Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C@@H:9]([C:12]2[O:13][CH:14]=[N:15][N:16]=2)[CH2:10][CH3:11])[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:29][C:28]=1[NH2:37].CCN(C(C)C)C(C)C>CC(C)CC(O)C>[O:13]1[CH:14]=[N:15][N:16]=[C:12]1[C@H:9]([N:8]([CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:6]1[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][N:3]=[C:2]([NH:37][C:28]2[CH:29]=[CH:30][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:32][C:27]=2[O:26][CH3:25])[N:7]=1)[CH2:10][CH3:11]
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: CC[C@H](c1nnco1)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Solvent: CC(C)CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](c1nnco1)N(c1nc(Nc2ccc(C(=O)OC)cc2OC)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 140 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
2-chloro-N-cyclopentyl-5-nitro-N-[(1R)-1-(1,3,4-oxadiazol-2-yl)propyl]pyrimidin-4-amine (61.5 mg, 0.1743 mmol) and methyl 4-amino-3-methoxy benzoate (37.9 mg, 0.2092 mmol) in 4-methylpentan-2-ol (600 L) were treated with DIPEA (33.8 mg, 45.6 mL, 0.2614 mmol) and the reaction mixture stirred at 140° C. for 4 hours. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography (50% EtOAc/Petrol) to give the sub-title compound as a brown oil (42 mg, 48%); 1H NMR (400.0 MHz, DMSO) d 0.75-0.89 (3H, m), 1.15-1.75 (8H, m), 2.24-2.34 (1H, m), 2.40-2.51 (1H, m), 2.61-2.72 (1H, m), 3.55-3.63 (1H, m), 3.84 (3H, s), 3.89 (3H, s), 7.44 (1H, s), 7.55-7.65 (2H, m), 7.75-8.03 (1H, br s), 8.12 (1H, s), 8.77 (1H, s); MS ES(+) 498.1.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:9]1[CH:16]=[CH:15][C:12]([NH:13][CH3:14])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[CH2:20][C:21]([N:23]=[C:24]=[S:25])=[O:22].C(=O)(O)[O-].[Na+]>C(COC)OC>[F:1][C:2]([F:17])([F:18])[C:3]([C:9]1[CH:16]=[CH:15][C:12]([N:13]([C:24]2[S:25][CH2:20][C:21](=[O:22])[N:23]=2)[CH3:14])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:6])([F:5])[F:7]
Reactant: O=C(CCl)N=C=S
Reactant: CNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CN(C1=NC(=O)CS1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To p-(hexafluoro-2-hydroxy-2-propyl)-N-methylaniline (2.73 gm., 0.01 mole) in dimethoxyethane (40 ml), add chloroacetyl isothiocyanate (1.50 gm., 0.011 mole) and stir 1 hr. Pour the reaction mixture onto water and neutralize with sodium bicarbonate. Extract with ether, dry and concentrate. Recrystallize from ether to obtain the product, m.p. 240°-242° C.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=[N:16][OH:17])[CH2:10][C:9]2([CH3:19])[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH:20]=[N+:16]([CH:11]2[CH2:12][C:13]([CH3:14])([CH3:15])[N:8]([O:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:9]([CH3:19])([CH3:18])[CH2:10]2)[O-:17])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: CC1(C)CC(=NO)CC(C)(C)N1OC1CCCCC1
Product: CC1(C)CC([N+]([O-])=Cc2ccccc2)CC(C)(C)N1OC1CCCCC1

