Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1.[Cl-].[CH3:15][O:16][C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[CH:19]=[N+:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[C:10]2[CH:19]([C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[O:16][CH3:15])[N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1
Reactant: COc1ccccc1C=[N+]1CCOCC1
Reactant: COc1ccc2ccc(O)cc2c1
Agent: [Cl-]
Product: COc1ccc2ccc(O)c(C(c3ccccc3OC)N3CCOCC3)c2c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-methoxy-2-naphthol and 4-(2-methoxy-benzylidene)-morpholin-4-ium chloride, which had been prepared in accordance with example 28.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH3:2].C([OH:16])C.[H][H].[OH-].[Na+]>O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:10])=[O:16])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C#N)c([N+](=O)[O-])c1
Reactant: CCO
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(C(N)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
A mixture of 2 parts of 4-ethyl-2-nitrobenzenecarbonitrile, 31.6 parts of ethanol, 27.8 parts of hydrogen perioxide (30%) and 1.7 ml of sodium hydroxide 6N was stirred for 1 hour at room temperature. The reaction mixture was diluted with water and the product was extracted with dichloromethane (3×). the combined extracts were washed with water, dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.3 parts (60.9%) of 4-ethyl-2-nitrobenzamide; mp. 175° C. (interim 4).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[C:6]([CH2:11][CH3:12])=[N:7][NH:8][C:9]=1[NH2:10].O=[C:19]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[CH2:20][C:21](OCC)=[O:22]>C(O)(=O)C.O>[Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[C:6]([CH2:11][CH3:12])=[N:7][N:8]2[C:21]([OH:22])=[CH:20][C:19]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[N:10][C:9]=12
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: CCc1n[nH]c(N)c1Cc1cccc(Cl)c1Cl
Solvent: O
Solvent: CC(=O)O
Product: CCc1nn2c(O)cc(-c3ccncc3)nc2c1Cc1cccc(Cl)c1Cl
Temperature: 120 °C
Reaction time: 20 h
Yield: 25.6 %

Procedure:
A mixture of 4-(2,3-dichlorobenzyl)-3-ethyl-1H-pyrazol-5-amine (250 mg, 0.93 mmol), ethyl 3-oxo-3-(pyridin-4-yl)propanoate (198 mg, 1.03 mmol) in acetic acid (10 mL) and water (0.5 mL) was stirred at 120° C. for 20 h, cooled and the pH was carefully adjusted to 8. The mixture was extracted with DCM (100 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column (PE:EA=10:1) to give the titled compound (95 mg, 26%); LC/MS: MS (ES+) m/e 399 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.5 Hz, 3H), 2.56 (q, J=7.5 Hz, 2H), 4.07 (s, 2H), 5.97 (s, 1H), 7.16-7.21 (m, 2H), 7.42 (d, 2.1 Hz, 1H), 7.90 (dd, J=1.5, 4.5 Hz, 1H), 8.56 (dd, J=1.5, 4.5 Hz, 1H).
Reaction SMILES: FC(F)(F)[C:3]([N:5](C)[C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[O:23][N:22]=4)[CH:16]=3)[N:14]=2)[N:11]=1)=O.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH3:3][NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4[N:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[O:23][N:22]=4)[CH:16]=3)[N:14]=2)[N:11]=1
Reactant: CN(C(=O)C(F)(F)F)c1ccc2nc(-c3cccc(-c4noc(C(F)(F)F)n4)c3)cn2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CNc1ccc2nc(-c3cccc(-c4noc(C(F)(F)F)n4)c3)cn2n1
Temperature: 60 °C

Procedure:
A mixture of 2,2,2-trifluoro-N-methyl-N-(2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)acetamide(0. 15 mmol) and K2CO3 (0.3 mmol)in 20 mL methanol -water(4:1) was heated at 60° C. for 1 h. The mixture was concentrated in vacuo and the crude product was purified by column chromatography on silica gel to give the N-methyl-2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazin-6-amine.
Reaction SMILES: [C:1]([C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1)#[N:2].[C:18](Cl)(Cl)=[O:19].[NH3:22]>C1(C)C=CC=CC=1.C(O)C>[C:1]([C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:18]([NH2:22])=[O:19])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1)#[N:2]
Reactant: O=C(Cl)Cl
Reactant: N#CC1=Cc2ccccc2Nc2ccccc21
Reactant: N
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#CC1=Cc2ccccc2N(C(N)=O)c2ccccc21

