Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:16]#[N:17].[Na+].[Cl:19][C:20]([Cl:30])=[CH:21][CH:22]1[C:24]([CH3:26])([CH3:25])[CH:23]1[C:27](Cl)=[O:28]>O.C1CCCCC1>[Cl:19][C:20]([Cl:30])=[CH:21][CH:22]1[C:24]([CH3:26])([CH3:25])[CH:23]1[C:27]([O:12][CH:11]([C:16]#[N:17])[C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)=[O:28]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1

Procedure:
A 500 ml. round-bottomed flask equipped with a stirrer operating at 500 rpm was charged with 0.2 mole of 3-phenoxybenzaldehyde, 20 ml. of water, 15.2 g. of sodium cyanide, 90 ml. of cyclohexane and a catalyst (if any). 0.2 mole of 2-(2',2'-dichlorovinyl)-3,3-dimethylcyclopropanecarbonyl chloride was added at 15°-20° over 30 minutes, followed by 10 ml. of cyclohexane. The mixture thus formed was stirred at 15°-20° C. At the end of the reaction, 100 ml. of water were added and the organic phase was filtered, washed with 100 ml. of water and the cyclohexane was then removed on a rotary evaporator. The catalysts used and the results obtained are shown in Table 1.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21]CC)=[O:20])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:5])=[O:4].[OH-].[Na+].O>C1COCC1>[F:24][C:2]([F:1])([F:25])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:4])=[O:5]
Reactant: CCOC(=O)c1cccc(-c2cccc(NS(=O)(=O)C(F)(F)F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cccc(NS(=O)(=O)C(F)(F)F)c2)c1
Temperature: 50 °C
Reaction time: 20 h
Yield: 65.2 %

Procedure:
Preparation H3, Step 3: 3′-Trifluoromethylsulfonamido-[1,1′-biphenyl]-3-carboxylic acid, ethyl ester (150 mg, 0.40 mmol, 1 eq.) and 1.000 N NaOH (0.80 mL, 0.80 mmol, 2 eq.) were dissolved in THF (5 mL) at room temperature and stirred for 20 hours. Little reaction. Added 100 mg of NaOH and heated at 50° C. for 20 hours. Worked up by adding water then rinsing 2 times with diethyl ether. The aqueous layer's pH was adjusted to 3 with 1N HCl. The acidic aqueous layer was extracted 3 times with ethyl acetate. The ethyl acetate layers were combined, dried over sodium sulfate and stripped to give 3′-trifluoromethylsulfonamido-[1,1′-biphenyl]-3-carboxylic acid (90 mg) of an amber solid. Yield=65%. Mass Spec (ESI) detects (M+H)+=344.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[CH2:18]([CH:22]([CH2:25]O)[CH2:23][OH:24])[CH2:19][CH2:20][CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:10][CH2:11][C@H:12]([CH:15]3[O:24][CH2:23][CH:22]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:25][O:16]3)[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCCC(CO)CO
Reactant: O=C[C@H]1CC[C@H](c2ccc(F)c(F)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC1COC([C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)OC1

Procedure:
A mixture of 2.2 g of trans-4-(3,4-difluorophenyl)-cyclohexanecarbaldehyde (obtainable by converting the corresponding acid into the chloride and Rosenmund reduction), 1.32 g of 2-butylpropane-1,3-diol, 0.01 g of p-toluenesulfonic acid and 15 ml of toluene is boiled on a water separator for 3 hours, cooled, washed with water and evaporated, to give 2-[trans-4-(3,4-difluorophenyl)cyclohexyl]-5-butyl-1,3-dioxane.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][CH2:14][C:9]21[CH2:13]CC[CH2:10]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1(C(N)(C)CN)C[CH2:21]1.CC(C)(O)C#N>>[CH2:1]([N:8]1[CH2:17][C:16]([CH:18]2[CH2:21][CH2:20]2)([CH3:19])[NH:15][CH2:14][C:9]1([CH3:10])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CN(Cc2ccccc2)C2(CCCC2)CN1
Reactant: CC(N)(CN)C1CC1
Agent: CC(C)(O)C#N
Product: CC1(C2CC2)CN(Cc2ccccc2)C(C)(C)CN1

