Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5]=[C:6](O)[C:7]2[S:13][CH2:12][CH2:11][CH2:10][C:8]=2[N:9]=1)#[N:2].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:6]1[C:7]2[S:13][CH2:12][CH2:11][CH2:10][C:8]=2[N:9]=[C:4]([CH2:3][C:1]#[N:2])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#CCc1nc(O)c2c(n1)CCCS2
Product: N#CCc1nc(Cl)c2c(n1)CCCS2

Procedure:
The title compound was prepared following substantially the same procedure described in Example 1, Step B using the product from Step A and phosphorus oxychloride. This procedure gave 1.2 g of product as a brown granular solid which was used in the next step.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][C:35](=[O:38])[NH:36][CH3:37])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:66])(=O)=O)CCCCCCCCCCCCCCC>>[I:66][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][C:35](=[O:38])[NH:36][CH3:37])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)OC(=O)NC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)OC(=O)NC

Procedure:
3-(3-Chloropropylsulfonylamino)-2-methylcarbamoyloxy-1-octadecylcarbamoyloxypropane IIIc2 is allowed to react and worked up by the same procedure as described in (5). m.p. 97°-99° C. The summary of the experimental condition and the physical data of the prodcut are listed in the Table 8.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([CH2:13][C:14]([F:17])([F:16])[F:15])[N:10]=[C:9]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:25]3[C@H:33]([C:34]([F:37])([F:36])[F:35])[CH2:32][C:31](=[O:38])[NH:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:20][CH2:19]1)(=O)=O.CN(C)C=O.[NH:44]1[CH2:47][CH2:46][CH2:45]1>C(OCC)(=O)C>[N:44]1([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([CH2:13][C:14]([F:17])([F:16])[F:15])[N:10]=[C:9]2[CH:18]2[CH2:19][CH2:20][N:21]([C:24]3[C:25]4[C@H:33]([C:34]([F:36])([F:35])[F:37])[CH2:32][C:31](=[O:38])[NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:22][CH2:23]2)[CH2:47][CH2:46][CH2:45]1
Reactant: C1CNC1
Reactant: CS(=O)(=O)OCCn1cc(CC(F)(F)F)nc1C1CCN(c2ncnc3c2[C@H](C(F)(F)F)CC(=O)N3)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1C[C@@H](C(F)(F)F)c2c(ncnc2N2CCC(c3nc(CC(F)(F)F)cn3CCN3CCC3)CC2)N1
Temperature: 50 °C

Procedure:
Combine (R)-2-(2-(1-(7-oxo-5-trifluoromethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-1-yl)ethyl methanesulfonate (1.04 g, 1.82 mmol), dimethylformamide (9.3 mL), and azetidine (1.11 mL, 9.0 eq) under nitrogen. Heat the reaction mixture at 50° C. overnight, then allow to cool to room temperature. Dilute with ethyl acetate. Wash the organic layer with water. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with 10% methanol/dichloromethane to 10% 2 M ammonia in methanol/dichloromethane, to give the title compound, (R)-4-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one, as a white solid (0.49 g, 51%). MS (ES) m/z=532 [M]+.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=O)[CH:17]=[CH:16]3)=[CH:9][CH:8]=1.N>>[Br:3][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=3)[CH:14]=2)[N:19]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1ccc2cc(-c3ccc(Cl)cc3)ccc2[nH]1
Agent: N
Product: Clc1ccc(-c2ccc3nc(Br)ccc3c2)cc1
Temperature: 110 °C

Procedure:
50 g (0.174 mol) phosphorus oxybromide are heated to 65° C., combined with 10 g (0.039 mol) 6-(4-chloro-phenyl)-1H-quinolin-2-one and heated to 110° C. for 3 h. The reaction mixture is then poured onto ice water and made alkaline with ammonia solution. The precipitate is filtered off and dried in the drying cupboard at 60° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15].[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([O:16][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])=[O:15]
Reactant: Cc1cc(C(C)(C)C)c(O)cc1CC(=O)O
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)Cc1cc(O)c(C(C)(C)C)cc1C
Yield: 95 %

