Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl>[OH:1][C@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[CH2:7][NH:8][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CNC(=O)OCc2ccccc2)[C@H](O)C1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@@H]1CNC[C@@H]1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a solution of (±)-1,1-dimethylethyl cis-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (15.3 g, 43.7 mmole) in DCM (150 mL) at RT was added TFA (50 mL). After 2 h, the reaction solution was concentrated under vacuum and the residue placed under high vacuum for 3 hr. The residue was dissolved in DCM (200 mL) and MP-carbonate resin (175 mmole, 65 g) was added with vigorous stirring at RT. After 4 h, the reaction contents were filtered through a scintered-glass funnel washing with MeOH (100 mL). The filtrate was concentrated under vacuum to give the title compound (10.38 g, 95%) as a white foam: LC-MS (ES) m/e 251 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl[C:36]1[N:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][N:37]=1>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([C:36]3[N:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][N:37]=3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Reactant: FC(F)(F)c1ccnc(Cl)n1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(c1nccc(C(F)(F)F)n1)CN2c1ccccc1Cl

Procedure:
The title compound, MS: m/e=651.9 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 2-chloro-4-(trifluoromethyl)-pyrimidine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][C:7]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=1.[H-].[Na+].[CH3:25][NH:26][C:27](=O)[O:28]C1C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O.O>[NH2:22][C:18]1[CH:17]=[C:16]([O:15][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[O:5][CH2:4][CH2:3][O:2][CH3:1])[N:12]([C:27]([NH:26][CH3:25])=[O:28])[CH:11]=[CH:10]3)[CH:21]=[CH:20][N:19]=1
Reactant: CNC(=O)Oc1ccccc1
Reactant: COCCOc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)c(OCCOC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
4-((6-(2-Methoxyethoxy)-1H-indol-5-yl)oxy)pyridin-2-amine described in Production Example 20-6 (2.60 g, 8.67 mmol) was dissolved in N,N-dimethylformamide (50 mL), then 50-72% oily sodium hydride (499 mg) was added under nitrogen atmosphere at room temperature. Phenyl methylcarbamate described in Production Example 1-7 (1.97 g, 13.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C. and ethyl acetate and water were added for partition. The aqueous layer was extracted with ethyl acetate twice, sodium chloride was added to the aqueous layer, and the resultant was extracted with ethyl acetate three times. The combined organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under vacuum, and then the resultant was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=1:4-0:1-ethyl acetate:methanol=49:1-24:1). The target fraction was concentrated under vacuum, and ethyl acetate was added and the precipitate was collected by filteration and washed to obtain the title compound (2.23 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:16]2[CH:17]=[CH:18][C:13]([C:12]3[O:11][N:10]=[C:9]([CH3:20])[C:8]=3[NH:7][C:6]([O:5][CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[Cl:1])=[O:21])=[CH:14][CH:15]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OCc1ccccc1Cl
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OCc3ccccc3Cl)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 2-chloro-benzyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide {4′-[4-(2-chloro-benzyloxycarbonylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 36, Step 7.
Reaction SMILES: Br[CH2:2][CH:3]1[O:15][C:14]2[C:13]3[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[CH2:4]1.C(OC([N:25]1[CH2:28][CH:27]([NH2:29])[CH2:26]1)=O)(C)(C)C.[O:30]=[C:31]1[NH:36][C:35]2[CH:37]=[C:38]([C:41](O)=[O:42])[CH:39]=[CH:40][C:34]=2[S:33][CH2:32]1>>[CH3:17][O:16][C:11]1[CH:10]=[CH:9][C:8]2[N:7]=[CH:6][C:5]3[CH2:4][CH:3]([CH2:2][N:25]4[CH2:26][CH:27]([NH:29][C:41]([C:38]5[CH:39]=[CH:40][C:34]6[S:33][CH2:32][C:31](=[O:30])[NH:36][C:35]=6[CH:37]=5)=[O:42])[CH2:28]4)[O:15][C:14]=3[C:13]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: COc1ccc2ncc3c(c2c1)OC(CBr)C3
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: COc1ccc2ncc3c(c2c1)OC(CN1CC(NC(=O)c2ccc4c(c2)NC(=O)CS4)C1)C3

Procedure:
The titled compound is prepared as a white lyophilized powder following Scheme 1 and in analogy to Example 1 using 2-bromomethyl-8-methoxy-2,3-dihydro-furo[3,2-c]quinoline, 3-amino-azetidine-1-carboxylic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting material.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][CH3:22])[C:17]([O:23][Si](C(C)(C)C)(C)C)=[C:16]([CH2:31][CH2:32][CH3:33])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:34])[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:15]=[C:16]([CH2:31][CH2:32][CH3:33])[C:17]([OH:23])=[C:18]([CH2:20][CH2:21][CH3:22])[CH:19]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:34])[CH:3]=1
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1O
Yield: 87.8 %

