Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:11][C:12]([NH:14][C:15]1[C:16]([S:24][CH3:25])=[N:17][C:18]([CH3:23])=[CH:19][C:20]=1[S:21][CH3:22])=[O:13].[SH:26][C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>O>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[S:26][CH2:11][C:12]([NH:14][C:15]1[C:16]([S:24][CH3:25])=[N:17][C:18]([CH3:23])=[CH:19][C:20]=1[S:21][CH3:22])=[O:13]
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CBr
Reactant: Sc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CSc1cc(C)nc(SC)c1NC(=O)CSc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
Potassium carbonate (46 mg, 0.33 mmol) was added to an acetonitrile (5 ml) solution of this amide (96 mg, 0.3 mmol) and 2-mercaptobenzoxazole (45 mg, 0.3 mmol), and the mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 10 g, eluent—hexane:acetone=5:2) to obtain 88 mg (yield 75%) of the desired compound as a colorless crystal.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[C:5]([CH3:12])[CH:4]=1.[Br-:13].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:13][CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][C:5]=1[CH3:12])=[O:11]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(CO)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: Cc1cc(CO)ccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-hydroxymethyl-2-methyl-phenyl)-ethanone (preparation 1a, 600 mg, 3.65 mmol) in CH2Cl2 (25 mL) is added tetrabutylammonium tribromide in several portions (1.76 g, 3.65 mmol). The reaction mixture is stirred for 30 min at room temperature. After washing with water, the organic layer is dried over MgSO4 and concentrated under reduced pressure. The remaining residue is dissolved in hexanes/EtOAc 3:7 and filtered over silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[OH:12])[O:8][C:7]([CH3:14])=[C:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:5]2O.O.[NH2:25][NH2:26]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[C:7]([CH3:14])[NH:26][N:25]=2)[C:9]([OH:8])=[C:10]([CH3:13])[C:11]=1[OH:12]
Reactant: NN
Reactant: COc1ccc(C2=C(C)Oc3c(cc(Cl)c(O)c3C)C2O)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2c(-c3cc(Cl)c(O)c(C)c3O)n[nH]c2C)cc1

Procedure:
6-Chloro-3-(4-methoxy-phenyl)-2,8-dimethyl-4H-chromene-4,7-diol (1 eq) was taken up in a 1:1 solution of EtOH:Hydrazine hydrate and heated under microwave conditions (120° C., 300 sec). The solution was concentrated in vacuo, residue quenched with cold water, extracted with ethyl acetate and purified by flash chromatography (neat DCM). The yellow oil was then triturated with ether:hexane to give 4-chloro-6-[4-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl-benzene-1,3-diol as a solid.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[NH:13][C:12]=2[C:22]([O:24]CC)=[O:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.O.[OH-].[Li+].Cl>O>[C:1]1([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[NH:13][C:12]=2[C:22]([OH:24])=[O:23])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1[nH]c2cc(Cl)cc(Cl)c2c1NS(=O)(=O)c1ccccc1
Temperature: 65 °C
Yield: 61.3 %

Procedure:
Mix 3-[(phenylsulfonyl)amino]-2-carbethoxy-4,6-dichloroindole (0.35 g, 0.847 mmol), tetrahydrofuran (10 mL) and water (7 mL). Add lithium hydroxide monohydrate (0.11 g, 2.54 mmol) and stir at room temperature overnight. Warm at 65° C. for 5 hours, pour into water and acidify to pH 1 with 1N hydrochloric acid. Extract into ethyl acetate, dry (MgSO4) and evaporate the solvent in vacuo. Recrystallize (ethyl acetate/hexane) to give the title compound (0.2 g, 61%); mp 229°-35° C. (dec).
Reaction SMILES: C(N)CC.CN.[ClH:7].[Cl:8][C:9]1[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[C:15]2[C:10]=1[C:11](=[O:27])[N:12]([CH2:24][CH2:25][CH3:26])[C:13]([CH2:21]NC)=[N:14]2>>[Cl:7][CH2:21][C:13]1[N:12]([CH2:24][CH2:25][CH3:26])[C:11](=[O:27])[C:10]2[C:15](=[C:16]([OH:20])[C:17]([Cl:19])=[CH:18][C:9]=2[Cl:8])[N:14]=1
Reactant: CCCn1c(CNC)nc2c(O)c(Cl)cc(Cl)c2c1=O
Reactant: Cl
Agent: CN
Solvent: CCCN
Product: CCCn1c(CCl)nc2c(O)c(Cl)cc(Cl)c2c1=O

