Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)=O>O>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:16][C:8]2[NH:9][C:10]3[C:15]([C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=C1Nc2ccccc2C1c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)Oc2[nH]c3ccccc3c2-c2ccccc2)cc1
Reaction time: 0.33 h
Yield: 33.5 %

Procedure:
3-Phenyloxindole (1.15 g), 4-methylbenzenesulfonyl chloride (1.06 g) and sodium carbonate (0.41 g) are introduced as initial charge in 5.5 ml of water and 11 ml of acetone and heated to 80° C. with stirring in a preheated oil bath. After 20 minutes, 5 ml of acetone and 1 ml of water are then added and the mixture is heated for a further 30 minutes. The hot solution is filtered, and the solid is washed with 20 ml of water/acetone (1:1) and methanol and dried in vacuo. This gives 0.59 g of product in an HPLC purity of 98% (29% of theory). A structural elucidation by NMR verifies that it is the O-sulfonylated product. A further 0.67 g of product in an HPLC purity of 40% can be isolated from the filtrate (13% of theory).
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][C:19]3[N:23]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][N:31]([C:33]6([CH2:39][C:40]#[N:41])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]6)[CH:32]=5)[CH:26]=[N:27][C:22]4=[N:21][CH:20]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>>[C:1]([N:36]1[CH2:37][CH2:38][C:33]([CH2:39][C:40]#[N:41])([N:31]2[CH:32]=[C:28]([C:25]3[CH:26]=[N:27][C:22]4[N:23]([C:19]([CH2:18][C:14]5[CH:13]=[C:12]6[C:17](=[CH:16][CH:15]=5)[N:8]=[CH:9][CH:10]=[CH:11]6)=[CH:20][N:21]=4)[N:24]=3)[CH:29]=[N:30]2)[CH2:34][CH2:35]1)(=[O:2])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: N#CCC1(n2cc(-c3cnc4ncc(Cc5ccc6ncccc6c5)n4n3)cn2)CCNCC1
Product: CC(=O)N1CCC(CC#N)(n2cc(-c3cnc4ncc(Cc5ccc6ncccc6c5)n4n3)cn2)CC1