Procedure:
A THF solution of 5.0 g (10.44 mmol) of the product of Step F was treated with tetrabutylammonium fluoride (1.2 equiv, 1M solution in THF) overnight. THF was removed in vacuo and the residue was flash chromatographed using 30-50% ethyl acetate in hexane as eluent to afford 3.35 g (88%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>O1CCCC1.O.C(O)(C)C>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[O:11])[CH2:7]1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CN1CCN(C(=O)N2CC(Oc3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
A stirred solution of 2.8 g (0.01 mole) of crude 3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 25 ml of tetrahydrofuran was treated with 1 g (0.01 mole) of 1-methylpiperazine then with 1.42 g (0.01 mole) of potassium carbonate. After stirring for 30 min, approximately 2 g of ice was added and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and an oil separated. Upon standing, this oil solidified and was collected by filtration, yielding 3.3 g of crude product. The solid was dissolved in 20 ml of isopropanol and treated with 1.16 g of fumaric acid dissolved in 25 ml of boiling isopropanol. The volume was reduced to 30 ml by heating under a stream of nitrogen and upon cooling, the precipitated salt was collected by filtration, yielding 1.35 g (95.9%) of white crystals, m.p. 187°-188° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].O1CCCC1.[C:11](Cl)(=[O:15])[C:12](Cl)=[O:13].C(OCC)(=O)C>O>[CH3:1][N:2]1[C:12](=[O:13])[C:11](=[O:15])[NH:5][C:3]1=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNC(N)=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1C(=O)NC(=O)C1=O
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
6.6 g of methylurea was added to 200 ml of anhydrous tetrahydrofuran and the suspension was stirred in an ice-water bath. 12.5 g of oxalyl chloride was added dropwise to the suspension, and the stirring was continued for 30 minutes in an ice-water bath. 200 ml of ethyl acetate and 70 ml of water were added to the reaction mixture and the organic layer was obtained by extraction. The water layer was further extracted with 130 ml of ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and evaporated to dryness, and the crude residue was recrystallized from ethyl acetate-hexane to give 10.0 g of 1-methylimidazolidinetrione in the form of colorless needle crystals. The resulting compound was stirred in 1N ammonia water for a hour at room temperature. The solution was evaporated to dryness and the residue was recrystallized from water-ethanol to give 7.7 g of 5-methyloxaluric acid ammonium salt (compound 1) in the form of colorless prism crystals.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5]([Cl:20])[C:4]=2[CH:3]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCCO)C.C(OCC)C>[ClH:20].[F:1][C:2]1[CH:18]=[CH:17][C:16]2[NH+:15]([CH3:19])[C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5]([O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:4]=2[CH:3]=1
Reactant: Oc1ccccc1
Reactant: Cn1c2c3ccccc3nc-2c(Cl)c2cc(F)ccc21
Solvent: CCOCCO
Solvent: CCOCC
Product: C[NH+]1C2=c3ccccc3=NC2=C(Oc2ccccc2)c2cc(F)ccc21
Product: Cl
Yield: 60.3 %

