Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[O:13])[CH:6]=[N:5]2.[OH:14]O>C(O)=O.Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[N:5]2
Reactant: OO
Reactant: O=Cc1cnc2cc(F)ccc2n1
Agent: Cl
Solvent: O=CO
Product: O=C(O)c1cnc2cc(F)ccc2n1
Temperature: 0 °C
Yield: 45 %

Procedure:
Using the method of Dodd (Synthesis, 1993, 295-297), a solution of 6-fluoroquinoxaline-2-carboxaldehyde (71 mg, 0.4 mmol) in formic acid (2 mL) was cooled in an ice bath and treated with hydrogen peroxide (2 mL of 30%). The reaction was stirred in the ice bath for 3 hours. After this time the reaction mixture was diluted with 10% HCl (25 mL) and extracted with dichloromethane (4×25 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated to afford 35 mg (45%) of 6-fluoroquinoxaline-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:15])[CH2:7][CH:8]2[CH2:11][C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl.C1C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:15])[CH2:7]/[C:8]/2=[CH:11]\[C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: NC(=O)CC1CC(=O)c2ccc(F)cc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: NC(=O)/C=C1\CC(=O)c2ccc(F)cc21
Temperature: 120 °C
Yield: 109.7 %

Procedure:
A mixture of 2-(6-fluoro-3-oxo-1-indanyl)acetamide (0.750 g, 0.0036 mol), N-bromosuccinimide (0.750 g, 0.0042 mol, Aldrich), benzoyl peroxide (0.270 g, 0.0011 mol, Aldrich) in tetrachloromethane (37 ml) and benzene (37 ml) was stirred while heating with an oil bath at 120° C. for 20 min. This reaction was combined with a similarly run reaction (except 0.0024 mol scale). The solution was slurried with Silica Gel 60 and the volatiles were removed by spin evaporation in vacuo. This silica gel was then applied to a column of Silica Gel 60 (51×450 mm) wet with dichloromethane and the product was removed by elution with methanol:dichloromethane (3:97). After the volatiles were removed from the combined fractions containing product by spin evaporation in vacuo, the residue was recrystallized from methanol to give 0.810 g (58%) of (E)-2-(6-fluoro-3-oxo-1-indanylidene)acetamide: m.p., 235° C. (dec.);
Reaction SMILES: [CH2:1]([S:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])[CH3:2].C(N=C=NC(C)C)(C)C.[C:22]([O:26][C:27]([NH:29][C@H:30]([C:35](=[O:46])[O:36][C:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:39])[CH3:38])[CH2:31][C:32](O)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C1C=CN=CC=1.ClCCl>[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH2:31][C:32]([O:12][C:6]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]=1[S:4][S:3][CH2:1][CH3:2])=[O:33])[C:35]([O:36][C:37]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([CH3:39])[CH3:38])=[O:46])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)c1ccccc1
Reactant: CCSSc1cccc(C)c1O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCSSc1cccc(C)c1OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
2-(Ethyldisulfanyl)-6-methylphenol (Compound 105) (423 mg, 2.11 mmol), N,N′-diisopropylcarbodiimide (0.329 ml, 2.11 mmol) and N,N-dimethylpyridin-4-amine (34.4 mg, 0.282 mmol) were added to a solution of (S)-3-((tert-butoxycarbonyl)amino)-4-oxo-4-((2-phenylpropan-2-yl)oxy)butanoic acid (Compound 109) (495 mg, 1.41 mmol) in dichloromethane (7 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was then purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→0/100) to afford 4-(2-(ethyldisulfanyl)-6-methylphenyl) 1-(2-phenylpropan-2-yl) (S)-2-((tert-butoxycarbonyl)amino)succinate (Compound 110) (249 mg, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C@H:4]([CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[N:5]=C(OC)[C@@H](C(C)C)N=1.FC(F)(F)C(O)=[O:28]>O.C(#N)C>[NH2:5][C@@H:4]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]([O:2][CH3:1])=[O:28]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1ccc2ncccc2c1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@@H](N)Cc1ccc2ncccc2c1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a solution of #211 (7.3 g, 22.5 mmol, 1 eq.) in water (25 mL) and acetonitrile (80 mL) was added trifluoroacetic acid (9 mL) at 0° C. and the solution was stirred at 10° C. overnight. The organic layer was removed in vacuo and the remaining aqueous layer was basified to pH 9 with sodium carbonate, which was directly used for the next step.