Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[CH:16](O)[CH:17]=[CH2:18])=[CH:4][CH:3]=1.C(OCC)C.[BrH:25].O>CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[CH:16]=[CH:17][CH2:18][Br:25])=[CH:4][CH:3]=1
Reactant: Br
Reactant: C=CC(O)c1c(F)cccc1Sc1ccc(F)cc1
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: Fc1ccc(Sc2cccc(F)c2C=CCBr)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-(2-(4-fluorophenylthio)-6-fluorophenyl)prop-2-en-1-ol (2.29 g, 8.23 mmol) is dissolved in 10 ml of hexane and 10 ml of diethyl ether and cooled in an ice bath. Concentrated HBr acid (4.6 ml, 41.2 mmol) is then added dropwise and the reaction mixture is stirred vigorously for 5 hours at room temperature. The reaction mixture is then poured into water and extracted twice with diethyl ether. The extracts are washed with water and then brine and dried over MgSO4 to afford the subtitle compound.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:16][CH2:17][C:18](N1CC(=O)N(C2C=CC=C(Cl)C=2C)C1)=[O:19]>>[Cl:16][CH2:17][C:18]([N:10]1[CH2:9][CH2:8][C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=2)([OH:13])[CH2:12][CH2:11]1)=[O:19]
Reactant: OC1(Cc2ccc(F)cc2)CCNCC1
Reactant: Cc1c(Cl)cccc1N1CN(C(=O)CCl)CC1=O
Product: O=C(CCl)N1CCC(O)(Cc2ccc(F)cc2)CC1

Procedure:
2-Chloro-1-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-ethanone was prepared from 4-(4-fluorobenzyl)piperidin-4-ol according to the procedure described for Compound 76 in Example 40.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)=[CH:8][C:4]=1[C:5]([OH:7])=O.[NH2:20][C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:22]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CCOC(C)=O>[Cl:2][C:3]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)=[CH:8][C:4]=1[C:5]([NH:20][C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:22]=1)=[O:7]
Reactant: O=C(O)c1cc(-c2ccc(F)cn2)c(Cl)cc1Cl
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3ccc(F)cn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Reaction time: 1 h
Yield: 55.8 %

Procedure:
2,4-dichloro-5-(5-fluoropyridin-2-yl)benzoic acid hydrochloride (Preparation 20, 900 mg, 3.15 mmol), ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (683 mg, 2.95 mmol) and diisopropylethylamine (3.28 mL, 18.88 mmol) were added to EtOAc (30 mL) and heated to reflux under an atmosphere of nitrogen. A 50% solution of propylphosphonic cyclic anhydride in EtOAc (9 g, 14.16 mmol) was added dropwise, and the reaction was kept at reflux for 3 hours. After cooling, the reaction was basified with saturated aqueous sodium hydrogen carbonate solution. The organic layer was collected, dried over magnesium sulphate and concentrated in vacuo. The residue was dissolved in ethanol (30 mL) and solid sodium carbonate (˜2 g) was added with rapid stirring for 1 hour. The mixture was filtered and the filtrate concentrated in vacuo. The residue was stirred with dilute aqueous sodium hydrogen carbonate, filtered, washed with water and dried in vacuo. The resulting solid was triturated with TBME to afford the title compound (822 mg, 52%).
Reaction SMILES: N.[Na].[CH2:3]([C@:6]1([CH2:32][O:33]CC2C=CC=CC=2)[C:11](=[O:12])[O:10][C@H](C2C=CC=CC=2)[C@H](C2C=CC=CC=2)[N:7]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:4]=[CH2:5].[Cl-].[NH4+]>C1COCC1.C(O)C>[C:28]([O:27][C:25]([NH:7][C@:6]([CH2:32][OH:33])([CH2:3][CH:4]=[CH2:5])[C:11]([OH:12])=[O:10])=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: C=CC[C@]1(COCc2ccccc2)C(=O)O[C@H](c2ccccc2)[C@H](c2ccccc2)N1C(=O)OC(C)(C)C
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CC[C@@](CO)(NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.33 h

