Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:27][C:28]([NH:39][CH2:40][CH:41]([OH:57])[CH2:42][O:43][C:44]1[C:49]2[C:50]3[C:55]([NH:56][C:48]=2[CH:47]=[CH:46][CH:45]=1)=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[N+:37]=[N-:38])=[CH:32][CH:31]=1)[CH3:29].[CH3:58][C:59]1[C@@H:76]([O:77][C:78]([C@H:80]([OH:97])[C@@H:81]([NH:88][C:89]([C:91]2[CH:92]=[CH:93][CH:94]=[CH:95][CH:96]=2)=[O:90])[C:82]2[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=2)=[O:79])[CH2:75][C@:71]2([OH:98])[C:72]([CH3:74])([CH3:73])[C:60]=1[C@@H:61]([O:116][C:117]([CH3:119])=[O:118])[C:62]([C@@:64]1([CH3:115])[C@H:69]([C@@H:70]2[O:99][C:100]([C:102]2[CH:103]=[CH:104][CH:105]=[CH:106][CH:107]=2)=[O:101])[C@:68]2([O:110][C:111]([CH3:113])=[O:112])[CH2:108][O:109][C@@H:67]2[CH2:66][C@@H:65]1[OH:114])=[O:63].N12CCCN=C1CCCCC2>O1CCCC1>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:29][C:28]([NH:39][CH2:40][CH:41]([OH:57])[CH2:42][O:43][C:44]1[C:49]2[C:50]3[C:55]([NH:56][C:48]=2[CH:47]=[CH:46][CH:45]=1)=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[N+:37]=[N-:38])=[CH:32][CH:31]=1)[CH3:27].[CH3:58][C:59]1[C@@H:76]([O:77][C:78]([C@H:80]([OH:97])[C@@H:81]([NH:88][C:89]([C:91]2[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=2)=[O:90])[C:82]2[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=2)=[O:79])[CH2:75][C@:71]2([OH:98])[C:72]([CH3:73])([CH3:74])[C:60]=1[C@@H:61]([O:116][C:117]([CH3:119])=[O:118])[C:62]([C@@:64]1([CH3:115])[C@H:69]([C@@H:70]2[O:99][C:100]([C:102]2[CH:107]=[CH:106][CH:105]=[CH:104][CH:103]=2)=[O:101])[C@:68]2([O:110][C:111]([CH3:113])=[O:112])[CH2:108][O:109][C@@H:67]2[CH2:66][C@@H:65]1[OH:114])=[O:63]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: CC(C)(NCC(O)COc1cccc2[nH]c3ccccc3c12)c1ccc(N=[N+]=[N-])cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
8 (0.50 g, 0.37 mmol) was treated with 1% of 1,8-Diazabicyclo[5.4.0]undec-7-en (DBU) in Tetrahydrofuran (THF) (10 mL) for 45 seconds at room temperature and the product was precipitated by 1 M HCl in diethyl ether (500 mL). Then it was purified on a silica gel column using chloroform/methanol (7:1) to afford 9 (350 mg, 84%) as a white powder. ESI-MS (5 kV, MeOH): m/z (%)=1116.1 (100) [M+H]+; HPLC (230 nm): >95%.
Reaction SMILES: C[N:2]1[CH2:20][CH2:19][N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C@H:4]2[CH2:3]1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[CH2:3]1[C@@H:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][C:7]3[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[CH2:19][CH2:20][N:2]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)Cl
Reactant: CN1CCN2c3ccccc3Cc3ccccc3[C@H]2C1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN2c3ccccc3Cc3ccccc3[C@H]2C1
Yield: 97.6 %