Procedure:
1-Benzyl-5-cyclopropyl-2,2,5-trimethyl-piperazine was synthesized in analogy to 6-benzyl-8,8-dimethyl-6,9-diaza-spiro[4.5]decane starting from 2-cyclopropyl-propane-1,2-diamine and acetone cyanohydrin.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.[H][H].O.CO>[Pd].C(O)(=O)C>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: OCCCc1ccncc1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: OCCCC1CCNCC1

Procedure:
The compound of formula (VI-S) may be prepared by for example, reacting 3-pyrid-4-yl-propan-1-ol, a known compound, with hydrogen gas at a pressure of about 300 psi, in the presence of a catalyst such as Pd/C, in a suitably selected solvent or mixture of solvents such as water or a mixture of about 3:1 methanol:acetic acid, at a temperature in the range of about 20-50° C. to yield the corresponding 3-piperidin-4-yl-propan-1-ol. The 3-piperidin-4-yl-propan-1-ol is then reacted with formaldehyde, a known compound, in the presence of hydrogen gas at about 85 psi and a catalyst such as Pd/C, in a suitably selected solvent or mixture of solvents such as water or a mixture of about 3:1 methanol:acetic acid, at a temperature of about 0-45° C. The preparation of a compound of formula (VI-S) in water, is outlined in more detail in Example 2 which follows herein.
Reaction SMILES: [N:1]#[N:2].[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:19]([NH:21][C@@H:22]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:23]([OH:38])[CH2:24][C@@:25]1([C:34]([NH2:36]=[O:37])=[O:35])[CH2:29][CH2:28][CH2:27][N:26]1[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:20])[CH2:15][S:16]([CH3:18])=[O:17])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ClC1C=CC=C(C(OO)=[O:54])C=1>CO>[N:1]#[N:2].[OH2:10].[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:19]([NH:21][C@@H:22]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C@H:23]([OH:38])[CH2:24][C@@:25]1([C:34]([NH2:36]=[O:37])=[O:35])[CH2:29][CH2:28][CH2:27][N:26]1[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:20])[CH2:15][S:16]([CH3:18])(=[O:54])=[O:17])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C[C@@]1(C(=O)[NH2+][O-])CCCN1C(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: N#N
Solvent: CO
Product: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CS(C)(=O)=O)NC(=O)OCc1ccccc1)C(=O)[NH2+][O-]
Product: O
Temperature: 20 °C
Reaction time: 16 h
Yield: 34.5 %

Procedure:
A solution of 154 mg of N2 -[3(S)-[[N-(benzyloxycarbonyl)-3-(methylsulphinyl)-L-alanyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide N2 -oxide (two diastereomers) in 5 ml of methanol was treated with 84 mg of 3-chloroperbenzoic acid and the solution was stirred at 20° C. for 16 hours. The solvent was removed by evaporation and the residue was partitioned between dichloromethane and 2M sodium hydroxide solution. The organic phase was evaporated and the residue was crystallized from ethyl acetate/n-hexane to give 28 mg of N2 -[3(S)-[[N-(benzyloxycarbonyl)-3-(methylsulphonyl)-L-alanyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide N2 -oxide monohydrate; MS: m/e 633 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:15][O:16][CH2:17][C:18]3[N:23]=[C:22]([C:24]#[N:25])[CH:21]=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=3)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:30]O.C([O:39][CH2:40]C)(OCC)OCC.B(F)(F)F.CCOCC>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:15][O:16][CH2:17][C:18]3[N:23]=[C:22]([C:24]4[N:30]=[CH:40][O:39][N:25]=4)[CH:21]=[C:20]([C:26]([F:27])([F:29])[F:28])[CH:19]=3)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(OCC)OCC
Reactant: CN1CCC(COCc2cc(C(F)(F)F)cc(C#N)n2)(c2ccc(F)cc2)CC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCO
Product: CN1CCC(COCc2cc(C(F)(F)F)cc(-c3ncon3)n2)(c2ccc(F)cc2)CC1
Reaction time: 2 h
Yield: 27.1 %

