Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([PH:5](=[O:7])[OH:6])[CH2:2][CH2:3][CH3:4].[CH2:8](N(CC)CC)[CH3:9].C(OC(Cl)=O)C>ClCCl>[CH2:8]([O:7][PH:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[O:6])[CH3:9]
Reactant: CCN(CC)CC
Reactant: CCCC[PH](=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CCCC[PH](=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
51 g of n-butyphosphinic acid are dissolved in 200 ml of dichloromethane, the solution is cooled to 10°, and 42.3 g of triethylamine are added dropwise. An exothermic reaction takes place. The mixture is cooled to 10° again and 45.3 g of chloroformic acid ethyl ester are added dropwise within a period of 75 minutes. A precipitate forms in an exothermic reaction with the evolution of gas. A further 200 ml of dichloromethane are then added and the mixture is allowed to warm to room temperature and is then stirred for 2 hours at room temperature, washed with water and dried over sodium sulfate, and the organic solvent is removed. The crude product is distilled under a high vacuum, yielding n-butylphosphinic acid ethyl ester having a boiling point of 95° (5×10-5 bar).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]([O:10][CH3:11])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(OO)(=[O:14])C>C(OCC)(=O)C>[C:1]([N+:5](=[N:6][C:7]([O:10][CH3:11])([CH3:9])[CH3:8])[O-:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(C)(C)N=NC(C)(C)C
Reactant: CC(=O)OO
Solvent: CCOC(C)=O
Product: COC(C)(C)N=[N+]([O-])C(C)(C)C

Procedure:
2-t-Butylazoxy-2-methoxypropane was prepared by oxidizing 7.9 grams (0.05 moles) 2-t-butylazo-2-methoxypropane with 50 ml. of 25% peracetic acid in ethyl acetate at 30°-40° C. for 2 hours. The yield was 7.3 grams (84% yield) of a colorless liquid. The infrared spectrum of the product was in agreement with the structure of 2-t-butylazoxy-2-methoxypropane (2 strong bands at 1450-1510 cm-1).
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O)[CH3:8]>>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)[CH3:8]
Reactant: Ic1cccs1
Reactant: CCOc1ccccc1B(O)O
Product: CCOc1ccccc1-c1cccs1

Procedure:
2-Iodothiophene and 2-ethoxyphenylboronic acid were treated in a manner similar to Reference Example 26-(2) to give 2-(2-ethoxyphenyl)thiophene as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:19]2[CH2:23][CH2:22][C@H:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20]2)=[C:5]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:6]2=[C:7]([CH:18]=1)[C:8](=[O:17])[N:9]([OH:16])[C:10]3=[O:15])#[N:2].[ClH:32]>CCO>[ClH:32].[NH2:24][C@H:21]1[CH2:22][CH2:23][N:19]([C:4]2[C:3]([C:1]#[N:2])=[CH:18][C:7]3[C:8](=[O:17])[N:9]([OH:16])[C:10](=[O:15])[C:11]4[C:6]=3[C:5]=2[CH:14]=[CH:13][CH:12]=4)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(C#N)cc3c4c(cccc24)C(=O)N(O)C3=O)C1
Agent: Cl
Solvent: CCO
Product: N#Cc1cc2c3c(cccc3c1N1CC[C@H](N)C1)C(=O)N(O)C2=O