Procedure:
With stirring, 21.8 g (0.1 mole) of 10-cyano-5H-dibenz[b,f]azepine are added to a solution of 19.8 g (0.2 mole) of phosgene in 700 ml of absolute toluene. The mixture is then stirred for 30 hours at 50°-53° C. and subsequently completely concentrated in a rotary evaporator, affording as residue crude 10-cyano-5H-dibenz[b,f]azepine-5-carbonyl chloride with a melting point of 148°-153° C. With stirring, the crude product is dissolved at 70° C. in 600 ml of absolute ethanol. Ammonia gas is then introduced into this solution in the course of 2 hours while constantly keeping the reaction mixture under reflux. The reaction mixture is then concentrated in a rotary evaporator and the residue is washed and dried. Recrystallisation from toluene yields 10-cyano-5H-dibenz[b,f]azepine-5-carboxamide with a melting point of 212°-215° C.
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[C:17]([NH:20][NH2:21])(=[O:19])[CH3:18]>CO.O.Cl.O1CCCC1>[OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=[N:21][NH:20][C:17](=[O:19])[CH3:18])[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6]
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Reactant: CC(=O)NN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(=O)NN=C(C)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (160 mg, 0.70 mmol) was suspended in methanol (3 ml) and water (1 ml). Acetic hydrazide (56 mg, 0.75 mmol, 1.2 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 50° C. for 48 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature and diluted with tetrahydrofuran. The resulting white precipitate was collected and washed with tetrahydrofuran to yield the product, a mixture of approximately 3:1 E:Z isomers, as a white solid: 129 mg (65%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[CH2:35]OS(C)(=O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][N:29]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: CS(=O)(=O)OCc1cnccn1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cnccn4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid pyrazin-2-ylmethyl ester (preparation described in WO 2002064574) gave the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH:14]([CH2:26][OH:27])[CH2:13]1.O>C(Cl)Cl>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH:14]([CH:26]=[O:27])[CH2:13]1
Reactant: CN1CCC(c2ccc(Cl)c(Cl)c2)C(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN1CCC(c2ccc(Cl)c(Cl)c2)C(C=O)C1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 111.3 %

Procedure:
To a solution of oxalyl chloride (3.3 mL, 37.9 mmol) in methylene chloride (100 mL) cooled below −40° C. was added dimethyl sulfoxide (5.6 mL, 79 mmol) in methylene chloride (5 mL). The reaction was stirred for another 30 min at −40° C. and 1-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)piperidine (9.0 g, 33 mmol) in methylene chloride (100 mL) was added over 15 min while keeping the temperature below −40° C. The reaction was stirred for another 30 min at this temperature and then allowed to heat to room temperature. Water (100 mL) was added and the organic phase separated off. The aqueous phase was extracted with methylene chloride (2×100 mL). The combined organic extracts were dried over magnesium sulphate and evaporated to dryness to give 10 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Cl[CH2:55][C:56]([N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1)=[O:57]>O>[N:58]1([C:56](=[O:57])[CH2:55][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: O=C(CCl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCC(=O)N2CCOCC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 86.3 %

Procedure:
In a 15 mL pressure tube, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 100 mg, 162 μmol) and cesium carbonate (63.4 mg, 195 μmol) were combined with dry dimethyl formamide (5 mL). 2-Chloro-1-morpholinoethanone (26.5 mg, 21.1 μL, 162 μmol) was added to the mixture with stirring. The tube was capped and heated at 50° C. After 1.5 h, the reaction mixture was cooled down to room temperature. It was poured into water and extracted with ethyl acetate (2×). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with flash chromatography (24 g pre-packed silica gel column, eluted with ethyl acetate in hexanes) to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-morpholin-4-yl-2-oxo-ethyl ester as an off-white solid (104 mg, 86% yield) as product. LCMS (ES+) m/z calcd. for C37H39Cl2F2N4O6 [(M+H)+]: 743. found: 743.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][N:17]=[C:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[C:19]#[N:20])(=[O:15])=[O:14])=[CH:9][CH:8]=1)(=O)C.Cl.C(OCC)C>O.O1CCCC1>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][N:17]=[C:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[C:19]#[N:20])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CC(=O)Oc1ccc(S(=O)(=O)ON=C(C#N)c2cccs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CC(=NOS(=O)(=O)c1ccc(O)cc1)c1cccs1
Reaction time: 1 h
Yield: 68.9 %

