Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][CH:12]3[CH:8]([C:9](=[O:17])[NH:10][C:11]3=[O:16])[C:7]=2[C:6]([CH3:18])=[CH:5][C:4]=1[O:19][CH3:20].[CH2:21](I)[CH3:22]>>[CH2:21]([N:10]1[C:9](=[O:17])[CH:8]2[CH:12]([CH2:13][CH2:14][C:15]3[C:3]([O:2][CH3:1])=[C:4]([O:19][CH3:20])[CH:5]=[C:6]([CH3:18])[C:7]=32)[C:11]1=[O:16])[CH3:22]
Reactant: COc1cc(C)c2c(c1OC)CCC1C(=O)NC(=O)C21
Reactant: CCI
Product: CCN1C(=O)C2CCc3c(OC)c(OC)cc(C)c3C2C1=O

Procedure:
Using the procedure as described for Example 64, but starting with 3,3a,4,5-tetrahydro-6,7-dimethoxy-9-methyl-1H-benz[e]isoindole-1,3-(2H)-dione, and using ethyl iodide in place of methyl iodide afforded the desired compound.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8]C1C2C(=CC(S(N(CC3C=CC=C(Cl)C=3)CC(O)=O)(=O)=O)=CC=2)C(NC(N)=N)=NC=1.Cl.[NH2:40][C:41]([NH2:43])=[NH:42].[C:44]([O:48][C:49](=[O:75])[CH2:50][N:51]([S:60]([C:63]1[CH:72]=[C:71]2[C:66]([C:67]([Cl:74])=[CH:68][N:69]=[C:70]2Cl)=[CH:65][CH:64]=1)(=[O:62])=[O:61])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([Cl:59])[CH:54]=1)([CH3:47])([CH3:46])[CH3:45]>COCCOC.CCOCC>[ClH:8].[C:44]([O:48][C:49](=[O:75])[CH2:50][N:51]([S:60]([C:63]1[CH:72]=[C:71]2[C:66]([C:67]([Cl:74])=[CH:68][N:69]=[C:70]2[NH:42][C:41]([NH2:43])=[NH:40])=[CH:65][CH:64]=1)(=[O:61])=[O:62])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([Cl:59])[CH:54]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)Cc3cccc(Cl)c3)cc12
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc(Cl)c1)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: N=C(N)N
Agent: Cl
Solvent: COCCOC
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CN(Cc1cccc(Cl)c1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 40.3 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-chlorobenzyl)glycine trifluoroacetate ##STR23## NaH (35 mg, 80% dispersion by wt in mineral oil, 1.16 mmol) was added in one portion to a suspension of guanidine hydrochloride (150 mg, 1.55 mmol) in DME (10 mL) and the mixture was heated at 60° C. under N2 for 30 min. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-N-(3-chlorobenzyl)glycine t-butyl ester (185 mg, 0.36 mmol) was added and the mixture heated at 90° C. for 5 h. The cooled mixture was diluted with Et2O, washed with water, dried (Na2SO4) and evaporated in vacuo. The residue was dissolved in Et2O and a solution of HCl in Et2O (1 M) was added to give a precipitate. The solvents were evaporated in vacuo, and the white solid triturated with EtOAc and then dried to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-chlorobenzyl)glycine t-butyl ester hydrochloride (85 mg, 0.145 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][CH2:20][CH3:21])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1.[NH2:22][C:23](N)=[O:24].Cl>O>[CH2:19]([O:18][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:23]([NH2:22])=[O:24])=[CH:7][C:6]=1[C:8]1[N:16]=[C:15]2[C:11](=[N:12][N:13]=[N:14]2)[C:10](=[O:17])[N:9]=1)[CH2:20][CH3:21]
Reactant: CCCOc1ccc(N)cc1C1=NC(=O)C2=NN=NC2=N1
Reactant: NC(N)=O
Agent: Cl
Solvent: O
Product: CCCOc1ccc(NC(N)=O)cc1C1=NC(=O)C2=NN=NC2=N1
Temperature: 175 °C
Yield: 30.4 %