Procedure:
Other 2,3-disubstituted-3H-quinazolin-4-ones (4-9B-4-9E) prepared via substitution of n-propylamine (Step 1) and methylamine (Step 3) in Example 3 for the appropriate amine(s) are given in Table 6.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[N:11][NH:12][CH:13]=2)=[CH:4][CH:3]=1.[O:14]1[C:16]([CH3:18])([CH3:17])[CH2:15]1.CC([O-])(C)C.[K+].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]([CH2:15][C:16]([CH3:18])([OH:14])[CH3:17])[N:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(Cl)ccc1-c1c[nH]nn1
Reactant: CC1(C)CO1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)ccc1-c1cnnn1CC(C)(C)O
Temperature: 60 °C

Procedure:
6-Chloro-2-methyl-3-(1H-1,2,3-triazol-4-yl)pyridine (131 mg, 0.68 mmol) and 1,2-epoxy-2-methylpropane (65 μl, 0.71 mmol) were taken-up in DMF (2.7 ml). Potassium 2-methylpropan-2-olate (114 mg, 1.01 mmol) was added, and the mixture was heated to 60° C. for seven hours. Saturated aqueous ammonium chloride was added and the resulting mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated, purified by reverse-phase HPLC (10-100% acetonitrile/water with 0.05% trifluoroacetic acid modifier). The appropriate fractions were neutralized with aqueous sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][CH:6]=2.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:16][C:17]1[N:18]=[CH:19][N:20]=[C:21]([NH:13][CH2:12][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:11]3)[CH:22]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1cc2cc(CNc3cc(Cl)ncn3)ccc2[nH]1
Temperature: 140 °C
Yield: 74.2 %

Procedure:
{[2-(Trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 34, 600 mg, 2.394 mmol), 4,6-dichloropyrimidine (357 mg, 2.394 mmol) and potassium carbonate (993 mg, 7.18 mmol) were added to DMSO (13 mL). The reaction mixture was heated in the microwave for 1.5 hours at 140° C. The LC/MS showed product. The reaction mixture was poured into water and extracted with ethyl acetate. Traces of water were removed with a phase separator and the solvent removed under reduced pressure to give the title compound (580 mg);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N2CCN(Cc3ccccc3)CC2)C1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC[C@H](N2CCNCC2)C1
Reaction time: 18 h

Procedure:
To a solution of (S)-3-(4-benzyl-piperazin-1-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.7 g, 10.83 mmol) in EtOH (75 mL) and acetic acid (50 mL) 10% Pd on carbon (0.58 g, 0.54 mmol) was added. The reaction mixture was hydrogenated under 1 atm H2 for 18 hours, filtered through Celite and concentrated in vacuo to afford (S)-3-piperazin-1-yl-pyrrolidine-1-carboxylic acid tert-butyl ester as an orange oil. The product was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH3:12][C:13]([CH3:18])([CH3:17])[CH:14]([NH2:16])[CH3:15]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:16][CH:14]([CH3:15])[C:13]([CH3:18])([CH3:17])[CH3:12])=[S:11]
Reactant: CC(N)C(C)(C)C
Reactant: Fc1ccc(N=C=S)c(F)c1
Solvent: ClCCl
Product: CC(NC(=S)Nc1ccc(F)cc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a solution of 2,4-difluoro-phenyl isothiocyanate (1.00 g, 5.84 mmol) in dichloromethane (20 mL) at room temperature was added (±) 3,3-dimethyl-2-aminobutane (1.02 mL, 7.6 mmol) and the reaction was stirred overnight at room temperature. The mixture was concentrated in vacuo and the resulting residue was triturated with diethyl ether and filtered to afford 1.34 g (84%) of 1-(2,4-difluoro-phenyl)-3-(1,2,2-trimethyl-propyl)-thiourea as a white solid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[CH:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([NH:8][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)Cc1ccccc1
Yield: 56.4 %

Procedure:
The title compound was synthesized substantially in the same manner as Example 3 by coupling of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (0.025 g, 0.096 mmol) with phenacetyl chloride (0.045 g, 0.288 mmol) in dichloromethane (3 mL) and pyridine (0.500 mL) to obtain 0.0205 g (56%) of the title compound.
Reaction SMILES: BrCCC(OC)=O.[C:8]([O:12][C:13]([N:15](C(OC(C)(C)C)=O)[C:16]1[N:21]=[CH:20][C:19]([C:22]2[N:30]=[C:29]3[C:25]([N:26]=[CH:27][N:28]3[CH2:31][CH2:32][C:33]([O:35]C)=[O:34])=[C:24]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:23]=2)=[CH:18][N:17]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[OH-].[Li+]>C1COCC1.O>[C:8]([O:12][C:13]([NH:15][C:16]1[N:17]=[CH:18][C:19]([C:22]2[N:30]=[C:29]3[C:25]([N:26]=[CH:27][N:28]3[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:24]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)[N:23]=2)=[CH:20][N:21]=1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: COC(=O)CCn1cnc2c(N3CCOCC3)nc(-c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3)nc21
Agent: COC(=O)CCBr
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CCC(=O)O)c3n2)cn1
Yield: 103 %