Procedure:
6-(((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-4-(trifluoromethyl)picolinonitrile (66 mg, 0.162 mmol) was dissolved in ethanol (1 mL) and treated with hydroxylamine (2 ml, 0.364 mmol), heated to reflux and allowed to stir for 2 hours. After cooling, the solvents were evaporated in situ. The resulting sold was dried under vacuum. The white solid was then redissolved in dichloromethane (2 mL), and treated with triethyl orthoformate (0.108 mL, 0.648 mmol) under nitrogen. The solution was then treated with boron trifluoride etherate (2.053 μL, 0.016 mmol) and allowed to stir for 2 hours at room temperature. Upon completion the reaction was concentrated in vacuo and purified via preparatory HPLC to yield the desired product (19.8 mg, 27.1%) as the TFA salt. 1H-NMR (CD3OD, 400 MHz) δ 9.48 (s, 1H), 8.29 (s, 1H), 7.58 (m, 3H), 7.18 (m, 2H), 4.73 (s, 2H), 3.59 (s, 2H), 3.50 (m, 2H), 2.89 (t, 2H), 2.79 (s, 3H), 2.75 (d, 2H), 2.22 (t, 2H), LC: Tr=1.736 min HPLC Method 1. Mass spec.: 451.46 (MH)+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]=[CH:12][CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dimethyl sulfoxide (7.43 mL, 0.105 mol) was added to oxalyl chloride (5.53 mL, 0.0654 mol) in DCM (244.2 mL) at −78° C. After 10 min, tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (from Aldrich, 10.0 g, 0.0436 mol) in DCM (488.4 mL) was added and the resultant mixture was stirred at −78° C. for 30 min. Triethylamine (30.4 mL, 0.218 mol) was then added and the mixture was stirred for 5 h and the temperature allowed to gradually warm up to RT. After being quenched with water, the mixture was extracted with DCM. The organic layers were combined, washed with brine, dried, and evaporated to dryness. LCMS calculated for C12H21NO3Na(M+Na)+: m/z=250.2; Found: 250.0.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6](Br)[CH:5]=1)([O-:3])=[O:2].[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC.O>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH3:24])[CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1C
Temperature: 115 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
Methyl 4-nitro-2-bromobenzoate (11.40 g, 43.85 mmol) was dissolved in 100 mL of DMF. Air was removed and the system was flushed with nitrogen. To this solution was added Pd(PPh3)4 (1.63 g, 3.1% eq). The pale yellow solution was stirred for 15 min until the color changed to deep brown. 2-Tolylboronic acid (6.6 g, 48.5 mmol) was added followed by anhydrous K2CO3 (18.2 g, 3.0 eq). The mixture was heated at 115° C. for 18 hr and then cooled down. This mixture was diluted with 100 mL of ether and 50 mL of water. The aqueous solution was extracted with ether. The ether solution was washed with 1N hydrochloric acid and then dried and evaporated. The residue was purified by flash column chromatography (10:1=hexane/ethyl acetate) to give a pale yellow oil which slowly solidifies (11.53 g, 97% yield). 1H NMR (CDCl3) δ 8.28 (d, J=8.7 Hz, 1H), 8.06-8.13 (s and d, 2H), 7.22-7.34 (m, 3H), 7.07 (d, J=7.3 Hz, 1H), 3.66 (s, 3H), 2.10 (s, 3H), 13C NMR (CDCl3) δ 165.7, 148.6, 143.5, 138.5, 135.9, 134.7, 130.5, 129.3, 127.9, 127.7, 125.1, 121.5, 51.8, 19.3; HRMS (EI) calcd for Cl5H13O4N 271.0844, obsd 271.0842.
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7](=O)OC(C)(C)C)=[CH:4][C:3]2[CH2:14][CH2:15][CH2:16][C:2]1=2.FC(F)(F)C(O)=O.C(OC=[C:28]1[C:33](=[O:34])[O:32][C:31]([CH3:36])([CH3:35])[O:30][C:29]1=[O:37])C>C(Cl)Cl>[S:1]1[C:5]([NH:6][CH:7]=[C:28]2[C:33](=[O:34])[O:32][C:31]([CH3:36])([CH3:35])[O:30][C:29]2=[O:37])=[CH:4][C:3]2[CH2:14][CH2:15][CH2:16][C:2]1=2
Reactant: CCOC=C1C(=O)OC(C)(C)OC1=O
Reactant: CC(C)(C)OC(=O)Nc1cc2c(s1)CCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)C(=CNc2cc3c(s2)CCC3)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a solution of tert-butyl N-[4H,5H,6H-cyclopenta[b]thiophen-2-yl]carbamate (480 mg, 2.01 mmol, 1.00 equiv) in 15 mL of DCM was added trifluoroacetic acid (460 mg, 4.03 mmol, 2.00 equiv) at 0° C. After stirring at room temperature for 4 h, the resulting solution was concentrated under vacuum. The pH value was adjusted to 8 with saturated aqueous NaHCO3 solution and extracted with dichloromethane (60 mL×3). Then 5-(ethoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione [prepared by heating 2,2-dimethyl-1,3-dioxane-4,6-dione (580 mg, 4.02 mmol, 2.00 equiv) in 6.0 g of (diethoxymethoxy)ethane at 100° C. for 1 h followed by cooling to room temperature] was added to the above extracts. Drying over sodium sulfate followed by concentration in vacuo afforded 5-[([4H,5H,6H-cyclopenta[b]thiophen-2-yl]amino)methylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (0.54 g, 92%) as a yellow solid which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15](B(O)O)=[CH:16][CH:17]=2)[CH:12]=[N:11]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:2]3[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11]1
Reactant: Oc1ncccc1Br
Reactant: Cn1ncc2cc(B(O)O)ccc21
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2cc(-c3ccc[nH]c3=O)ccc21
Temperature: 90 °C