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:19]I>CN(C)C=O>[CH3:18][C:12]([C:9]1[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=1)([CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A suspension of 924 (23 mmol) of sodium hydride (60% in oil) in 21 mL of dry N,N-dimethylformamide was stirred under nitrogen in an ice bath as a solution of 4.68 g (21 mmol) of ethyl (+/-)-2-(4-nitrophenyl)propionate in 20.5 mL of dry N,N-dimethylformamide was added gradually over about 10 minutes. An intense violet color developed during the addition. The mixture was then allowed to warm to room temperature. After about 1 hour, the mixture was again cooled in an ice bath as a solution of 1.44 mL (3.28 g; 23 mmol) of methyl iodide in 5 mL of dry N,N-dimethylformamide was added dropwise by syringe over about 10 minutes, while maintaining the internal temperature at 10-15° C. The mixture was allowed to warm to room temperature, and the color changed to brown. After 1 hour, an additional 187 mL (426 mg, 3 mmol) of iodomethane was added. By the next day, the mixture consisted of a suspension of some grayish solid in a golden liquid. It was stirred vigorously and quenched by gradual addition of 10 mL of 5% aqueous potassium bisulfate solution. The mixture was partitioned between 400 mL of diethyl ether and 400 mL of water. The organic layer was washed with an additonal 3×400 mL of water and then with 50 mL of saturated aqueous sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue on silica gel (elution with 19:1 hexane-ethyl acetete) yielded 4.31 g (87%) of an oil; homogeneous by TLC in 9:1 hexane-ethyl acetete. 400 MHz 1H NMR (CDCl3) was consistent with the assigned structure.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])[CH:17]=[C:16]([Cl:31])[C:12]=1[C:13]([OH:15])=O.Cl.[CH3:33][C:34]([CH3:47])([O:36][C:37]([NH:39][CH2:40][C@@H:41]([C:43]([O:45][CH3:46])=[O:44])[NH2:42])=[O:38])[CH3:35].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[Cl:31][C:16]1[CH:17]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])[CH:19]=[C:11]([Cl:10])[C:12]=1[C:13]([NH:42][C@H:41]([C:43]([O:45][CH3:46])=[O:44])[CH2:40][NH:39][C:37]([O:36][C:34]([CH3:47])([CH3:35])[CH3:33])=[O:38])=[O:15]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: O=C(NCc1cccc(O)c1)c1cc(Cl)c(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
Diisopropylethylamine (14 mL, 80.6 mmol) was added to a cooled (˜0° C.) solution of 2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid (Example 29; 7.44 g, 21.9 mmol), 3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester, hydrochloride (6.15 g, 24.1 mmol), HOBT (3.12 g, 22.8 mmol), and HBTU (8.64 g, 22.8 mmol) in N,N-dimethyl-formamide (200 mL). The mixture was stirred at room temperature for 16 h. The solvent was evaporated and ethyl acetate (200 mL) was added. The solution was washed with 1 M HCl (100 mL) and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate, and brine (200 mL each), dried (MgSO4), filtered, evaporated, and chromatographed (70% ethyl acetate/hexanes) to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester (8.64 g, 73%) as a white foam.
Reaction SMILES: [N:1]#[C:2][NH2:3].[H-].[Na+].Cl[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=2)=[CH:9][C:8]=1[N+:21]([O-:23])=[O:22].[Cl-].[NH4+]>CN(C)C=O>[C:2]([NH:3][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=2)=[CH:9][C:8]=1[N+:21]([O-:23])=[O:22])#[N:1]
Reactant: COc1ccnc(-c2ccc(Cl)c([N+](=O)[O-])c2)c1
Reactant: N#CN
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccnc(-c2ccc(NC#N)c([N+](=O)[O-])c2)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 89.4 %

Procedure:
To a solution of cyanamide (101 mg) in N,N-dimethylformamide (15 ml) was added sodium hydride (60% dispersion in mineral oil, 90 mg), and the resultant suspension was stirred at ambient temperature for 30 minutes. To the suspension was added 1-chloro-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (264 mg), and the mixture was stirred at 80° C. for 4 hours. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate three times. The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, filtered and dried under reduced pressure to give N-cyano-4-(4-methoxypyridin-2-yl)-2-nitroaniline (241 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6](#[N:9])[CH:7]=[CH2:8].C=O.C#N.C=O.C#N.S([O-])(O)=O>>[C:6]([CH2:7][CH2:8][NH:1][CH2:2][CH2:3][CH2:4][OH:5])#[N:9]
Reactant: C=CC#N
Reactant: NCCCO
Agent: C#N
Agent: C=O
Agent: O=S([O-])O
Product: N#CCCNCCCO

