Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li].[CH3:2][Si:3]([CH3:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)Cl.[SiH3][Li].[F:14][C:15](F)=[CH2:16]>C1COCC1>[F:14][C:15]([Si:3]([CH3:11])([CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:16]
Reactant: C=C(F)F
Reactant: C[Si](C)(Cl)c1ccccc1
Agent: [Li]
Agent: [Li][SiH3]
Solvent: C1CCOC1
Product: C=C(F)[Si](C)(C)c1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of 4.4 g of lithium wire cut into small pieces in 200 mL of anhydrous THF stirred under argon and cooled on ice (internal temperature <10° C.) was added dimethylphenyl-chlorosilane in 5 mL portions over 1 hour. The deep red color of the silyl lithium reagent appeared after approximately 0.75 hour. The mixture was stirred on ice for an additional 5 hours (internal temperature remained between 5° C. and 10° C.). The mixture was cooled on a dry ice/acetone bath and 1,1-difluoroethylene was introduced by filling a balloon connected to the reaction mixture and the reagent cylinder using a three-way valve. The balloon was filled with 1,1-difluoroethylene and emptied into the reaction mixture 10 times. The mixture was allowed to warm to room temperature (effervescence observed, probably from unreacted 1,1-difluoroethylene). The mixture was diluted with 200 mL of hexanes and filtered through a cotton wool plug. The filtrate was washed with water, dried, filtered, and concentrated in vacuo. Four fractional distillations under vacuum through a Vigreux column gave 4.6 g of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]23[O:16][C:15](=[O:17])[CH:14]2[CH2:13][CH2:12][CH2:11][CH2:10]3)=[O:8])=[CH:5][CH:4]=1.[NH:20]([CH2:24][CH2:25][OH:26])[CH2:21][CH2:22][OH:23].C(N(CC)C(C)C)(C)C.Cl>C(Cl)Cl>[OH:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][OH:26])[C:15]([CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1([OH:16])[C:7](=[O:8])[C:6]1[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:17]
Reactant: OCCNCCO
Reactant: COc1ccc(C(=O)C23CCCCC2C(=O)O3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)C2(O)CCCCC2C(=O)N(CCO)CCO)cc1

Procedure:
A solution of 26.03 g (0.100 mol) of 6-(4-methoxy-benzoyl)-7-oxa-bicyclo[4.2.0]octan-8-one in 200 ml of methylene chloride is added to 10.5 g (0.100 mol) of diethanolamine and 32 ml of N,N-diisopropylethylamine. The reaction mixture is heated at reflux for several hours and monitored by thin layer chromatography. Upon completion of the reaction, the mixture is cooled and poured into 1N hydrochloric acid solution. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.FC(F)(F)C(O)=O.[NH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH3:38])=[C:30]([CH:34]=1)[C:31]([OH:33])=[O:32].O1CCCC1.C(N(CC)CC)C>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH3:38])=[C:30]([CH:34]=1)[C:31]([OH:33])=[O:32]
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CCCOc1ccc(CN)cc1C(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1C(=O)O
Temperature: 50 °C
Yield: 57.2 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (67 mg, 0.24 mmol) and 5-(aminomethyl)-2-propoxybenzoic acid trifluoroacetate (50 mg, 0.16 mmol) were coupled in N,N-dimethylformamide (2 mL) and tetrahydrofuran (2 mL) with triethylamine (0.13 mL). The mixture is heated at 50° C. for 30 minutes and then at 65° C. overnight. Water is added and resulting mixture purified by reverse-phase HPLC to give a white solid material which is collected by filtration, washed with water, methanol, and diethyl ether and then dried under house vacuum to give 5-({[(Z)-(6-bromo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)-2-propoxybenzoic acid (42 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:20])[C:10]([C:15]1C=CN[N:16]=1)=[CH:11][N:12]([CH3:14])[CH3:13].[N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2NC=1CC(C1C=CC(Cl)=CC=1Cl)=O>>[N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:16][C:15]=1[C:10](=[CH:11][N:12]([CH3:13])[CH3:14])[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:20]
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1cc[nH]n1
Reactant: O=C(Cc1nc2ccccc2[nH]1)c1ccc(Cl)cc1Cl
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1nc2ccccc2[nH]1

