40][C:41]4[CH:42]=[CH:43][C:44]([NH2:47])=[N:45][CH:46]=4)=[N:25][CH:26]=[C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:32][CH2:31]4)[CH:28]=3)[N:17]=2)=[CH:12][CH:11]=1.N1C=CC=CC=1.O>CN(C=O)C>[CH3:56][O:55][C:52]1[CH:51]=[CH:50][C:49]([CH2:48][N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:58][CH:57]=2)[C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C:23]3[C:24]([NH:40][C:41]4[CH:42]=[CH:43][C:44]([NH:47][C:1](=[O:3])[CH3:2])=[N:45][CH:46]=4)=[N:25][CH:26]=[C:27]([CH2:29][N:30]4[CH2:31][CH2:32][N:33]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:34][CH2:35]4)[CH:28]=3)[N:17]=2)=[CH:54][CH:53]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(N)nc3)n2)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(NC(C)=O)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.3 %

Procedure:
Acetic anhydride (Aldrich) (0.13 mL, 1.4 mmol) was added slowly at 0° C. to a stirred solution of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)pyridine-2,5-diamine (0.0864 g, 0.122 mmol) and pyridine (0.60 mL, 7.4 mmol) in DMF (2mL). The mixture was stirred at rt for 1.5 h. Water was added and the resulting solid was collected by filtration and washed with water and air-dried to give N-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)pyridin-2-yl)acetamide (0.0857 g, 94% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.86 (s, 1H); 8.72 (d, J=2.15 Hz, 1H); 8.51 (d, J=2.54 Hz, 1H); 8.24 (d, J=2.35 Hz, 1H); 8.09 (s, 1H); 7.96 (d, J=2.15 Hz, 1H); 7.91 (s, 1H); 7.20 (dd, J=8.22, 6.26 Hz, 4H); 6.86 (t, J=8.61 Hz, 4H); 4.84 (d, J=8.80 Hz, 4H); 3.80 (d, J=7.43 Hz, 6H); 3.51 (s, 2H); 3.18 (br. s., 4H); 2.71 (s, 3H); 2.60 (s, 3H); 2.55 (t, J=4.21 Hz, 4H); 2.20 (s, 3H). m/z (ESI, +ve ion) 753.0 (M+H)−.
Reaction SMILES: S(=O)(=O)(O)O.[C:6](O)([CH3:9])([CH3:8])[CH3:7].[OH:11][C:12]1[CH:17]=[C:16]([CH3:18])[O:15][C:14](=[O:19])[C:13]=1[SH:20]>>[C:6]([S:20][C:13]1[C:14](=[O:19])[O:15][C:16]([CH3:18])=[CH:17][C:12]=1[OH:11])([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1cc(O)c(S)c(=O)o1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Product: Cc1cc(O)c(SC(C)(C)C)c(=O)o1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Ice (50g.) was added slowly with stirring to 175 g. of concentrated sulfuric acid, keeping the temperature below 35°C. by means of an ice-salt bath. The temperature of the diluted acid was adjusted to 5°C., and 38.6 g. (0.460 mole) of tert.-butyl alcohol was slowly added with stirring, keeping the temperature between 5° and 10°C. 4-Hydroxy-3-mercapto-6-methyl-2-pyrone (36.4 g., 0.230 mole) was then added with vigorous stirring over a period of about 15 minutes, keeping the temperature of the reaction mixture at 5°C. The cooling bath was then removed from the reaction vessel, and stirring was continued for one hour, 20 minutes, while the temperature of the reaction mixture rose to 24°C. The mixture was then poured into ice water, and the gummy precipitate crystallized to a gray solid (weight 42.4 g. (86 percent), m.p. 108.5°-112.5°C.) upon standing at room temperature overnight. The crude product was suspended in 200 ml. of water and then dissolved by the addition of 100 ml. of 10% sodium hydroxide solution. The solution was stirred at room temperature for one hour with decolorizing charcoal, filtered and acidified with with dilute hydrochloric acid. The cream-colored solid precipitate (37.7 g., m.p. 116.5°C.) was collected on a filter, washed with water and dried. Recrystallization from 2-propanol gave the pure 3-tert.-butylthio-4-hydroxy-6-methyl-2-pyrone as white crystals, m.p. 117°-117.5°C.
Reaction SMILES: [OH-:1].[K+].[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6]>>[O:3]=[CH:4][C@@H:5]([C@H:7]([C@@H:7]([C@@H:5]([CH2:4][OH:3])[OH:6])[OH:1])[OH:8])[OH:6]
Reactant: [OH-]
Reactant: OCC(O)CO
Agent: [K+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.17 h