Procedure:
Into a 300-ml four-necked flask, were charged 22.2 g of 2-methyl-4-t-butyl-5-hydroxyphenylacetic acid, 150 ml of toluene, 27.0 g of octadecyl alcohol and 1 g of p-toluenesulfonic acid. The mixture was heated under reflux for about one hour while removing the liberated water from the reaction system. After completion of the reaction, the reaction mixture was freed from the catalyst by washing with water and from the solvent by distillation under reduced pressure to obtain 45.0 g (95% yield) of pale yellow octadecyl 2-methyl-4-t-butyl-5-hydroxyphenylacetate which was recrystallized from methanol to yield white crystals melting at 53.0°-54.5° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:12]([NH2:17])[CH:13]=[N:14]2)=[CH:9][CH:8]=1>ClCCl>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:18][CH2:19][CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[C:12]([NH:17][C:3](=[O:4])[CH2:2][Cl:1])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: Nc1cnc2cc(Br)ccc2c1NCC1CCOCC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: O=C(CCl)Nc1cnc2cc(Br)ccc2c1NCC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
Chloroacetyl chloride (5.2 mL, 65 mmol) was added to 7-bromo-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (55 mmol) dissolved in 273 mL of dichloromethane at 0° C. A solid formed after adding half of the chloroacetyl chloride at which point additional dichloromethane (100 mL) was added. The reaction was stirred for 1 hour at ambient temperature. The yellow suspension was quenched first with aqueous saturated sodium bicarbonate followed by 50% aqueous sodium hydroxide until a pH of 14 was reached. Filtration provided 10 g of N-{7-bromo-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]quinolin-3-yl}-2-chloroacetamide as a tan solid. The filtrate was placed in a separatory funnel and the layers were separated. The aqueous layer was extracted with additional dichloromethane. The combined organic extracts were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford additional N-{7-bromo-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]quinolin-3-yl}-2-chloroacetamide as a yellow oil. The yellow oil was carried forward without further purification assuming a 50% yield (27.3 mmol). The oil was combined with ethanol (100 mL) and triethylamine (7.5 mL, 54 mmol). The resulting yellow solution was refluxed for 2 hours. The reaction was cooled to ambient temperature and the solvent was removed under reduced pressure to provide 7-bromo-2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline as a brown oil that was used without further purification assuming quantitative yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[CH3:10][C:11]1(C)[O:18]C(=O)[CH2:15][C:13](=O)[O:12]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:9]=[C:7]([CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH2:10][C:11]([O:12][CH2:13][CH3:15])=[O:18]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)Cc1ccsc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Cc1ccsc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
A stirred solution of 711 mg (5.0 mmol) of 3-thienylacetic acid, 720 mg (5.0 mmol) of Meldrum's acid, and 610 mg (5.0 mmol) of 4-dimethylaminopyridine in 10 mL of DCM was treated with a solution of 1.03 g (5.0 mmol) of DCC in 10 mL of DCM. The resulting solution was stirred at room temperature for 16 h, during which time a white precipitate appeared in the reaction mixture. The reaction mixture was filtered through a pad of Celite to remove the precipitated dicyclohexylurea and the filtrate was washed successively with 1 N HCl (1×15 mL), H2O (1×15 mL), brine (1×15 mL). The filtrate was dried (MgSO4) and solvents were removed in vacuo. The resulting crude oil was dissolved in 8 mL of absolute ethanol and heated to 80° C. for 4 h. The reaction mixture was cooled to room temperature and ethanol was removed in vacuo. Purification of the resulting oil by silica gel flash column chromatography eluting with hexanes/EtOAc 2:1 afforded 1.02 g (97%) of the title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 7.27 (m, 1H), 7.06 (s, 1H), 6.92 (m, 1H), 4.09 (q, 2H, J=6.8), 3.83 (s, 2H), 3.41 (s, 2H), 1.22 (t, 3H, J=6.8).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:12][CH:11]=1>C(O)CCC>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:1][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: C=Cc1ccccn1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Solvent: CCCCO
Product: Fc1ccc(Cn2c(NC3CCN(CCc4ccccn4)CC3)nc3ccccc32)cc1
Yield: 23 %