Procedure:
A solution of 5.52 g of (S)-1,2,3.4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepine (prepared as described in preparation 6) in 30 ml of toluene was added dropwise to a solution of 6.8 g of ethyl chloroformate in 50 ml of toluene at 80° C. over a period of 10 minutes, and the mixture was heated under reflux for 3 hours. At the end of this time, the crystals which precipitated were removed by filtration, and solvent was removed from the filtrate by evaporation under reduced pressure, to give 6.57 g (yield 98%) of the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([N:8]([CH3:19])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>CC(C)=O>[C:1]([N:8]([CH3:19])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:14][CH:13]=1)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CN(CC(=O)c1ccc(O)cc1)C(=O)OC(C)(C)C
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(CC(=O)c1ccc(OCC(=O)OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A mixture of 4-[2-(BOC-methylamino)acetyl]phenol (5.04 g, 19.0 mmol) and K2CO3 (2.63 g, 19.0 mmol) in acetone (100 mL) was stirred at reflux under argon for 1 h. The mixture was cooled to RT and benzyl bromoacetate (5.23 g, 22.8 mmol) was added. The reaction was heated at reflux for 18 h, then was cooled and filtered. The filter cake was washed with acetone, and the filtrate was concentrated on the rotavap. The residue was dissolved in CH2Cl2 (300 mL) and washed sequentially with H2O (50 mL) and brine (50 mL). Drying (Na2SO4), concentration, and silica gel flash chromatography (1:3 EtOAc/hexanes) yielded the title compound (7.28 g, 93%): 1H NMR (250 MHz, CDCl3) δ 6.85-7.95 (m, 9 H), 5.23 (s, 2H), 4.71 (s, 2H), 4.55 (d, 2H), 2.95 (d, 3H), 1.45 (d, 9H).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([SH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17]>>[C:1]1([CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[S:7][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17]
Reactant: Cc1ccccc1S
Reactant: CC(C)=CCCC(C)=CCBr
Product: CC(C)=CCCC(C)=CCSc1ccccc1C

Procedure:
thio-o-cresol is reacted with 1-bromo-3,7-dimethyl-octa-2,6-diene to produce 3,7-dimethyl-octa-2,6-dienyl o-tolyl sulphide (boiling point = 125° C/0.08 mmHg);
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[NH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: CCCN
Product: CCCNc1c(C(=O)OCC)cnc2c(OC)cccc12

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 1-aminopropane following general procedure B to afford 8-methoxy-4-propylamino-quinoline-3-carboxylic acid ethyl ester (260 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into 8-methoxy-4-propylamino-quinoline-3-carboxylic acid ethylamide (200 mg) following general procedure E. The above ethylamide (0.70 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-propyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (26 mg). LCMS: m/z 314 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]([NH:7][CH2:8][CH2:9][N:10]([C:20]1[N:25]=[C:24]([N:26]([CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][CH2:43][OH:44])=[O:40])[CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][CH2:34][OH:35])=[O:31])[N:23]=[C:22](Cl)[N:21]=1)[CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH2:18][OH:19])=[O:15])=[O:6].[C:46](=[O:49])([OH:48])[O-].[Na+]>C(O)CO>[OH:1][CH2:2][CH2:3][O:4][C:5]([NH:7][CH2:8][CH2:9][N:10]([CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH2:18][OH:19])=[O:15])[C:20]1[N:25]=[C:24]([N:26]([CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][CH2:43][OH:44])=[O:40])[CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][CH2:34][OH:35])=[O:31])[N:23]=[C:22]([N:10]([CH2:9][CH2:8][NH:7][C:5]([O:4][CH2:3][CH2:2][OH:1])=[O:6])[CH2:11][CH2:12][NH:13][C:46]([O:48][CH2:18][CH2:17][OH:16])=[O:49])[N:21]=1)=[O:6]
Reactant: O=C(NCCN(CCNC(=O)OCCO)c1nc(Cl)nc(N(CCNC(=O)OCCO)CCNC(=O)OCCO)n1)OCCO
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Product: O=C(NCCN(CCNC(=O)OCCO)c1nc(N(CCNC(=O)OCCO)CCNC(=O)OCCO)nc(N(CCNC(=O)OCCO)CCNC(=O)OCCO)n1)OCCO
Temperature: 115 °C

Procedure:
To 6.7 g of (I) (Example 1, TECT) were added 2.8 g HEC, 0.84 g sodium bicarbonate and 25 g ethylene glycol. The reaction mixture was then heated to 115° C. in an oil bath for 4 hours, after which most of the HEC had reacted with TECT as indicated by amine titration of the reaction mixture. Ethylene glycol was distilled off under reduced pressure. The residue was poured into methanol. Separated solids were filtered and recrystallized from methanol. Yield 5.6 g (60% of theoretical), m.p. 192° C. The nmr and fab mass spectra confirmed the product to be of FORMULA II: ##STR21##
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].S([N:21]=[N+:22]=[N-])(C1C=CC(C)=CC=1)(=O)=O>>[N+:21](=[C:5]([C:1](=[O:4])[CH2:2][CH3:3])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N-:22]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)CC
Product: CCOC(=O)C(=[N+]=[N-])C(=O)CC

