Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:27])[N:14]([CH3:26])[C:15]([CH2:24][OH:25])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[CH3:35][S:36]([O:25][CH2:24][C:15]1[N:14]([CH3:26])[C:13](=[O:27])[C:12]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=[CH:10][C:11]=2[C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(CO)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(COS(C)(=O)=O)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c1=O
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A suspension of 1-benzyl-4-(4-chlorophenyl)-5-(hydroxymethyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (4 g, 10.6 mmol) in Dichloromethane (DCM) (50 mL) was treated with Et3N (4.38 mL, 31.5 mmol) and MsCl (1.839 mL, 23.60 mmol) at 0° C. and then stirred for 30 min. The mixture was diluted with Dichloromethane, washed with 0.1N HCl and NaHCO3, dried over Na2SO4, filtered and concentrated to afford (1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl methanesulfonate as a pale yellow solid (4.8 g, 10.5 mmol, 95% yield) which was used for in next step without any further purification. A solution of (1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl methanesulfonate (4.8 g, 10.5 mmol) in N,N-Dimethylformamide (DMF) (30 mL) was treated with KCN (6.15 g, 94 mmol) and the resultant was stirred at ambient temperature overnight. The mixture was quenched with water and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetonitrile (2.7 g, 7.0 mmol, 67% yield) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.47-7.52 (m, 2H) 7.31-7.35 (m, 3H) 7.27-7.30 (m, 4H) 7.04-7.09 (m, 1H) 5.94-5.98 (m, 1H) 5.83-5.88 (s, 2H) 3.81 (s, 3H) 3.64 (s, 2H); LCMS (m/z) ES+=388 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 129.6 %

Procedure:
To a solution of tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.00 g, 4.97 mmol, 1.0 equiv) and Et3N (1.06 g, 10.5 mmol, 2.1 equiv) in DCM (15 mL) was added dropwise MsCl (0.85 g, 7.40 mmol, 1.5 equiv) at 0° C. Then the reaction mixture was stirred at room temperature for 3 h. After the mixture was washed with brine, the organic layer was separated, dried over Na2SO4, filtered, and concentrated to give 1.8 g of the crude product, which was used for the nest step without further purification.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:15])[C:5]1=[O:16].S(Cl)([Cl:19])=O>ClC(Cl)Cl>[Cl:19][CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:15])[C:5]1=[O:16]
Reactant: Cn1c(=O)n(CCO)c(=O)c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)n(CCCl)c(=O)c2ccccc21
Yield: 95 %

Procedure:
A mixture of 4.5 parts of 3-(2-hydroxyethyl)-1-methyl-2,4-(1H,3H)quinazolinedione, 8 parts of thionyl chloride and 75 parts of trichloromethane was stirred and refluxed for 5 hours. The reaction mixture was evaporated, yielding 4.5 parts (95%) of 3-(2-chloroethyl)-1-methyl-2,4(1H,3H)-quinazolinedione as a residue (intermediate 171).
Reaction SMILES: [C:1]([C@H:4]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[NH:34][C:33]2=[O:43])[CH2:28][CH2:27]1)=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:10]=[CH:9]2)(O)=[O:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:73][N:74]1[CH2:79][CH2:78][N:77]([CH:80]2[CH2:85][CH2:84][NH:83][CH2:82][CH2:81]2)[CH2:76][CH2:75]1>CN(C=O)C>[CH3:15][C:13]1[CH:14]=[C:6]([CH2:5][C@@H:4]([O:23][C:24]([N:26]2[CH2:27][CH2:28][CH:29]([N:32]3[CH2:38][CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=4[NH:34][C:33]3=[O:43])[CH2:30][CH2:31]2)=[O:25])[C:1]([N:83]2[CH2:82][CH2:81][CH:80]([N:77]3[CH2:76][CH2:75][N:74]([CH3:73])[CH2:79][CH2:78]3)[CH2:85][CH2:84]2)=[O:2])[CH:7]=[C:8]2[C:12]=1[N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[N:10]=[CH:9]2
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2cnn(C(=O)OC(C)(C)C)c12
Reactant: CN1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc2cnn(C(=O)OC(C)(C)C)c12

