Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([C:18]2[N:22]4[CH:23]=[C:24]([CH:27]([N:32]5[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]5)[C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=2)[CH:14]=[CH:13]3)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[C:47](OC(=O)C)(=[O:49])[CH3:48]>ClCCl>[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([C:18]2[N:22]4[CH:23]=[C:24]([CH:27]([N:32]5[CH2:36][CH2:35][C@H:34]([NH:37][C:47](=[O:49])[CH3:48])[CH2:33]5)[C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=2)[CH:14]=[CH:13]3)[CH2:5][CH2:4]1
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1CCN(C(c2ccc3nnc(-c4ccc5cccc(OCC6CC6)c5n4)n3c2)C(F)(F)F)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1CCN(C(c2ccc3nnc(-c4ccc5cccc(OCC6CC6)c5n4)n3c2)C(F)(F)F)C1
Yield: 53.7 %

Procedure:
A solution of (3S)-1-(1-(3-(8-(cyclopropylmethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-amine (Example 5; 0.15 g, 0.27 mmol), DIEA (0.14 mL, 0.81 mmol) and acetic anhydride (0.038 mL, 0.41 mmol) in dichloromethane (4 mL) was stirred at ambient temperature for 18 hours. The mixture was partitioned between ethyl acetate (15 mL) and water (5 mL). The organic layer was separated and washed with aqueous 1N HCl (5 mL), water and brine, then dried (MgSO4), filtered and concentrated under reduced pressure to afford N-((3S)-1-(1-(3-(8-(cyclopropylmethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-yl)acetamide (0.076 g, 54%). LCMS APCI (+) m/z 525 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[O:5][N:4]=1.[CH:14]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][S:24]([CH2:27][CH2:28][NH:29][C:30]([C:32]2[S:33][C:34]([Cl:37])=[CH:35][CH:36]=2)=[O:31])(=[O:26])=[O:25])[CH2:19][CH2:18]1)([CH3:16])[CH3:15]>>[Cl:13][C:10]1[S:9][C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][N:23]([CH:20]3[CH2:21][CH2:22][N:17]([CH:14]([CH3:16])[CH3:15])[CH2:18][CH2:19]3)[S:24]([CH2:27][CH2:28][NH:29][C:30]([C:32]3[S:33][C:34]([Cl:37])=[CH:35][CH:36]=3)=[O:31])(=[O:25])=[O:26])[CH:7]=2)=[CH:12][CH:11]=1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Product: CC(C)N1CCC(N(Cc2cc(-c3ccc(Cl)s3)on2)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-(1-isopropyl-piperidin-4-yl)-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described in example 15 starting from 141 mg (2 equiv.) 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole and 100 mg (0.25 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-Chloro-thiophene-2-carboxylic acid {2-[[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-(1-isopropyl-piperidin-4-yl)-sulfamoyl]-ethyl}-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[S:13][CH2:14][C:15]([OH:17])=O)([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]2[S:13][CH2:14][C:15](=[O:17])[NH:1][C:4]=2[CH:9]=1
Reactant: O=C(O)CSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)NC(=O)CS2
Yield: 61.7 %

Procedure:
A solution of 2-(2,4-dinitrophenylthio)-acetic acid (2.3 g, 9 mmol) and tin (II) chloride dihydrate (22.6 g, 0.1 mol) in ethanol (30 mL) was refluxed overnight. After removal of the solvent under reduced pressure, the residual slurry was diluted with water (100 mL) and basified with 10% Na2CO3 solution to pH 8. The resulting suspension was extracted with ethyl acetate (3×100 mL). The ethyl acetate extract was washed with water and brine, dried over Na2SO4, and concentrated. The residue was washed with CH2Cl2 to yield 6-amino-2H-benzo[b][1,4]thiazin-3(4H)-one (DC-7) as a yellow powder (1 g, 52%). 1H NMR (DMSO-d6) δ 10.24 (s, 1H), 6.88 (d, 1H, J=6 Hz), 6.19-6.21 (m, 2H), 5.15 (s, 2H), 3.28 (s, 2H); ESI-MS 181.1 m/z (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[Br:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][O:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2/[CH:24]=[CH:23]/[CH:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(Br)cc2)CCc2ccc(C#N)cc2)cc1
Yield: 87.5 %

