Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5ccc(Cl)cc5s4)cc3CC[C@@H]12
Yield: 52.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2,6-dichloro-benzothiazole (155 mg, 0.76 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 86 mg (53%) of the title compound as an amorphous solid. mp 156°-162°. FDMS: m/e =429. α[D]589 =+63.53 (c=0.66, chloroform).
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 11 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: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C[O-].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)Cl>C(#N)C>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: Clc1ccccc1C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1c[nH]cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1ccccc1C(c1ccc(-c2ccccc2)cc1)n1ccnc1

Procedure:
A solution of 13.6 g (0.2 mol) of imidazole in 100 ml of acetonitrile is added dropwise to a suspension of 10.8 g (0.13 mol) of sodium methylate in 200 ml of acetonitrile. The resulting sodium imidazole is filtered off and suspended in 300 ml of acetonitrile, and 31.3 g (0.1 mol) of (2-chlorophenyl)-(biphenyl-4-yl)-chloromethane are added. After heating for 24 hours to 80° C., the mixture is allowed to cool, and is filtered. The filtrate is freed from the solvent by distilling the latter off in vacuo. The oil which remains is dissolved in ethyl acetate and the solution is washed with water, dried over sodium sulfate, filtered and freed from the solvent in vacuo. The oily residue is dissolved in chloroform and chromatographed on a silica gel column. After separating off a chloroform fraction containing a compound of melting point 150° C., the chloroform fraction containing desired end product is obtained. After distilling off the solvent, 10.7 g (31% of theory) of (2-chlorophenyl)imidazol-1-yl-(biphenyl-4-yl)-methane of melting point 90° C. are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][NH2:10].[C:11](N1C(=O)C2C(=CC=CC=2)C1=O)(=[S:13])[CH3:12]>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][NH:10][C:11](=[S:13])[CH3:12]
Reactant: CC(=S)N1C(=O)c2ccccc2C1=O
Reactant: NCCOc1ccccn1
Solvent: ClC(Cl)Cl
Product: CC(=S)NCCOc1ccccn1
Reaction time: 0.25 h
Yield: 49.3 %

Procedure:
Add 2-(pyridin-2-yloxy)ethylamine (500 mg, 3.62 mmol) to a solution of 2-thioacetyl-isoindole-1,3-dione (743 mg, 3.62 mmol) in CHCl3 (18 mL) at 0° C. After stirring for 15 minutes, concentrate the solution, redissolve in ethyl acetate (25 mL), filter, and concentrate again. Flash chromatography (SiO2, 1:1 EtOAc/Hex) gives N-(2-(pyridin-2-yloxy)ethyl)thioacetamide (350 mg, 49%) as a beige/pink solid. 1H NMR (CDCl3) δ 8.79 (br s, 1H), 8.10-8.08 (m, 1H), 7.58-7.65 (m, 1H), 6.92-7.00 (m, 1H), 6.76-6.82 (m, 1H), 4.57-4.65 (m, 2H), 3.98-4.05 (m, 2H), 2.56 (s, 3H).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+:15]>CO.O.[Pd]>[C:1]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:15])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)N1CCC(=O)CC1
Agent: [Pd]
Agent: O=C[O-]
Solvent: O
Solvent: CO
Product: CC(C)(C)N1CCC(N)CC1
Reaction time: 8 h

Procedure:
To a solution of 1-tert-butylpiperidin-4-one (5.0 g) in methanol (100 mL) and water (10 mL) was added ammonium formate (20.3 g) and 0.5 g of Pd/C (10%). The mixture was stirred overnight. The mixture was filtered and the filtrate was concentrated under vacuum and the residue was diluted with ethyl acetate (500 mL) and washed with water and brine. After drying over Na2SO4 and filtration, the solvent was evaporated under vacuum to provide the title compound.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[N:3]=[C:2]1[C:18]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21])=[CH:10][CH:9]=[CH:8][CH:7]=3.C(=O)([O-])[O-].[Cs+].[Cs+].O.C(OCC)(=O)C.[Cl:41][CH2:42]I>>[Cl:41][CH2:42][N:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[N:3]=[C:2]1[C:18]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: N#Cc1cccc(C#N)c1-c1nc2c3ccccc3c3ccccc3c2[nH]1
Reactant: ClCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(C#N)c1-c1nc2c3ccccc3c3ccccc3c2n1CCl
Temperature: 80 °C
Yield: 31 %