Procedure:
450 ml of ammonia were condensed at −78° C. 4.4 g of sodium were added in 4 portions at an interval of 10 min each time, and the mixture was stirred for 20 min. At −60° C., a solution of 9.8 g of tert-butyl (3S,5S,6R)-3-allyl-3-benzyloxymethyl-2-oxo-5,6-diphenylmorpholine-4-carboxylate and 11.2 ml of ethanol in 150 ml of THF was added dropwise thereto. The mixture was stirred at −45° C. for 1.5 h, and the reaction was stopped by adding solid ammonium chloride until the blue color disappeared. The ammonia was then allowed to evaporate off, and 400 ml of water were added to the residue. The THF was removed in vacuo. The aqueous was adjusted to pH 2 with 1 N HCl and extracted 3 times with 200 ml of ethyl acetate each time. The combined organic phases were dried with MgSO4. The solvents were removed in vacuo and the residue was purified by chromatography on silica gel.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][OH:14].C(N(CC)CC)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.Cl>ClCCl.O>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: OCCOc1ccc2ccccc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(OCCOc1ccc2ccccc2c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
To a solution of 2-(2-naphthyloxy)-1-ethanol (1.5 g, 7.97 mmol) and triethylamine (1.21 g, 11.95 mmol) in dichloromethane (20 mL) at 0° C. was added 4-bromobenzenesulfonyl chloride (2.12 g, 8.36 mmol) in dichloromethane (10 mL) dropwise over 30 minutes. The reaction was then warmed to room temperature and stirred for 16 hours before more 4-bromobenzenesulfonyl chloride (0.20 g, 0.80 mmol) was added and stirring was continued for 2 hours. The mixture was then poured into water (50 mL) and acidified with 2N aqueous hydrochloric acid (15 mL). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a crude residue. This was purified by column chromatography on silica gel (50 g), eluting with hexane:ethyl acetate (9:2), to give the title compound (0.56 g, 17%) as a white crystalline solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][CH:9]([OH:11])[CH2:8][C@@H:7]([O:12][C:13](=[O:15])[CH3:14])[CH2:6]1)(=[O:3])[CH3:2].[K+].[Br-].C([O-])(O)=O.[Na+].[O-]Cl.[Na+].Cl>ClCCl.O>[C:1]([O:4][C@@H:5]1[CH2:10][C:9](=[O:11])[CH2:8][C@@H:7]([O:12][C:13](=[O:15])[CH3:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC(O)C[C@@H](OC(C)=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CC(=O)C[C@@H](OC(C)=O)C1

Procedure:
To a solution of 30.00 g of (1R,3R)-1,3-diacetoxy-5-hydroxy-cyclohexane in 400 ml of dichloromethane was subsequently added at 0° a solution of 1.155 g of KBr in 200 ml of water and 325 mg of 2,2,6,6-tetramethyl-piperidine-1-oxyl, radical and the pH was adjusted to 7.0 by addition of 1 ml of aqueous sat. NaHCO3. The stirred mixture was treated simultaneously within 40 min with 107 g of NaOCl (10.6%) and 520 ml of aqueous 0.1 N hydrochloric acid keeping the pH at 7-8. The layers were separated, the organic layer was washed with 15% aqueous NaCl, dried over MgSO4 and evaporated to give 28.93 g of the pure (t.l.c.) title compound as a yellow oil. IR (nujol): 1728s, br. (C═O).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>>[CH3:39][O:38][C:36]([C:35]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=4[CH:26]=3)[C:10]([F:13])([F:11])[F:12])=[C:4]([Cl:28])[CH:3]=2)=[CH:31][C:30]=1[F:29])=[O:37]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid to give the title compound as an off-white solid. MS (m/e)=552.2 [M+H+].
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[Br:18][C:19]1[CH:30]=[CH:29][C:22]([C:23](N(OC)C)=[O:24])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:30]=[CH:29][C:22]([C:23]([C:2]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[O:24])=[CH:21][CH:20]=1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(Br)cc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 4-bromo-N-methoxy-N-methylbenzamide. It is used in crude form in the following reaction.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]([CH3:28])([CH3:27])[C:11](=O)[CH2:12][NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=2)=[S:15])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C1(C)C=CC=CC=1>CC(O)=O>[F:9][C:8]1[CH:7]=[CH:6][C:5]([C:10]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:14]([SH:15])=[N:13][CH:12]=2)([CH3:28])[CH3:27])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: COc1cc(NC(=S)NCC(=O)C(C)(C)c2ccc(F)c(C#N)c2)ccc1F
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1cc(-n2c(C(C)(C)c3ccc(F)c(C#N)c3)cnc2S)ccc1F
Yield: 65.1 %