Procedure:
The suspension of 3-bromo-2-hydroxypyridine (80 mg, 0.46 mmol), 1-methyl-1H-indazol-5-ylboronic acid (121 mg, 0.69 mmol) and sodium carbonate (146 mg, 1.38 mmol) in DMF (2.0 mL) and H2O (0.4 mL) was degassed with N2 for 5 minutes. To the mixture was added bis(triphenylphosphine)palladium (II) dichloride (67 mg, 0.09 mmol), and the resulting mixture was heated at 90° C. for 2 h. The reaction mixture was filtered and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give the product. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H12N3O: 226.25; Found: 226.2.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6](Cl)=[N:5][S:4][N:3]=1.[OH:10][C:11]1[CH:21]=[CH:20][C:14]([CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[Na+].Cl>O>[C:17]([CH:16]=[CH:15][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:6]2[C:7](=[O:8])[C:2]([Cl:1])=[N:3][S:4][N:5]=2)=[CH:21][CH:20]=1)([OH:19])=[O:18]
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: O=c1c(Cl)nsnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C=Cc1ccc(Oc2nsnc(Cl)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a stirred suspension of 14.6 grams (0.08 mole) of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one in 350 ml of water was added dropwise a previously prepared solution of 13.1 grams (0.08 mole) of p-hydroxycinnamic acid in 80 ml of aqueous 1 N sodium hydroxide. The reaction mixture was stirred for 2 hours at ambient temperature, then acidified with aqueous 6 N hydrochloric acid. A yellow precipitate was collected by vacuum filtration and washed with water, then dried for 5 hours/50° C. The solid was triturated with hot ethanol and collected by vacuum filtration, to give 23.3 grams (93.8%) of 3-[4-(2-carboxyethenyl)phenoxy]-5-chloro-4H-1,2,6-thiadiazin-4-one; m.p. >280° C. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH2:4][CH2:3]1.[CH2:16]([O:23][C:24](=[O:33])[NH:25][CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH3-]C#N.[Na+].C1COCC1>CO.C(O)(=O)C>[CH2:16]([O:23][C:24](=[O:33])[NH:25][CH2:26][CH:27]1[CH2:28][CH2:29][N:30]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]#[N:11])[CH2:4][CH2:3]2)[CH2:31][CH2:32]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(NCC1CCNCC1)OCc1ccccc1
Reactant: N#Cc1ccccc1N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1ccccc1N1CCC(N2CCC(CNC(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-(4-oxo-piperidin-1-yl)-benzonitrile (5) (653 mg, 3.26 mmol) and 4 (890 mg, 3.58 mmol) in 40 ml of methanol was added 4 g of powdered 4 Å molecular sieves. The resulting suspension was stirred at room temperature for 24 hours. The suspension was subsequently acidified to pH 5 with acetic acid and a 1M solution of NaCNBH3 in THF (6.0 ml 5.6 mmol) was added slowly with a syringe pump over 24 hours. When the addition was complete, the solvent was removed in vacuo and the residue taken up in chloroform and filtered. The solution was then washed with 10% Na2CO3, dried over MgSO4, and the solvent removed in vacuo to give the crude amine. The crude product was purified by chromatography on silica gel (5% MeOH/CHCl3) to give the title compound.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.NCC1CCN([C:27]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=2[S:35]([NH2:38])(=[O:37])=[O:36])CC1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:11][CH2:10][CH:18]2[CH2:6][CH2:7][N:38]([S:35]([C:28]3[CH:27]=[CH:32][C:31]([O:33][CH3:34])=[CH:30][CH:29]=3)(=[O:36])=[O:37])[CH2:16][CH2:17]2)=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: COc1ccc(S(N)(=O)=O)c(N2CCC(CN)CC2)c1
Product: COc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)COc3cccc4[nH]c5ccccc5c34)CC2)cc1
Yield: 124.9 %