Procedure:
With vigorous stirring, a solution of 12 g of NaOH in 20 ml of water is added to a solution of 27 g (0.08 mole) of α-(4-acetoxybenzenesulfonyloxyimino)thienylacetonitrile (3c) in 125 ml of tetrahydrofuran. After 1 hour, the reaction mixture is acidified with 20% hydrochloric acid and, after the addition of water and diethyl ether, the phases are separated. The aqueous phase is extracted with ether, the combined organic phases are dried over MgSO4, and the solvent is distilled off. The residual crude product is recrystallised from toluene, affording 17 g of beige-coloured crystals which melt at 151°-152° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1CCN.C(OCC)(=O)C>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:12]
Reactant: NCCc1ccccc1Cl
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: S=C(NCCc1ccccc1Cl)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(2-chlorophenyl)ethylamine (0.81 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.67 g (40%) of the titled product as a white solid:
Reaction SMILES: C(O[K])(C)(C)C.[CH3:7][C:8]1[NH:9][CH:10]=[CH:11][N:12]=1.[OH:13][CH:14]([CH2:17][OH:18])[CH2:15]Br.Cl>C(O)(C)(C)C.O1CCCC1>[OH:13][CH:14]([CH2:17][OH:18])[CH2:15][N:9]1[CH:10]=[CH:11][N:12]=[C:8]1[CH3:7]
Reactant: Cc1ncc[nH]1
Reactant: OCC(O)CBr
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: Cc1nccn1CC(O)CO
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
A200 ml flask was charged with 2.0 g of t-butoxypotassium, 70 ml of tetrahydrofuran, 1.23 g of 2-methylimidazole. After stirring for 30 minutes, a solution of 2.5 g of 2,3-dihydroxyl-n-propyl bromide in 5 ml of t-butanol was added. After refluxing for one hour, 5 ml of 1 N HCl solution was added and the mixture was allowed to stand over night. The solvent was evaporated under reduced pressure. The residue was extracted with dichloromethane, washed with saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous magnesium sulfate. After removing anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (development solvent: methyl acetate/methanol=90/10) to obtain 1.9 g of 1-(2′,3′-dihydroxylpropyl)-2-methylimidazole (compound (A-1)). 1H-NMR spectrum of the resulting compound is shown in FIG. 1.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:12]=2[C:13]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O>C1COCC1.CO.[OH-].[Na+]>[C:1]1([S:7]([NH:10][C:11]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:12]=2[C:13]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccccc2)cc1
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of methyl 4-(2-phenylsulfonylamino-5-chlorobenzoyl-amino)benzoate (122 mg; prepared in Example 1.) in THF-MeOH (4 ml+2 ml), 2N NaOH aqueous solution (0.5 ml) was added at room temperature. The mixture was stirred overnight. To the reaction mixture, 2N HCl (0.6 ml) and water were added. The mixture was extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under reduced pressure. The residue was purified by recrystallization from the mixture of AcOEt-hexane to give the title compound (80 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]3[NH:22][C:21](=[O:23])[N:20]=[CH:19][CH:18]=3)=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].Cl.Cl[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][N:20]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[C:21](=[O:23])[N:22]=3)=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:24]([F:25])([F:26])[F:27]
Reactant: ClCc1cccnc1
Reactant: O=c1nccc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cn2)[nH]1
Agent: Cl
Product: O=c1nc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cn2)ccn1Cc1cccnc1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 6-{[(5-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-2-pyridinyl)methyl]oxy}-2(1H)-pyrimidinone and 3-(chloromethyl)pyridine hydrochloride. LC-MS (ESI): m/z 489 [M+H]+; 2.67 min (ret time).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1[CH:11]=[N:12][C@@:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])([Cl:17])[NH:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:17].[CH3:9][C:10]1[C:11]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])=[N:12][C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@H:19]2[CH3:28])=[N:14][C:15]=1[CH3:16]
Reactant: CNc1ccccc1
Reactant: CC1=C(C)N[C@@](Cl)(N2CCc3ccccc3C2C)N=C1
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3ccccc3[C@H]2C)nc(N(C)c2ccccc2)c1C
Product: Cl
Yield: 52.8 %