Procedure:
A solution of 1-(3-(3-cyano-4-fluorophenyl)-3-methyl-2-oxobutyl)-3-(4-fluoro-3-methoxyphenyl)thiourea (3.7 g, 9.17 mmol) in AcOH (50 mL) was refluxed 2 h at 110° C. After the reaction was complete, it was cooled to room temperature and co-evaporated with toluene in vacuo. The residue was purified by flash column chromatography (Hex:EA=1:3) to give 2-fluoro-5-(2-(1-(4-fluoro-3-methoxyphenyl)-2-mercapto-1H-imidazol-5-yl)propan-2-yl)benzonitrile (2.3 g, 65%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.6 (bs, 1H), 7.26-7.23 (m, 1H), 7.08 (t, J=9.2 Hz, 1H), 6.96 (t, J=8.8 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.25-6.25 (m, 1H), 6.17-6.15 (m, 1H), 3.59 (s, 3H), 1.51 (s, 6H).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)([Cl:15])=[O:14]>O1CCCC1>[Cl:15][C:13]([N:9]1[CH2:10][CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:12])=[O:14]
Reactant: O=C1NCCN1c1ccccc1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Cl)N1CCN(c2ccccc2)C1=O
Reaction time: 4 h

Procedure:
16.2 parts by wt. of 1-phenyl-2-oxo-imidazolidine were suspended in 160 parts by vol. of tetrahydrofurane and 12.0 parts by wt. of phosgene, dissolved in 30 parts by vol. of tetrahydrofurane, were added dropwise at 10° C. The mixture was then stirred for a further 4 hrs. at 10° C and left to stand overnight at 20° C, and the precipitate present was then filtered off, washed with tetrahydrofurane and dried.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.[OH-].[Na+]>O.CCOCC>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: BrCCCCCCBr
Reactant: OCCCCCCc1ncccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: BrCCCCCCOCCCCCCc1ncccn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 2-pyrimidinehexanol (1.18 g), 1,6-dibromohexane (4 ml), 50% sodium hydroxide (4 ml) and TAB (100 mg) was vigorously stirred at room temperature for 17 h, then diluted with water (40 ml) and ether (50 ml). The organic phase was dried and evaporated in vacuo to an oil which was purified by FCC. Elution with hexane followed by hexane-ether (1:1) gave the title compound as a colourless oil (670 mg), t.l.c. (ether) Rf 0.24
Reaction SMILES: O(CC1C=CC=CC=1)CC1C=CC=CC=1.C([O:23][C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2)C1C=CC=CC=1>>[C:24]12([OH:23])[CH2:31][CH:30]3[CH2:29][CH:28]([CH2:27][CH:26]([CH2:32]3)[CH2:25]1)[CH2:33]2
Reactant: c1ccc(COC23CC4CC(CC(C4)C2)C3)cc1
Solvent: c1ccc(COCc2ccccc2)cc1
Product: OC12CC3CC(CC(C3)C1)C2

Procedure:
A mixture of pyridinium triflate 1 (100 mg, 0.29 mmol), benzotrifluoride (PhCF3, 0.29 mL), MgO (11.5 mg, 0.29 mmol), and 28 (21.8 mg, 0.14 mmol) was subjected to the standard procedure to afford 0.0363 g of a yellow oil, which was determined by 1H NMR analysis to consist of 8.7 mg of Bn2O and 0.0276 g (80%) of 1-benzyloxyadamantane (3i). Spectroscopic analysis was consistent with the data reported previously for 3i.
Reaction SMILES: CS[C:3]([S:12][CH3:13])=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:10]([C:4](=[C:3]([S:12][CH3:13])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:11]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(C#N)=C(SC)SC
Solvent: CCO
Product: CCOC(=O)C(C#N)=C(Nc1ccccc1)SC
Yield: 87.8 %