Procedure:
This compound was synthesised from ethyl propionylacetate (CAS 4949-44-4) and polymer-bound tosylazide using similar protocol as described in Intermediate 1-7. Crude material (0.9 g, 95%) was taken directly to next step.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH2:15][CH2:16][OH:17]>C1COCC1>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH2:15][CH2:16][O:17][C:1]([Cl:4])=[O:2]
Reactant: O=[N+]([O-])c1cccc(Cl)c1CCO
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Cl)OCCc1c(Cl)cccc1[N+](=O)[O-]
Yield: 97 %

Procedure:
Phosgene was introduced in a solution of 2-(2-chloro-6-nitrophenyl)ethanol (31 g, 154 mmol) in THF (190 ml, dist. over CaH2) at room temperature under stirring. After 2.5 h the excess phosgene and the solvent were removed by distillation in a high vacuum. 2-(2-chloro-6-nitrophenyl)ethoxycarbonyl chloride (39.4 g, 97%) was obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:17])[CH3:16].O=S(Cl)[Cl:21]>C(Cl)(Cl)Cl>[OH:1][C:2]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:5]([C:6]([Cl:21])=[O:7])=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O

Procedure:
4-Hydroxy-3,5-di-tert-butyl benzoic acid (12.5 g, 50 mM) was dissolved in 80 ml of chloroform. To the resulting solution was added dropwise a solution of SOCl2 (chlorination agent, 10 ml) in chloroform (20 ml), followed by heating under reflux for 3 hours. The reaction solution was then distilled off under reduced pressure to yield 4-hydroxy-3,5-di-tert-butylbenzoyl chloride.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]3[N:16]([CH:24]4[CH2:26][CH2:25]4)[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[C:19](=[O:20])[C:11]3=[CH:10][C:9]=2[F:27])[CH2:3]1.[S:28](=[O:32])(=[O:31])([OH:30])[OH:29]>>[S:28]([O-:32])([O-:31])(=[O:30])=[O:29].[CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]3[N:16]([CH:24]4[CH2:26][CH2:25]4)[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[C:19](=[O:20])[C:11]3=[CH:10][C:9]=2[F:27])[CH2:3]1
Reactant: O=S(=O)(O)O
Agent: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Product: O=S(=O)([O-])[O-]

Procedure:
A method of treating an industrial waste liquor containing gatifloxacin, comprising adding aqueous sulfuric acid to said liquor to form a sulfate of said gatifloxacin, and/or a hydrate of said sulfate, as a sediment; and recrystallizing the sulfate from water, whereby a hydrate of a sulfate of gatifloxacin is obtained.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:13][CH2:14][C:15]([CH2:20][OH:21])([CH3:19])[C:16]([OH:18])=[O:17].C(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:1]([O:13][CH2:14][C:15]([CH2:20][O:21][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([CH3:19])[C:16]([OH:18])=[O:17])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC(CO)(CO)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCC(=O)OCC(C)(COC(=O)CCCCCCCCC)C(=O)O
Temperature: 25 °C

Procedure:
n-Decanoyl chloride (23.6 mL) was combined with 5.0 grams of 2,2-bis(hydroxymethyl)propionic acid and 100 mL of chloroform (filtered through activity I basic alumina). Triethylamine (17.1 mL) and 4-dimethylaminopyridine (2.28 grams) were then added and the resulting mixture was heated at reflux under nitrogen for 16 hours. The reaction was then cooled to room temperature and quenched with 200 mL of water. The solution was cooled to 0° C. and acidified to pH 3 with concentrated aqueous hydrochloric acid. The solution was extracted three times with methylene chloride and the combined methylene chloride layers were washed once with 1% aqueous hydrochloric acid and once with saturated aqueous sodium chloride. The organic layer was then dried over anhydrous magnesium sulfate, filtered and the solvents removed in vacuo to yield 26.01 grams of a mixture of a yellow oil and solid. The mixture was chromatographed on silica gel eluting with hexane/ethyl acetate/acetic acid (95:4:1) to yield 20.6 grams of the desired product as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:9])=[C:6]([CH:8]=1)[NH2:7].N1C=CC=CC=1.[C:16](Cl)(=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:9])=[C:6]([NH:7][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: CCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCCCCCCCC(=O)Nc1cc(Cl)ccc1O
Reaction time: 2 h