Procedure:
Following the general procedure of Example 1, the title compound is prepared from 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-one oxime (2.7 g, 10 mmol) and 1.1 g (10 mmol) of benzaldehyde in a yield of 2.0 g (56%) as a white solid after flash chromatography on silica gel (8:1, heptane:ethyl acetate) which solid melts at 149°-151° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([Br:9])[C:5]([Br:10])=[C:4]([Br:11])[C:3]=1[Br:12].[N:13]1[C:20](Cl)=[N:19][C:17](Cl)=[N:16][C:14]=1Cl>>[Br:1][C:2]1[C:7]([O:8][C:14]2[N:16]=[C:17]([O:8][C:7]3[C:2]([Br:1])=[C:3]([Br:12])[C:4]([Br:11])=[C:5]([Br:10])[C:6]=3[Br:9])[N:19]=[C:20]([O:8][C:7]3[C:6]([Br:9])=[C:5]([Br:10])[C:4]([Br:11])=[C:3]([Br:12])[C:2]=3[Br:1])[N:13]=2)=[C:6]([Br:9])[C:5]([Br:10])=[C:4]([Br:11])[C:3]=1[Br:12]
Reactant: Oc1c(Br)c(Br)c(Br)c(Br)c1Br
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: Brc1c(Br)c(Br)c(Oc2nc(Oc3c(Br)c(Br)c(Br)c(Br)c3Br)nc(Oc3c(Br)c(Br)c(Br)c(Br)c3Br)n2)c(Br)c1Br

Procedure:
Tris-(pentabromophenoxy)-s-triazine was prepared from pentabromophenol and cyanuric chloride using the process described in Example 1, above. The compound was found to have a melting point of 320°-325°C.
Reaction SMILES: C([O:9][C:10]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:11][C:12]1[N:16](C(=O)C2C=CC=CC=2)[C:15]2[CH2:25][CH2:26][CH2:27][CH2:28][C:14]=2[N:13]=1)(=O)C1C=CC=CC=1.O.[ClH:36]>>[ClH:36].[C:29]1([C:10](=[O:9])[CH2:11][C:12]2[NH:16][C:15]3[CH2:25][CH2:26][CH2:27][CH2:28][C:14]=3[N:13]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(OC(=Cc1nc2c(n1C(=O)c1ccccc1)CCCC2)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Product: O=C(Cc1nc2c([nH]1)CCCC2)c1ccccc1
Yield: 65 %

Procedure:
16.23 g (36.18 mmol) crude compound of Example VIII are refluxed 1.5 h in 300 ml concentrated hydrochloric acid. The mixture is cooled to rT and 200 mL water are added. The solution is extracted twice with toluene and the aqueous phase is concentrated under vacuum. The residue is stirred with ethanol, filtered, washed once with ethyl acetate and once with petrol ether and dried. The filtrate is concentrated and stirred with ethanol, the solid is filtered, washed with petrol ether and dried to yield a total of 6.55 g (65% of th.) 1-phenyl-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:19](N(OC)C)=[O:20])=[C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]1([Mg]Cl)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+]>C1COCC1>[C:19]([C:11]1[S:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:13][C:12]=1[C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)(=[O:20])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
Compound 134 (10.7 g, 30.3 mmol) was dissolved in THF (240 ml), and a THF solution of 2.0 mol/L phenylmagnesium chloride (60.6 mL, 121 mmol) was added thereto at 0° C. in an atmosphere of argon, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=3:1) to afford the entitled Compound 135 (6.18 g, 55%).
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH:30]=O)=[O:25]>>[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)=[O:25]
Reactant: CCCNC1CCc2ncsc2C1
Reactant: O=CCCCNC(=O)NC1Cc2ccccc2C1
Product: CCCN(CCCCNC(=O)NC1Cc2ccccc2C1)C1CCc2ncsc2C1
Yield: 11 %

Procedure:
Compound 60 is prepared from 1C and 60C as described for 1. The salt of maleic acid is crystallized from acetonitrile/diethylether.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][C:9](=[O:11])[O:8][C:6]1=[O:7])(=[O:3])[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16]>C1(C)C(C)=CC=CC=1>[Cl:12][C:13]1[CH:14]=[C:15]([N:16]=[C:6]([OH:7])[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:10][C:9]([OH:8])=[O:11])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)OC1CC(=O)OC1=O
Solvent: Cc1ccccc1C
Product: CC(=O)OC(CC(=O)O)C(O)=Nc1cc(Cl)cc(Cl)c1