Procedure:
A solution of ethyl 3,3-bis(methylthio)-2-cyanoacrylate (20.0 g, 91.2 mmol) and aniline (9.1 mL, 100 mmol) in ethanol (200 mL) was heated under reflux for 16 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate, hexane:ethyl acetate=98:2→1:1) to give the title compound (21.0 g, 88%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:12][NH:13][O:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:13]([O:14][CH3:15])[CH3:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-bromophenyl)acetic acid (4.4 g, 20.56 mmol) in N,N-dimethylformamide (125 ml) was successively added N,O-dimethylhydroxyamine (4.5 g, 46.26 mmol), triethylamine (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.9 g, 46.26 mmol) and 1-hydroxybenzotriazole (6.24 g, 46.26 mmol). The reaction mixture was stirred at room temperature overnight, and partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated. The residue was purified by flash chromatography on silica gel (50% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 258 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH2:15][CH2:14]3)[S:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:30]1SN=C(C2C=CN=C(Cl)C=2)N=1.Cl.Cl.Cl.COC1C=C(CCN2CCNCC2)C=CN=1>>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:11]3[S:10][N:9]=[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:30])[CH:7]=4)[N:12]=3)[CH2:14][CH2:15]2)[CH:26]=[CH:25][N:24]=1
Reactant: COc1cc(CCN2CCN(c3nc(-c4ccnc(Cl)c4)ns3)CC2)ccn1
Reactant: Clc1cc(-c2nsc(Cl)n2)ccn1
Agent: COc1cc(CCN2CCNCC2)ccn1
Agent: Cl
Product: COc1cc(CCN2CCN(c3nc(-c4ccnc(C)c4)ns3)CC2)ccn1

Procedure:
In analogy to the procedure described for the synthesis of 3-(2-chloropyridin-4-yl)-5-(4-(2-(2-methoxypyridin-4-yl)ethyl)piperazin-1-yl)-1,2,4-thiadiazole (Example 168), the tile compound was prepared from 5-chloro-3-(2-chloropyridin-4-yl)-1,2,4-thiadiazole and 1-(2-(2-methoxypyridin-4-yl)ethyl)piperazine trihydrochloride.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]3[CH:14]([C:15](=[O:18])[NH:16][N:17]=2)[CH2:13]3)=[CH:7][CH:6]=1)(=O)C.CO.[OH-].[Na+].Cl>O>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]3[CH:14]([C:15](=[O:18])[NH:16][N:17]=2)[CH2:13]3)=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(C2=NNC(=O)C3CC23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 93.1 %

Procedure:
25 g (103 millimoles) of 2-(p-acetylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 7c), 215 ml of methanol and 215 ml of 10 N sodium hydroxide solution are refluxed for 3 hours. The methanol is then stripped off under reduced pressure. 500 ml of water are added to the residue and the mixture is brought to pH 4 with dilute hydrochloric acid. After filtering off the product and drying it under reduced pressure at 50° C., 19.3 g (93% of theory) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are isolated as almost colorless crystals, of melting point 230°-231° C. after recrystallization from methanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.C1(OP([N:34]=[N+:35]=[N-:36])(=O)OC2C=CC=CC=2)C=CC=CC=1.N1CCCN2CCCCCC=12>C1(C)C=CC=CC=1>[N:34]([CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)=[N+:35]=[N-:36]
Reactant: OCc1cncc(Cl)c1COC1CCCCO1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cncc(Cl)c1COC1CCCCO1

Procedure:
A solution of [5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridin-3-yl]-methanol (1.3 g, 4.9 mmol), phosphorazidic acid diphenyl ester (1.4 mL, 6.4 mmol) and 2,3,4,6,7,8,9,10-octahydro-pyrimido[1,2-a]azepine (0.96 mL, 6.4 mmol) in toluene (0.15 mL) was stirred at RT overnight. Solvents were concentrated in vacuo and the residue was partitioned between DCM (10 mL) and saturated NaCl solution (10 mL). After extraction of the aqueous layer with DCM (2×10 mL) the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexanes/EA 3:1) to give the title compound. MS (m/z): 282.9 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[C:22]([C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[C:27]([O:36][CH3:37])[CH:26]=1)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:32][CH2:31][CH2:30][O:29][C:28]3[CH:34]=[CH:35][C:25]([C:22](=[O:24])[CH3:23])=[CH:26][C:27]=3[O:36][CH3:37])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(O)(c2ccccc2)c2ccc(F)cc2)CC1
Yield: 27.4 %

