Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][CH2:16][CH2:17][OH:18].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][CH2:16][CH2:17][OH:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(NCCO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-Oxo-piperidine-1-carboxylic acid tert-butyl ester (0.2 g, 1 mmol) in dichloromethane (5 mL) was added 2-Amino ethanol (0.073 mg, 1.2 mmol) and NaBH(OAc)3 (0.3 g, 1.4 mmol). The resulting mixture was stirred at room temperature overnight and partitioned between dichloromethane and water. The combined organic extracts were washed with brine, dried, and evaporated. The residue was directly used into the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:25][N:26]([CH2:30][CH2:31]Cl)[CH2:27][CH2:28]Cl>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:28][CH2:27][N:26]([CH2:25][C:24]2[CH:33]=[CH:34][C:35]([Cl:36])=[C:22]([Cl:21])[CH:23]=2)[CH2:30][CH2:31]1)=[O:20])[CH3:2]
Reactant: CCCCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Reactant: ClCCN(CCCl)Cc1ccc(Cl)c(Cl)c1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83. Starting from (4-butoxy-benzenesulfonyl)acetic acid ethyl ester (13.2g 44 mmol) (3,4dichloro-benzyl)-bis-(2-chloro-ethyl)-amine (14.3g, mmol). Yield 14.1g (60%), white solid, MP 86° C.; MS: 527.9 (M+H)+
Reaction SMILES: [OH:1][C@:2]1([C:14]2[S:15][C:16]([C:19]3[CH:24]=[C:23]([NH:25][C:26]4[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=4)[CH:22]=[C:21]([CH2:36]OS(C)(=O)=O)[CH:20]=3)=[CH:17][N:18]=2)[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[C:4]([CH3:13])([CH3:12])[CH2:3]1.[N-:42]=[N+:43]=[N-:44].[Na+]>CN1C(=O)CCC1>[N:42]([CH2:36][C:21]1[CH:20]=[C:19]([C:16]2[S:15][C:14]([C@@:2]3([OH:1])[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[C:4]([CH3:12])([CH3:13])[CH2:3]3)=[N:18][CH:17]=2)[CH:24]=[C:23]([NH:25][C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH:22]=1)=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(COS(C)(=O)=O)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CN=[N+]=[N-])cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Temperature: 23 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
A solution of the product of Step 1 (250 mg, 0.407 mmol) in anhydrous NMP (5 ml) was treated with sodium azide (132 mg, 2.034 mmol, 5.0 equiv) and stirred at 23° C. for 18 h. The reaction was partitioned between EtOAc (2×75 ml) and water (85 ml) and the combined organic layers were dried over Na2SO4, filtered and concentrated to afford methyl(1S,4R)-4-{5-[3-(azidomethyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (220 mg, 96%), as an orange oil. MS ESI: [M+H]+ m/z 562.1
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCC1=O
Reaction time: 1 h
Yield: 70 %

Procedure:
The nitrogen purged vessel containing about 4-oxo-1,3-piperidinedicarboxylic acid 1-(1,1-dimethylethyl) 3-methyl ester (prepared according to Preparation Five, Step C, 53 kg, 49 L, 1.0 eq.) was charged with tetrahydrofuran (THF, 536 L) and potassium carbonate (72 kg, 2.5 eq.). The slurry was treated with benzyl bromide (36.0 kg, 1.01 eq.) over 10 to 15 minutes. The reaction mixture was heated at reflux temperature until reaction was complete (generally between 12 and 18 hours). The mixture was cooled to between 20° C. and 25° C., filtered to remove the salts, and the filter cake washed with THF (134 L). The THF was removed from the mixture by partial vacuum distillation and replaced with heptanes (402 L). The resulting slurry was cooled to between −5° C. and 5° C. and stirred for about one hour. The solids were collected by filtration, washed with heptanes (57 L) cooled between 0° C. to 10° C., and dried under vacuum between 45° C. to 55° C. to give 50.1 kg of 4-oxo-3-(phenylmethyl)-1,3-piperidinedicarboxylic acid 1-(1,1-dimethylethyl) 3-methyl ester (69.2% yield). HPLC assay showed a product peak of 99.2% at about 12 minutes. HPLC conditions: Intersil C-8 column, 4.6×150 mm; mobile phase: 50% acetonitrile/water; aqueous phase: 1 L water, 3 mL triethylamine and 1 mL H3PO4 at pH 6.5; flow rate 1.0 mL/min.; detected by UV at 210 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14]([C:16]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:20][CH2:19][NH:18][CH2:17]1)=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[CH2:20][CH2:19][N:18]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Reactant: O=C=Nc1ccc(Cl)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)Nc2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation using 4-chloro phenyl isocyanate and 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 65) to afford the racemate as a white solid (220 mg, 76%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2O.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:5]1[C:4]2[C:9](=[CH:10][N:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:12]#[N:13]
Reactant: N#Cc1cnc2cnc(Cl)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc2cnc(Cl)cc2c1Cl