Procedure:
This compound was prepared as a TFA salt starting from (4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidin-4-yl)acetonitrile using procedures analogous to those for Example 203, Step 4. LCMS: (M+H)=492.4.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:32])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([CH2:17][S:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)[CH:14]=[C:13]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]3[CH3:31])[N:12]=2)=[CH:7][CH:6]=1.C1C=C(Cl)C=C(C(OO)=[O:41])C=1.[Mn]([O-])(=O)(=O)=O.[Na+].[OH2:50]>O1CCOCC1>[CH3:1][NH:2][C:3](=[O:32])[NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[C:15]([CH2:17][S:18]([C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)(=[O:41])=[O:50])[CH:14]=[C:13]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]3[CH3:31])[N:12]=2)=[CH:9][CH:10]=1
Reactant: O
Reactant: CNC(=O)Nc1ccc(-c2nc(CSc3nccn3C)cc(N3CCOC[C@@H]3C)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2nc(CS(=O)(=O)c3nccn3C)cc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Methyl-1-[4-[4-[(1-methylimidazol-2-yl)sulfanylmethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea (0.23 mmol) was dissolved in 1,4-Dioxane (4 mL) and water (1 mL). m-CPBA (75%) (80 mg), followed immediately by sodium permanganate (92 mg), was added to the solution. The reaction was allowed to stir at RT for 18 h then loaded onto a SCX-2 (10 g) column, which was washed with methanol and the product eluted with 7N ammonia in methanol. The reaction was vacuumed to dryness and purified by prep-HPLC (basic) to give the desired material (37 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[NH:10][CH:9]=2)=[CH:4][CH2:3]1.CN1CCCC1=O.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1>ClCCl>[Si:25]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN1C=CC(c2c[nH]c3ccc(O)cc23)=CC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CN1CCC(c2c[nH]c3ccc(O[Si](C)(C)C(C)(C)C)cc23)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 3-(1-methyl-pyridin-4-yl)-5-hydroxy-1H-indole (8.0 g, 34.7 mmol) and 1-methyl-2-pyrrolidinone (10 mL) in dichloromethane (90 mL) stirring at 0° C., was added tert-butyldimethylsilyl chloride in small portions (5.50 g, 36.5 mmol), followed by imidazole also in small portions (2.48 g, 36.5 mmol). The reaction mixture was stirred for 1 hour at 0° C., then overnight at room temperature. The mixture was concentrated in vacuo to a solid residue, which was directly purified on silica gel. Elution with a 9:1 mixture of dichloromethane and methanol provided 7.60 g (63%) of the title compound as a white solid: mp=191-195° C.; 1H NMR (400 MHz, dmso-d6): 10.46 (s, 1H), 7.02 (d, 1H, J=8.4 Hz), 6.87 (d, 1H, J=2.4 Hz), 6.74 (d, 1H, J=2.4 Hz), 6.45 (dd, 1H, J=8.6, 2.6 Hz), 2.69 (br d, 2H, J=11.2 Hz), 2.46 (tt, 1H, J=11.8, 3.6 Hz), 2.04 (s, 3H), 1.92-1.80 (m, 2H), 1.75-1.67 (m, 2H), 1.50 (qd, 2H, J=12.4, 3.6 Hz), 0.81 (s, 9H), 0.00 (s, 6H); MS (APCI): m/e 345 0.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Si:20]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]O)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(C=P(CCCC)(CCCC)CCCC)#N.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Si:20]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:11]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([C:33]([CH3:34])([CH3:35])[CH3:36])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](OCCCCCCO)(c1ccccc1)c1ccccc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Yield: 79.4 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (470 mg, 1.55 mmol) obtained in Example 5 and 6-(t-butyldiphenylsilyloxy)-1-hexanol (740 mg, 2.08 mmol) were dissolved in toluene (20 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (500 mg, 2.07 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 7 hours. After the reaction mixture was allowed to cool down, the residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=10:1 eluate was concentrated under reduced pressure, whereby the title compound (786 mg, 1.23 mmol, 79%) was obtained as a pale yellowish brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:25])[N:13]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=2)[C:10](=O)[CH2:9]1.[C:27]([NH:30][NH2:31])([NH2:29])=[NH:28].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:25])[N:13]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=2)[C:10](=[N:31][NH:30][C:27]([NH2:29])=[NH:28])[CH2:9]1
Reactant: Cc1c2c(nn1CCc1ccccc1)CC(c1ccccc1Cl)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1c2c(nn1CCc1ccccc1)CC(c1ccccc1Cl)CC2=NNC(=N)N
Yield: 135.6 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-2-(2-phenylethyl)-4,5,6,7-tetrahydroindazol-4-one (0.20 g), aminoguanidine hydrochloride (0.073 g), concentrated hydrochloric acid (0.14 ml), water (0.14 ml) and ethanol (15 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-2-(2-phenylethyl)-4,5,6,7-tetrahydroindazole hydrochloride (Compound 152) (0.17 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH:7]1([N+:13]#[C-:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:15][C:16]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH:18]=O>Cl(O)(=O)(=O)=O>[CH:7]1([NH:13][C:14]2[N:6]3[C:2]([S:3][CH:4]=[CH:5]3)=[N:1][C:18]=2[C:17]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:16]=2[CH3:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: [C-]#[N+]C1CCCCC1
Reactant: Nc1nccs1
Reactant: Cc1ccc(C)c(C=O)c1
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1ccc(C)c(-c2nc3sccn3c2NC2CCCCC2)c1

Procedure:
Compound 51 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 2-aminothiazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) cyclohexylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2,5-dimethylbenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([C:17]1[CH:42]=[CH:41][C:20]([C:21]([NH:23][CH:24]([C:31]2[NH:35][C:34]3[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:33]=3[N:32]=2)[CH2:25][C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)=[O:22])=[CH:19][C:18]=1[Cl:43])=[O:16])=O)(C)(C)C.FC(F)(F)C(O)=O.ClCl>ClCCl.CO>[NH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([C:17]1[CH:42]=[CH:41][C:20]([C:21]([NH:23][CH:24]([C:31]2[NH:35][C:34]3[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:33]=3[N:32]=2)[CH2:25][C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)=[O:22])=[CH:19][C:18]=1[Cl:43])=[O:16]
Reactant: CC(C)(C)OC(=O)NCC1CCCN1C(=O)c1ccc(C(=O)NC(Cc2c[nH]cn2)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Agent: ClCl
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCCN1C(=O)c1ccc(C(=O)NC(Cc2c[nH]cn2)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 98 %