Procedure:
A mixture of 2.1 parts of 2-(ethenyl)pyridine, 3.25 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine and 80 parts of 1-butanol is stirred and refluxed overnight. The reaction mixture is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 1 part (23%) of 1-[(4-fluorophenyl)methyl]-N-{1-[2-(2-pyridinyl)ethyl]-4-piperidinyl}-1H-benzimidazol-2-amine; mp. 133.4° C.
Reaction SMILES: Cl.[S:2]1[C:6]([NH2:7])=[N:5][CH:4]=[N:3]1.[O:8]=[C:9]1[CH2:14][N:13]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11][N:10]1[C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[O:8]=[C:9]1[CH2:14][N:13]([C:15](=[O:20])[C:16]([F:18])([F:17])[F:19])[CH2:12][CH2:11][N:10]1[C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:7][C:6]2[S:2][N:3]=[CH:4][N:5]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: Nc1ncns1
Reactant: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Nc2ncns2)cc1
Yield: 48 %

Procedure:
Synthesized according to general procedure 12, method A. The reaction was set up with 1,2,4-Thiadiazol-5-ylamine hydrochloride (0.56 g, 4.0 mmol), anhydrous pyridine (3.5 mL), and 4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzene-1-sulfonyl chloride (1.5 g, 4.0 mmol). The dark oil was purified via silica gel chromatography using 5% MeOH in CH2Cl2 followed by a second purification on silica gel using 80% EtOAc in hexanes to obtain the desired sulfonamide as a white solid (0.73 g, 1.92 mmol, 48% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=436.1; tR=2.27 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: ClCc1ccccn1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Agent: Cl
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2ccccn2)c1Cl

Procedure:
Synthesized as described in Example 39 from 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile and 2-(chloromethyl)pyridine hydrochloride. MS (ESI) m/z 318.07 (M+1).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[C:6]([N:8]([C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[O:7].[NH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32].[OH-].[K+]>C(O)C>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[C:6]([N:8]([C:15]([CH3:21])([CH3:22])[CH2:16][C:17]([CH3:20])([CH3:18])[CH3:19])[CH2:9][CH2:10][CH2:11][C:12]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:13])=[O:7]
Reactant: CCOC(=O)CCN
Reactant: CC(C)(C)CC(C)(C)N(CCCC(=O)O)C(=O)c1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)CC(C)(C)N(CCCC(=O)NCCC(=O)O)C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(m-trifluoromethylbenzoyl)-4-[(1,1,3,3-tetramethylbutyl)amino]butyric acid and ethyl 3-aminopropionate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(m-trifluoromethylbenzoyl)-4-(1,1,3,3-tetramethylbutylamino)butyryl]-3-aminopropionic acid.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[CH:26]1[C:35]2[C:30](=[C:31]([NH:36][NH2:37])[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1>>[CH:26]1[C:35]2[C:30](=[C:31]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:16][CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:37]3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc2cnccc12
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc2cnccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and isoquinolin-5-yl-hydrazine according to the method described for example 91. MS: M=450.1 (M+H)+
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[C:15](Cl)(=[O:19])/[CH:16]=[CH:17]/[CH3:18]>>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:19])[CH:16]=[CH:17][CH3:18])=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: C/C=C/C(=O)Cl
Reactant: CC(=O)NCCCCc1ccccc1
Product: CC=CC(=O)c1ccc(CCCCNC(C)=O)cc1