Procedure:
Made using the same procedure as for 1-(2,4-dichlorophenyl)-3-(dimethylamino)-2-pyrazolylprop-2-en-1-one except that 2-benzimidazolyl-1-(2,4-dichlorophenyl)ethan-1-one (V, 1.0 g, 3.3 mmol) was used. The crude residue was used without purification.
Reaction SMILES: [C:1]1([NH:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([C@@H:20]([NH:22][C:23]3[N:28]=[C:27]([N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=[CH:30]4)[CH:26]=[CH:25][N:24]=3)[CH3:21])[CH2:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:38]1[CH:43]=[CH:42][C:41]([CH:44]=O)=[CH:40][CH:39]=1.C([BH3-])#N.[Na+]>>[N:38]1[CH:43]=[CH:42][C:41]([CH2:44][N:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[NH:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:15][C@H:16]2[C@@H:20]([NH:22][C:23]2[N:28]=[C:27]([N:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=[CH:30]3)[CH:26]=[CH:25][N:24]=2)[CH3:21])=[CH:40][CH:39]=1
Reactant: O=Cc1ccncc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1Cc1ccncc1

Procedure:
The title compound was prepared from (S,S)-2-[1-(4-(N-naphth-1-yl-carbamoyl)-piperazin-2-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 36, Step C; 12.5 mg), 4-pyridinecarboxaldehyde (16.4 mg), and sodium cyanoborohydride (3.1 mg) according to the procedure described in Example 14, Step G. Mass spectrum (ESI) 585.0 (M+2).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[OH:11][C:12]1[CH:17]=[C:16]([CH3:18])[O:15][C:14](=O)[CH:13]=1>O>[OH:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:7]([CH2:6][C:5]2[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=2)[C:2]#[N:1])[C:14](=[O:15])[CH:13]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: N#Cc1cccc(CN)c1
Solvent: O
Product: Cc1cc(O)cc(=O)n1Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A nitrogen flushed pyrex reaction tube was charged with 3-(aminomethyl)benzonitrile (1 g, 7.9 mmol), 4-hydroxy-6-methyl-2-pyrone (1 g, 7.9 mmol) and water (20 mL). The tube was capped and was heated to reflux. After 1.5 h, the product precipitated from solution. The reaction mixture was cooled to room temperature, filtered and washed with water. The product was used without further purification (1.67 g, 88%) 1H NMR (400 MHz, dmso-d6) δ 10.53 (s, 1H), 7.61 (d, J=8 Hz, 1H), 7.52 (t, J=8 Hz, 2H), 7.38 (d, J=8 Hz, 1H), 5.79 (dd, J=1 and 2.5 Hz, 1H), 5.56 (d, J=2.7 Hz, 1H), 5.18 (s, 2H), 2.14 (s, 3H) ppm. ES-HRMS m/z 241.0968 (M+H calcd for C14H13N2O2 requires 241.0972).
Reaction SMILES: COC([CH:5]1[C:9]2([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[S:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=5[N:11]([C:12]=34)[C:10]2=[O:25])[C:8](=[O:26])[NH:7][C:6]1=[O:27])=O>C(O)(=O)C>[C:10]1(=[O:25])[N:11]2[C:12]3[C:17]([S:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=42)=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]21[CH2:5][C:6](=[O:27])[NH:7][C:8]2=[O:26]
Reactant: COC(=O)C1C(=O)NC(=O)C12C(=O)N1c3ccccc3Sc3cccc2c31
Solvent: CC(=O)O
Product: O=C1CC2(C(=O)N1)C(=O)N1c3ccccc3Sc3cccc2c31
Yield: 73.8 %

Procedure:
The above product from part (a) (2.2 g, 0.0058 mole) was refluxed in acetic acid (20 ml) for 9 hours. After cooling, the resultant precipitate was collected by filtration and recrystallized from acetic acid-DMSO to afford 1.38 g (73.8%) of spiro[pyrrolidine-3,2'-pyrrolo[3,2,1-kl]phenothiazine]-1',2,5-(2'H)-trione, mp. above 300° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: ClCc1ccncc1
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c(=O)n1Cc1ccncc1
Temperature: 0 °C
Yield: 63 %