Procedure:
Prepared analogously to Example 17 from 4-[2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]-3-chloro-N-[1-(5-chloro-1H-benzimidazol-2-yl)-2-(1H-imidazol-4-yl)ethyl]benzamide and trifluoroacetic acid. Yield: 98% of theory; Rf value: 0.47 (silica gel; dichloromethane/methanol=7:3); C25H25C12N7O2 (526.43); mass spectrum: (M+H)+=526/528/530 (chlorine isotope).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([PH4])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[CH3:15][C:16]1[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:10]([O:9][C:7](=[O:8])[CH2:6]/[C:5](/[C:3]([O:2][CH3:1])=[O:4])=[CH:21]\[C:19]1[O:20][C:16]([CH3:15])=[CH:17][CH:18]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)C([PH4])CC(=O)OC(C)(C)C
Reactant: Cc1ccc(C=O)o1
Solvent: Cc1ccccc1
Product: COC(=O)/C(=C/c1ccc(C)o1)CC(=O)OC(C)(C)C
Yield: 99.2 %

Procedure:
A solution of 1-methoxycarbonyl-2-t-butoxycarbonyl ethyl phosphorane (JCS Perkin II, 1975, p1030; 2.69 g, 6 mmol, 1.2 eq) and 5-methylfuran-2-al (0.5 ml, 5 mmol) in dry toluene (10 ml) was stirred at 80° C. for 48 hrs, and then evaporated to dryness. The residue was chromatographed (50 g Bondelut, eluting with hexane containing 10% v/v ethyl acetate) to yield the title compound as a brown oil (1.39 g, 100%). NMR: 1.38 (s, 9H), 2.33 (s, 3H), 3.62 (s, 2H), 3.71 (s, 3H), 6.31 (d, 1H), 6.85 (d, 1H), 7.42 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][S:7][C@H:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:25]([O:27][CH2:28][CH3:29])=[O:26].C1C=CC=CC=1>C(OCC)(=O)C>[C:41]([O:40][C:38]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C@@H:24]([NH:1][C@H:2]1[CH2:8][S:7][C@H:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)CN1C[C@@H](c2cccs2)SC[C@H](N)C1=O
Reactant: CCOC(=O)C(Br)CCCCCCCNC(=O)OC(C)(C)C
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](CCCCCCCNC(=O)OC(C)(C)C)N[C@H]1CS[C@H](c2cccs2)CN(CC(=O)OC(C)(C)C)C1=O
Yield: 9.7 %

Procedure:
1.3 g of t-butyl α-[6(R)-amino-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate was treated with 1.73 g of ethyl 2-bromo-9-t-butoxycarbonylaminononanoate prepared as described in Preparation 4) in a similar manner to that described in Example 4. The product was then subjected to column chromatography through silica gel using a mixture of benzene and ethyl acetate in the ratio 5:1 by volume as the eluent. 237 mg of t-butyl α-{6(R)-[8-t-butoxycarbonylamino-1(R)-ethoxycarbonyloctylamino]-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl}acetate was obtained as a syrup from the fractions eluted first.
Reaction SMILES: Cl.[CH2:2](N=C=NCCCN(C)C)[CH3:3].Cl.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[N:24]1[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1.C(O)C>CN(C1C=CN=CC=1)C.ClCCl>[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[N:24]1[CH2:25][CH2:26][CH:27]([C:30]([O:32][CH2:2][CH3:3])=[O:31])[CH2:28][CH2:29]1
Reactant: O=C(O)C1CCN(c2ccc3ccccc3n2)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C1CCN(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.79 g, 9.34 mmol) was added to a solution of 1-(quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride (1.14 g, 3.89 mmol), N,N-dimethyl-4-aminopyridine (1.42 g, 11.6 mmol), and ethanol (546 μL, 9.34 mmol) in dichloromethane (20 mL), and the mixture was stirred overnight at room temperature. Then, the solvent in the reaction solution was distilled off under reduced pressure. A solution of the obtained residue in ethyl acetate was washed with water twice and brine once and dried over anhydrous sodium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=95/5-60/40 (gradient)] to obtain the title compound (1.07 g, yield: 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:27])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:15]=3[N+:24]([O-:26])=[O:25])=[C:11]([C:28]([O:30]CC)=[O:29])[N:10]=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:27])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:15]=3[N+:24]([O-:26])=[O:25])=[C:11]([C:28]([OH:30])=[O:29])[N:10]=[N:9]2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnc(C(=O)O)c2C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])cc1