Procedure:
2-(1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile from Step 2 (1 g, 2.91 mmol) was mixed with cesium carbonate (1.14 g, 3.49 mmol) in chloroiodomethane (10 mL). The mixture was heated to 80° C. overnight. The reaction was cooled to room temperature and poured into 200 mL water and 500 mL ethyl acetate. The layers were separated, and the organic layer was washed with 200 mL water, 200 mL saturated aqueous sodium bicarbonate solution, 100 mL brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The crude solid was purified by flash column chromatography using 40% ethyl acetate in hexane to give 357 mg of 2-[1-(chloromethyl)-1H-phenanthro[9,10-d]imidazol-2-yl]isophthalonitrile (31%) plus 650 mg of a mixture of product and starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(Cl)nc3)c2cc1OC
Temperature: 140 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
2-Chloro-5-hydroxypyridine (100 mg), 4-chloro-6,7-dimethoxyquinoline (861 mg), and 4-dimethylaminopyridine (283 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 140° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (164 mg, yield 67%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Cl:16]N1C2C=CC=CC=2N=N1>ClCCl>[Cl:16][C:15]1[CH:14]=[N:13][N:12]2[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:8][CH:9]=[N:10][C:11]=12
Reactant: Cln1nnc2ccccc21
Reactant: c1cc(-c2ccnc3ccnn23)ccn1
Solvent: ClCCl
Product: Clc1cnn2c(-c3ccncc3)ccnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.01 mole of 7-(4-pyridyl)pyrazolo[1,5-a]pyrimidine in cold dichloromethane is added 0.011 mole of N-chlorobenzotriazole. The mixture is stirred at room temperature for one hour and heated on a steam bath for 15 minutes. The product is worked up as for Example 62 to give the product of the example, m.p. 183°-184° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:6]=[CH:5][N:4]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][N:21]3[CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:8]=[C:7]([C:9]5[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=5)[CH:6]=[CH:5][N:4]=4)[CH2:23][CH2:22]3)[CH:8]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2ccnc(CCl)c2)cc(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc(-c2ccnc(CN3CCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)ccn4)CC3)c2)cc(OC)c1OC

Procedure:
2-Chloromethyl-4-(3,4,5-trimethoxyphenyl)pyridine (195 mg) and piperazine (28 mg) were reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)C(C(O)=O)=[CH:9]1.CN(C=O)C>C(Cl)Cl>[CH3:9][N:8]1[C:16]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:7]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1cc(C(=O)O)c2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Oxalyl chloride (5.0 mL, 57.3 mmol) was added under nitrogen to a solution of 1-methylindole-3-carboxylic acid (2.00 g, 11.4 mmol) in 150 mL of methylene chloride at room temperature. A catalytic amount of DMF (10 μL) was added and the reaction stirred at room temperature for 3 h. The solvent and excess oxalyl chloride were removed under reduced pressure. To remove any residual oxalyl chloride the residue was taken up in benzene and then concentrated under reduced pressure to give 1-methyl-1H-indole-3-carbonyl chloride (2.21 g, 99%) as a yellow solid that was used in the next step without additional purification
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[C:5]([NH:8][C@@H:9]1[C:14](=[O:15])[CH2:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C@H:10]1[O:20][CH:21]([CH3:23])[CH3:22])(=[O:7])[CH3:6]>C1COCC1>[C:5]([NH:8][C@@H:9]1[C@@:14]([OH:15])([CH:1]=[CH2:2])[CH2:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C@H:10]1[O:20][CH:21]([CH3:23])[CH3:22])(=[O:7])[CH3:6]
Reactant: COC(=O)C1=C[C@@H](OC(C)C)[C@H](NC(C)=O)C(=O)C1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=C[C@@]1(O)CC(C(=O)OC)=C[C@@H](OC(C)C)[C@@H]1NC(C)=O
Reaction time: 2 h