Procedure:
A solution of 230 mg (0.56 mmol) of methyl E-4-[2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-enyl]benzoate from Example 17A in 5 ml of dry acetonitrile is mixed with 209 mg (0.84 mmol) of 4-bromobenzyl bromide and 116 mg (0.84 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The resulting organic phase is concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane). 286 mg (0.49 mmol, 88% yield) of a solid are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][C:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)=[O:19]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (2.6 g, 10 mmol) in anhydrous dichloromethane (10 mL) was added dropwise thionyl chloride (10 mL) at 0° C. After the addition, the solution was stirred at room temperature overnight, and then the solvent was removed in vacuum to give benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate. Then it was added to a solution of ethyl 3-amino-2-hydroxybenzoate (1.34 g, 8 mmol) and triethylamine (3 g, 30 mmol) in anhydrous dichloromethane (20 mL) at 0° C. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed with water (30 mL×3), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=20:1 to 2:1) to give benzyl 4-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)piperidine-1-carboxylate (2.63 g, yield 80%). 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.46-1.56 (m, 2H), 1.79-1.82 (d, J=11.6 Hz, 2H), 2.75-2.87 (m, 3H), 3.92 (s, 3H), 4.04-4.07 (d, J=11.2 Hz, 2H), 5.08 (s, 2H), 6.90-6.94 (t, J=8 Hz, 1H), 7.30-7.40 (m, 5H), 7.54-7.56 (m, 1H), 8.09-8.11 (d, J=7.2 Hz, 1H), 9.34 (s, 1H), 10.99 (brs, 1H); LC-MS (ESI) m/z: 413 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][C:5]([C:9]#[N:10])=[C:4]([C:11]#[N:12])[N:3]=1.[NH3:13].O>O1CCCC1>[NH2:13][C:7]1[C:2]([Cl:1])=[N:3][C:4]([C:11]#[N:12])=[C:5]([C:9]#[N:10])[N:6]=1
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Reactant: N
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1nc(N)c(Cl)nc1C#N
Reaction time: 1 h
Yield: 93.6 %

Procedure:
5.0 g (0.025 mol) of 2,3-dichloro-5,6-dicyanopyrazine was dissolved in 50 ml of dry tetrahydrofuran, and 6.1 g (0.050 mol) of 28% aqueous ammonia was dropwise added at a temperature of from -15°to 0° C. After completion of the dropwise addition, the mixture was stirred for 1 hour, and the reaction solution was poured into 500 ml of water. The precipitated solid was collected by filtration and recrystallized from a solvent mixture of toluene and ethyl acetate to obtain 4.2 g of slightly yellow crystals (yield: 93.6%, melting point: 205-208° C.).
Reaction SMILES: Cl[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].[NH2:13][C:14]1[C:29]([Cl:30])=[CH:28][C:17]([C:18]([O:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:19])=[C:16]([O:31][CH3:32])[CH:15]=1.C(N(CC)CC)C>CN(C=O)C>[NH2:13][C:14]1[C:29]([Cl:30])=[CH:28][C:17]([C:18]([O:20][CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:4][CH2:3][CH2:2][O:5][C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[CH2:26][CH2:27]2)=[O:19])=[C:16]([O:31][CH3:32])[CH:15]=1
Reactant: CCC(Cl)Oc1ccc(F)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)OCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)OCC1CCN(CCCOc2ccc(F)cc2)CC1
Temperature: 70 °C
Reaction time: 48 h
Yield: 25.8 %

Procedure:
A mixture of 1-chloro-(4-fluorophenoxy)propane (2.3 g), intermediate 11 (3 g) and N,N-diethylethanamine (2.8 ml) in DMF (50 ml) was stirred for 48 hours at 70° C. The reaction mixture was cooled and the solvent was evaporated. The residue was partitioned between DCM and water. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from ACN (0° C.). The precipitate was filtered off and dried (vacuum; 50° C.), yielding 1.17 g (26%) [1-[3-(4-fluorophenoxy)propyl]-4-piperidinyl]methyl 4-amino-5-chloro-2-methoxybenzoate (compound 1, mp. 140.0° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:17])=O)C.C(O)(=O)C.[CH:22](N)=[NH:23]>C(O)C>[C:11]1([C:10]2[C:6]3[C:4](=[O:3])[NH:23][CH:22]=[N:17][C:7]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]cnc2scc(-c3ccccc3)c12
Temperature: 25 °C