Procedure:
158 g (1 mole) of 2-acetoxysuccinic acid anhydride and 162 g (1 mole) of 3,5-dichloroaniline are heated under reflux for three hours, in 1 liter of xylene. The resulting water is azeotropically separated off by means of a water separator. The xylene is then distilled off and the crude product is recrystallized from ethyl acetate. The yield of end product is 70.3% of the theoretical yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:39])=[C:4]([CH:36]=[CH:37][CH:38]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:34][CH3:35])=[C:13]([O:16][C@@H:17]3[CH2:21][N:20]([C:22](OC(C)(C)C)=O)[C@H:19]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C=O>C(O)=O>[Cl:1][C:2]1[C:3]([F:39])=[C:4]([CH:36]=[CH:37][CH:38]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:34][CH3:35])=[C:13]([O:16][C@@H:17]3[CH2:21][N:20]([CH3:22])[C@H:19]([C:29](=[O:33])[N:30]([CH3:31])[CH3:32])[CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1C[C@@H](C(=O)N(C)C)N(C(=O)OC(C)(C)C)C1
Agent: C=O
Solvent: O=CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1C[C@@H](C(=O)N(C)C)N(C)C1
Yield: 72.2 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-[(2S,4S)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline (prepared as described in Example 24; 0.18 g), formic acid (0.31 ml) and formaldehyde (0.51 ml) were heated at 85° C. for 6 hours. The reaction mixture was cooled and evaporated under vacuum. The resulting residue was partitioned between methylene chloride/n-propanol and saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, adsorbed onto silica and purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the desired product were combined and evaporated under vacuum to yield a white crystalline solid. The solid was washed with water, dissolved in methylene chloride and dried over magnesium sulfate. The solvent was removed under vacuum to give the title product (0.11 g); 1H NMR Spectrum: (DMSO d6) 1.87 (t, 1H), 2.24 (s, 3H), 2.61-2.68 (m, 1H), 2.83 (s, 3H), 2.85-2.94 (m, 1H), 3.10 (s, 3H), 3.22-3.31 (m, 2H), 3.92 (s, 3H), 5.04 (m, 1H), 7.22 (s, 1H), 7.29 (t, 1H), 7.45-7.56 (m, 2H), 7.64 (s, 1H), 8.35 (s, 1H), 9.56 (s, 1H); Mass Spectrum: (M+H)+ 474.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=O)[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1ncc2c(n1)N1CCOCC1CN2
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
2-Chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x1, 17.3 g, 71.9 mmol) was dissolved in THF (250 mL). To the resulting suspension was added lithium aluminum hydride in THF (2.0 M, 46.7 mL, 93 mmol) dropwise through an addition funnel at 0° C. to give a clear light-brown solution. The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. Ethyl acetate (˜25 mL) was added at 0° C. in portions; a saturated aqueous solution of NH4Cl (125 mL) was then added dropwise until bubbling ceased. The upper organic layer was decanted, concentrated in vacuo and then partitioned between brine and ethyl acetate. The murky bottom layer was then extracted with ethyl acetate (3×) and the combined organic layers were dried over MgSO4, filtered, and concentrated. The product was triturated with ether/ethyl acetate and collected by filtration under nitrogen to give the title compound (9.6 g, 59%). 1H NMR (DMSO-d6) δ 2.88-2.94 (m, 2 H), 3.12 (t, 1 H), 3.26-3.28 (m, 1 H), 3.42-3.51 (m, 2 H), 3.86-3.92 (m, 2 H), 4.19-4.21 (d, J=8.0 Hz, 1 H), 5.96 (br s, 1 H), 7.36 (s, 1 H). ESI-MS m/z [M+H]+ calc'd for C9H9ClN4O2, 241.04; found 241.1.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[CH:10][CH:11]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1ccc(CCCCOC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(CCCCO)cc1
Temperature: 55 °C