Procedure:
1-(3-Nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (12.0 g, 42.2 mmoles) was added into 2 liters of acetone and warmed with stirring until a solution was formed. To the solution was added powdered potassium carbonate (23.4 g, 169.3 mmoles) and 4-chloromethylpyridine hydrochloride (10.4 g, 63.4 mmoles). The solution was stirred at reflux temperature for 18 hours. The solution was filtered while hot. Three quarters of the solvent was removed resulting in the formation of a precipitate. The solution was cooled to 0° C. and the precipitate was removed by filtration. The precipitate was washed with ethyl ether and air dried yielding 10.0 g (26.6 mmole, 63% yield) of 1-(3-nitrophenyl)-3-(4-pyridylmethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (mp 207°-209° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([F:9])=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[CH3:18][C:19]1([OH:24])[CH2:23][CH2:22][NH:21][CH2:20]1>C1COCC1.CO>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][C:19]([CH3:18])([OH:24])[CH2:20]2)[C:5]([F:9])=[C:6]([Cl:8])[N:7]=1
Reactant: Fc1c(Cl)nc(Cl)nc1Cl
Reactant: CC1(O)CCNC1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1(O)CCN(c2nc(Cl)nc(Cl)c2F)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.4 %

Procedure:
To a solution of 2,4,6-trichloro-5-fluoropyrimidine (0.476 g, 2.36 mmol) and triethylamine (0.36 mL, 2.60 mmol) in THF was added 3-methyl-3-pyrrolidinol (0.239 g, 2.36 mmol) in THF and MeOH (2 mL). The reaction was stirred at room temperature for 2.5 hours, and then the solvent was removed in vacuo. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organics were dried (Na2SO4) and evaporated to provide 1-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-3-methyl-3-pyrrolidinol as an orange solid (0.486 g, 77%). LCMS: (M+H)+=266.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]([OH:11])=O.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[O:21][N:20]=[C:19]([NH2:22])[CH:18]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[O:21][N:20]=[C:19]([NH:22][C:9](=[O:11])[CH:8]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:18]=1
Reactant: Nc1cc(-c2ccco2)on1
Reactant: O=C(O)C=Cc1ccccn1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccccn1)Nc1cc(-c2ccco2)on1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.6 %

Procedure:
To a solution of 6 mg of 3-pyridin-2-yl-acrylic acid and 6 mg of 5-furan-2-yl-isoxazol-3-ylamine in DMF were added 8 mg of HOBt, 9 mg of EDC and 0.014 mL of TEA. The reaction solution was stirred for 18 hrs at room temperature, followed by concentration under reduced pressure. The concentrate was purified by preparative HPLC to provide 4 mg of N-(5-furan-2-yl-isoxazol-3-yl)-3-pyridin-2-yl-acrylamide. (Yield: 36%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:38])[CH:7]([NH:22][CH:23]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:20])[CH:16]=2)[C:11]1=[O:21])([CH3:4])[CH3:3].ClCCl.[C:42]1([S:48](Cl)(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>N1C=CC=CC=1>[CH3:1][C:2]([O:5][C:6](=[O:38])[C@H:7]([NH:22][C@H:23]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:20][S:48]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)(=[O:50])=[O:49])[CH:16]=2)[C:11]1=[O:21])([CH3:4])[CH3:3]
Reactant: CC(C)CC(NC(CCN1C(=O)c2ccc(N)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2ccc(NS(=O)(=O)c3ccccc3)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
58 mg of 2-[1-(benzylamino)carbonyl-3-methyl-butylamino]-4-(5-amino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid-1,1-dimethylethyl ester, prepared as in Example 73 where the protecting group Rp, 1,1-dimethylethyl, was not removed following the condensation reaction seen in Scheme 2, was added to 4 mL dichloromethane under nitrogen. The mixture was cooled to 0° C. and 0.015 mL benzenesulfonyl chloride was added immediately followed by 0.1 mL pyridine. The mixture was allowed to warm to room temperature and was stirred for 18 h. The solvent was removed by evaporation and the residue was purified by reverse phase H.P.L.C. The solvent was removed by evaporation to afford the title compound; 31.8 mg
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH3:18])[C:13](O)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:22][CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH3:18])[C:13]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:24][CH:25]=2)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(O)=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Yield: 16 %