Procedure:
A stirred mixture of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (350.43 g, 1.535 mol), formamidine acetate (799.13 g, 7.7 mol) and ethanol (1500 ml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with a little cold ethanol, then crystallised from ethanol to give 5-Phenyl-3H-thieno[2,3-d]pyrimidin-4-one as a yellow solid which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:11](S(C(F)(F)F)(=O)=O)=[C:10]([F:19])[C:9]([F:20])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC.[Cl-].[Li+]>O1CCOCC1.CCOCC>[CH:21]([C:11]1[C:2]([F:1])=[C:3]([CH:8]=[C:9]([F:20])[C:10]=1[F:19])[C:4]([OH:6])=[O:5])=[CH2:22]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(F)c(F)c(S(=O)(=O)C(F)(F)F)c1F
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: C=Cc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 98 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
To a solution of 2,4,5-trifluoro-3-trifluoro methanesulfonyl benzoic acid, methyl ester (22.0 g, 0.065 mol) in dioxane (100 mL) was added tri-n-butyl vinyl tin (21.6 g, 0.068 mol), lithium chloride (16.7 g, 0.37 mL) 2,6-di-t-butyl-4-methylphenol (0.08 g) and palladium-tetra-triphenyl phosphine (1.1 g). The mixture was heated at 98° C. for 12 hours, cooled, diluted with ether and filtered through celite. The ether layer was concentrated and the resulting residue suspended in hexane and filtered. The filtrate was concentrated to a yellow oil which was immediately dissolved in methanol (250 mL) and 1 N sodium hydroxide (150 mL). The mixture was stirred at room temperature for 4 hours, diluted with water and ether. The aqueous layer was acidified (pH ~2) with 6 N HCl and extracted with methylene chloride. The organic layer was dried and concentrated to provide the desired product (9.6 g, 77%); mp 108°-110° C.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.[ClH:12]>>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][Cl:12]
Reactant: COc1cccc(CO)c1F
Reactant: Cl
Product: COc1cccc(CCl)c1F
Temperature: 25 °C
Reaction time: 21 h
Yield: 76 %

Procedure:
2-Fluoro-3-methoxybenzyl alcohol from Step 2 (12.16 g, 78 mmol) was dissolved in concentrated hydrochloric acid (60 mL) and hydrochloric acid gas was bubbled through the solution for 3 minutes. The flask was capped and the reaction stirred at room temperature (21 hours). The reaction mixture was extracted with ether, dried over MgSO4 and concentrated in vacuo to give 2-fluoro-3-methoxybenzyl chloride (10.36 g, 76%) as a green oil: 1H NMR (acetone-d6) 300 MHz 7.12 (m, 2H) 7.05 (m, 1H) 4.73 (s, 2H) 3.89 (s, 3H); 19F NMR (acetone-d6) 300 MHz -142.07(m).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=1)O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:31])=O>ClCCl>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[Cl:31])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C)S(=O)(=O)c1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc(C(Cl)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1

Procedure:
The alcohol (88.8 g, 0.21 mol) was treated with thionyl chloride in dichloromethane as described in Example 1 to give 93.7 g of 4-(3-(tert-butyldimethylsilyloxy)-α-chlorobenzyl)-N,N-dimethylbenzenesulfonamide as a brown oil. The crude benzhydryl chloride (93.7 g, 0.21 mol) was combined with trans-2,5-dimethylpiperazine (71.8 g, 0.63 mol) in 400 mL of dimethylformamide and heated to 140° C. for 1 hour. The mixture was cooled to room temperature, poured into ice water and extracted with diethyl ether. The ether extracts were washed with 1M sodium hydroxide, water, and saturated aqueous sodium chloride, and dried over sodium sulfate. The solvent was removed and the residue was purified by chromatography on silica gel with dichloromethane:methanol to give 28.9 g (27%) of trans-4-(α-(2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-N,N-dimethylbenzenesulfonamide as a brown oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].Cl[C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[CH3:3]
Reactant: Clc1nc2ccccc2o1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNc1nc2ccccc2o1
Temperature: 0 °C