Procedure:
A solution of 2-fluoro-5-methyl-11-chloroquindoline from Example 24 (510 mg, 1.79 mmol) and phenol (1.5 g, 15.96 mmol) in EtOCH2CH2OH (50 mL) was heated at 100° C. for 10 min. During this time the color of the reaction mixture changed from purple to yellow, and a yellow precipitate formed. After cooling, the reaction mixture was diluted with diethyl ether (150 mL) and the precipitate was collected, washed thoroughly with diethyl ether and dried, providing 410 mg (60.5%) of the title compound, mp 249.5°-249.8° C.; 1H NMR (DMSO-d6) δ 12.94 (s, 1H), 8.98 (dd, J=4.4, J=10.00, 1H), 8.84 (d, J=8.4, 1H), 8.19-8.13 (m, 1H), 8.01 (dd, J=2.8, J=8.8, 1H), 7.94 (t, J=8.4, 1H), 7.77 (d, J=8.4, 1H), 7.55 (t, J=8.4, 1H), 7.44-7.40 (m, 2H), 7.22 (t, J=8.4, 1H), 7.15-7.12 (m, 2H), 5.06 (s, 3H); 13C NMR (DMSO-d6) δ 160.90, 157.69 (d, J=152.9), 145.58, 144.49 (d, J=5.2), 141.74, 134.57, 134.30, 130.29, 127.14, 126.18, 124.21, 122.41 (d, J=8.2), 122.23 (d, J=9.6), 122.02 (d, J=10.4), 121.85, 116.10, 114.57, 113.51, 106.46 (d, J=26.2), 40.60; MS (EI, m/z) 341 (M+ -H) .
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][NH:28][C:29](=[NH:40])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([S:36](=[O:39])(=[O:38])[NH2:37])[CH:31]=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:27][N:28]=[C:29]([C:30]4[CH:31]=[C:32]([S:36]([NH2:37])(=[O:38])=[O:39])[CH:33]=[CH:34][CH:35]=4)[N:40]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:4]=1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) (188 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (ethyl acetate/MeOH/hexane) as a yellow solid (175 mg, 63%). MS (ISN) 552.8 [(M−H)−]; mp 262° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12](=[O:20])[CH:13]([NH2:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].O>ClCCl>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:19][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=1)[C:12]([O:11][CH2:9][CH3:10])=[O:20])[CH3:18]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1cccc(F)c1)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
36.1 ml of triethylamine were added to a solution of 25 g of aminomalonic acid diethyl ester hydrochloride in 200 ml of dichloromethane with cooling in an ice bath. Then a solution of 18.7 g of 3-fluoro-benzoyl chloride in 100 ml of dichloromethane was added dropwise. After stirring for 2 h at 0° C., 100 ml of water were added dropwise. The layers were separated, and the aqueous layer was extracted with 100 ml of dichloromethane. The combined organic layers were dried with magnesium sulfate, filtered and evaporated to give 33.2 g of the crude title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)=O.Cl.[NH2:31][OH:32].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[CH2:9]/[C:10](/[C:12]1[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)=[N:31]\[OH:32]
Reactant: Cn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2ccccc2Cl)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(S(C)(=O)=O)cc2)c2ccccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(2-chloro-phenyl)-3-(4-methanesulfonyl-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=445.2 [M+H]+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[CH3:20][CH2:21][N:22](CC)CC.ClCC[S:30](Cl)(=[O:32])=[O:31]>C1COCC1.CN(C1C=CN=CC=1)C.C([O-])(O)=O.[Na+]>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH:20]=[CH:21][NH:22][SH:30](=[O:32])=[O:31])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[SH](=O)NC=Cc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a stirred solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (J Med Chem, 1995;38:3482) (0.30 g, 0.95 mmol) in THF (20 mL) under nitrogen was added Et3N (3.5 mol eq., 3.33 mmol, 245 μL), a catalytic amount of DMAP and chloroethanesulfonyl chloride (1.2 mol eq., 1.14 mmol, 119 μL) dropwise. The reaction was stirred at 25° C. for 1 hour and then diluted with saturated NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and chromatographed on silica gel eluting with MeOH/CH2Cl2/EtOAc (3:47:50). Crystallization from CH2Cl2/hexane gave N-[4-[(3-bromophenyl)amino]-quinazolin-6-yl]vinylsulfonamide (210 mg, 54%) as a cream powder, mp 217° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl-:1].[Cl:1][C:2]1[N:11]=[C:10]([N+:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: c1ccncc1
Product: Clc1nc(-[n+]2ccccc2)c2ccccc2n1
Product: [Cl-]
Reaction time: 8 h