Procedure:
The medium was adjusted to pH 7.0 with KOH, autoclaved at 115° C. for 10 minutes (provided that glycerol or glucose and MgSO4.7H2O were separately sterilized) and then 30 g/L of CaCO3 defined in Japanese Pharmacopoeia (subjected to hot air sterilization at 180° C. for 2 hours) was added.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20](=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH:14]([CH:20]([OH:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1nsc(NC(=O)OC(C)(C)C)n1
Reactant: O=CCCc1ccccc1
Product: CCOC(=O)C(c1nsc(NC(=O)OC(C)(C)C)n1)C(O)CCc1ccccc1

Procedure:
1.0 g (3.5 mMol) of product from Example 28 were reacted with 1.4 ml (~10 mMol) of dihydrocinnamaldehyde for 5 days in the manner described in Example 29 and, after working up by aqueous extraction, the product was chromatographed on 25 g of silica gel using toluene/ethyl acetate (4:1) and separated into the erythro and threo forms.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10](=[O:18])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10](=[O:18])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(=O)[nH]n1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(=O)[nH]n1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ethyl 1-(3-chloro-2-pyridinyl)-2,3-dihydro-3-oxo-1H-pyrazole-5-carboxylate (i.e. the product of Step B) (1.0 g, 3.7 mmol) in methanol (15 mL) was added water (3 mL). An aqueous solution of sodium hydroxide (50%, 1.0 g, 12.5 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 3 hours, during which time the reaction mixture turned a clear yellow. Water (20 mL) was added and the reaction mixture was extracted with ethyl ether, which was discarded. The aqueous phase was acidified to pH 2 using concentrated hydrochloric acid and then extracted with ethyl acetate (50 mL). The ethyl acetate extract was washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate and concentrated to give the title compound, isolated as a white solid (0.76 g).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.CN1CCOCC1>CO>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: COc1ccc(CN)cc1
Solvent: CO
Solvent: CN1CCOCC1
Product: COc1ccc(CNS(=O)(=O)c2ccc3nc(-c4c(C)n[nH]c4N)sc3c2)cc1
Yield: 11.6 %

Procedure:
the title compound (15 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), 4-methoxybenzylamine (79 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 430.5 (M+1, 100%). Yield=11%.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:9]>>[CH2:1]([OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:9][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: ClCc1ccccc1
Product: OCc1ccccc1
Product: c1ccc(COCc2ccccc2)cc1
Yield: 5.4 %