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-4-methylthiobutanoic acid (7.86 g) and ethyl 4-aminophenylacetate (3.64 g) were condensed in dichloromethane (80 ml) in the presence of N,N'-dicyclohexylcarbodiimide (5.28 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (1.67 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[Br-].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24]Cl.[H-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=2)[CH2:10][O:9]1
Reactant: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Reactant: CN(C)CCCCl
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 62.5 °C
Reaction time: 7 h
Yield: 66.1 %

Procedure:
Under nitrogen atmosphere, to a solution of 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (3.0 g) in N,N-dimethylformamide (15 ml) were added tetra n-butfylammonium bromide (0.12 g) and N,N,N′,N′-tetramethylethylened amine (2.92 g). Thereto was added dropwise a solution of 3-(dimethyiamino)propyl chloride (2.0 g) in toluene (12 ml), and then a suspension of 60% sodium hydride (0.58 g) and liquid paraffin (1.5 ml) over 1.5 hr. The mixture was stirred at 61-64° C. for 7 hr. The reaction mixture was treated in the same manner as in Example 22 to give 1-(3-(dimethylamino)propyl)-1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram base) as a viscous oil (2.69 9, yield 66.1%). Hydrobromide thereof showed the same HPLC retention time and melting point as obtained in Example 22.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[SH:21])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]2[NH:13][C:11](=[O:12])[C:3]3[C:4]4[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]=3[S:21][C:15]=2[CH:16]=1
Reactant: Cc1ccc(NC(=O)c2c(Br)sc3c2CCCC3)c(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)Sc1sc3c(c1C(=O)N2)CCCC3

Procedure:
In the same manner as in Example 18 and using 2-bromo-4,5,6,7-tetrahydro-N-(2-mercapto-4-methylphenyl)-benzo[b]thiophene-3-carboxamide, dimethyl sulfoxide and potassium carbonate, 1,2,3,4-tetrahydro-8-methyl-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one (1.87 g) is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:8]=[N:7][C:6]=12.[CH3:17][N:18](C)C=O>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:10]2[N:5]3[N:4]=[CH:3][C:2]([C:17]#[N:18])=[C:6]3[N:7]=[CH:8][CH:9]=2)[CH:12]=1
Reactant: Brc1cnn2c(-c3cccnc3)ccnc12
Reactant: CN(C)C=O
Product: N#Cc1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 1.0 g. of 3-bromo-7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine, 0.45 g. of cuprous cyanide and 25 ml. of N,N-dimethylformamide is refluxed for 16 hours. The solvent is removed and the residue triturated with dichloromethane. The dichloromethane extract is passed through a column of hydrous magnesium silicate. The eluent is concentrated and hexane added to give the product of the example, m.p. 258°-260° C.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1[N:7]([CH3:25])[C:8]([C:17]([C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:18])=[C:9]([CH3:16])[C:10]=1[C:11]([O:13]CC)=[O:12])C.[OH-].[Na+]>C(O)C>[CH3:25][N:7]1[C:8]([C:17]([C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:18])=[C:9]([CH3:16])[C:10]([C:11]([OH:13])=[O:12])=[C:6]1[CH2:5][C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)c(C(=O)c2cccn2C)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)O)c(CC(=O)O)n(C)c1C(=O)c1cccn1C
Temperature: 25 °C
Yield: 88 %