Procedure:
5-Chloro-2-hydroxy aniline, 10.3 g (0.072 mole), is dissolved in 200 ml dichloroethane, containing 25 ml pyridine. The solution is stirred at 70° C. while nonanoyl chloride is added slowly. The solution is stirred for 2 hours. Excess pyridine is removed by washing the product with 4N hydrochloric acid. The product is then passed through a florisil column and crystallized at -20°. There is obtained N-(5-chloro-2-hydroxyphenyl) nonanamide (M.P. 93.5-94.0). Analysis shows 4.94% nitrogen and 12.53% chlorine as against calculated values of 49.4% and 12.49% respectively, for C15H22ClNO2.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2.C(OCC)C.[CH3:20][N:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22]1>CCCCCC>[CH3:20][N:21]1[CH2:26][CH2:25][CH2:24][C:23]([C:10]2[S:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=2)([OH:27])[CH2:22]1
Reactant: c1ccc2sccc2c1
Reactant: CN1CCCC(=O)C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CN1CCCC(O)(c2cc3ccccc3s2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
26.5 ml of a 2N solution of n-butyllithium in hexane is added dropwise within 30 minutes to a solution of 7.0 g of benzo[b]thiophene in 50 ml of abs. diethyl ether at a reaction temperature of 5° to 10°. The solution is then stirred for a further 1 hour at 0°. There is then added dropwise, in the course of 30 minutes, a solution of 5.9 g of 1-methyl-3-piperidone in 50 ml of abs. diethyl ether, with the reaction temperature being maintained at 0° by external cooling. The reaction solution is stirred for a further 15 hours at room temperature, and is then poured, with stirring, onto 100 g of ice; the aqueous phase is separated, and extracted 3 times with 100 ml of ethyl acetate each time. The combined organic extracts are dried with sodium sulphate, filtered under suction and concentrated by evaporation. The residue is dissolved in 250 ml of 2N hydrochloric acid, and the acid solution is washed with diethyl ether. The aqueous solution is subsequently brought to a pH-value of 12 by the addition of 10 sodium hydroxide solution, and extracted with 500 ml of chloroform. The chloroform solution is dried with sodium sulphate, filtered with suction and concentrated by evaporation to obtain crude 1-methyl-3-(benzo[b]thien-2-yl)-3-piperidinol; the oxalate thereof is prepared, for example, from 1.8 g of free base in ethyl actate and 0.7 g of oxalic acid in 10 ml of ethyl acetate, and it melts at 165°-168° after recrystallisation from ethyl acetate.
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1>CN(C)C=O>[N:13]1([C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:12])[NH:7]3)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: c1nc[nH]n1
Reactant: O=c1ccc2c(Br)nccc2[nH]1
Solvent: CN(C)C=O
Product: O=c1ccc2c(-n3cncn3)nccc2[nH]1
Yield: 52.8 %

Procedure:
A mixture containing 5.6 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 100 ml of dimethylformamide and 6.9 g of 1,2,4-triazole was refluxed on an oil bath for 21 hours and then allowed to cool. The separated solid was collected, washed with ethanol and dried in a vacuum oven at 90° C. to yield 2.8 g of 5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p.>300° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH:16]=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:20](CC)CC)C.CC(C)(O)C#N>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH:16]([OH:17])[C:18]#[N:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(C)[C@@H](C=O)NC(=O)OCc1ccccc1
Agent: CC(C)(O)C#N
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(O)C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 143 %