Procedure:
The (S)-[1-(5-cyano-2-hydroxy-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-6-yl)-pyrrolidin-3-yl]-carbamic acid, tert-butyl ester from above was dissolved in EtOH and reacted with a stream of HCl gas forming a precipitate which was collected by filtration and dried to give 0.021 g of the title compound, mp >250° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:16][CH:15]([OH:17])[CH2:14][CH:13]2[CH2:12][O:11][N:10]3[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[F:8].I[CH:28]([CH3:30])[CH3:29]>ClCCl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[Br:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:16][CH:15]([O:17][CH:28]([CH3:30])[CH3:29])[CH2:14][CH:13]2[CH2:12][O:11][N:10]3[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(CN2OCC3CC(O)CC32c2ccc(F)c(Br)c2)cc1
Reactant: CC(C)I
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN2OCC3CC(OC(C)C)CC32c2ccc(F)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
To a mixture of racemic (3aRS,5RS,6aSR)-6a-(3-bromo-4-fluorophenyl)-1-(4-methoxybenzyl)hexahydro-1H-cyclopenta[c]isoxazol-5-ol (1.72 g, 4.07 mmol) in dichloromethane (2.5 mL) is added silver trifluoromethanesulfonate (2.62 g, 10.2 mmol) and powdered dried 4A sieves (1.50 g). A solution of 2-iodopropane (1.73 g, 10.2 mmol) in dichloromethane (0.5 mL) is added to the mixture over 15 minutes. The thick mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane and is filtered through diatomaceous earth. The solvent is removed under reduced pressure and the residue is purified by silica gel chromatography with a linear gradient of 0% to 10% ethyl acetate in dichloromethane over 15 minutes to give the title compound (0.466 g, 25%). ES/MS m/e (79Br/81Br) 464, 466 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([F:12])[C:5]=1[F:13].[Li+].[BH4-]>C1COCC1.CCOC(C)=O>[F:13][C:5]1[C:6]([F:12])=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1cc(OC)cc(F)c1F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)c(CO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3-difluoro-5-methoxy-benzoic acid methyl ester (925 mg, 4.58 mmol) in THF (25 mL), cooled to 0° C., was added a solution of LiBH4 (199 mg, 9.15 mmol) in THF (5 mL). The reaction mixture was stirred at RT for overnight. An additional aliquot of LiBH4 (4 equiv) was added and stirring was continued at RT for 6 h, and subsequently at 60° C. overnight. The mixture was diluted with EtOAc, the organics were washed with 1N aqueous NaOH solution (50 mL), dried (Phase separator) and evaporated in vacuo to afford the title compound as a white solid. TLC Rf (c-hexane/EtOAc 1:1)=0.57; MS (LC/MS): 198.0 [M+Na]+; tR (HPLC conditions c): 3.74 min.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:25]([C:26]([NH2:28])=[O:27])=[C:17]3[NH:18][C:19]4[CH2:24][CH2:23][NH:22][CH2:21][C:20]=4[N:16]3[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](O)(=[O:33])[CH:30]=[CH:31][CH3:32]>>[C:29]([N:22]1[CH2:23][CH2:24][C:19]2[NH:18][C:17]3[N:16]([N:15]=[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)[C:25]=3[C:26]([NH2:28])=[O:27])[C:20]=2[CH2:21]1)(=[O:33])[CH:30]=[CH:31][CH3:32]
Reactant: CC=CC(=O)O
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c3c([nH]c12)CCNC3
Product: CC=CC(=O)N1CCc2[nH]c3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn3c2C1

Procedure:
The desired compound was prepared from 2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide and but-2-enoic acid according to the procedure similar to that for compound 54. 1H NMR (400 MHz, DMSO-d6) δ 11.78-11.71 (m, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.46-7.39 (m, 2H), 7.18 (t, J=7.6 Hz, 1H), 7.11-7.04 (m, 4H), 6.73-6.63 (m, 2H), 4.80-4.71 (m, 2H), 3.90 (s, 2H), 2.76-2.70 (m, 2H), 1.88-1.86 (m, 3H). MS (ESI) m/e [M+1]+ 441.9.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].CCCCCC>CC(O)C>[C:5]1([C@H:3]([OH:4])[CH2:2][OH:1])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CO)c1ccccc1
Solvent: CCCCCC
Solvent: CC(C)O
Product: OC[C@@H](O)c1ccccc1

Procedure:
Regarding Example 31, except that the use amount of RuCl[(S)-xylbinap][(S)-daipen] was changed (3.0 mg, 0.0025 mol, 1/1,000 molar fold of 2-hydroxyacetophenone) and 2-propanol (2.5 mL) was used instead of methanol, the same procedure as Example 31 was carried out. As a result of analysis of the reaction solution by using gas chromatography (HP-1), the conversion rate was found to be 99% or more. The optical purity was measured by high performance liquid chromatography (CHIRALPAK AS-H, eluent; hexane:2-propanol=92:8), and it was found to be 90% ee.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:43]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][N:44]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:43]4[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][N:44]=4)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.2 %