Procedure:
126.5 g (1 mol) of benzyl chloride and 180 g (10 mol) of water were rapidly heated to reflux in a flask with baffles and propeller stirrer with vigorous stirring (250 rpm) under nitrogen. After 240 min reaction time, the mixture was rapidly cooled, the organic phase was separated off after addition of toluene, and analyzed by gas chromatography. It was found that 48 g of the benzyl chloride had been converted to give a yield of benzyl alcohol of 37 g and about 3.6 g dibenzyl ether, corresponding to a conversion of 38% and a yield of benzyl alcohol of 91%. The hydrochloric acid formed had a concentration of about 7.4%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:15](=[O:27])[NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][N:21]=[CH:22]3)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].CCO>[Pt](=O)=O.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:15](=[O:27])[NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][NH:21][CH2:22]3)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)Nc2cccc3cnccc23)Cc2ccccc2C1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1(C(=O)Nc2cccc3c2CCNC3)Cc2ccccc2C1
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A 100 mL Parr reaction vessel is charged with 2-(Isoquinolin-5-ylcarbamoyl)-indan-2-carboxylic acid ethyl ester (320, 500 mg, 1.39 mmol) and EtOH (10 mL). The reaction vessel is agitated by swirling until dissolution ° C. curred. Acetic acid (10 mL) and platinum (IV) oxide (117 mg, 0.52 mmol) are added. The vessel is fitted on a Parr hydrogenation apparatus, flushed with N2 and then evacuated. The vessel is charged with hydrogen to 50 psi. The apparatus is set to agitate. After 4 h, agitation is ceased. The reaction vessel is evacuated and flushed with nitrogen. This process is repeated. The contents of the reaction vessel are diluted with iPrOH (50 mL) and filtered through a pad of celite. Solvent is removed from the filtrate under reduced pressure. The resulting residue is reconstituted in iPrOH (15 mL) and toluene (15 mL). The solvent is removed under reduced pressure. This process is repeated. Pumping to constant weight yields light beige solid (0.5 g, 99%).
Reaction SMILES: [OH:1][C@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.O>CN(C=O)C>[Si:9]([O:1][C@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: COC(=O)C[C@@H](C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
In 10 ml of DMF was dissolved 1.2 g of methyl (R)-β-hydroxybutyrate, and 1.8 g of t-butyldimethylsilyl chloride and 1.0 g of imidazole were added to the solution and reaction was carried out at room temperature overnight. Water was added to the solution and the mixture was extracted with ether. The extract was subjected to distillation to obtain 2 g of methyl (R)-β-t-butyldimethylsilyloxybutyrate. The obtained compound was dissolved in anhydrous ether and the solution was added dropwise into a suspension of 0.5 g of lithium aluminum hydride in anhydrous ether. After the dropwise addition, the mixture was refluxed for 3 hours. After the reaction, 0.5 ml of water, 0.5 ml of 15% NaOH and 1.5 ml of water were added in turn to the reaction mixture, 20 ml of THF was further added, and the mixture was stirred for 30 minutes. The precipitate was removed by filtration, and the filtrate was dried over magnesium sulfate and concentrated under a reduced pressure. The residue was subjected to distillation under reduced pressure to obtain
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[I:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>>[I:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:10]([C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)cc1
Reactant: ClCc1ccc(I)cc1
Product: O=[N+]([O-])c1ccc(N(Cc2ccc(I)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-nitrophenyl)amino]pyrimidine and 4-iodobenzyl chloride
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.[OH-].[K+].[C:18](=[S:20])=[S:19].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[OH:1][CH2:2][C@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:18]([S:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[S:19]
Reactant: OC[C@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: BrCc1ccccc1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OC[C@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
(3R)-3-Hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (1.01 g) is dissolved in 70% ethanol (20 ml), and thereto is added dropwise 2N KOH (2.5 ml) and is further added CS2 (0.30 ml). The mixture is stirred at room temperature for 30 minutes, and thereto is added dropwise benzyl bromide (0.86 g). The mixture is stirred at room temperature for 4 hours and distilled to remove the solvent. The residue is dissolved in ethyl acetate, and the solution is washed with 10% HCl and water in order, dried over sodium sulfate, and distilled to remove the solvent. The residue is purified with silica gel column chromatography (solvent: CHCl3 :methanol=10:1) to give the title compound (1.29 g, 70%) as white powder, [α]D20 -117.3° (c=0.99, methanol). NMR (CDCl3,δ): 4.58 (s, 2H, CSSCH2C6H5), Mass m/e: 368 (M+), 244 (M+ --C6H5CH2SH).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.S(Cl)(Cl)=O.[CH3:14][C:15]([CH3:20])=[CH:16][C:17](O)=[O:18]>ClCCl>[N:1]1([C:17](=[O:18])[CH:16]=[C:15]([CH3:20])[CH3:14])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CC(C)=CC(=O)O
Reactant: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)=CC(=O)n1nnc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
1H-Benzotriazole (2.14 g, 18.0 mmol, 4 equiv.) was dissolved in dichloromethane (25 ml) and thionyl chloride (330 μl, 4.5 mmol, 1 equiv.) was added at room temperature. (450 mg, 4.5 mmol) 3-Methyl-but-2-enoic acid [CAS 541-47-9] was added and the mixture was stirred for 2 hours at room temperature. The suspension was filtered and the filtrate was extracted once with 2N NaOH solution and twice with dichloromethane. The organic extracts were combined, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:cyclohexane gradient 0:100 to 50:50. The desired 1-benzotriazol-1-yl-3-methyl-but-2-en-1-one (810 mg, 90% yield) was obtained as a light yellow solid, MS: m/e=202.1 (M+H+).