Procedure:
An intimate mixture of 2-(5-amino-2-propoxyphenyl)-8-azapurin-6-one (2 g) and urea (6 g) was heated at 175° C. for one hour. The mixture was then dissolved in water (50 ml) and the solution was acidified by treatment with concentrated hydrochloric acid. The resulting suspension was heated to boiling point and filtered. The solid was dissolved in dilute aqueous ammonia solution (2 N) and this hot solution was acidified by treatment with concentrated hydrochloric acid. The cooled suspension was filtered to give 2-(2-propoxy-5-ureidophenyl)-8-azapurin-6-one (0.7 g), in the form of a microcrystalline solid, m.p. 264°-268° C. (with decomposition).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:13]=2[O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:13]=2[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1c(CNc2ccc(C(C)=O)cc2)cccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cccc(CNc2ccc(C(C)=O)cc2)c1OCCCC(=O)O
Yield: 71.5 %

Procedure:
4-[2-[[(4-Acetylphenyl)amino]methyl]-6-methoxy-phenoxy]butanoic acid, ethyl ester (250 mg, 0.65 mmol) is dissolved in 5 mL of methanol/water (3:2) and treated with 313 mg (2.27 mmol) of potassium carbonate according to the procedure described for Example 4 to give 166 mg (71%) of 4-[2-[[(4-acetylphenyl)amino]methyl]-6-methoxy-phenoxy]butanoic acid as a red colored solid: m.p. 85°-95° C.; The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 3400, 1720, 1630, 1580 cm-1 ; MS (CI) m/e calculated for C20H23 O5NNa: 380.1473, found 380.1482; 358 (M+H), 233, 223, 221, 136.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=O)=[C:8]([CH3:12])[N:7]=[C:6]([S:13][CH3:14])[N:5]=1)[CH3:2].[C:15]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])/[CH:20]=[CH:10]/[C:9]1[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]([S:13][CH3:14])=[N:7][C:8]=1[CH3:12])[CH3:19]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNc1nc(SC)nc(C)c1C=O
Solvent: C1CCOC1
Product: CCNc1nc(SC)nc(C)c1/C=C/C(=O)OCC
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of 4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carbaldehyde (38 g, 180 mmol) in THF (500 mL) was added (Carbethoxymethylene) triphenylphosphorane (95%, Aldrich, 85.18 g, 244 mmol). The reaction mixture was heated to reflux for 1.5 h and was monitored by TLC (4:1 hexanes/ethylacetate). The reaction was cooled to room temperature and was concentrated on a rotary evaporator. It was directly subjected to column chromatography (4:1 hexanes/ethylacetate) to give (E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate as a white crystal, 46.14 g (91% yield).
Reaction SMILES: [CH3:1][S-:2].[Na+].[N+]([C:7]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])([O-])=O>CC(C)=O>[CH3:1][S:2][C:7]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CSc1cc(C(F)(F)F)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Sodium thiomethoxide (366 g of a 21% aqueous solution, 1.1M) was added during 3 hours to a solution of 2-nitro-4-trifluoromethylbenzonitrile (220.5 g, 1.0M) in acetone (340 g) with stirring at 20-30° C. Stirring was continued for a further 1 hour and the two liquid phases separated. The upper layer (a solution of the product in acetone) was kept at 20° C. when 2-methylthio-4-trifluoromethylbenzonitrile crystallised (213 g), m.p.82° C. The yield was 97%, with product purity >96%.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1)[NH2:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30]3)[C:25](=[O:32])N(CCO)N=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH:28]=[CH:29][CH2:30]3)[C:25](=[O:32])[N:1]([C:3]3[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[CH:7][CH:8]=3)[N:2]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: NNc1ccc(CCO)cc1
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(c3ccc(CCO)cc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 2-(4-hydrazinophenyl)ethanol as described for compound 35. Crystallized from diethyl ether. M.p. 137°-139° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=O)[C:9]2=[O:18])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([F:27])[CH:26]=1)[NH2:23].C(O)(=O)C>C(Cl)Cl>[F:19][C:20]1[CH:21]=[C:22]([N:23]=[C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[C:9]2=[O:18])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: O=C1C(=O)N(c2ccc(O)cc2)c2ccccc21
Reactant: Nc1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1C(=Nc2cc(F)cc(F)c2)c2ccccc2N1c1ccc(O)cc1