Procedure:
After N-methylaniline(0.6 ml, 5 mmol) was added to a mixture solution of (R)-5,6-dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(0.7 g, 2.4 mmol) prepared in the Step 2 of Example 61 and dimethylformamide(10 ml), 0.50 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24](Cl)=[C:23]([Cl:30])[N:22]=1)COCC[Si](C)(C)C)(=[O:11])=[O:10].[OH:31][CH2:32][C@@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1C(OC(C)(C)C)=O.[H-].[Na+].Cl>CN1CCCC1=O>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24]([O:31][CH2:32][C@H:33]2[CH2:37][CH2:36][CH2:35][NH:34]2)=[C:23]([Cl:30])[N:22]=1)(=[O:10])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: COc1nc(Cl)c(Cl)nc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1nc(OC[C@H]2CCCN2)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl
Yield: 145.9 %

Procedure:
Procedure as for Example 115 using 2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulphonamide (Example 66a) (0.29 g), tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.15 g) and sodium hydride (0.04 g of a 60% dispersion in oil) in N-methylpyrrolidinone (20 mL). The adduct was deprotected with HCl (4M in dioxane) to afford the titled adduct (0.2 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7](F)=[CH:8][CH:9]=1.C([N:30]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31]1)(OC(C)(C)C)=O.[H-].[Na+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([O:35][CH:32]2[CH2:33][CH2:34][NH:30][CH2:31]2)=[CH:8][CH:9]=1
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(OC3CCNC3)ccc21
Yield: 13.7 %

Procedure:
In a similar fashion using route 51 general procedure 119, 12-chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (0.2 g, 0.6 mmol), 1-boc-3-pyrrolidinol (0.45 g, 2.3 mmol), NaH (60% in mineral oil; 57 mg, 2.3 mmol) and NMP (2 ml) gave the title compound (33 mg, 14%) after purification by preparative HPLC (acidic conditions 2). Boc deprotection occurred in situ during heating.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1([O:18][C:19](=O)[NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=3)[CH:24]=[CH:23][CH:22]=2)C=CC=CC=1>CS(C)=O>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([NH:11][C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Nc1cccc2ccc(O)cc12)Oc1ccccc1
Reactant: CC(C)(C)C1CCC(N)CC1
Solvent: CS(C)=O
Product: CC(C)(C)C1CCC(NC(=O)Nc2cccc3ccc(O)cc23)CC1

Procedure:
4-tert-Butyl-cyclohexylamine (69 mg, 0.44 mmol) and (7-hydroxy-naphthalen-1-yl)-carbamic acid phenyl ester (125 mg, 0.44 mmol) were combined and stirred at ambient temperature in DMSO (3 mL) overnight. The product was purified by directly injecting the crude reaction onto a reverse phase prep-HPLC (90–10% water:acetonitrile gradient). The appropriate fractions were lyophilized to yield 1-(4-tert-Butyl-cyclohexyl)-3-(7-hydroxy-naphthalen-1-yl)-urea
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:24]([Si:28](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:27])([CH3:26])[CH3:25].O>CN(C=O)C>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OC1CN(C(c2ccccc2)c2ccccc2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 1-Benzhydrylazetan-3-ol (2.0 g, 8.4 mmol) in DMF (20 ml) at 0° C. is treated with imidazole (0.57 g, 8.4 mmol) and t-butylchlorodiphenyl silane (2.31 g, 8.4 mmol). The reaction mixture is allowed to warm up to room temperature and stirred overnight. The mixture is poured into water (250 ml) and extracted with EtOAc (3×100 ml). The combined organic extracts are washed with water (2×100 ml), brine (100 ml) and dried over MgSO4. The solvent is removed in vacuo to yield the titled compound.