Procedure:
22.3 g (0.16 mole) of glycine ethyl ester hydrochloride were stirred in small portions into a mixture of 23.0 g (0.15 mole) of 2-chlorobenzoxazole, 250 ml of absolute acetonitrile and 44.2 g (0.32 mole) of anhydrous K2CO3 at 50° C. in the course of 3 hours, with stirring. The mixture was subsequently stirred under gentle reflux (80°-82° C.) for a further 4 hours, cooled in an ice-water bath and poured into about 750 ml of ice-water.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[I:12].N([O-])=O.[Na+].[N-:17]=[N+:18]=[N-].[Na+]>C1COCC1.Cl.O>[N:1]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[I:12])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(N)c(I)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=Nc1ccc(C(=O)O)cc1I
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a solution of methyl 4-amino-3-iodobenzoate (10.0 g, 36.1 mmol) in THF (200 ml), 1M hydrochloric acid (75 ml) and water (300 ml) was added sodium nitrite (2.5 g, 36.1 mmol) under ice-cooling, and the mixture was stirred for 30 min. Sodium azide (2.5 g, 36.1 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hr and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (370 ml), 8M aqueous sodium hydroxide solution (20 ml) and water (30 ml), and the reaction mixture was stirred at room temperature for 18 hr. Methanol was evaporated under reduced pressure, and the obtained residual aqueous solution was acidified (pH<3) with 6M hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with water and dried to give the title compound as a pale-yellow powder (9.05 g, 95%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28](Cl)=[O:29].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28]([NH:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2)=[O:29]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2cccc(CNC(=O)c3ccc(Cl)c(Cl)c3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.46 g, 1.4 mmol) in acetonitrile (10 mL), was added 3,4-dichloro-benzoyl chloride (0.34 g, 1.6 mmol) and N,N-diisopropyl ethylamine (0.54 mL, 3.3 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 3,4-dichloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-benzamide as a white solid (450 mg, 70% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.60 min (99.6%); mp, 271-273° C.; 1HNMR (DMSO-d6)2.17-2.22 (m, 1H, CHH), 2.58-2.90 (m, 6H, CHCH2, CH3), 4.97-5.09 (m, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.34-8.17 (m, 6H, Ar), 9.14 (t, J=5 Hz, 1H, CH2NH), 11.04 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.80, 23.29, 30.60, 42.30, 56.52, 117.66, 124.17, 125.56, 127.58, 129.28, 130.76, 131.31, 133.97, 134.11, 134.56, 140.39, 148.50, 154.86, 161.06, 164.10, 169.53, 172.62. LCMS MH=473, 475; Anal Calcd For C22H18N4O4Cl2+0.1 CH2Cl2: C, 55.09; H, 3.81; N, 11.63; Cl, 16.19. Found: C, 54.88; H, 3.60; N, 11.46; Cl, 16.38.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][NH:30][CH3:31])[CH:26]=[CH:27][CH:28]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([N:30]([CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)[CH3:31])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CNCc1cccc(OC)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COc1cccc(CN(C)C(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-(3-methoxyphenyl)-N-methyl-methanamine (18.0 mg, 0.12 mmol). The title compound was obtained as a solid (18.5 mg, 38% yield). MS m/z: 484.01, 486.01 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7](Cl)=[O:8].C(N(C(C)C)C(C)C)C.[CH3:29][O:30][C:31]([CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH2:35][CH2:34]1)=[O:32]>CN(C=O)C>[CH3:29][O:30][C:31]([CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]([C:7]([C:6]2[C:5]([O:4][C:3]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:2]=3[Cl:1])=[N:13][CH:12]=[C:11]([F:14])[CH:10]=2)=[O:8])[CH2:35][CH2:34]1)=[O:32]
Reactant: COC(=O)C1CCNc2ccccc21
Reactant: O=C(Cl)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(C(=O)c2cc(F)cnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.8 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinoyl chloride (48.1 mg, 0.15 mmol, 1.0 equiv; Example 146, Step 1) in anhydrous DMF (1 mL) was added N-ethyldiisopropylamine (97 mg, 128 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and 1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (31.6 mg, 0.165 mmol, 1.1 equiv; [CAS RN 68066-85-3]) and the reaction mixture stirred at rt for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 9.1 mg (13%) of the title compound as a light yellow solid. MS (ISP): 475.1 [M+H]+.
Reaction SMILES: Cl.CN[O:4]C.C(N(CC)CC)C.[CH2:13]([N:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[S:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([N:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[S:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:4])=[O:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.3 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (7.37 g; 75.6 mmoles) and triethylamine (21.8 ml; 151 mmoles) in methylene chloride (150 ml), another solution of 4-(dibenzylsulfamoyl)benzoyl chloride (25 g) in methylene chloride (150 ml) was slowly added and the resulting mixture stirred at room temperature for 16 hours. The solid was filtered off, the solvent removed under reduced pressure and the residual oil purified by column chromatography with silica gel and n-hexane-ethyl acetate 1:1 as eluent. N,O-dimethylamide of 4-(dibenzylsulfamoyl)benzoic acid (22 g) was obtained, m.p. 75° C.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.[C:36]([N:40]=[C:41]=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([NH:40][C:41](=[O:42])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:34][CH:35]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(N)cc1
Reactant: CC(C)(C)N=C=O
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(NC(=O)NC(C)(C)C)cc1
Yield: 77.3 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-methoxyphenyl)benzamide (77.7 mg, 0.164 mmol) and tertbutyl isocyanate (0.022 ml, 0.196 mmol), the procedure of inventive Example 144 was repeated to obtain 72.9 mg (77.6%) of the title compound in a colorless oily form.