Procedure:
To 650 mg of 6-chloro-4-hydroxy-[1.7]naphthyridine-3-carbonitrile under an inert atmosphere was added 20 mL of phosphorous oxychloride. After two hours at reflux, the excess phosphorous oxychloride was removed in vacuo and ice-water and chloroform were added. Solid potassium carbonate was then added carefully to a pH of about 8. The chloroform layer was washed with brine, dried with sodium sulfate, and stripped to give a crude product. This material was further purified by passing it through a plug of silica gel with 5% ethyl acetate/chloroform to give approximately 600 mg of 4,6-dichloro-[1.7]naphthyridine-3-carbonitrile as a yellowish solid, which was used in the following step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C)C=O.O.C(OCC)(=O)C.C(N(CC)CC)C>[F:22][C:23]([F:33])([F:34])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:28]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1n[nH]c2cc(-c3ccc(N)cc3)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1n[nH]c2cc(-c3ccc(NC(=O)c4cccc(C(F)(F)F)c4)cc3)ccc12
Temperature: 70 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
To a stirred solution of ethyl 6-(4-aminophenyl)-1H-indazole-3-carboxylate (40 mg), 3-trifluoromethyl-benzoic acid (35.2 mg), triethylamine (40 and HOBt (25 mg) in N,N-dimethylformamide, was added EDCI (40.6 mg). The mixture was stirred at 70° C. for 12 h. The mixture cooled to room temperature and ethyl acetate and water were added. The mixture was extracted with ethyl acetate three times. The combined organic layer was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was triturated by ethylacetate/hexane to give ethyl 6-(4-(3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxylate (46.6 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][OH:29])[CH:24]=[CH:25][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][OH:29])[CH:24]=[CH:25][CH:26]=2)=[N:3][CH:4]=1
Reactant: COc1cccc(CCNc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CCO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(CCNc2nc(Nc3cccc(CCO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 94.4 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.50 g, 1.7 mmol) (prepared according to Example 8, step A) and 2-(3-aminophenyl)ethanol (0.31 g, 2.3 mmol) (prepared according to Example 22, Step B) in 1,4-dioxane (14.3 mL) was added p-toluenesulfonic acid monohydrate (0.12 g, 0.61 mmol). The mixture was heated at 100° C. for 16 h and the reaction was complete. To the mixture was added NaHCO3 (saturated aqueous solution). The organic solvent was removed under vacuum and water/EtOAc was added. After layer separation, the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as a light brown powder (0.64 g, 96%). LCMS for C21H24ClN4O2 (M+H)+: m/z=399.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:8]([O:10][CH2:11]Cl)[CH3:9]>CS(C)=O>[CH2:8]([O:10][CH2:11][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:9]
Reactant: c1c[nH]cn1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOCn1ccnc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 9.1 %