Procedure:
By treating [4-(acetylamino)butyl]benzene and crotonoyl chloride in the same manner as in Example 79-(1), 4-[4-(acetylamino)butyl]-1-(2-butenoyl)benzene was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][S:12]2(=[O:17])=[O:16])[CH:3]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]2[CH2:30][CH2:31][N:26]([C:20]3[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=3[CH3:18])[CH2:27][CH2:28]2)=[O:8])=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][S:12]2(=[O:17])=[O:16])[CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)cc1N1CCCS1(=O)=O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 101.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)benzoic acid (661 mg) described in Preparation Example 178 and 1-(2,4-dimethylphenyl)piperazine (431 mg), the title compound (1.03 g) was obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]#[CH:17])=[CH:14][C:13]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]#[CH:17])=[CH:14][C:13]([C:18]3[CH:23]=[N:22][C:21]([N:24]4[CH2:25][CH2:26][C:27]([CH3:35])([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]4)=[N:20][CH:19]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: C#Cc1cc(-c2cnc(N3CCC(C)(C(=O)OCC)CC3)nc2)cc2nc(NC(=O)NCC)sc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C#Cc1cc(-c2cnc(N3CCC(C)(C(=O)O)CC3)nc2)cc2nc(NC(=O)NCC)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To an ice-cold solution of ethyl 1-[5-[2-(ethylcarbamoylamino)-7-ethynyl-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (1.1 g, 2.23 mmol) in DMSO (10 mL) was added potassium tert-butoxide (1.25 g, 11.1 mmol) and the mixture stirred at rt for 1 h. After completion of reaction (by TLC), water (100 mL) was added, followed by extraction with EtOAc (2×100 mL) and the organic layer then discarded. The pH of the aqueous layer was adjusted up to 4-5, extracted with hot EtOAc (3×100 mL) and the combined organic layer dried over Na2SO4, filtered and evaporated under reduced pressure. The residue thus obtained was triturated with ether to obtain the desired product as off-white solid (0.9 g, 87% yield). 1H NMR (DMSO-d6): δ 1.14 (t, J=7.20 Hz, 3H), 1.21 (s, 3H), 1.42 (m, 2H), 2.04 (m, 2H), 3.20 (m, 2H), 3.33 (q, J=7.20, 2H), 4.25 (m, 2H), 4.67 (s, 1H), 6.80 (br s, 1H), 7.61 (s, 1H), 7.94 (s, 1H); 8.86 (s, 2H), 10.78 (br s, 1H) and 12.46 (br, s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[C:6]([N+:11]([O-])=O)=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][O:16][C:17]1[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].[N+]([O-])(O)=O>C(O)(=O)C>[CH3:15][O:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]2[C:8]3[CH:7]=[N:11][C:6]4[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[C:3]=3[CH:4]=[CH:5][C:19]=2[CH:18]=1
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1OC
Reactant: COc1ccc(Br)cc1OC
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: COc1cc2ccc3c4cc(OC)c(OC)cc4ncc3c2cc1OC
Temperature: 10 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
3,4-Dimethoxy-6-nitro-bromobenzene (16). 3,4-Dimethoxybromobenzene (5 g, 23 mmol) was slowly added to a stirred solution of 35 mL concentrated nitric acid and 105 mL glacial acetic acid maintained at 10° C. The reaction mixture was stirred at 15° C. for 1 h and then diluted with 200 mL ice cold water. The resulting mixture was extracted thrice with 200 mL portions of ether. The combined organic phase was dried and evaporated in vacuo. The crude product was recrystallized from ethanol to give bright yellow needle shaped crystals of compound 16 in 92% yield; mp=122-124° C.; IR (Nujol) 1510, 1312; 1H NMR δ 3.94 (3H, s), 3.97 (3H, s), 7.12 (1H, s), 7.57 (1H, s); 13C NMR δ 56.9, 57.2, 108.0, 109.5, 117.0, 148.7, 153.3; Anal. calcd for C8H8NO4Br: C, 36.72, H, 3.14, N, 5.30; Found: C, 36.70, H, 3.13, N, 5.29.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N-:20]=[N+]=[N-].[Na+]>>[CH:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12](=[O:14])[NH:20][C:13]=2[CH:1]=[CH:2][CH:3]=1
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1[nH]c2ccccc2c2ccccc12