Procedure:
Ethyl-1,4-dimethyl-3-ethoxycarbonyl-5-(1-methylpyrrol-2-oyl)pyrrole-2-acetate (7 g) is dissolved in 20 ml of ethanol, aqueous 50% sodium hydroxide solution (50 ml) is added, and the resulting solution is heated at reflux for about one hour. It is cooled to room temperature, and acidified to yield a white precipitate which in turn is filtered and dried to afford 5.2 g of 1,4-dimethyl-3-hydroxycarbonyl-5-(1-methylpyrrol-2-oyl)pyrrole-2-acetic acid (a diacid). The diacid is partially esterified by treatment with 200 ml of ethanol containing 1.0 g of Bio-Rad® 50W×8 H+ resin at reflux for two hours. After filtration and removal of the excess ethanol, the crude product is purified by HPLC to yield 3.8 g (55%) of white crystalline ethyl 1,4-dimethyl-3-hydroxycarbonyl-5-(1-methylpyrrol-2-oyl)pyrrole-2-acetate.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH:8]2[CH2:10][CH:5]1[CH2:6][NH:7]2)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:36]=[C:35]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[C:33]2[C:28]=1[CH2:29][N:30]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1)[C:31](=[O:49])[N:32]2[C:41]1[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][C:42]=1[Cl:48]>C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:36]=[C:35]([S:37]([N:7]2[CH2:6][CH:5]3[CH2:10][CH:8]2[CH2:9][N:4]3[CH:1]([CH3:3])[CH3:2])(=[O:39])=[O:38])[CH:34]=[C:33]2[C:28]=1[CH2:29][N:30]([CH2:50][C:51]1[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=1)[C:31](=[O:49])[N:32]2[C:41]1[C:42]([Cl:48])=[CH:43][CH:44]=[CH:45][C:46]=1[Cl:47]
Reactant: CC(C)N1CC2CC1CN2
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(S(=O)(=O)Cl)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(S(=O)(=O)N4CC5CC4CN5C(C)C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-isopropyl-2,5-diazabicyclo[2.2.1]heptane (INTERMEDIATE ABA2) (35 μL, ca. 0.249 mmol) and diisopropylethylamine (32 mg, 0.249 mmol) were added to a mixture of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-sulfonyl chloride (103 mg, 0.166 mmol) (COMPOUND CCC8) in 2 mL THF at 0° C. The mixture was warmed to rt, stirred at this temperature for 0.5 h, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and added to 6 mL of 1M aqueous HCl The phases were separated and the aqueous was extracted with 3×15 mL of ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The product was purified by preparative thin-layer chromatography, eluting with 93:7 CH2Cl2-methanol to yield the 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)sulfonyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one. Mass spectrum (ESI) 725 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](OCC)=O)[S:5][C:6]=1[Cl:7].[H-].C([Al+]CC(C)C)C(C)C.[ClH:28]>O1CCCC1>[Cl:28][CH2:13][C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:4]1[S:5][C:6]([Cl:7])=[C:2]([Cl:1])[CH:3]=1
Reactant: Cl
Reactant: CCOC(=O)c1cnoc1-c1cc(Cl)c(Cl)s1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: ClCc1cnoc1-c1cc(Cl)c(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of ethyl 5-(4,5-dichloro-2-thienyl)isoxazole-4-carboxylate (3.30 g) in tetrahydrofuran (60 ml) was gently added diisobutylaluminum hydride (0.95 M hexane solution, 29.7 ml) at 0° C. and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in toluene (60 ml), thionyl chloride (2.02 g) was added dropwise at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 4-chloromethyl-5-(4,5-dichloro-2-thienyl)isoxazole (2.41 g, yield 79%) was obtained as crystals from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio) and recrystallized from hexane to give a colorless prism. melting point: 60–61° C.
Reaction SMILES: [C:1]([C:4]1[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].O.[OH-].[Li+]>>[C:1]([C:4]1[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)nc1C(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1nc(Cl)ccc1C(=O)O

Procedure:
Sodium bicarbonate (0.42 g, 5.0 mmol) is added to the above bromide (1.33 g, 4.55 mmol) in 13 ml of dry DMSO. The mixture is heated at 90° for 1.75 hours, then cooled, worked up and dried. The solvent is removed and the crude product is purified by prep. TLC to give ethyl 2-acetyl-6-chloronicotinate. Following the procedure of Example 11, the ethyl 2-acetyl-6-chloronicotinate is reacted with lithium hydroxide monohydrate to give 2-acetyl-6-chloronicotinic acid.