Procedure:
A solution of 440 mg tert.-butyl 5-{(R)-2-carboxy-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-ethyl}-7-methyl-indazol-1-carboxylate, 256 mg (0.8 mmol) TBTU, 146 μL (1.0 mmol) triethylamine and 147 mg (0.8 mmol) 1-methyl-4-piperidin-4-yl-piperazine in 8 mL DMF was stirred for 2 h at RT. The reaction solution was filtered through an injection filter and purified directly by HPLC without any further working up. The fractions containing the product were combined, evaporated down i.vac., made alkaline with 15% K2CO3 solution, extracted three times with 30 mL DCM, the combined organic phases were dried over Na2SO4 and the solvent was eliminated i. vac.
Reaction SMILES: C(O[C:9]([N:11](C)[C@H:12]([C:14]([NH:16][C@H:17]([C:19]([NH:21][C@H:22]([C:24]([NH:26][C@H:27]([P:29](=[O:32])([OH:31])[OH:30])[CH3:28])=[O:25])[CH3:23])=[O:20])[CH3:18])=[O:15])[CH3:13])=O)C1C=CC=CC=1.CO>C(O)C>[CH3:9][NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:19]([NH:21][C@H:22]([C:24]([NH:26][C@H:27]([P:29](=[O:30])([OH:32])[OH:31])[CH3:28])=[O:25])[CH3:23])=[O:20])[CH3:18])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)N(C)C(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: CCO
Solvent: CO
Product: CN[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 19(B)(ii), from (1R)-1-[(N-benzyloxycarbonyl-N-methyl-L-alanyl-L-alanyl-L-alanyl)amino]-ethylphosphonic acid, but carrying out the hydrogenation in aqueous ethanol instead of aqueous methanol, there was obtained (1R)-1-(N-methyl-L-alanyl-L-alanyl-L-alanylamino)-ethylphosphonic acid of melting point 318°-320° C. (decomposition); [α]D20 =-121°; [α]36520 =-418° (c=0.5% in water).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2=[O:12].[BH4-].[Na+].Cl.[CH2:17](Cl)Cl>CO>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][CH:5]2[O:12][CH3:17]
Reactant: ClCCl
Reactant: Cc1c(Br)ccc2c1C(=O)CCS2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC1CCSc2ccc(Br)c(C)c21
Temperature: 0 °C

Procedure:
4.4 Grams (0.017 mol) of 6-bromo-5-methylthiochroman-4-one was dissolved in 10 ml of methylene chloride and 10 ml of methanol. The solution was cooled to 0° C. with a salt water-ice bath. 0.32 Grams (0.0085 mol) of sodium borohydride was gradually added so that the temperature did not exceed 10° C. While the mixture was cooled with the ice bath, it was allowed to react for 1 hour. Then, the reaction mixture was poured into 100 ml of 5% hydrochloric acid, and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Added to the resultant oil were 20 ml of methanol and 0.3 g of concentrated sulfuric acid, and the mixture was refluxed under heat for 2 hours. The reaction mixture was allowed to cool, poured into 200 ml of water and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 4.3 g of 6-bromo-4-methoxy-5-methylthiochroman as oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.C(N(CC)CC)C.Cl[Si:35]([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[CH3:13][C:9]1([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[CH:5]=[CH:4][C:3]=2[CH:2]([O:1][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH2:11][CH2:10]1
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O[Si](C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a solution of 0.23 g (0.54 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 9) in 4 ml of dry CH2Cl2 was added 0.06 ml of triethylamine (0.81 mmol). The solution was flushed with nitrogen and then 0.12 g (0.81 mmol) of chlorotrimethylsilane was slowly added by syringe. The mixture was stirred at room temperature (flushed with nitrogen) for 30 minutes, concentrated in vacuo to an oil and purified by flash chromatography (silica, 10% EtOAc-hexane) to yield the title compound as a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=1)[CH3:2].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[C:11]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=2)[N:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)CSc1cc(Cl)ncn1
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1cc(NCc2ccc(Cl)cc2)ncn1

Procedure:
A mixture of the residual oil [(6-chloro-4-pyrimidinylthio)acetic acid ethyl ester], 5.6 g. of p-chlorobenzylamine and 4.26 g. of sodium carbonate in 150 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and was cooled. The precipitate thus formed was collected and recrystallized from ethanol to afford 5.2 g. of product, m.p. 116°-120°C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:17]3[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH:16]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CN1CCC(=O)CC1
Product: CN1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Yield: 81.2 %

Procedure:
Beginning with 2.00 gm (12.3 mMol) 6-nitro-1H-indole and 3.00 mL (24.7 mMol) 1-methyl-4-piperidone, 2.57 gm (81%) of the title compound were recovered as a yellow solid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[OH:12]S(O)(=O)=O.N([O-])=O.[Na+].C(OCC)(=O)C>O>[OH:12][C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C#N)c1cccc(N)c1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C#N)c1cccc(O)c1
Temperature: 4 °C
Reaction time: 0.33 h