Procedure:
A mixture of 1-(4-hydroxyphenyl)-1H-indole-2,3-dione (30 mg, 0.126 mmol), 3,5-difluoroaniline (170 mg, 1.32 mmol), and a drop of acetic acid was heated at 140° C. for 4 hours in a 3 mL vial. The crude product was suspended in CH2Cl2 and purified by preparative TLC [Eluent: EtOAc/hexane (1:1)] giving the desired product. Procedure D
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1)=[CH2:9].[C:18](=[S:20])=[S:19]>>[C:18]([S:20][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([CH:8]=[CH2:9])=[CH:11][CH:12]=1)(=[S:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:18]([S-:20])=[S:19])=[CH:12][CH:11]=1)=[CH2:9]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: Brc1ccccc1
Reactant: S=C=S
Product: C=Cc1ccc(CSC(=S)c2ccccc2)cc1
Product: C=Cc1ccc(Cc2ccccc2C(=S)[S-])cc1
Temperature: 50 °C

Procedure:
4-vinylbenzyl dithiobenzoate (VBThB) was prepared according to reaction scheme 4, as follows. A 500 mL round bottom flask was dried with 3 vacuum/heat/nitrogen cycles. 100 mL of dry THF was added along with 3.3 grams of magnesium turnings. The mixture was placed in an oil bath set to 40° C., and 13.8 grams (0.088 moles) bromobenzene was added. 7.91 mL (0.088 moles) of dry carbon disulfide was added dropwise over the next 15 minutes. When all the carbon disulfide was added, the temperature was increased to 50° C., and 18.62 grams (0.088 moles) of 4-vinylbenzyl chloride was added. The solvent was removed. The crude product was purified via column chromatography over activated alumina (Brockman activity II). The final product was obtained as a red oil. The conversion was estimated at 48% after eluent removal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[N:8]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cccc(Cl)c1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Cl)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 3-chloro-N2-phenylbenzene-1,2-diamine (495 mg, 2.26 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (470 mg, 2.48 mmol), HOAt (338 mg, 2.48 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (477 mg, 2.48 mmol) and 4-methylmorpholine (0.550 mL, 4.97 mmol) in anhydrous DCM (15 mL) was stirred at RT for 19 h. The reaction mixture was diluted with DCM (100 mL) and washed with a saturated solution of NaHCO3. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (20 mL) and heated at 70° C. for 22 h. After cooling to RT, volatiles were removed in vacuo and the residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in DCM) affording [(S)-1-(7-Chloro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester as pale yellow oil (quantitative). LCMS: RT 3.83 min [M+H-tBu]+ 316.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:31]([F:30])=[CH:32][CH:33]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)c1ccc(F)cc1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 96 (step e), the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-benzamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 4-fluorobenzoyl chloride instead of 4-methoxy-3-(trifluoromethyl)benzoyl chloride and was obtained as a light brown foam. MS m/e: 560.1 [M]+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=O)[O:12][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(O)(O)O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.S(Cl)([Cl:44])=O.[CH3:46][OH:47]>>[CH3:46][O:47][C:13](=[O:12])[C:14]1[CH:15]=[CH:16][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][C:10]=1[CH2:11][Cl:44]
Reactant: O=C1OCc2cc(Oc3ccccc3)ccc21
Reactant: O=S(Cl)Cl
Reactant: CO
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: OB(O)O
Product: COC(=O)c1ccc(Oc2ccccc2)cc1CCl

Procedure:
To a solid mixture of 5-phenoxy-3H-isobenzofuran-1-one (65.54 g, 0.29 mol), boric acid (538 mg, 8.7 mmol) and triphenylphosphine oxide (2.42 g, 8.7 mmol) was added thionyl chloride (42.3 mL). The resulting mixture was refluxed overnight. After cooled, methanol (300 mL) was slowly added to the reaction mixture. It was then refluxed for 1 h and concentrated. Residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to provide the title compound (87.02 g, 0.31 mol) as an oil. It was used directly to the next reaction without further purification. 1H NMR in CDCl3, δ in ppm: 7.91 (d, 1H, 8.6 Hz), 7.5-6.9 (m, 7H), 5.06 (s, 2H), 3.83 (s, 3H).
Reaction SMILES: CC1C(C)=CC=CC=1OCCCC(N1C2C(=C(C3C=CN=C(C(OC)=O)C=3)C=CC=2)CCC1)=O.[Br:35][C:36]1[CH:37]=[N:38][N:39]([CH2:41][C:42]2[CH:43]=[C:44]([CH:49]=[CH:50][CH:51]=2)[C:45]([O:47]C)=[O:46])[CH:40]=1>>[Br:35][C:36]1[CH:37]=[N:38][N:39]([CH2:41][C:42]2[CH:43]=[C:44]([CH:49]=[CH:50][CH:51]=2)[C:45]([OH:47])=[O:46])[CH:40]=1
Reactant: COC(=O)c1cccc(Cn2cc(Br)cn2)c1
Agent: COC(=O)c1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)ccn1
Product: O=C(O)c1cccc(Cn2cc(Br)cn2)c1