Procedure:
In the same manner as above, a solution of ethyl 1-(4-methoxybenzyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate (b-2) (3.12 g, 6.63 mmole) in tetrahydrofuran (100 ml) was hydrolyzed with a 1N aqueous sodium hydroxide solution (13 ml) at room temperature for 3.5 hours to give 1-(4-methoxybenzyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylic acid (c-2': MP) (2.32 g, 79%)
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>O.CN(C)C=O.C1C=CC=CC=1>[CH3:3][S:4]([NH:7][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:6])=[O:5]
Reactant: CS(N)(=O)=O
Reactant: CCOC(=O)CCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCNS(C)(=O)=O
Temperature: 25 °C

Procedure:
A stirred suspension of sodium hydride (57%) (2.33 g., 0.055 mole) in a solvent mixture of benzene (50 ml.) and dimethylformamide (50 ml.) is treated, over 30 minutes with methanesulfonamide (4.75 g., 0.055 mole). This mixture is heated on the steam bath for 1.5 hours, then cooled to room temperature. At this temperature is added ethyl 7-bromoheptanoate (13 g., 0.055 mole) and the reaction is heated at 90° C. for twenty hours. The reaction is poured into water (200 ml.), neutralized with hydrochloric acid and extracted with ethyl acetate (2 × 100 ml.). The ethyl acetate layer is washed with brine, dried over sodium sulfate, then concentrated in vacuo. The yield of ethyl 7-(methanesulfonamido)heptanoate is 7.1 g. (51%) boiling 165°-168°/0.1 mm.
Reaction SMILES: [C:1](/[N:3]=[C:4](/[S-:7])\[S:5][CH3:6])#[N:2].[K+].Cl[CH2:10][C:11]([NH2:13])=[O:12].C[O-].[Na+].O>C(O)C>[NH2:2][C:1]1[N:3]=[C:4]([S:5][CH3:6])[S:7][C:10]=1[C:11]([NH2:13])=[O:12]
Reactant: CS/C([S-])=N\C#N
Reactant: NC(=O)CCl
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSc1nc(N)c(C(N)=O)s1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
A mixture of potassium (Z)-methyl cyanocarbonimidodithioate (10.0 g, 58.7 mmol) and 2-chloroacetamide (6.04 g, 64.6 mmol) in ethanol (20 mL) was refluxed for 1 h. After cooling to ambient temperature, sodium methoxide (3.49 g, 64.6 mmol) was added to the mixture. The mixture was stirred at reflux for 3 hours. The mixture was cooled to ambient temperature and water (50 mL) was added. The precipitate formed was collected by filtration. The precipitate was further washed with water and dried in vacuo. The product was obtained as a yellow solid (3.372 g, 30%). 1H NMR (300 MHz, d6-DMSO) δ 6.96 (s, 2H), 6.89 (s, 2H), 2.64 (s, 3H); LC-MS: 190 (MH+).
Reaction SMILES: CO.[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([S:19][CH3:20])([CH3:18])[C:14]([O:16]C)=[O:15])=[CH:9][CH:8]=1)[CH:4]([CH3:6])[CH3:5].[OH-].[K+]>O>[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([S:19][CH3:20])([CH3:18])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)[CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(SC)c1ccc(CC(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSC(C)(C(=O)O)c1ccc(CC(C)C)cc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 99 %

Procedure:
Water (2 ml) and 4 ml of methanol were added to 420 mg of methyl α-(p-isobutylphenyl)-α-(methylthio)propionate. Then, 280 mg (85% content) of potassium hydroxide was added, and the mixture was stirred at 60° C. for 2.5 hours. The reaction mixture, initially heterogeneous, became uniform. Water (30 ml) was added, and the mixture was extracted with 10 ml of methylene chloride. The aqueous layer was acidified with conc. hydrochloric acid to a pH of 1, and extracted three times with 20 ml of diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the diethyl ether. Thus, 394 mg of crude α-(p-isobutylphenyl)-α-(methylthio)propionic acid was obtained as an oil in a yield of 99%. The oil soon crystallized, and recrystallization from water/methanol afforded colorless crystals having a melting point of 89° to 92° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1[Cl:20].Br[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C.O>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1[Cl:20]
Reactant: COc1nc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: BrCC1CCCCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1nc(N)c(Cl)cc1C(=O)NCC1CCN(CC2CCCCC2)CC1
Temperature: 90 °C
Reaction time: 10 h
Yield: 65.8 %