Procedure:
Vinylmagnesium bromide can be added to a −78° C. solution of Example 16A in THF. The reaction mixture can be stirred for 2 hours and quenched with saturated aqueous NH4Cl. The quenched reaction mixture can be extracted several times with dichloromethane. The combined dichloromethane layers can be dried (MgSO4), filtered and concentrated. The concentrate can be purified by column chromatography to afford the desired product.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](N(OC)C)=[O:13].[CH3:18][Mg]Br.CCOCC>O1CCCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:13])[CH3:18]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc2ccccc2c1Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-bromo-N-methoxy-N-methyl-2-naphthamide (0.708 g, 0.00241 mol) in tetrahydrofuran (10 mL) was added 3.00 M of methylmagnesium bromide in ether (8.19 mL, 0.0246 mol). The reaction was stirred at room temperature for 2 h, quenched with water at 0° C., then acidified with 1 N HCl, and extracted with EtOAc. The combined organic layers were washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The residue was used directly in next step (488 mg, 81%). LCMS calculated for C12H10BrO(M+H)+: m/z=249.0.; found: 249.2.
Reaction SMILES: CS(O[CH2:6][C:7]1([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1)(=O)=O.FC(F)(F)C1C=CC(C2(C[C:40]#[N:41])CCCC2)=CC=1>>[F:20][C:18]([F:19])([F:21])[C:16]1[CH:17]=[C:12]([C:7]2([CH2:6][C:40]#[N:41])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:13]=[C:14]([C:22]([F:24])([F:25])[F:23])[CH:15]=1
Reactant: CS(=O)(=O)OCC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1
Reactant: N#CCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: N#CCC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1

Procedure:
2-(1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)acetonitrile (459) was synthesized as a brown solid from (1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methyl methanesulfonate (458) following the procedure described for [1-(4-trifluoromethyl-phenyl)-cyclopentyl]-acetonitrile (241).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].B([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[C:3]([CH3:10])[CH:4]=1)#[N:7]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(C#N)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C#N)ccc1-c1ccc(C(=O)O)cc1
Yield: 67.4 %

Procedure:
A stirred solution of 4-bromo-3-methylbenzonitrile (5.0 g, 0.026 mole) and 4-boronobenzoic acid (4.2 g, 0.026 mole) in a mixture of DME (100 ml) and water (100 ml) under argon was treated with sodium carbonate (11.6 g, 0.11 mole) and tetrakis (triphenylphosphine) palladium (O) (0.55 g) and heated under reflux for 20 h. The solution was concentrated in vacuo to approx. 100 ml volume, then washed with ethyl acetate and acidified with 5M HCl acid. The solid which was produced was filtered off, washed with water and dried in vacuo to afford the title compound as a white solid (4.16 g, 69%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[CH2:22]([N:27]=[C:28]=[O:29])[CH2:23][CH2:24][CH2:25][CH3:26]>O1CCCC1>[O:14]=[C:4]1[CH:3]([CH2:2][O:1][C:28](=[O:29])[NH:27][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]1=2
Reactant: CCCCCN=C=O
Reactant: O=C1c2ccccc2SCCC1CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCNC(=O)OCC1CCSc2ccccc2C1=O

Procedure:
To a solution of 4-hydroxymethyl-3,4-dihydro-2H-benzo[b]thiepin-5-one (264 mg, 1.27 mmol) in 16 ml of tetrahydrofuran were added, at 0° C., triethylamine (0.2 ml, 1.4 mmol) and n-pentyl isocyanate (492 μl, 4.9 mmol). The mixture was heated under reflux for 15 hours, concentrated and purified by column chromatography on silica gel (eluent: 4:1 diisopropyl ether/hexane). The product was obtained in a yield of 145 mg (35%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, off-white solid, m.p. 128° C. and MS: m/e=319 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]([CH3:23])([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([OH:22])[CH:16]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Cs+].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>CN(C)C=O>[OH:22][C:17]1[CH:16]=[C:15]([CH2:14][C@@:10]([NH:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:23])[C:11]([O:13][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:12])[CH:20]=[CH:19][C:18]=1[OH:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)NNC(C)(Cc1ccc(O)c(O)c1)C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COC(=O)[C@](C)(Cc1ccc(O)c(O)c1)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a stirred solution of 102 (650 mg, 2 mmol) in anhydrous N,N-dimethylformamide (7 mL) in a 50 mL capacity screwcap-septum vial was added cesium hydrogencarbonate (480 mg, 2.5 mmol). After having stirred at room temperature for 30 min, a solution of tert-butyl α-bromoacetate (2.5 mmol) was introduced into the reaction mixture. The resulting mixture was stirred at room temperature for 3 h and then, at 45° C. overnight (˜12 h). The reaction mixture was cooled to room temperature and filtered. The residue was washed with ethyl acetate (25 mL×4). The combined filtrates were washed with water (25 mL×2), dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed over silica gel using a gradient of 10–100% ethyl acetate and hexane to afford 710 mg (81%) of the title compound as a light yellow thick liquid. MS (ESI) m/z 463.16 (M+Na+) and 439.02 (M−H−).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[CH:10]=[C:11]1[CH2:16][CH2:15][O:14][N:13]([CH3:17])[C:12]1=[O:18])([CH3:6])([CH3:5])[CH3:4].[CH3:27]S(C)=O.CI>O>[C:3]([C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[O:22][CH3:27])[CH:10]=[C:11]1[CH2:16][CH2:15][O:14][N:13]([CH3:17])[C:12]1=[O:18])([CH3:6])([CH3:5])[CH3:4]
Reactant: CN1OCCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1c(C(C)(C)C)cc(C=C2CCON(C)C2=O)cc1C(C)(C)C
Reaction time: 50 h
Yield: 71 %