Procedure:
In Scheme I, a 9-fluorenone (A) is treated with sulfuric acid and aqueous sodium azide in a ring-expansion, or Schmidt, reaction to produce 6(5H)-phenanthridinone (B). Nitration of (B) produces 2-nitro-6(5H)-phenanthridinone (C) as a major product, which is then reduced by Fe, NH4Cl and DMF, or catalytic dehydrogenation, to produce 2-amino-6(5H)-phenanthridinone (D). In general, a compound falling within Formula II is prepared by modifying the parent molecule 6(5H)-Phenanthridinone. See, e.g., U.S. Pat. Nos. 3,291,801 and 3,932,643; Taylor et al., J. Am. Chem. Soc. 78:5104-5108 (1956). The 2-nitro (Compound C)-and 2-amino (Compound D)-6(5H)-phenanthridinones are synthesized by a slight modification of procedures described in Andrievskii, et al., Chem. Heterocycl. Compds (English Transl.) 21:8, 924-931 (1985), and Migachev, et al. Chem. Heterocycl. Compds (English Transl.) 17:3, 394-397 (1981)
Reaction SMILES: C(OC([NH:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:10]=1)=O)(C)(C)C.[ClH:24].O1CCOCC1>C(Cl)Cl>[ClH:24].[NH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:10]=1
Reactant: CCOC(=O)Cn1cc(NC(=O)OC(C)(C)C)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)Cn1cc(N)c2ccccc21
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of ethyl 2-(3-(tert-butoxycarbonylamino)-1H-indol-1-yl)acetate (275 mg, 0.864 mmol) in dry DCM (8 ml), cooled at 0° C. and under nitrogen, 4N HCl in dioxane (2.159 ml, 8.64 mmol) was added, and the mixture was stirred at room temperature for 36 hours. The solvent was removed under reduced pressure without heating to give ethyl 2-(3-amino-1H-indol-1-yl)acetate hydrochloride (220 mg, 0.864 mmol, quantitative yield). MS/ESI+ 219.1 [MH]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24].O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][C:38]([F:41])([F:40])[F:39])[NH2:30].CCN(C(C)C)C(C)C>>[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]2[O:20][N:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][C:38]([F:39])([F:40])[F:41])[N:28]=2)=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24]
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCCN1c1ccc(-c2nc(-c3ccccc3OC(F)(F)F)no2)cc1C(F)(F)F

Procedure:
Oxalyl chloride (106 μL; 1.25 mmol; 3 eq.), Intermediate 24 (120 mg; 0.42 mmol; 1 eq.), Intermediate 2 (92 mg; 0.42 mmol, 1 eq.) and DIEA (93 μL; 1.25 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 80/20) followed by precipitation from n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([NH:12][CH2:13][C:14](=O)[CH2:15][C:16]3([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])[CH2:19][CH2:18][CH2:17]3)[CH:10]=[CH:11][C:6]=2[C:5](=[O:31])[O:4][N:3]=1.[NH2:32][OH:33].Cl>CCO.O.CC([O-])=O.[Na+]>[CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([NH:12][CH2:13][C:14](=[N:32][OH:33])[CH2:15][C:16]3([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])[CH2:19][CH2:18][CH2:17]3)[CH:10]=[CH:11][C:6]=2[C:5](=[O:31])[O:4][N:3]=1
Reactant: NO
Reactant: Cc1noc(=O)c2ccc(NCC(=O)CC3(c4ccccc4C(F)(F)F)CCC3)cc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1noc(=O)c2ccc(NCC(CC3(c4ccccc4C(F)(F)F)CCC3)=NO)cc12

Procedure:
A solution of 29 mg of 4-methyl-6-{2-oxo-3-[1-(2-trifluoromethyl-phenyl)-cyclobutyl]-propylamino}-benzo[d][1,2]oxazin-1-one in EtOH (8 ml) was treated with 1 ml of 50% NH2OH HCl solution in H2O and NaOAc (15 mg). The solution was heated under reflux for 2 h and evaporated. The residue was purified by column chromatography on silica gel (10%-40% EtOAc-hexane) to yield 2 mg of product.