Procedure:
2-(3-aminophenyl)propionitrile (1.0 g, 6.75 mmol), was suspended in water (12 mL), then under vigorous stirring, H2SO4 (1.5 ml, 27 mmol) was added dropwise. After stirring 20 min, the mixture was cooled to 4° C., a solution of NaNO2 (0.466 g, 6.75 mmol) in water (5 mL) was added dropwise and the resulting solution was left stirring at reflux 1 h. After cooling at room temperature, ethyl acetate (10 mL) was added to the mixture, the crude was extracted and the organic phase washed with water (3×10 mL) and brine (3×10 mL). After drying over Na2SO4 and solvent evaporation under reduced pressure 2-(3-hydroxyphenyl)propionitrile was obtained as yellow oil in nearly quantitative yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][NH:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1>ClCCl.C(N(CC)CC)C>[CH3:13][N:14]([C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[C:11]([NH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12]
Reactant: CCOC(=O)CCc1ccc(-c2cccc(NC)c2)cc1
Reactant: O=C=NCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(-c2cccc(N(C)C(=O)NCCCc3ccccc3)c2)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
188 μL (1.2 mmol, 1.5 eq) 3-phenylpropyl isocyanate are added to a solution of 230 mg (0.81 mmol, 1 eq) of ethyl 3-(3′-methylaminobiphenyl-4-yl)propanoate (prepared in Example 7c) in 10 mL of an 8/2 dichloromethane/triethylamine mixture. The reaction medium is stirred at 40° C. for 12 hours and then hydrolyzed with water and extracted with ethyl acetate. The organic phases are combined, washed with sodium chloride solution and dried over sodium sulfate. The solvents are evaporated off and the residual oil is chromatographed on silica (7/3 heptane/ethyl acetate). 348 mg of ethyl 3-{3′-[1-methyl-3-(3-phenylpropyl)ureido]biphenyl-4-yl}propanoate are obtained in solid form. Yield=96%
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH:24]4[CH2:26][CH2:25]4)=[CH:22][C:21]([CH:27]4[CH2:29][CH2:28]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:30]1(=[O:36])(=[O:35])[CH2:34][CH2:33][CH2:32][NH:31]1>>[CH:24]1([C:23]2[C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:10]([C:5]4[CH:4]=[CH:3][C:2]([N:31]5[CH2:32][CH2:33][CH2:34][S:30]5(=[O:36])=[O:35])=[CH:9][C:6]=4[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]3)=[N:19][CH:20]=[C:21]([CH:27]3[CH2:29][CH2:28]3)[CH:22]=2)[CH2:26][CH2:25]1
Reactant: N#Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=S1(=O)CCCN1
Product: N#Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 90.2 %

Procedure:
Using 5-bromo-2-[4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (451 mg) described in Preparation Example 245 and isothiazolidine 1,1-dioxide (158 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (443 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[N:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1>>[N:12]1([C:18]([O:11][C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([C:18]([N:12]3[CH2:17][CH2:16][S:15][CH2:14][CH2:13]3)=[O:19])[N:7]=2)=[O:19])[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1
Reactant: Oc1n[nH]c2cc(F)ccc12
Reactant: O=C(Cl)N1CCSCC1
Product: O=C(Oc1nn(C(=O)N2CCSCC2)c2cc(F)ccc12)N1CCSCC1

Procedure:
In analogy to example 1, 200 mg (1.315 mmol) of 6-fluoro-1H-indazol-3-ol were reacted with 261.4 mg (1.578 mmol) of thiomorpholine-4-carbonyl chloride.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24]>>[Cl:17][C:18]1[CH:19]=[C:20]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][Cl:1])[S:6]2(=[O:16])=[O:15])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Product: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccc(F)c(Cl)c1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (522 mg) was coupled to 3-chloro-4-fluorophenylboronic acid to provide 1-(3-chloro-4-fluorophenyl)-3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (138 mg):
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([Cl:16])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2ccccc2[nH]1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2ccccc2[nH]1
Reaction time: 18 h