Procedure:
A mixture of 6-amino-5-chloro-2-(methyloxy)-N-(4-piperidinylmethyl)-3-pyridinecarboxamide (step 1, 150 mg, 0.50 mmol), (bromomethyl)cyclohexane (107 mg, 0.60 mmol), and triethylamine (140 μl, 1.00 mmol) in N,N-dimethylformamide (5 ml) was stirred at 90° C. for 10 h. After cooling to room temperature, the mixture was poured into water (50 ml) and the aqueous layer was extracted with ethyl acetate/toluene (2:1, 80 ml×2). The combined organic layer was washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with 25% ammonia/methanol/dichloromethane (0.1:1:20) to give 130 mg (65%) of the title compound as a yellow amorphous solid.
Reaction SMILES: N1(C[C:8]2[N:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:11]=[CH:10][CH:9]=2)CCCCC1.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[C:22](C)[N:21]=1.Br[C:28]1C=C(C)C=CN=1>>[N:21]1([CH2:28][C:10]2[CH:9]=[CH:8][N:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:11]=2)[CH2:20][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NCCCOc1cccc(CN2CCCCC2)n1
Reactant: Cc1ccnc(Br)c1
Reactant: Cc1cccc(Cl)n1
Product: NCCCOc1cc(CN2CCCCC2)ccn1

Procedure:
When the general procedure for the preparation of 3-(6-piperidinomethyl-2-pyridyloxy)propylamine described in U.K. Patent Application No. 2,098,988 was followed except that the 2-chloro-6-methylpyridine utilized therein was replaced by 2-bromo-4-methylpyridine, then the title compound was produced as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([OH:20])=[O:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:18]([OH:20])(=[O:19])[CH3:17].[CH3:17][C:11]1[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=1[NH:9][C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C(O)Cc1cc(O)ccc1Nc1c(Cl)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(=O)O
Product: Cc1cc(O)ccc1Nc1c(Cl)cccc1Cl
Yield: 90 %

Procedure:
A solution of the acid of Step E, above (2.0 g, 6.4 mmol) in 20 mL of methanol containing a few mg of p-toluene sulfonic acid monohydrate is heated at reflux for 3 hours. The solvent is evaporated in vacuo and the residue dissolved in ethyl acetate. The organic phase is washed with saturated NaHCO3, brine and dried (MgSO4). Removal of solvent affords the product (1.9 g, 90%) as a brown foam. It is used as such in the next step.
Reaction SMILES: [OH-:1].[Li+:2].C([O:5][P:6]([CH2:15][C@@H:16]([OH:29])[CH2:17][NH:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#N)[CH:22]=1)[CH3:20])([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])C.P(=O)(O)(O)[OH:31]>O.C(O)C>[C:27]([C:23]1[CH:22]=[C:21]([CH:19]([NH:18][CH2:17][C@H:16]([OH:29])[CH2:15][P:6]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)(=[O:7])[O-:5])[CH3:20])[CH:26]=[CH:25][CH:24]=1)([OH:31])=[O:1].[Li+:2]
Reactant: CCOP(=O)(CC1CCCCC1)C[C@@H](O)CNC(C)c1cccc(C#N)c1
Reactant: O=P(O)(O)O
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: CCO
Product: CC(NC[C@H](O)CP(=O)([O-])CC1CCCCC1)c1cccc(C(=O)O)c1

Procedure:
A solution of 0.4 g of lithium hydroxide in 10 ml of water is added to a solution of 3.0 g of 3-{N-[1-(3-cyanophenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid ethyl ester in 10 ml of ethanol and the batch is heated under reflux for 24 hours. It is cooled to 4° and neutralised with aqueous phosphoric acid. The solvent is removed and the residue is taken up in warm methanol and filtered. Removal of the solvent and crystallisation from ethanol/acetone gives lithium 3-{N-[1-(3-carboxyphenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohexylmethyl)phosphinate having a melting point of 160°-184°.