Procedure:
To a solution of imidazole (10.0 g, 146.9 mmole) in 100 ml dimethyl sulfoxide at room temperature under nitrogen is added sodium hydride (6.46 g, 161.6 mmole). The solution is stirred at 80° C. for 2 hours. Chloromethyl ethyl ether (16.35 ml, 176.3 mmole) is added dropwise. The reaction mixture is stirred for another 2 hour at 80° C., cooled to room temperature, poured into 5% aqueous solution and extracted with dichloromethane (4×200 ml). The combined organic extracts are dried over sodium sulfate, filtered, concentrated in vacuo. The residue is fresh chromatographed in hexane/ethyl acetate from 5:1 to 2:1 to give 1-ethoxymethyl-1H-imidazole as a brown oil 1.68 g (90%) MS (ES+): (M+H)=127.0
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:11]=[CH:10][NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1>>[CH2:2]([C:10]1[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)[C:7](=[O:8])[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[N:11]=1)[CH2:1][CH2:6][CH3:5]
Reactant: O=c1[nH]cnc2ccccc12
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1nc2ccccc2c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
The quinazolinone prepared as described in Example 17 was alkylated with 4-bromomethyl-2'-cyanobiphenyl. The product was purified by MPLC Lobar C silica column eluting with 25% EtOAc/hexane. Rf 0.13 in 30% EtOAc/hexane. 1H-NMR (300 MHz, CDCl3): 8.32 (m, 1H), 7.84-7.59 (m, 7H), 5.46 (bs, 2H), 2.79 (3 line m, 2H), 1.80 (m, 2H), 1.44 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([N:14]1[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[F:1])[CH2:12][CH2:13]1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A stirred solution of 1-(2-fluoro-4-nitrophenyl)piperazine (15 g, 66.6 mmol) in DCM (160 ml) was cooled to 0° C. Triethylamine was then added (11.23 ml, 79.92 mmol) followed by dropwise addition of acetyl chloride (5.68 ml, 79.92 mmol). The solution was allowed to warm to ambient temperature and stir for 1.5 hour. The reaction mixture was diluted with DCM, washed with water, sat. sodium hydrogen carbonate and brine. It was dried and the solvent was evaporated to give the title compound as a solid which was dried in vac oven overnight at 50° C. (17.46 g, 98%). NMR (400 MHz) 2.05 (s, 3H), 3.30 (dt, 4H, under H2O signal), 3.61 (m, 4H), 7.18 (t, 1H), 8.02 (d, 1H), 8.02 (dd, 1H); m/z 268.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[S:9]1[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[N:15]=2)=[CH:12][C:11]2[CH:24]=[CH:25][CH:26]=[CH:27][C:10]1=2>C(#N)C>[CH3:23][S:20]([C:16]1[N:15]=[C:14]([C:13]2[S:9][C:10]3[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=3[C:12]=2[N+:7]([O-:8])=[O:6])[CH:19]=[CH:18][N:17]=1)(=[O:21])=[O:22]
Reactant: O=[N+]=O
Reactant: CS(=O)(=O)c1nccc(-c2cc3ccccc3s2)n1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CS(=O)(=O)c1nccc(-c2sc3ccccc3c2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.7 %

Procedure:
Nitronium tetrafluoroborate (3.4 mL, 0.5 M in sulfolane, 1.72 mmol) was slowly added at 0° C. to a suspension of 4-(benzo[b]thiophen-2-yl)-2-(methylsulfonyl)pyrimidine (0.50 g, 1.72 mmol) in acetonitrile (10 mL). The resulting mixture was stirred at rt for 14 h and concentrated in vacuo. The product was purified by flash chromatography eluting with ethyl acetate/hexane (1:3) to afford the title compound (0.35 g, 57%). MS (M+H)+ 336.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl>C(O)C>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][S:1][C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1
Reactant: ClCc1ccccc1Cl
Reactant: FC(F)(F)c1nnc(S)s1
Solvent: CCN(CC)CC
Solvent: CCO
Product: FC(F)(F)c1nnc(SCc2ccccc2Cl)s1
Yield: 64.4 %

Procedure:
9.3 g (0.05 mole) of 2-mercapto-5-trifluoromethyl-1,3,4-thiadiazole, 5.1 g (0.05 mole) of triethylamine and 8.1 g (0.05 mole) of o-chlorobenzyl chloride in 80 ml of absolute ethanol were stirred for 2 hours under nitrogen at 50° C and then poured onto ice. The precipitate was filtered off and purified by low temperature crystallization from petroleum ether. 10 g (64% of theory) of 2-(o-chlorobenzylthio)-5-trifluoromethyl-1,3,4-thiadiazole of melting point 36°-37° C were obtained. A solution of 9.8 g (0.048 mole) of m-chloroperbenzoic acid (85% pure) in 85 ml of methylene chloride was added dropwise to 5 g (0.016 mole) of the above compound in 10 ml of methylene chloride. The mixture was stirred for 4.5 hours under reflux and then mixed successively with a solution of 6.4 g of sodium sulfite in a little water, followed by a solution of 2.7 g of sodium carbonate in a little water, and stirred thoroughly for 15 minutes. The organic phase, after concentration and recrystallization from cyclo-hexane/ethyl acetate, gave colorless crystals. 4.8 g (87% of theory) of 2-(o-chlorobenzylsulfonyl)-5-trifluoromethyl-1,3,4-thiadiazole of melting point 103° C were obtained.
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([NH2:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>CC(=O)CC.CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([C:9]([NH:11][CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])=[O:10])[NH2:8])=[CH:12][CH:13]=1
Reactant: O=S1(=O)CCCO1
Reactant: NC(=O)[C@@H](N)Cc1ccc(I)cc1
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: N[C@@H](Cc1ccc(I)cc1)C(=O)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 17.6 %