Procedure:
The title compound was prepared using a procedure analogous to Example 2 except that methyl 4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)picolinate was replaced by methyl 3-((4-bromo-1H-pyrazol-1-yl)methyl)benzoate. LCMS, [M+H]+=281.0.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[ClH:31].[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:20]1[C:19]2[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=2[C:17]2[N:16]=[C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:37]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[CH3:36])=[CH:13][CH:12]=3)[N:24]=[CH:23][C:22]=2[CH2:21]1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2Cl)C3)cc1
Reactant: CNC1CCCCC1
Product: CN(CCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2Cl)C3)cc1)C1CCCCC1
Product: Cl

Procedure:
This product was synthesized as described in general procedure 2 except 4-(6-(2-chlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate was used instead of 4-(6-(3-bromophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate and N-methylcyclohexanamine instead of piperidine to afford 6-(2-chlorophenyl)-N-(4-(2-(cyclohexyl(methyl)amino)ethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine hydrochloride. 1H-NMR 400 MHz (CDCl3) δ 8.45 (d, J=7.8 Hz, 1H), 8.12 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.46-7.39 (m, 3H), 7.21-7.20 (m, 3H), 7.13 (t, J=7.4 Hz, 1H), 7.02 (d, J=7.4 Hz, 2H), 6.73 (d, J=7.8 Hz, 1H), 4.85 (t, J=2.2 Hz, 1H), 3.22-3.17 (m, 2H), 2.75-2.71 (m, 4H), 2.44-2.42 (m, 1H), 2.36 (s, 3H), 1.84-1.79 (m, 4H), 1.64-1.61 (m, 1H), 1.27-1.21 (m, 4H), 1.15-1.10 (m, 1H). LCMS m/e 523 (M+H).
Reaction SMILES: [CH3:1][C:2]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3]1.[F:9][C:10]1[CH:11]=[C:12]([CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]2[CH:26]=[CH:27][C:28]3[N:29]([C:31]([C:34](O)=[O:35])=[CH:32][N:33]=3)[CH:30]=2)[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1>>[F:9][C:10]1[CH:11]=[C:12]([CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]2[CH:26]=[CH:27][C:28]3[N:29]([C:31]([C:34]([NH:8][S:5]([C:2]4([CH3:1])[CH2:4][CH2:3]4)(=[O:7])=[O:6])=[O:35])=[CH:32][N:33]=3)[CH:30]=2)[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: O=C(O)c1cnc2ccc(N3CCCC3c3cc(F)cc4c3OCCO4)cn12
Product: CC1(S(=O)(=O)NC(=O)c2cnc3ccc(N4CCCC4c4cc(F)cc5c4OCCO5)cn23)CC1

Procedure:
The title compound was prepared by the method similar to that of Example 31 employing 1-Methylcyclopropane-1-sulfonamide (int-50) and 6-(2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (Int 38) to afford an enantiomeric mixture which was separated by chiral chromatography using CHIRALPAK AD-H column and n-HEXANE:ETHANOL, 60:40 Isocratic solution as eluent to afford 6-(2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidin-1-yl)-N-((l-methylcyclopropyl)sulfonyl)imidazo[1,2-a]pyridine-3-carboxamide (Isomer-I)
Reaction SMILES: [NH2:1][C:2](=[N:5][C:6](=[O:9])OC)[S:3][CH3:4].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1.[Na]>C(Cl)Cl.CO>[F:10][C:11]([F:21])([F:22])[C:12]1[CH:13]=[C:14]([N:18]2[C:19](=[O:20])[NH:1][CH:2]([S:3][CH3:4])[NH:5][C:6]2=[O:9])[CH:15]=[CH:16][CH:17]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)N=C(N)SC
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: CSC1NC(=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.9 %