Procedure:
A suspension of indole-2-carboxylic acid (0.742 g, 4.6 mmol) in dichloromethane (3 mL) was treated with oxalyl chloride (0.700 g, 5.52 mmol) and one drop of dimethyl formamide. The reaction mixture was shaken for 18 h. The solvent was removed under reduced pressure and dried under high vacuum to afford a quantitative amount of 1H-2-indolecarbonyl chloride. The oil was directly used in the following reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.C([Li])CCC.CC(O)C.C(=O)=O.CN(C)[C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[OH:39][C:32]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:5]2[C:6](=[CH:16][CH:17]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:7](=[O:8])[N:9]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)C(=O)c1ccccc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(O)(c1ccccc1)N(c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
While cooling in a dry ice/isopropanol bath, to a solution of 1 (3.00 g, 13.2 mmol) in tetrahydrofuran at −78° C. was added dropwise n-butyllithium (2.5M in hexanes, 11.1 mL, 27.8 mmol). After stirring for 0.5 h the reaction mixture was warmed over 0.5 h to −15° C. It was recooled in the IPA/dry ice bath then a tetrahydrofuran solution of N,N-dimethylbenzamide (2.38 g, 15.8 mmol) was added. The reaction mixture was warmed to room temperature and quenched with water. The solvent was removed in vacuo. Sat. sodium bicarbonate was added and the mixture extracted with ethyl acetate (3×). The combined organic portions were dried with sodium sulfate (anh.), filtered, and concentrated. A solid resulted. It was triturated with ether to give 2 as a white solid (3.11 g, 71%)
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=O)=O)=[CH:15][CH:14]=1>C(O)(=O)C.CO>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:21]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[N:1][C:2]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[N+:9]([O-:11])=[O:10])[N:8]=2)=[CH:15][CH:14]=1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(-c2nc3cccc([N+](=O)[O-])c3nc2-c2ccc(C)cc2)cc1
Reaction time: 4 h

Procedure:
1.84 g (12 mmol) of 2,3-diaminonitrobenzene and 2.38 g (10 mmol) of 4,4′-dimethylbenzil were dissolved in 40 g of a 1:1 mixed solvent of acetic acid/methanol, and reaction was allowed at 80° C. for 4 hr. After the reaction was over, the solvent was removed, and the reaction product was extracted on a silica gel column.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[Cl:11][C:12]1[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=1[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH3:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19].[OH-].[Na+]>C(O)C.O>[Cl:11][C:12]1[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=1[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH:22]=[CH:4][C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(Cc1ccccc1Cl)(C(=O)C=Cc1c(Cl)cccc1Cl)c1ccccc1
Temperature: 25 °C

Procedure:
2,6-Dichlorobenzaldehyde (4.38 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of levo-4-(o-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (4.89 g., 0.015 mole) and sodium hydroxide (0.8 g., 0.02 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (200 ml.) and extracted with ether to remove the excess 2,6-dichlorobenzaldehyde. Ether is expelled from the aqueous phase by warming. The solution is cooled to room temperature, acidified with dilute hydrochloric acid (10 ml.), and the gummy oil which separates is extracted into ether. The ether extract is washed with brine solution, and dried (Na2SO4). Removal of the ether in vacuo, yields a yellowish residue which after recrystallization from a mixture of n-butyl chloride and petroleum ether (30°-60°C.) gives a white material, 1.75 g., m.p. 140.5°-143°C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:14][C:15]3[S:19][C:18]([C:20]4([C:25]([OH:27])=[O:26])[CH2:24][CH:23]=[CH:22][CH2:21]4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:5]2=[C:4]([CH3:28])[CH:3]=1.[CH:29]1(C2NC3C(N=2)=NC(C)=CC=3C)C[CH2:30]1>>[CH2:29]([O:26][C:25]([C:20]1([C:18]2[S:19][C:15]([CH2:14][N:8]3[C:6]4=[N:7][C:2]([CH3:1])=[CH:3][C:4]([CH3:28])=[C:5]4[N:10]=[C:9]3[CH:11]3[CH2:13][CH2:12]3)=[CH:16][CH:17]=2)[CH2:24][CH:23]=[CH:22][CH2:21]1)=[O:27])[CH3:30]
Reactant: Cc1cc(C)c2[nH]c(C3CC3)nc2n1
Reactant: CCCc1nc2c(C)cc(C)nc2n1Cc1ccc(C2(C(=O)O)CC=CC2)s1
Product: CCOC(=O)C1(c2ccc(Cn3c(C4CC4)nc4c(C)cc(C)nc43)s2)CC=CC1

Procedure:
Alkylation was performed on (11) as described in Example 1, Step 5, using 2-cyclopropyl-5,7-dimethylimidazo[4,5-b]pyridine (13) to obtain the title compound (12).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:6](=[O:8])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[Cl:1]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccccc1N
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1NC(=O)COc1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To (2,4-dichloro-phenoxy)-acetic acid (110.6 mg, 0.5 mmol), 2-aminobenzoic acid methyl ester (151.2 mg, 1.0 mmol), and benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (pybop) (520.3 g, 1.0 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine, redistilled (DIPEA) (0.17 mL, 1.0 mmol). The mixture was stirred overnight and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeOH=6:3:1) to give 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid methyl ester as a white solid (118.0 mg, 66.6% yield).