Procedure:
The amide (1.3 g, 4.4 mmol) was dissolved in 15 mL of 2-butanone with a few drops of DMF before 1,3-propane sultone (560 mg, 4.9 mmol) was added. The reaction mixture was stirred at reflux for 2 hours. The mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×20 mL) and dried in vacuo. The solid was suspended in MeOH (25 mL) and a small amount of water (1 mL). The suspension was stirred at reflux. The solid material was collected by filtration while the mixture was still hot. The solid was washed with hot MeOH (2×10 mL). Compound CO was obtained as a white solid (320 mg).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].Br[CH2:6][CH:7]([CH2:11]Br)[C:8]([OH:10])=[O:9].Cl>[OH-].[K+]>[C:1]([S:3][CH2:6][CH:7]([CH2:11][S:3][C:1](=[O:4])[CH3:2])[C:8]([OH:10])=[O:9])(=[O:4])[CH3:2]
Reactant: O=C(O)C(CBr)CBr
Reactant: CC(O)=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(=O)SCC(CSC(C)=O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.36 g (40 mmoles) of thioacetic acid in 40 ml of N-potassium hydroxide is added dropwise to a solution of 2-bromomethyl-3-bromopropanoic acid in 1.0N potassium hydroxide (20 ml). The mixture is stirred at room temperature overnight, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and concentrated in vacuo. The residue is converted into a dicyclohexylammonium salt (m.p. 116°-118°) and the salt converted back into the free acid, 2-(acetylthiomethyl)-3-(acetylthio)propanoic acid, by distribution between ethyl acetate and 10% potassium bisulfate.
Reaction SMILES: [C:1]([C:3]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)([CH2:10][CH2:11][C:12]([O-])=[O:13])[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:2]>COCCO.[Ni]>[Cl:22][C:17]1[CH:16]=[C:15]([C:3]2([CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:1][NH:2][C:12](=[O:13])[CH2:11][CH2:10]2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)CCC(C#N)(CCC(=O)[O-])c1ccc(Cl)c(Cl)c1
Agent: [Ni]
Solvent: COCCO
Product: COC(=O)CCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)NC1
Reaction time: 72 h

Procedure:
40 g of the compound prepared in stage A are dissolved in 500 ml of 2-methoxyethanol, 2 g of Raney® nickel are added and the mixture is hydrogenated at 40° C. at atmospheric pressure for 3 days. The mixture is filtered, evaporated and the expected product is obtained in the form of an oil (39 g).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([O:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49])[CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([O:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49])[CH:38]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCOc1cc(CCl)ccc1C
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C

Procedure:
Analogously to Method D, 0.238 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.125 g of 4-chloromethyl-2-(3-methoxypropoxy)-1-methylbenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rt=6.39.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=O)(C)(C)C>CO>[NH:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN1CCOCC1
Agent: Cl
Solvent: CO
Product: C1CN[C@H](CN2CCOCC2)C1
Reaction time: 0.08 h
Yield: 119.9 %

Procedure:
HCl (g) was introduced into a solution of (S)-2-morpholin-4-ylmethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, 1.47 mmol) in MeOH. After 5 min., the reaction solution was concentrated under reduced pressure to give a white solid (300 mg, 99%). MS: 170.9 (MH+); HPLC Rf: n.d.; HPLC purity: n.d.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[C:13]1([S:19]([CH2:21][CH2:22][CH2:23][CH2:24]Br)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: O=S(CCCCBr)c1ccccc1
Product: O=c1ccc2cc(OCCCCS(=O)c3ccccc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 92 from 6-hydroxy-carbostyril and 4-phenylsulfinyl-butyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:14][C@H:15]([C:17]([C:19]1([NH2:42])[C:25](=[O:26])[N:24]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[N:21]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:20]1=[O:41])=[O:18])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:14][C@H:15]([C:17]([C:19]2([NH2:42])[C:25](=[O:26])[N:24]([CH2:27][C:28]([CH3:31])([CH3:29])[CH3:30])[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:20]2=[O:41])=[O:18])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O

Procedure:
Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-V), the title compound was prepared as a white solid (melting point=194-195° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (2:1 gradient to 3:2). Rf=0.46 (CH2Cl2/EtOAc, 2:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1.[H-].[Na+].Cl[CH2:20][C:21](=O)[CH3:22]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[C:12]2[C:21]([CH3:22])=[CH:20][O:16][C:11]=2[CH2:10]1
Reactant: Cc1ccc(C)c(C2CC(=O)CC(=O)C2)c1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(C2CC(=O)c3c(C)coc3C2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(2,5-dimethylphenyl)cyclohexane-1,3-dione (mp194-195° C.; 1.08 g) in DMF (20 ml) was added 60% sodium hydride (0.22 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added chloroacetone (0.45 ml), and the mixture was stirred at 150° C. overnight (16 hours). The reaction solution was cooled, and to the mixture was added ice-water. The mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(2,5-dimethylphenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.36 g).