Procedure:
2-(2-(2-(Bis(tert-butoxycarbonyl)amino)pyrimidin-5-yl)-6-morpholino-9H-purin-2-yl (400 mg) was reacted with methyl 3-bromopropionate via General Procedure C. The product, 468 mg of crude methyl 3-(2-(2-(bis(tert-butoxycarbonyl)amino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)propanoate, was reacted with 3 eq of lithium hydroxide in 1:1 THF/Water solution. After completion, the THF was removed under vacuum and the water solution was acidified to pH 2 using a concentrated HCl solution. The product precipitated as a white solid and was filtered to yield 388 mg 3-(2-(2-(tert butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)propanoic acid of which 88 mg was subjected to Boc deprotection via General Procedure E to give 15.5 mg 114 as white solid following reverse phase purification. MS (Q1) 371.2 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:11]([CH3:31])[CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]3[C:30]4[C:29]5[CH2:28][CH2:27][CH2:26][C:25]=5[S:24][C:23]=4[N:22]=[CH:21][N:20]=3)[CH2:14][CH2:13]2)=O)[CH:5]=[CH:6][CH:7]=1.[H-].[H-].[H-].[H-].[Al+3].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:11]([CH3:31])[CH:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19]3[C:30]4[C:29]5[CH2:28][CH2:27][CH2:26][C:25]=5[S:24][C:23]=4[N:22]=[CH:21][N:20]=3)[CH2:16][CH2:17]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)Cc1cccc(Cl)c1)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(CCc1cccc(Cl)c1)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 2.5 °C
Reaction time: 0.03 h
Yield: 5.8 %

Procedure:
A solution of Compound I-102 (364 mg, 0.80 mmol, 1.00 equiv) in tetrahydrofuran (30 mL) was added dropwise into a solution of lithium aluminium tetrahydride (152 mg, 4.01 mmol, 5.00 equiv) in tetrahydrofuran (20 mL) with stirring at 0-5° C. The resulting solution was stirred for 5 h at 80° C. in an oil bath. The reaction was then quenched by the addition of 5 mL of water. The solids were filtered off. The filtrate was extracted with 3×100 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC (2#-Waters 2767-2(HPLC-08)) under the following conditions: column: Xbridge Prep Phenyl, 5 um, 19*150 mm; mobile phase: Water (50 mM ammonium bicarbonate) and acetonitrile (10.0% acetonitrile up to 33.0% in 2 min, up to 53.0% in 8 min, up to 100.0% in 1 min, down to 10.0% in 1 min); detector, UV 220 nm, to yield 20.3 mg (6%) of Compound I-107 as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.36 (1H, s), 7.26-7.07 (4H, m), 4.85-4.83 (1H, d), 4.12-4.02 (1H, m), 3.00-2.97 (4H, m), 2.76-2.70 (4H, m), 2.58-2.49 (3H, m), 2.37 (3H, s). 2.27-2.23 (2H, d), 1.94-1.89 (2H, d), 1.71-1.47 (2H, q), 1.29-1.25 (2H, q). MS: m/z 441 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C:43]([CH3:47])([CH3:46])[CH:44]=O)[CH2:10]2)=[CH:5][CH:4]=1.[NH2:48][CH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][NH:48][CH:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(C)(C)C=O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: NC1CCOCC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(C)(C)CNC4CCOCC4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 43a, 430 mg of 3-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionaldehyde and 79 mg of 4-aminotetrahydropyran are used to afford the title compound as a yellow oil. Rf=0.05 (EtOAc-heptane 1:1); Rt=4.65.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1>>[Cl:20][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:9][C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:19]=[CH:18][CH:17]=1
Reactant: Clc1cccc(CCCBr)c1
Reactant: CCc1cnccc1C
Product: CCc1cnccc1CCCCc1cccc(Cl)c1
Yield: 61 %

Procedure:
1.83 g (15.1 mmol) of 3-ethyl-4-methylpyridine and 3.53 g (15.1 mmol) of 1-bromo-3-(3-chlorophenyl)-propane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 2.52 g of the desired compound (yield: 61.0%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[S:13][C:6]=12.[NH4+].[Cl-]>[Fe].CCO.O>[NH2:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:26]=1
Reactant: COc1cccc(Nc2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cccc(Nc2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Yield: 73.6 %