Procedure:
To a solution of 19.3 g (0.077 mole) of acetic acid, 4-[4-(acetylamino)phenyl]butyl ester in 300 ml of ethanol, add a solution of 21 g potassium carbonate in 300 ml of water. Heat the resulting solution at 55° C. for 4 hrs. following the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile: ammonium hydroxide, 90:10). At the completion of the reaction, filter off any insolubles and remove the ethanol in vacuo. Extract the aqueous residue with 3×300 ml methylene chloride Wash the combined organic layers with 100 ml water, dry over potassium carbonate, filter and remove the solvent in vacuo. Recrystallize the resulting solid from 140 ml acetonitrile to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[O:19][CH2:20][C@@H:21]([CH:23](O)[CH3:24])[N:22]=1)=[CH:5]2.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[O:19][CH2:20][C@H:21]([CH2:23][CH2:24][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:22]=1)=[CH:5]2
Reactant: Cc1cc(NC2CCOCC2)c2[nH]c(C3=N[C@H](C(C)O)CO3)cc2c1
Reactant: C1COCCN1
Product: Cc1cc(NC2CCOCC2)c2[nH]c(C3=N[C@@H](CCN4CCOCC4)CO3)cc2c1

Procedure:
The compound obtained in Example 104 and morpholine were reacted according to the procedures as Preparation 33 and Example 15 in the order to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][NH:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([N+:13]([O-])=O)=[C:7]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:6]=1.[H][H]>[Pd]>[NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][NH:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([NH2:13])=[C:7]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[N:6]=1
Reactant: [H][H]
Reactant: Cn1c(NC[C@@H](N)Cc2ccccc2)nc(-c2ccncc2)c([N+](=O)[O-])c1=O
Agent: [Pd]
Product: Cn1c(NC[C@@H](N)Cc2ccccc2)nc(-c2ccncc2)c(N)c1=O

Procedure:
A suspension of 2-(2 (S)-amino-3-phenyl-propylamino)-3-methyl-5-nitro-6-pyridin-4-yl-3H-pyrimidin-4-one (0.2 mmol) and Pd/C was stirred over a hydrogen filled balloon for 1 h at room temperature. The product was filtered through a bed of celite, and the solvents removed under vacuum. The product was purified on reverse phase HPLC M+1=351.
Reaction SMILES: CC1(C)[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][N:17]4[C:21]5[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][OH:29])=[CH:25][C:20]=5[N:19]=[CH:18]4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:30][CH2:31][CH2:32][CH2:33][C@H:4]2[O:3]1.C(N(CC)CC)C>C(Cl)Cl.Cl>[OH:29][CH2:28][CH2:27][O:26][C:24]1[CH:23]=[CH:22][C:21]2[N:17]([CH2:16][C:14]3[CH:13]=[CH:12][C:10]4[N:11]=[C:7]([NH:6][C@@H:5]5[CH2:30][CH2:31][CH2:32][CH2:33][C@H:4]5[OH:3])[S:8][C:9]=4[CH:15]=3)[CH:18]=[N:19][C:20]=2[CH:25]=1
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cc(OCCO)ccc43)cc2s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCOc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
To a stirred mixture of 2-((1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)oxy)ethanol (70 mg, 0.15 mmol) from the previous step in DCM (5 mL) at 0° C. was added methanolic HCl (3 drops). The reaction mixture was stirred at 0° C. for 10 min. The mixture was adjusted to pH˜7 by the addition of triethylamine and concentrated under reduced pressure. The residue was purified directly by reverse-phase preparative HPLC to afford ((1R,2R)-2-((6-((5-(2-hydroxyethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (30 mg, 47%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.95 (d, J=7.2 Hz, 1H), 7.62 (s, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.16-7.18 (m, 2H), 6.84 (m, 1H), 5.41 (s, 2H), 4.83 (br s, 1H), 4.72 (d, J=4.5 Hz, 1H), 3.98 (t, J=9.6 Hz, 2H), 3.71 (d, J=4.5 Hz, 2H), 3.52 (m, 1H), 3.33 (br s, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.61-1.63 (m, 2H), 1.22-1.28 (m, 4H); LCMS (ESI) m/z 439 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([Cl:24])[CH:3]=1.[S:25]1(=[O:31])(=[O:30])[CH2:29][CH2:28][CH2:27][NH:26]1>>[Cl:24][C:4]1[CH:3]=[C:2]([N:26]2[CH2:27][CH2:28][CH2:29][S:25]2(=[O:31])=[O:30])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3Cl)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3Cl)CC2)c(C)c1
Yield: 13.2 %