Procedure:
A mixture of 59 mg (0.1 mmol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate, 42 mg (0.3 mmol) of 2-chloro-5-nitropyridine and 65 mg (0.2 mmol) of cesium carbonate in 0.5 mL of dimethyl formamide was stirred at rt for 12 h. The mixture was diluted with ethyl acetate and extracted with water. Evaporation of the solvent and chromatography on silica gel (1:1 ethyl acetate/hexane) gave the title compound (38 mg) as a white foam. 1H-NMR:0.83(6H,dd), 1.7(2H,m),1.8(2H,m), 2.8-3.2(7H,m), 3.7(3H.m), 3.8-4(4H,m), 5.0(2H,m), 5.62(1H,d), 6.03(2H,s), 6.85(1H,d), 6.97(1H,d), 7.02(2H,d), 7.18(1h,s), 7.35(2H,d), 7.4(1H,d), 8.42(1H,d), 8.90(1H,d). MS: 715
Reaction SMILES: Cl[CH:2]([C:4]1[C:13]([C:14]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[O:15])=[C:12]([OH:22])[C:11]2[C:6](=[C:7]([C:23]([F:26])([F:25])[F:24])[CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3]>C(O)(=O)C>[CH3:3][CH:2]1[C:4]2=[N:5][C:6]3[C:7]([C:23]([F:26])([F:25])[F:24])=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]([OH:22])=[C:13]2[C:14](=[N:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[O:15]1
Reactant: CC(Cl)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Solvent: CC(=O)O
Product: CC1OC(=Nc2nccs2)c2c1nc1c(C(F)(F)F)cccc1c2O
Temperature: 140 °C
Reaction time: 0.15 h
Yield: 99 %

Procedure:
A mixture of 6 g of 2-(1-chloroethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide [described in Examples 5 and 14 of U.S. patent application Ser. No. 262,952]and 50 ml of acetic acid was placed in an oil bath heated to 140° C. and held there for 9 minutes and then cooled to room temperature. The mixture was held at 16° C. for one hour and was vacuum filtered. The product was washed with acetic acid, then with ether and dried under reduced pressure at 80° C. to obtain 5.4 g of 1,3-dihydro-3-methyl-1-[(2-thiazolyl)-imino]-5-trifluoromethyl-furo[3,4-b]quinoline-9-ol in the form of an acetate. The latter was added to 100 water to which was added an aqueous saturated sodium bicarbonate solution to adjust the pH to 6. The mixture was vacuum filtered and the product was washed with water and dried under reduced pressure at 70° C. to obtain 4.2 g of 1,3-dihydro-3-methyl-1-[(2-thiazolyl)-imino]-5-trifluoromethyl-furo [3,4-b]quinoline-9-ol melting at 260° C. (decomposition).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[SH:12].Br[C:14]1[N:15]([CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[C:16]2[C:21]([N:22]=1)=[C:20]([NH2:23])[N:19]=[CH:18][N:17]=2>CN(C=O)C>[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[S:12][C:14]1[N:15]([CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[C:16]2[C:21]([N:22]=1)=[C:20]([NH2:23])[N:19]=[CH:18][N:17]=2
Reactant: CC(C)=CCCn1c(Br)nc2c(N)ncnc21
Reactant: COc1ccc(I)c(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(I)c(Sc2nc3c(N)ncnc3n2CCC=C(C)C)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a suspension of sodium hydride (96 mg, 4 mmol) in DMF (3 ml) was added 2-iodo-5-methoxy-benzenethiol (1.06 g, 4 mmol; J Org. Chem, 2001, 66(13), 4525-4542). After 30 min, a solution of 8-bromo-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine (296 mg, 1 mmol) in DMF (3 ml) was added, and the mixture was stirred for 12 h at 70° C. The reaction was quenched by addition of MeOH (2 ml), diluted with EtOAc (200 ml), washed with Na2CO3 (3×50 ml), brine (3×50 ml), dried (Na2SO4), evaporated, and purified by flash chromatography (CH2Cl2: MeOH=100:5) to give 8-(2-Iodo-5-methoxy-phenylsulfanyl)-9-(4-methyl-pent-3-enyl)-9H-purin-6-ylamine as a colorless powder (280 mg, 58%).
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]([OH:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[C:3]([CH2:1][CH3:2])[C:11]=1[CH3:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CCc1c(C(=O)O)ccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCc1c(C(=O)O)ccc(OCc2ccccc2)c1C
Reaction time: 0.5 h