Procedure:
A 50-g portion of 2,4-dichloroquinazoline was added to 500 ml of pyridine at ambient temperature. The reaction was stirred overnight under a calcium sulfate drying tube, chilled and filtered. The solid was rinsed thoroughly with pyridine and dried in vacuo giving 65 g of solid 1-(2-chloroquinazoline-4-yl)pyridinium chloride (m.p. 105°-107° C.; mixture melting point with 2,4-dichloroquinazoline 80°-87° C.).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([N:25]([CH3:31])[N:26]=[N:27][CH2:28][CH2:29]O)([O:22][CH2:23][CH3:24])=[O:21].C(Cl)(Cl)(Cl)[Cl:33]>CCCCC>[C:20]([N:25]([CH3:31])[N:26]=[N:27][CH2:28][CH2:29][Cl:33])([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)N(C)N=NCCO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Product: CCOC(=O)N(C)N=NCCCl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6a. A solution of triphenylphosphine (2.83 g, 1.08×10-2 mol) and 3-carboethoxy-1-(2-hydroxyethyl)-3-methyltriazene, 5a. (1.89 g, 1.08×10-2 mol) in 25 mL of carbon tetrachloride (dried over 3A molecular sieves) was refluxed overnight under nitrogen. The reaction mixture was cooled to room temperature and diluted with pentane (100 mL). After standing at 10° C. for four hours, the reaction mixture was filtered through a pad of Celite to remove precipitated triphenylphosphine oxide. The filtrate was concentrated on a rotary evaporator at 22° C., redissolved in a minimum amount of ether and chromatographed on a column of 40 g of Silica Gel 60 packed in 1:10 ether-pentane and eluted with 200 mL each of 10%, 20% and 30% ether in pentane. The first 200 mL of eluent contained 1.4 g of a yellow oil. Distillation of that oil at reduced pressure with a short path distillation apparatus produced 1.22 g (6:30×10-3 mol, 58.3%) of the desired compound, 3-carboethoxy-(2-chloroethyl)-3-methyltriazene, 6a:bp 60°-62° C. (0.003 mm); IR (CCl4) 2990, 2970, 1730, 1155, 990 cm10-1 ; UV (CH3CN) λ max 2333 (log ε 4.19); 1H NMR 9CDCl3, Me4Si) δ 1.39 (0-CH2CH3,t,J=7 Hz), 3.28 (NCH3,s), 3.88 (Cl-CH2,t,J=6 Hz), 4.12 (CH2CH-N.t,J=6Hz), 4.39 (0--CH2CH3,q,J=7 Hz); proton decoupled 13C NMR (CDCl3, Me4Si) δ 14.47 (0--CH2CH3), 29.76 (N--CH3), 41.92 (Cl--CH2), 62.50 (CH2 --N), 63.17 (0--CH2CH3), 154.27 (C50 0); (1H and 13C NMR assignments made via 13C -APT and 2D-heteronuclear correlated spectrum (2D-COSY) experiments); exact mass calcd m/z for C6H12N23O2Cl 193.0618, found 193.0629 (by EI).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([O:36]CC)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of ethyl {2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (16.1 g) in ethanol (100 mL) and tetrahydrofuran (100 mL) was added 1N aqueous sodium hydroxide solution (58 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, water was added to the residue, and the mixture was washed with ethyl acetate. To the aqueous layer was added 1N hydrochloric acid (58 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (15 g, yield 98%) as a brown amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.CI.[C:14](=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH3:14][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: Oc1cccc2cnccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.6 g (38.6 mmol) of 5-hydroxyisoquinoline was dissolved in 70 ml of DMF. 2.63 ml (38.6 mmol) of methyl iodide and 7.99 g (57.9 mmol) of potassium carbonate were added to the obtained solution, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extracting solvent in an ordinary manner, the crude product was obtained. It was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8]2([C:21]3[C:13](=[CH:14][C:15]4[CH2:16][CH2:17][NH:18][C:19]=4[CH:20]=3)[O:12][CH2:11]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:28]=[C:27]([N:29]2[CH2:33][CH2:32][CH2:31][C:30]2=[O:34])[CH:26]=[CH:25][C:24]=1[C:35]1[CH:40]=[CH:39][C:38]([C:41](O)=[O:42])=[CH:37][CH:36]=1>>[C:1]([N:5]1[CH2:6][CH2:7][C:8]2([C:21]3[C:13](=[CH:14][C:15]4[CH2:16][CH2:17][N:18]([C:41]([C:38]5[CH:37]=[CH:36][C:35]([C:24]6[CH:25]=[CH:26][C:27]([N:29]7[CH2:33][CH2:32][CH2:31][C:30]7=[O:34])=[CH:28][C:23]=6[CH3:22])=[CH:40][CH:39]=5)=[O:42])[C:19]=4[CH:20]=3)[O:12][CH2:11]2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)N1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C(C)(C)C)CC2)CO4)cc1

Procedure:
The title compound was prepared from 1'-tert-butyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine) (D61) and 2'-methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carboxylic acid (D47) using the method outlined in Example 15.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:17])[NH:13][C:14](=[O:16])[CH3:15])=[CH:8][C:7]=1[N+:18]([O-])=O)(=[O:3])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)C.O>O1CCCC1>[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:17])[NH:13][C:14](=[O:16])[CH3:15])=[CH:8][C:7]=1[NH2:18])(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccc(C(=O)NC(C)=O)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(C(=O)NC(C)=O)cc1N
Yield: 118.8 %

Procedure:
2-((N-Acetyl)aminomethyl)-5-((N-acetyl)carbamoyl)-1-nitrobenzene (1.00 g) and sodium hydrosulfite (7.0 g) in a mixture of tetrahydrofuran (5 ml), ethanol (5 ml) and water (20 ml) were heated under reflux for 1 hr. After cooling, the organic layer was separated, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the objective compound (1.06 g).