Procedure:
Using (4-bromo-2-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (408 mg) described in Preparation Example 119 and isothiazolidine 1,1-dioxide (121 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (59 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:35][Zn]C.C1(C)C=CC=CC=1>>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:35])[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:33]=[CH:32][O:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: C[Zn]C
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (100 mg, 0.192 mmol) and dimethyl zinc in toluene (0.192 mL, 0.383 mmol), the title compound was obtained as a solid (50 mg, 49% yield). MS (ESI): 502 [M+H]+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[S:19][CH:20]=[CH:21][N:22]=1>>[O:3]=[C:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH:9]1[C:18]1[S:19][CH:20]=[CH:21][N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1nccs1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(=O)C(c2nccs2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
Add sodium hydride (3.61 g, 90.3 mmol) to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (12.0 g, 60.2 mmol) and stir for one hour at ambient temperature. Add 2-chlorothiazole (7.92 g, 66.3 mmol) and stir one additional hour at ambient temperature. Heat to reflux and stir for 14 hours at reflux. Cool mixture to ambient temperature and quench with sufficient HCl (2N) to adjust the pH of the mixture to less than 5. Extract the mixture three times with EtOAc; combine the organic extracts; sequentially wash with water then brine; dry over magnesium sulphate; filter; collect the filtrate; and then concentrate under vacuum at 40° C. Purify the crude material by silica gel flash column chromatography eluting with 10% EtOAc in hexane to give the title compound as a white solid (4.0 g, 23.5%). 1HNMR (d6-DMSO) δ 1.3 (s, 9H), 2.3-2.5 (m, 2H), 3.5 (t, J=6.1 Hz, 2H), 4.1-4.3 (m, 3H), 7.5 (s, 1H), 7.7 (s, 1H).
Reaction SMILES: COC1C=C(OC)C=CC=1[CH2:5][N:6](C)[C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][O:12][C:13]2=[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][OH:26])[C:17]2=[O:27])=[CH:9][CH:8]=1>C1COCC1.Cl>[OH:26][CH2:25][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](=[C:13]2[C:14]3[C:10](=[CH:9][CH:8]=[C:7]([NH:6][CH3:5])[CH:15]=3)[CH2:11][O:12]2)[C:17]1=[O:27]
Reactant: COc1ccc(CN(C)c2ccc3c(c2)C(=C2C(=O)N(CO)c4ccccc42)OC3)c(OC)c1
Agent: Cl
Solvent: C1CCOC1
Product: CNc1ccc2c(c1)C(=C1C(=O)N(CO)c3ccccc31)OC2
Temperature: 50 °C
Yield: 6.2 %

Procedure:
A solution of 3-{6-[(2,4-dimethoxy-benzyl)-methyl-amino]-3H-isobenzofuran-1-ylidene}-1-hydroxymethyl-1,3-dihydro-indol-2-one (600 mg, 1.31 mmol) in a mixture of THF (20 ml) and 2M HCl aqueous solution (20 ml) was heated at 50° C. for 16 hours. The mixture was concentrated, and then partitioned between CHCl3 (200 ml) and saturated NaHCO3 solution (200 ml). The aqueous layer was extracted with CHCl3 (2×100 ml). The combined organic layers were washed with water (100 ml), dried over anhydrous Na2SO4, and evaporated to give a dark brown oil as a crude product. Purification of the crude product by silica gel column chromatography, eluted with a gradient of MeOH in EtOAc, yielded 1-hydroxymethyl-3-(6-methylamino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one as a yellow solid (25 mg, 6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12](=[O:14])[CH3:13]>CO.C(Cl)(Cl)Cl>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])cc1C(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(N)cc1C(C)=O

Procedure:
The above-identified compound (2.13 g) was obtained by processing Intermediate 72 (2.50 g) through reaction and after-treatment in accordance with the procedures of the step C of Example 63. Rf=0.38 (methanol/chloroform of 1/19).