Procedure:
Methyl N-[1-(amino)-1-(methylthio)methylene]carbamate (14.8 g.) was dissolved in methylene chloride (150 ml.). 3-Trifluoromethylphenyl isocyanate (18.7 g.) was added to the solution during 5 minutes and the mixture was stirred at room temperature for 2.5 hours. A freshly prepared solution of sodium (2.3 g.) in methanol (20 ml.) was then added during 5 minutes and the subsequent mixture was stirred at room temperature for 16 hours. The mixture was then evaporated and the residue was dissolved in water (400 ml.). The aqueous solution obtained, was extracted with ethyl acetate (2×400 ml.) to remove neutral byproducts, and then acidified with concentrated hydrochloric acid to pH1. The solid which precipitated was separated by filtration, washed with water (3×500 ml.), and dried (over phosphorus pentoxide) to give 3-(3-trifluoromethylphenyl)-6-methylthio-tetrahydro-1,3,5-triazine-2,4-dione (25.9 g., 86%) as a white solid, m.p. 225°-228° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:39]=[CH:38][C:20]([O:21][C:22]2[C:27]([F:28])=[CH:26][C:25](/[CH:29]=[C:30](\[CH3:36])/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:24][C:23]=2[F:37])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[CH3:40][N:41]([CH:43]=[O:44])C>>[O:44]=[C:43]([NH:41][CH2:40][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([O:21][C:22]2[C:23]([F:37])=[CH:24][C:25]([CH:29]=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:36])=[CH:26][C:27]=2[F:28])=[CH:38][CH:39]=1)(=[O:16])=[O:15])[NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:39]=[CH:38][C:20]([O:21][C:22]2[C:23]([F:37])=[CH:24][C:25]([CH:29]=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:36])=[CH:26][C:27]=2[F:28])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCN)cc2)c(F)c1
Reactant: CN(C)C=O
Product: CCOC(=O)C(C)=Cc1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)NCCOCCOCCOCCNS(=O)(=O)c3ccc(Oc4c(F)cc(C=C(C)C(=O)OCC)cc4F)cc3)cc2)c(F)c1
Reaction time: 23 h

Procedure:
Carbonyldiimidisole (16.2 mg, 0.10 mmol) was added to a solution of (E)-ethyl 3-(4-(4-(N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-3,5-difluorophenyl)-2-methylacrylate (intermediate 44.2) (125 mg, 0.22 mmol) in DMF (2 mL) and stirred for 23 hours at which time the solvent was removed under vacuum. The residue was dissolved in EtOAc, washed with water (4×10 mL), dried (Na2SO4) and concentrated to give the title compound (132 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:34]=[CH:33][C:13]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][C:23]3=[O:24])[CH2:18][CH2:17]2)=[O:15])=[CH:12][CH:11]=1)([OH:3])=[O:2].[NH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][C:41]=1[NH2:42].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:57]S(O)(=O)=O.[OH-].[Na+]>>[NH:42]1[C:41]2[CH:40]=[CH:39][N:38]=[CH:37][C:36]=2[N:35]=[C:57]1[CH:4]([C:1]([OH:3])=[O:2])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:34]=[CH:33][C:13]([C:14]([N:16]2[CH2:17][CH2:18][CH:19]([N:22]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][C:23]3=[O:24])[CH2:20][CH2:21]2)=[O:15])=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)O
Reactant: O=C(O)CCCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: Nc1ccncc1N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(CCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1)c1nc2cnccc2[nH]1
Temperature: 0 °C

Procedure:
To 1-{1-[4-(5-carboxypentyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (2.00 g) are added 3,4-diaminopyridine (0.47 g), phosphorus pentoxide (1.00 g) and methanesulfonic acid (7.0 ml) and the mixture is stirred with heating at 100°-120° C. for 3 hours. After cooling, the reaction solution is poured into ice-water (30 ml) and the mixture is adjusted to around pH 11 with aqueous sodium hydroxide solution and extracted with dichloromethane. The extract is dried with magnesium sulfate and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (solvent: dichloromethane:methanol=20:1→9:1) to give 1-{1-[4-(5-(imidazo[4,5-c]pyridine-2-yl)carboxypentyloxy)benzoyl]-4-piperidinyl]-3,4-dihydrocarbostyril (1.32 g) as white amorphous form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[CH:14]=1>>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: BrCc1cccc(Br)c1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCc2cccc(Br)c2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromo-3-bromomethyl-benzene using the conditions described in Example 237C to provide 4-(3-Bromo-benzyloxy)-1-chloro-2-nitro-benzene which was treated sequentially using the procedures from Examples 237D and 237E to provide 4-[2-Amino-4-(3-bromo-benzyloxy)-phenylsulfanyl]-phenol.