Procedure:
A mixture of 6.5 g (0.023 mole) of α-(p-fluorophenyl)-α-phenyl-4-piperidinemethanol, 5.5 g (0.023 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.92 g (0.023 mole) of sodium bicarbonate in 80 ml of dimethylformamide was heated at 100°-110° C. for 2 hrs. The reaction mixture was cooled and filtered and the dimethylformamide was removed at reduced pressure. The residual oil was dissolved in chloroform and filtered. The chloroform was removed at reduced pressure. The solid residue which remained weighed 8.6 g (77%) and was recrystallized from ethanol to give 3.1 g of material melting at 147°-148° C. A sample was dried over refluxing toluene and submitted for analysis. (See Ex. 14, U.S. Pat. No. 3,956,296).
Reaction SMILES: ClCCl.Cl.[NH2:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1.[C:15](Cl)(=[O:18])[CH2:16][CH3:17].Cl>C(N(CC)CC)C>[CH2:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH:6]1[NH:5][C:15](=[O:18])[CH2:16][CH3:17]
Reactant: NC1Cc2ccccc2C1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NC1Cc2ccccc2C1
Reaction time: 12 h
Yield: 87.2 %

Procedure:
200 ml of dichloromethane, then 15 ml, i.e. 10.9 g (107.6 mmmol) of triethylamine were added to 5 g (29.5 mmol) of 2-aminoindan hydrochloride. The mixture was stirred, then 2.6 ml (29.5 mmol) of propionyl chloride were added and stirring was continued at room temperature for 12 h. Dilute hydrochloric acid was added, the precipitate was filtered, washed, dried and purified by chromatography on a silica gel column, eluted with an 80:20 mixture of dichloromethane/ethyl acetate. 4.87 g of beige solid were isolated.
Reaction SMILES: [O:1]1[C@H:5]([CH2:6][CH2:7][C:8]([F:11])([F:10])[F:9])[C@H:2]1[CH2:3][OH:4]>C(Cl)(Cl)Cl>[O:1]1[C@H:5]([CH2:6][CH2:7][C:8]([F:9])([F:10])[F:11])[C@H:2]1[CH:3]=[O:4]
Reactant: OC[C@H]1O[C@@H]1CCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C[C@H]1O[C@@H]1CCC(F)(F)F

Procedure:
The title compound is prepared analogously to Example 5a) from (2R,3R)-2,3-epoxy-6,6,6-trifluoro-hexanol; colourless liquid having a boiling point of 80°-81°/26 mbar.; [α]D20 (chloroform, 0.15%)=-10.7°±6.7°.
Reaction SMILES: [C:1]1([C:7]([NH:9][NH2:10])=[S:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=O>C(O)C>[C:1]1([C:7]2[S:8][CH:12]([C:11]([O:15][CH2:16][CH3:17])=[O:14])[NH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=S)c1ccccc1
Reactant: CCOC(=O)C=O
Solvent: CCO
Product: CCOC(=O)C1NN=C(c2ccccc2)S1
Yield: 112.7 %

Procedure:
A solution of benzenecarbothioic acid hydrazide (0.4g) and ethyl glyoxylate (0.4g) in ethanol (1 ml) was stirred at room temperature for 2 hours. The solvent was removed by evaporation and the residue re-evaporated with toluene (x2) to yield the sub-title product (0.7g) as a gum.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:20])[CH:14]=[C:15]([CH2:16][N:17]=[N+]=[N-])[C:7]1=2)C.Cl>C1COCC1.O.[Pd]>[NH2:17][CH2:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:21])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([OH:20])[CH:14]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(CN=[N+]=[N-])c21
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(O)cc2c1C(CC(=O)O)OB2O
Reaction time: 8 h
Yield: 16.4 %

Procedure:
To a solution of (4-azidomethyl-1,6-dihydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (15 mg) in THF/water (2:1, 1 mL) was added 10% Pd/C (5 mg), and a drop of 1N HCl. The reaction was degassed and stirred under hydrogen overnight and filtered off. The filtrate was purified by HPLC, yielded 2 mg of product. MS (ESI) m/z: 237.9 [M+1]+; 1H NMR (300 MHz, CD3OD) δ 8.25 (s, 3H), 7.06 (d, 1H), 6.98 (d, 1H), 8.20 (s, 1H), 5.68 (dd, 1H), 4.17 (s, 2H), 3.67 (s, 1H), 2.99-3.04 (m, 1H), 2.71-2.87 (m, 2H), 2.45-2.52 (m, 1H).