Procedure:
To a solution containing N-benzyloxycarbonyl-L-valinal 22.2 g, 0.094 mol) in methylene chloride (500 mL) and triethylamine (5.81 g, 8.0 mL, 0.057 mol) was added acetone cyanohydrin (24.23 g, 26.0 mL, 0.2847 mol). The reaction was allowed to stir at room temperature overnight and then concentrated under reduced pressure. The residue was taken up into ether and washed with brine (3×). The solvent was removed under reduced pressure and purified by column chromatography (silica gel; 1:2 acetone:hexane) to give 21.38 g (86.6%) of 3-(S)-[(benzyloxycarbonyl)amino]-2-hydroxy-4-methylpentanenitrile as a pale yellow oil; TLC Rf =0.33 (silica gel; 1:2 acetone:hexane).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[C:3]=1[C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][N:37]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:26]([C:3]1[C:2]([C:39]2[CH:38]=[N:37][C:36]([O:35][CH3:34])=[CH:41][CH:40]=2)=[N:7][C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:21])([F:22])[O:20][C:16]=4[CH:15]=3)[CH2:12][CH2:13]2)=[O:10])=[CH:5][C:4]=1[CH3:25])#[N:27]
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C#N)cn1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
N-(6-chloro-5-cyano-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (369 mg, 0.94 mmol), potassium carbonate (1.45 g, 942.0 μL of 2 M, 1.88 mmol), tetrakis(triphenylphosphine)palladium (0) (54 mg, 0.047 mmol), 1,2-dimethoxyethane (9 mL), and 2-methoxypyridine-5-boronic acid (230.5 mg, 1.51 mmol) were combined in a 40 mL scintillation vial. The reaction mixture was heated to 80° C. for 6 hours. The reaction mixture was allowed to cool to room temperature, the layers were separated, and the crude material was purified on 40 g of silica gel utilizing a gradient of 0-80% ethyl acetate in hexanes to yield the pure product (0.437 g, 71%). ESI-MS m/z calc. 464.1. found 465.1 (M+1)+. Retention time 2.08 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:26]=[CH:30][CH:29]=[CH:28]3)=[CH:21][CH:22]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NCCCCOc2ccc(N)cc2)cc1
Reactant: COC1CCC(OC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCCCCOc2ccc(-n3cccc3)cc2)cc1
Temperature: -10 °C

Procedure:
A mixture of 3.2 g of 4-methyl-N-[4-(4-aminophenyl-oxy)butyl]benzenesulfonamide (Example 36), 1.5 g of 2,5-dimethoxytetrahydrofuran, and 50 ml of acetic acid is stirred and heated on the steam bath for 16 hours. The reaction mixture is taken to dryness in vacuo. The residue is shaken with 150 ml of dichloromethane and 150 ml of saturated sodium bicarbonate solution. The dichloromethane layer is separated, dried over Na2SO4, and diluted with 100 ml of hexane. The solution is concentrated until turbid, then cooled at -10° C. The precipitate that forms is collected, washed with hexane, and air dried; m.p. 124°-126° C.; yield, 0.2 g.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:10]([I:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CI.[BH4-].[Na+].[C:26](=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14][CH2:15][C:16]3[CH2:17][CH2:18][N:19]([CH3:26])[CH2:20][CH:21]=3)=[C:10]([I:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(SCc3ccncc3)c(I)cc21
Reactant: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)N1CCc2cc(SCC3=CCN(C)CC3)c(I)cc21
Temperature: 0 °C

Procedure:
1-Acetyl-2,3-dihydro-6-iodo-5-(pyridin-4-ylmethylthio)-1H-indole (D50) (0.390 g, 0.951 mmol) was dissolved in dry DMF (5 ml) and was treated with methyl iodide (0.089 ml, 1.430 mmol) with stirring. After 24 hours the reaction mixture was evaporated under reduced pressure and was triturated with ethyl acetate (~20 ml). The resultant brown solid was then filtered off, washed with diethyl ether and dried in vacuo (0.513 g). The solid was then redissolved in a mixture of ethanol (20 ml) and water (10 ml) and was cooled to 0° C. Sodium borohydride (0.069 g, 1.824 mmol) was then added. After 0.5 h a further amount of sodium borohydride (0.035 g, 0.912 mmol) was added. The reaction mixture was then allowed to warm to room temperature. After 1.5 hours the reaction mixture was treated with sodium bicarbonate solution (~15 ml) and was partitioned between dichloromethane and water. The aqueous layer was then extracted with dichloromethane (1X) and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give a yellow solid which was purified by silica-gel chromatography (5% MeOH/CH2Cl2 as eluant) to give the title compound as an off white solid (0.208 g, 53%).