Procedure:
To a solution of 403 (408 mg, 0.99 mmol) and NH4Cl (45 mg, 084 mmol) in 2:1 EtOH/water (15 mL) was added iron powder (472 mg, 8.43 mmol) and the suspension was heated to reflux for 1 hour. The reaction mixture was filtered through celite and concentrated to provide 404 (278 mg, 74% yield), that was used without further purification. MS (m/z): (M+1) 382.0 (100%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16][C:17](Cl)=O.B.C1(N(CCCBr)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:8]1([N:7]([CH2:17][CH2:16][CH2:15][Cl:14])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)CCCl
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: B
Agent: BrCCCN(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: ClCCCN(c1ccccc1)c1ccccc1

Procedure:
3-(N,N-diphenylamino)-1-chloropropane is prepared by the reaction of diphenylamine with 3-chloropropionyl chloride, followed by reduction with borane in tetrahydrofuran, by a procedure analogous to the preparation of 3-[N,N-diphenylamino]-1-bromopropane in Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[Br:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1I.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([S:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]1=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: Brc1ccccc1I
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2Br)cc1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
A microwave vial was charged with INTERMEDIATE M (0.100 g, 0.240 mmol), Xantphos (0.028 g, 0.048 mmol), 1-bromo-2-iodobenzene (0.045 mL, 0.359 mmol), Pd2(dba)3 (0.022 g, 0.024 mmol) and sodium tert-butoxide (0.046 g, 0.479 mmol). The mixture was diluted with toluene (2.395 mL), and purged with nitrogen, and stirred at 130° C. in the microwave for 20 minutes. After completion, the reaction was diluted with water, and washed with DCM. The organics were dried via phase separator, and concentrated under a vacuum. The material was then purified via 2 g SCX column. The material was concentrated to provide 4-(2-bromophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide, which was taken forward without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[C:5]2[C:13]([NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+].O.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[OH:12][C:7]1[CH:6]=[C:5]([C:13]([NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:14])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:3]=2)[N:8]=1
Reactant: O=C(Nc1cccnc1)c1cc(O)nc2ccc(Br)cc12
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(O)nc2ccc(-c3ccccc3)cc12
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a round-bottomed flask under argon atmosphere was added 6-bromo-2-hydroxy-N-(pyridin-3-yl)quinoline-4-carboxamide (3.00 g) in DMF (50 ml), and the vessel was purged with argon under stirring for 5 minutes. After 5 minutes, 2N solution of potassium carbonate in water (11 eq) was added and the flask was purged with argon under stirring for 5 minutes. Phenylboronic acid (1.5 eq) was then added and the tube was purged with argon under stirring for 15 minutes. Finally, palladium(0)tetrakis triphenylphosphine (0.03 eq) was added under argon and the flask was affixed to a reflux condenser and heated to 80° C. for 5 hours. The completion of the reaction was monitored on TLC using ethyl acetate:hexanes (5:5) as a mobile phase. After completion of the reaction, reaction mixture was diluted with ethyl acetate (100 ml) and then washed with water (5*100 ml). The ethyl acetate layer was dried over anhydrous sodium sulphate and then solvent was distilled out and the crude was subjected to purification by silica gel column chromatography to provide 9.0 g of 2-hydroxy-6-phenyl-N-(pyridin-3-yl)quinoline-4-carboxamide.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][C@H:21]([CH2:26][OH:27])[CH2:22][CH2:23][CH2:24][CH3:25]>>[C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:17]([NH:20][C@H:21]([CH2:26][OH:27])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC[C@H](N)CO
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CCCC[C@@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Yield: 58 %

Procedure:
N-[(phenylmethoxy)carbonyl]-L-leucine was used instead of 1-[[(phenylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid, and L-norleucinol was used instead of L-valinol in the process according to Reference Example 178 to obtain 421 mg (58%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]([O:20][CH2:21]C)=[O:19])=[C:4]([NH:16]C)[C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:14])[C:6]=2[N:15]=1.C([O-])(=O)/C=C\C([O-])=[O:27]>>[NH2:16][C:4]1[C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:27])[CH:12]=3)[N:7]([CH3:14])[C:6]=2[N:15]=[C:2]([CH3:1])[C:3]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C([O-])/C=C\C(=O)[O-]
Reactant: CCOC(=O)c1c(C)nc2c(c1NC)c1ccccc1n2C
Product: COC(=O)c1c(C)nc2c(c1N)c1cc(O)ccc1n2C

Procedure:
2,9-dimethyl-4-methylamino-9H-pyrido[2,3-b]indole-3-carboxylic acid, ethyl ester, (Z)-2-butenedioate, or