Procedure:
Prepared from 4-[(2S)-Oxiranylmethoxy]-9H-carbazole (0.125 g, 0.52 mmol) and (4-aminomethyl-1-piperidinyl) 4-methoxybenzenesulfonamide (0.255 g, 0.9 mmol) according to procedure used for Example 2 to give 0.170 g of the title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.BrC[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: BrCC1CCCCO1
Product: Cl
Product: Clc1ccc2c(c1SCC1CCCCO1)CCNCC2

Procedure:
Use a method similar to the Example 330, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-(bromomethyl)tetrahydropyran to give, after deprotection by the General Procedure 1-4, the title compound as a white solid. MS (APCI+) m/z: 312 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][NH2:9])=[O:7].[CH2:15]([C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=O)[CH3:16].C(O)C>C(O)(=O)C.O>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17](=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][CH:12]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[CH2:15][CH3:16])[CH:20]=1
Reactant: NNC(=O)c1cccc(C(F)(F)F)c1
Reactant: CCC(=O)c1cccnc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCC(=NNC(=O)c1cccc(C(F)(F)F)c1)c1cccnc1
Temperature: 25 °C
Yield: 74 %

Procedure:
A mixture of 10.21 gm (0.05 mole) of 3-trifluoromethylbenzoic acid hydrazide, 6.76 gm (0.05 mole) of ethyl-3-pyridyl ketone, 10 drops of glacial acetic acid and 100 ml of absolute ethanol was refluxed 15 hr. The reaction mixture was diluted with water to the cloud point and cooled to room temperature then chilled in the refrigerator. The solids that separated were collected, washed with Skellysolve B and dried to give 11.88 gm (74%) of product having a melting point of 119.4° C.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2.C(=O)([O-])O.[Na+].Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=1.[I-].[Na+]>CN(C)C=O.O.C(OCC)C>[NH3:5].[CH2:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:5]2[CH2:6][CH:7]3[CH:3]([C:2]3([C:8]3[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=3)[CH3:1])[CH2:4]2)=[CH:27][CH:28]=1)[CH3:33]
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Reactant: CCc1ccc(CCl)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCc1ccc(CN2CC3C(C2)C3(C)c2cccc(NS(C)(=O)=O)c2)cc1
Product: N
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 82.1 %

Procedure:
To a solution of the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 57 mg, 0.19 mmol) in N,N-dimethylformamide (2 ml) was added sodium hydrogen carbonate (630 mg, 7.52 mmol), 1-(chloromethyl)-4-ethylbenzene (32 mg, 0.20 mmol) and sodium iodide (catalytic) and the reaction mixture was heated at 50° C. for 20 h. After cooling, diethyl ether (5 ml) and water (7 ml) were added and the reaction mixture was stirred vigorously for 5 min. The phases were separated and the aqueous layer was further extracted with diethyl ether (2×5 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual oil was purified by flash column chromatography using a Sep-Pak™ cartridge packed with silica gel (5 g) eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford the title compound as an oil (30 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:14])/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CO[CH2:24][N:25]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][Si](C)(C)C.CCN(CC)CC>C(Cl)Cl>[CH3:13][O:12][C:10]([C:9]1([CH3:14])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:24][N:25]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:26]1)=[O:11]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC(=O)/C(C)=C/c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(C)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
A mixture of 8.8 g (41.8 mmol) (E)-methyl 3-(4-chlorophenyl)-2-methylacrylate (freshly distilled) 0.476 g (4.18 mmol) TFA, and 12.4 g (52 2 mmol) N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine in 100 mL DCM was stirred at 0-5° C. for 1 h and at room temperature. NEt3 was added and the mixture was concentrated. The residue was purified by column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 7.55 g (53%) of the title compound as colorless oil. MS m/e: 344.1 [M+H]+.