Procedure:
2.10 g of 2-ethyl-4-hydroxy-3-methylbenzoic acid (E1) are dissolved in 50 ml of acetone. 3.30 ml of benzyl bromide and 5.10 g of K2CO3 are subsequently added. The reaction suspension is heated under reflux for 18 h overnight, subsequently filtered off with suction, and the filtrate obtained is evaporated to dryness in vacuo. The residue is dissolved in 40 ml of ethanol, and 40 ml of 2.0 N NaOH solution are added. The mixture is then heated under reflux for 3 h. The clear solution is diluted with 150 ml of water and adjusted to pH 1 using 20% hydrochloric acid. After stirring for 30 min, the precipitate formed is filtered off with suction, rinsed with water and dried at 90° C. in vacuo overnight, giving 2.45 g of the title compound as a beige, amorphous solid having a melting point of 169° C.; MS: 270.0 (M+); TLC: Rf=0.36 (cyclohexane/ethyl acetate 2:1 parts by volume).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[C:48]1([CH3:66])[CH:53]=[CH:52][C:51]([C:54]([O:56][C:57]2[CH:65]=[CH:64][CH:63]=[CH:62][C:58]=2[C:59](O)=[O:60])=[O:55])=[CH:50][CH:49]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:59](=[O:60])[C:58]3[CH:62]=[CH:63][CH:64]=[CH:65][C:57]=3[O:56][C:54]([C:51]3[CH:50]=[CH:49][C:48]([CH3:66])=[CH:53][CH:52]=3)=[O:55])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: Cc1ccc(C(=O)Oc2ccccc2C(=O)O)cc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3OC(=O)c3ccc(C)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 2-[4-toloyloxy]benzoic acid (8.0 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][Cl:22])=[N:19][N:18]=[C:17]2[CH2:23][NH:24][C:25]([O:27]CC2C=CC=CC=2)=O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].Br.[C:36](O)(=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][Cl:22])=[N:19][N:18]=[C:17]2[CH2:23][NH:24][C:25](=[O:27])[CH3:36])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CC(=O)O
Reactant: O=C(NCc1nnc(CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1)OCc1ccccc1
Agent: Br
Product: CC(=O)NCc1nnc(CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of 5-chloro-2-[3-(N-carbobenzoxyaminomethyl)-5-chloromethyl-4H-1,2,4-triazol-4-yl]-benzophenone (0.995 g) and 30% hydrogen bromide-acetic acid (2 ml) is stirred at room temperature for 1.25 hours, and the mixture is washed with ether (50 ml) twice. The obtained free base is mixed with benzene (10 ml), acetyl chloride (0.5 g) and dimethylformamide (6 ml), and the resultant mixture is stirred at room temperature for 2 hours, and allowed to stand overnight. The reaction mixture is neutralized with aqueous sodium bicarbonate, and the precipitated crystals are filtered and washed with ether and chloroform in order to give 5-chloro-2-(3-acetamidomethyl-5-chloromethyl-4H-1,2,4-triazol-4-yl)-benzophenone (0.6 g) as crystals melting at 193° to 199° C. (decomp.).
Reaction SMILES: [CH2:1]([C:6]1[S:7][C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH:18]C(=O)C(Cl)(Cl)Cl)[C:9]=2[N:25]=1)[CH2:2][CH2:3][CH2:4][CH3:5].N.ClCCl>CO>[CH2:1]([C:6]1[S:7][C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:18])[C:9]=2[N:25]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1nc2c(NC(=O)C(Cl)(Cl)Cl)nc3ccccc3c2s1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCCCCc1nc2c(N)nc3ccccc3c2s1

Procedure:
Trichloroacetyl isocyanate (0.51 mL) was added to a solution of 2-pentylthiazolo[4,5-c]quinoline-5N-oxide (0.78 g) in dichloromethane (50 mL). The reaction mixture was stirred at ambient temperature for about 75 minutes and then concentrated under vacuum to provide crude N-(2-pentylthiazolo[4,5-c]quinolin-4-yl)trichloroacetamide. The amide was combined with a solution of ammonia in methanol (40 mL of 2M). Dichloromethane was added to bring all of the material into solution. When the reaction was completed as indicated by thin layer chromatography, the reaction mixture was concentrated under vacuum. The residue was mixed with dichiloromethane and sodium bicarbonate. The organic layer was separated, washed with sodium bicarbonate then with water, dried over magnesium sulfate and then concentrated under vacuum to provide a white solid. This material was recrystallized from ethyl acetate to provide 2-pentylthiazolo[4,5-c]quinolin-4-amine as an off-white crystalline solid, m.p. 119-121° C. Analysis: Calculated for C15H17N3S: %C, 66.39; %H, 6.3 1; %N, 15.48; Found: %C, 66.21; %H, 6.35; %N, 15.39.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([F:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=3)[CH2:36][CH2:35]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Product: COc1nc2ccccc2nc1NC(=S)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 59 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[F:20].[CH3:21]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[F:20][C:3]1[C:2]2[N:1]=[CH:21][O:11][C:10]=2[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1c(O)cc(C(=O)O)c(Nc2ccccc2F)c1F
Solvent: O
Solvent: COC(OC)OC
Product: O=C(O)c1cc2ocnc2c(F)c1Nc1ccccc1F
Reaction time: 1 h
Yield: 1842.8 %