Procedure:
Sodium hydride (0.33 g, 8.3 mmol), 60% in mineral oil dispersion, kept under nitrogen purge, was washed twice with 20 ml portions of hexane. Dimethyl sulfoxide (10 ml) was added, followed by the addition of 2.5 g (7.6 mmol) of dihydro-4-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-methyl-2H-1,2-oxazin-3(4H)-one. Gas evolution was observed and the mixture became yellow following which an additional 5 ml of dimethyl sulfoxide was added. One hour later, 1.1 g (7.7 mmol) of methyl iodide was added and the mixture was stirred for 50 hours. The reaction mixture was diluted with 75 ml of water and precipitation occurred in the form of crystals which were collected and air dried to yield 3.3 g of crude product. Recrystallization from acetone-hexane afforded 1.85 g (5.4 mmol, 71%) of dihydro-4-(3,5-di-tert-butyl-4-methoxybenzylidene)-2-methyl-2H-1,2-oxazin-3(4H)-one having a melting point of 119°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]([CH2:19][CH2:20][CH2:21]Cl)[S:10]2(=[O:24])=[O:23])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:25][NH2:26].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]([CH2:19][CH2:20][CH2:21][NH:26][CH3:25])[S:10]2(=[O:23])=[O:24])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccc(F)c(Cl)c1
Reactant: CN
Agent: Cl
Product: CNCCCN1Cc2ccccc2N(c2ccc(F)c(Cl)c2)S1(=O)=O

Procedure:
In an analogous manner to Example 1, step 8, 1-(3-chloro-4-fluorophenyl)-3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (73 mg) was reacted with methylamine and then treated with HCl to provide 3-[1-(3-chloro-4-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine hydrochloride (61 mg):
Reaction SMILES: [S:1]([CH:5]([N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[C:6](Cl)=[O:7])([OH:4])(=[O:3])=[O:2].[C:14]([O:17][CH2:18][C:19]1[CH2:26][S:25][CH:24]2[N:21]([C:22](=[O:28])[CH:23]2[NH2:27])[C:20]=1[C:29]([OH:31])=[O:30])(=[O:16])[CH3:15].C(=O)(O)[O-].[Na+]>CCOCC.O>[C:14]([O:17][CH2:18][C:19]1[CH2:26][S:25][CH:24]2[N:21]([C:22](=[O:28])[CH:23]2[NH:27][C:6](=[O:7])[CH:5]([S:1]([OH:4])(=[O:3])=[O:2])[N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[C:20]=1[C:29]([OH:31])=[O:30])(=[O:16])[CH3:15]
Reactant: O=C(Cl)C(n1cccc1)S(=O)(=O)O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(n3cccc3)S(=O)(=O)O)C2SC1

Procedure:
A solution of 2-sulfo-2-(1-pyrryl)acetyl chloride (1 equivalent) in ether is added to 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid (1 equivalent) and sodium bicarbonate (about 3 equivalents) in water at about 0° C. After about 30 minutes the phases are separated, the pH adjusted to about 6.5 and the aqueous phase extracted with ethyl acetate. The ethyl acetate is dried over megnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([CH2:30][CH2:31][CH3:32])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]4[O:11][CH2:1][O:2][C:3]=4[CH:4]=3)[C:24]3[CH:29]=[C:28]([CH2:30][CH2:31][CH3:32])[S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CCCc1cc2c(Cl)nc(-c3ccc(C(=O)OC)cc3)nc2s1
Product: CCCc1cc2c(NCc3ccc4c(c3)OCO4)nc(-c3ccc(C(=O)OC)cc3)nc2s1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxy-benzylamine is reacted with 4-(4-chloro-6-propyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxybenzylamino)-6-propyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester