Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][C:21]=2[O:29][CH3:30])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:16]([O-])=O)[C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:19].Cl.O>C(O)C.[Fe]>[NH2:16][C:7]1[C:8]([NH:12][C:13](=[O:15])[CH3:14])=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:19])[C:2]([OH:1])([C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:27])[CH3:28])=[CH:22][C:21]=1[O:29][CH3:30])[C:10]2=[O:11]
Reactant: COc1cc(C(C)C)ccc1C1(O)C(=O)c2ccc([N+](=O)[O-])c(NC(C)=O)c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(C)C)ccc1C1(O)C(=O)c2ccc(N)c(NC(C)=O)c2C1=O
Yield: 98.1 %

Procedure:
N-(2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-5-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (0.10 g, 0.24 mmol) was completely dissolved in anhydrous ethanol (3 ml). This solution was added with iron (0.098 g), conc. HCl (0.05 ml) and water (0.3 ml). The reaction mixture was heated for 2 hrs under reflux. After filtration at high temperature to remove iron, the filtrate was concentrated in a vacuum and purified using column chromatography (ethylacetate 100%) to afford the title compound (90 mg, 98%).
Reaction SMILES: [N:1]1(C(N2C=CN=C2)N)C=CN=[CH:2]1.[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:17]=1[NH2:23]>C1COCC1.CCOC(C)=O>[NH2:1][C:2]1[O:22][C:18]2[C:17](=[C:16]([C:15]([O:14][CH3:13])=[O:24])[CH:21]=[CH:20][CH:19]=2)[N:23]=1
Reactant: NC(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1cccc(O)c1N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc2oc(N)nc12
Temperature: 25 °C
Yield: 46.7 %

Procedure:
To a solution of di(1H-imidazole-1-yl)methanamine (2.05 g, 12.26 mmol) in THF (60 mL) was added methyl-2-amino-3-hydroxybenzoate (1.98 g, 12.26 mmol) at room temperature and the resulting reaction mixture was heated to reflux for 17 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL) and washed with H2O (3×100 mL), saturated ammonium chloride (2×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by recrystallization from diethyl ether to afford methyl 2-aminobenzoxazole-4-carboxylate (1.10 g, 50%) as a brown solid. 1H NMR and MS consistent.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl.[NH:9]1[CH2:12][CH:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:15]=3[N:14]=2)[CH2:10]1.[Cl:23][C:24]1[C:25](F)=[N:26][CH:27]=[CH:28][CH:29]=1>CN1C(=O)CCC1>[Cl:23][C:24]1[C:25]([N:9]2[CH2:12][CH:11]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:15]=4[N:14]=3)[CH2:10]2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1ccc2[nH]c(C3CNC3)nc2c1
Reactant: Fc1ncccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cc1ccc2[nH]c(C3CN(c4ncccc4Cl)C3)nc2c1
Temperature: 100 °C
Yield: 9.6 %

Procedure:
To a mixture of cesium carbonate (435 mg, 1.34 mmol) and 2-(azetidin-3-yl)-5-methyl-1H-benzo[d]imidazole dihydrochloride (0.100 g, 0.384 mmol) was added NMP (1 mL) and 3-chloro-2-fluoropyridine (0.105 g, 0.798 mmol). The reaction mixture was degassed and heated to 100° C. for 1 h, then heated to 130° C. for 2 h. The reaction was diluted with EtOAc. The organic phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (30% to 90% EtOAc in hexanes) followed by purification by reverse phase HPLC (10% to 50% water/MeCN followed by neutralization of the TFA salt with saturated NaHCO3) gave 2-(1-(3-chloropyridin-2-yl)azetidin-3-yl)-5-methyl-1H-benzo[d]imidazole (0.011 g, 0.037 mmol, 10% yield) as a dark yellow foam.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH2:21][CH3:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.Cl>[OH-].[Na+]>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH2:21][CH3:22])(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: CCN1CCCC1CNS(=O)(=O)c1ccc(NC(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCN1CCCC1CNS(=O)(=O)c1ccc(N)cc1
Reaction time: 2 h
Yield: 86.5 %

Procedure:
4-Acetylamino-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzenesulphonamide (6.5 g, 0.02 mole) was dissolved in 50 ml of 2N aqueous sodium hydroxide. The solution was heated to reflux, with stirring, for 11/2 hours. The solution was cooled and the pH was adjusted to about 8 with hydrochloric acid (2N). The mixture was extracted with chloroform (3×50 ml) and the combined extracts were dried (MgSO4) and evaporated under reduced pressure to give a solid (4.9 g). The solid was purified by column chromatography (basic Al2O3 : 1% ethanol/chloroform), followed by recrystallisation from water, to give the pure title compound m.p. 109°-110° C.
Reaction SMILES: [C:1]1([CH:7]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[C:1]1([CH:7]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[CH2:8][C:9]([NH2:24])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(c1ccccc1)N1Cc2ccccc2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)CC(c1ccccc1)N1Cc2ccccc2C1=O
Reaction time: 1.5 h
Yield: 57.5 %

Procedure:
To a stirred solution of 3-phenyl-3-(1-oxoisoindolin-2-yl)propionic acid (0.703 g, 2.50 mmol) in 15 mL of tetrahydrofuran under nitrogen was added carbonyldiimidazole (0.438 g, 2.70 mmol), and a few crystals of 4-N,N-dimethylaminopyridine [DMAP]. The reaction mixture was stirred for 1.5 hours and then 0.25 mL of 15 N ammonium hydroxide was added. After 20 minutes, the reaction mixture was concentrated in vacuo and the residue slurried in water. The resulting solid was isolated by filtration and dried in vacuo to afford 0.58 g (80%) of crude product as an off-white powder. The crude product was recrystallized from ethanol to afford 0.403 g (57%) of 3-phenyl-3-(1-oxoisoindolin-2-yl)-propionamide as white prisms: 1H NMR (DMSO-d6, 250 MHz) 7.8-7.2 (m, 10H), 6.92 (br s, 1H), 5.81 (overlapping dd, 1H) 4.59 (d, J=17.5 Hz, 1H), 4.16 (d, J=17.5 Hz, 1H), 3.1-2.8 (m, 2H); 13C NMR (DMSO-d6) 171.3, 167.0, 140.7, 132.2, 131.4, 128.6, 127.9, 127.5, 126.9, 123.5, 122.8, 51.5, 46.3, 37.9; Anal. Calcd for C17H16N2O2: Theory C, 72.84; H, 5.75; N, 9.99. Found: C, 72.46; H, 5.68; N, 9.91.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@H:10]([CH:14]2[CH2:17][NH:16][CH2:15]2)[CH:11]([CH3:13])[CH3:12])[CH:6]=[C:7]([F:9])[CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:25]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]>C(#N)C>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([C@H:25]([N:16]2[CH2:15][CH:14]([C@@H:10]([C:5]3[CH:6]=[C:7]([F:9])[CH:8]=[C:3]([F:2])[CH:4]=3)[CH:11]([CH3:13])[CH3:12])[CH2:17]2)[C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:39][CH:38]=1
Reactant: CC(C)[C@H](c1cc(F)cc(F)c1)C1CNC1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 106 mg (0.5 mmole) of 3-[(1S)-1-(3,5-difluorophenyl)-2-methylpropyl]azetidine hydrochloride from Step 3 and 0.650 g (2 mmole) of Cs2CO3 in 5 mL dry acetonitrile was stirred at rt in a flask fitted with a small Dean-Stark trap. After 15 minutes, 0.306 g (1 mmole) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile was added and the mixture was heated at 60° C. After 18 h, the solution was partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over Na2SO4. The solution was filtered and the filtrate was concentrated to an oil. The residue was purified by chromatography on a Chiralpak-AD column using 4% isopropanol-heptane to afford two enantiomers. Fractions containing the slower product diastereomer were pooled and concentrated to afford the title compound; Mass Spectrum: m/e=451 (M+1, 35Cl) and 453 (M+1, 37Cl).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10]C(=O)CCC(=O)C1C=CC=CC=1)[C:3]([NH2:5])=[O:4].[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[C:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]([NH2:1])[C:3](=[O:4])[NH2:5])=[O:32])=[CH:33][CH:34]=1)(=[O:25])[CH3:24]
Reactant: NC(=O)[C@@H](N)CCCCNC(=O)CCC(=O)c1ccccc1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: CC(=O)c1ccc(C(=O)NCCCC[C@H](N)C(N)=O)cc1

Procedure:
1.65 g of the title compound was prepared as described for (2S)-2-amino-6-(4-oxo-4-phenylbutyrylamino)hexanoic acid amide, using 4-acetylbenzoic acid instead of benzoylpropionic acid.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][N:6]=1.O>CO>[CH3:1][O:2][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][N:6]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C)c([N+](=O)[O-])cn1
Yield: 55.1 %

Procedure:
Sodium methoxide (26.1 g) was added to a solution of 2-chloro-4-methyl-5-nitropyridine (19.0 g) in methanol (100 ml) and the resulting mixture was refluxed for 12 hours. Upon cooling, the mixture was poured over water (1 L), and the product was extracted with ethyl acetate and washed with water. The organic phase was dried (anhydrous magnesium sulfate) and concentrated, and the residue dissolved in hot ether and filtered. Crystallization from ether provided 10.2 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[CH3:25][C:26]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:27]=1[C:28]([NH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][C:32]=1[Cl:40])=[O:29]>C(Cl)Cl>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:35]([C:34]3[CH:38]=[CH:39][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:41]=[CH:42][CH:43]=[C:44]([F:45])[C:26]=4[CH3:25])=[C:32]([Cl:40])[CH:33]=3)=[O:36])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Reactant: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
A mixture of 1.0 g of 6,11-dihydro-5H-dibenz-[b,e]azepine, 0.80 g of N,N-diisopropylethylamine and 2.01 g of 4-[(2-methyl-3-fluorobenzoyl)amino]-3-chloro-benzoyl chloride in 100 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water, saturated NaHCO3, dried (Na2SO4) and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 1.79 g of the desired product as a crystalline solid, m.p. 254°-256° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1)=[O:14].[N:30]1([C:34]([C:36]2[S:37][C:38](Br)=[CH:39][CH:40]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1>>[N:30]1([C:34]([C:36]2[S:37][C:38]([C:18]3[CH:19]=[CH:20][C:15]([C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@H:8]4[CH2:7][N:3]4[CH2:4][CH2:5][CH2:6][C@H:2]4[CH3:1])=[O:14])=[CH:16][CH:17]=3)=[CH:39][CH:40]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C(c1ccc(Br)s1)N1CCC1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ccc(C(=O)N3CCC3)s2)cc1
Yield: 21 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure A using [2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (367 mg, 0.92 mmol) and azetidin-1-yl-(5-bromo-thiophen-2-yl)-methanone) (226 mg, 0.92 mmol) to give 80 mg (21% yield). MS (ES+) 438.3 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][CH2:13][CH2:14][O:15]C(=O)C.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>CO.O>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CC(=O)OCCCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=Cc1ccc(OCCCCO)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 908.7 %

Procedure:
In a 1 L three neck distillation flask, p-hydroxybenzaldehyde (24.4 g, 20 mmol), 4-chlorobutylacetate (36.1 g, 240 mmol), potassium carbonate (33.2 g, 240 mmol) and dimethylformamido (150 ml) were placed and stirred for 3 hours at 120° C. After the reaction mixture was cooled, water was added and the resulting mixture was extracted with ethyl acetate. The solvent was removed to obtain an oily product. The product was dissolved in methanol (100 ml), and potassium hydroxide (22.4 g, 0.4 mmol) dissolved in water (50 ml) was dropwise added to the solution. The mixture was refluxed for 2 hours, and then cooled. Water was added and the resulting mixture was extracted with ethyl acetate. The solvent was removed to obtain an oily product. The product was purified through column chromatography to prepare the titled compound (35.3 g, yield: 91%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].Cl[CH2:10][C:11]1[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH:15]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([N:14]2[CH:15]=[C:11]([CH2:10][N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])[CH:12]=[N:13]2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: ClCc1cnn(-c2ccc(Cl)c(Cl)c2)c1
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Product: Cc1nccn1Cc1cnn(-c2ccc(Cl)c(Cl)c2)c1

Procedure:
2-Methylimidazole was deprotonated with sodium hydride and then treated with 4-chloromethyl-1-(3,4-dichloro-phenyl)-1H-pyrazole. Extractive and chromatographic workup gave the title compound as a white crystalline solid. Mp. 176-177° C. (AcOEt), MS: m/e=307(M+H+).
Reaction SMILES: Cl.[CH3:2][C:3]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:7])[C:4]([OH:6])=O.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[CH2:28]([N:30]([CH2:31][CH3:32])[C:4](=[O:6])[C:3]([CH3:2])([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)[CH3:7])[CH3:29]
Reactant: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)O)ccc21
Reactant: CCNCC
Agent: Cl
Product: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)N(CC)CC)ccc21

Procedure:
The above compound was prepared from 2-methyl-2-[2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-5-yloxy]propanoic acid hydrochloride and diethylamine using a procedure analogous to that of Example 128.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:21].C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C>[Br:29][C:9]1[C:8]2[N:7]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:5][C:4]=2[C:3]([NH2:21])=[C:2]([CH3:1])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N)c(C)ccc32)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N)c(C)cc(Br)c32)cc1
Temperature: 0 °C

Procedure:
To a solution of 5-methyl-1-tosyl-1H-indol-4-amine (Example 110-F) (1.06 g, 3.53 mmol) in DMF (35.3 mL) at 0° C. was added NBS (0.628 g, 3.53 mmol), and the mixture was stirred at 0° C. After 5 minutes the reaction was quenched with sat. aq. NaHCO3, then with sat. aq. sodium thiosulfate, extracted with EtOAc (2×), dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-80% EtOAc in heptanes) to provide the title compound, which was used in the next reaction without any further purification. MS (ESI+) m/z 379.0, 380.9 (M+H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:13][C:14]1[N:15]=[C:16]([CH:19]2[CH2:24][CH:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)[CH2:22][N:21]([C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:20]2)[S:17][CH:18]=1>CN1CCCC1=O>[CH:1]1([NH:4][CH2:13][C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH:23]([C:25]4[CH:26]=[CH:27][C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=4)[CH2:22][N:21]([C:33]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[O:34])[CH2:20]3)[S:17][CH:18]=2)[CH2:3][CH2:2]1
Reactant: CCc1ccc(C2CC(c3nc(CCl)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC1CC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCc1ccc(C2CC(c3nc(CNC4CC4)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
24 mg (0.411 mmol) of cyclopropylamine and 70 mg (0.685 mmol) of triethylamine were added to a solution of 119 mg (0.274 mmol) of the compound from Example 141A in 2 ml of N-methylpyrrolidone. The reaction mixture was stirred at 80° C. overnight. Diastereomer separation of 13 mg of the cis/trans isomer mixture according to Method 15C gave 5 mg of the title compound.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[OH:3].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CO.O.O>[OH:3][CH:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[C:1]([O:9][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:8]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)C[C@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: COc1ccc(COC(=O)C(O)CC(C)C)cc1
Reaction time: 8 h

Procedure:
To D/L-leucic acid (7.58 g, 57.36 mmol) in MeOH/H2O (9:1, 100 mL) was added a 20% solution of Cs2CO3 in water until the pH reached 7.0. The reaction mixture was concentrated in vacuo to dryness, DMF was added and concentrated in vacuo to dryness again. The solid was suspended in DMF (100 mL) at 0° C., 4-methoxybenzyl chloride (7.8 mL, 51.6 mmol) was added dropwise and the reaction mixture stirred overnight. The mixture was added to water and the product extracted with Et2O, dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 2/8, then 3/7) to afford 4-methoxybenzyl 2-hydroxy-4-methylpentanoate.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].[NH3:24]>C1COCC1>[NH2:24][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(S(=O)(=O)Cl)c1
Reactant: N
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(S(N)(=O)=O)c1
Reaction time: 18 h

Procedure:
To a solution of methyl 3-(chlorosulfonyl)-5-[(dipropylamino)carbonyl]benzoate (XXXVII, PREPARATION 11, 0.100 g, 0.300 mmol) in dry THF (3 mL) is added ammonia (7 N solution in methanol, 0.214 mL, 1.50 mmol). The mixture is stirred for 18 hours and solvent is then removed. The residue is partitioned between ethyl acetate and water. The organic phase is separate and washed with saline, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound, NMR (300 MHz, CDCl3) delta 8.45, 8.07, 8.01, 6.05, 3.93, 3.44, 3.09, 1.67, 1.52, 0.96 and 0.73; MS (ESI+) for C12H22N2O5S m/z (M+H)+=343.3.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[N:15]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:27])[CH:12]=2)[N:7]=1>CS(C)=O>[CH3:1][NH:2][C:3]([NH:5][C:6]1[N:15]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:27])[CH:12]=2)[N:7]=1)=[O:4]
Reactant: Nc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Reactant: CN=C=O
Solvent: CS(C)=O
Product: CNC(=O)Nc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 12.3 %

Procedure:
4 ml of dimethyl sulfoxide and 260 mg of methyl isocyanate were added to 500 mg of 2-amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was stirred at 50° C. for 3 hours and distilled under a reduced pressure to remove excess methyl isocyanate, followed by the addition of chloroform and water. The mixture thus obtained was filtered and the filtrate was extracted with chloroform twice. The organic layers were combined, washed with water twice, dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (benzene/acetone) and recrystallized (from benzene/chloroform/ethanol) to give 72 mg of the title compound.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:26]([O:28][CH3:29])=[O:27])=[CH:11][C:12]([CH:23]2[CH2:25][CH2:24]2)=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:14]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1>[CH:23]1([C:12]2[CH:11]=[C:10]([C:26]([O:28][CH3:29])=[O:27])[C:9]([OH:8])=[CH:14][C:13]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:25][CH2:24]1
Reactant: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)cc1O
Yield: 95.8 %

Procedure:
A mixture of methyl 5-(benzyloxy)-2-cyclopropyl-2′,4′-difluorobiphenyl-4-carboxylate (20.3 g), 10% palladium carbon (containing 55% water, 10.0 g), and THF (100 mL) was stirred at room temperature for 1 hour in a hydrogen atmosphere of balloon pressure. The catalyst was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (15.0 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH3:22])[C:17](I)=[C:18]([CH3:20])[CH:19]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[Br:13][C:14]1[CH:15]=[C:16]([CH3:22])[C:17]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:18]([CH3:20])[CH:19]=1
Reactant: Brc1ccccc1
Reactant: Cc1cc(Br)cc(C)c1I
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
2.5 M n-Butyllithium, in tetrahydrofuran, (1.42 ml, 3.54 mmol, 1.1 equiv.) was added dropwise to a solution of bromobenzene (0.34 ml, 3.22 mmol, 1.0 equiv.) in dry tetrahydrofuran (18 ml), under nitrogen at −78° C. and the mixture stirred for 30 minutes. Zinc chloride (0.48 g, 3.54 mmol, 1.1 equiv.) was added and the mixture allowed to warm to room temperature while stirring for 2 hours. Palladium tetrakistriphenylphosphine (0.19 g, 0.16 mmol, 0.05 equiv.) and a solution of 5-bromo-2-iodo-1,3-dimethyl-benzene (1.00 g, 3.22 mmol, 1.0 equiv.) in tetrahydrofuran (2 ml) were added and the mixture stirred at room temperature for 16 hours. The tetrahydrofuran was evaporated under reduced pressure and the crude product purified by column chromatography (SiO2, heptane). The fractions were combined to afford 4-bromo-2,6-dimethylbiphenyl, 278 mg (33% yield) as a clear oil δH (400 MHz; d4-methanol) 7.28-7.39 (3H, m), 7.18 (2H, s), 7.03 (2H, d), 1.90 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=[O:5].O.[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:5]
Reactant: COC(=O)CCCCCNC(=O)c1cccc(-c2ccc(OC)cc2OC)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cccc(C(=O)NCCCCCC(=O)O)c2C)c(OC)c1
Yield: 93.4 %

Procedure:
The procedure of the step 2 in Example 92 was repeated except that methyl 6-(2-methyl-3-(2,4-dimethoxyphenyl)-benzamido)hexanoate (30 mg, 0.075 mmol) and lithium hydroxide monohydrate (6 mg, 0.15 mmol) were dissolved in 3 mL of THF/H2O (2:1) to obtain the title compound (27 mg, 94%).