Procedure:
To a solution of 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxy benzoic acid (7.58 g, 27.05 mmol) in trimethyl orthoformate (50 mL) was added p-TsOH (0.23 g, 1.35 mmol). The reaction mixture was stirred for 1 h and treated with water (200 mL). The precipitate was filtered off and the filter cake was washed with water to afford the desired product (7.22 g, 82.7% yield for two steps). 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.14 (m, 1H), 7.05 (m, 2H), 6.86 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10][CH:9]2[O:21][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(O)C1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2(O)c2ccc(Cl)cc2)cc1
Reaction time: 18 h
Yield: 36.1 %

Procedure:
A solution of 128 mg (0.392 mmol) of tert-butyl (3RS,4RS)-4-(4-chlorophenyl)-3,4-dihydroxy-piperidine-1-carboxylate in 1.5 ml of dimethyl sulphoxide was added dropwise to a suspension of 16 mg (0.4 mmol) of sodium hydride (60% dispersion in refined oil) in 3 ml of dimethyl sulphoxide. After 15 minutes a solution of 61 mg (0.39 mmol) of p-methoxybenzyl chloride in 1 ml of dimethyl sulphoxide was added dropwise at room temperature within 10 minutes and the mixture was stirred for 18 hours. Subsequently, the reaction mixture was partitioned between ethyl acetate and water, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product (200 mg) was purified by chromatography on silica gel with a 3:1 mixture of hexane and ethyl acetate as the eluent. There were obtained (in addition to starting material and bisalkylated product) 63 mg (38% of theory) of tert-butyl (3RS,4RS)-4-(4-chlorophenyl)-4-hydroxy-3-(4-methoxy-benzyloxy)-piperidine-1-carboxylate as a colourless oil; MS: 448, 450 [M+H]+.
Reaction SMILES: Cl.[Si]([O:9][CH2:10][CH2:11][C:12]1[S:16][C:15]([CH2:17][CH2:18][N:19]2[CH2:37][CH2:36][C:22]3([O:27][CH2:26][CH2:25][N:24]([C:28]([C:30]4[N:31]=[C:32]([CH3:35])[S:33][CH:34]=4)=[O:29])[CH2:23]3)[CH2:21][CH2:20]2)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C>CO>[OH:9][CH2:10][CH2:11][C:12]1[S:16][C:15]([CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][C:22]3([O:27][CH2:26][CH2:25][N:24]([C:28]([C:30]4[N:31]=[C:32]([CH3:35])[S:33][CH:34]=4)=[O:29])[CH2:23]3)[CH2:36][CH2:37]2)=[CH:14][CH:13]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCO[Si](C)(C)C(C)(C)C)s4)CC3)C2)cs1
Agent: Cl
Solvent: CO
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCO)s4)CC3)C2)cs1
Reaction time: 1 h

Procedure:
Concentrated hydrochloric-acid (0.5 mL) was added to a solution of (9-(2-(5-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylthiazol-4-yl)methanone (example 4, step i) (0.235 g) in methanol (5 mL) and the resulting solution stirred for 1 h. The solvent was evaporated in vacuo and the residue azeotroped with toluene and re-dissolved in methanol (˜2 mL). The residue was dissolved in methanol (10 mL) and applied to a SCX cartridge pre-wetted with methanol. The cartridge was washed with methanol (100 mL) and eluted with 1M ammonia in methanol solution (100 mL). The eluent was evaporated in vacuo to give the subtitled compound as a yellow oil. Yield 0.12 g.