Procedure:
75 grams (1 mole) of 3-amino-propanol were treated with 53 grams (1 mole) of acrylonitrile within one hour at 25° C. The mixture was allowed to react further for 1 hour at 40° C. The thus obtained reaction product (128 grams) was directly reacted further with formaldehyde/hydrocyanic acid or formaldehyde/alkali salt of hydrocyanic acid in the presence of alkali hydrogen sulfite.
Reaction SMILES: [Br-].[Br-].[Br-].[Al+3].[C:5]([Si:9]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[O:10][CH2:11][C:12]([C:15]1[CH:19]=[C:18]([NH:20][C:21](=[O:37])[C:22]([S:25]([CH2:28][CH:29]2[CH2:34][CH2:33][CH:32]([O:35]C)[CH2:31][CH2:30]2)(=[O:27])=[O:26])([CH3:24])[CH3:23])[O:17][N:16]=1)([CH3:14])[CH3:13])([CH3:8])([CH3:7])[CH3:6]>C(S)C>[C:5]([Si:9]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[O:10][CH2:11][C:12]([C:15]1[CH:19]=[C:18]([NH:20][C:21](=[O:37])[C:22]([S:25]([CH2:28][CH:29]2[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]2)(=[O:27])=[O:26])([CH3:24])[CH3:23])[O:17][N:16]=1)([CH3:14])[CH3:13])([CH3:6])([CH3:7])[CH3:8]
Reactant: COC1CCC(CS(=O)(=O)C(C)(C)C(=O)Nc2cc(C(C)(C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)no2)CC1
Agent: [Al+3]
Agent: [Br-]
Solvent: CCS
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(NC(=O)C(C)(C)S(=O)(=O)CC2CCC(O)CC2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
In a round bottom flask, aluminium tribromide (0.59 g, 2.2 mmol) is added portionwise to ethanethiol (3 mL), followed by a solution of 0.72 g (1.1 mmol) of N-{3-[2-(tert-Butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-isoxazol-5-yl}-2-(4-methoxy-cyclohexylmethanesulfonyl)-2-methyl-propionamide in ethanethiol (4 mL). The reaction mixture is stirred at room temperature for 1 h. The reaction is quenched by addition of 4M aqueous HCl solution (2 mL), diluted with ice water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic extracts are washed with brine, dried (MgSO4), filtered and the solvent is removed under reduced pressure. The residue is dissolved (DCM, 20% ethyl acetate) and filtered through a plug of silica to remove colouration and the filtrate is concentrated under reduced pressure to give 0.21 g of N-{3-[2-(tert-butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-isoxazol-5-yl}-2-(4-hydroxy-cyclohexylmethanesulfonyl)-2-methyl-propionamide which is used in the next step without further purification. Yield: 33%, ES-MS: 639 [M−H]
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=O.[C:23]([CH2:25][C:26]([NH2:28])=[O:27])#[N:24].CO.[H-].[Na+]>CN(C=O)C>[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:5]1[NH:28][C:26](=[O:27])[C:25]([C:23]#[N:24])=[CH:3][C:4]=1[C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Reactant: N#CCC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Temperature: 95 °C

Procedure:
A solution of 3-dimethylamino-1-(2,4-dichlorophenyl)-2-(4-chlorophenyl)prop-2-en-1-one (14.4 mmol assumed) from Step A, cyanoacetamide (1.33 g, 15.8 mmol), and methanol (1.3 mL, 32 mmol) in DMF (35 mL) was added dropwise to a suspension of sodium hydride (60% in mineral oil) (1.45 g, 36 mmol) in DMF (16 mL) at rt. After the slow addition was complete, the reaction was heated to 95° C. for 2.5 h. Most of the DMF was then removed in vacuo before the reaction was diluted with aqueous 18% citric acid solution. The mixture was extracted twice with methylene chloride and the organic layers were washed with a portion of brine. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The solid residue was triturated with ether, filtered, and air dried to afford 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-nitrile. HPLC/MS: 375 (M+1), 377 (M+3); Rt=3.47 min; 1HNMR (CDCl3): δ 6.96 (br d, J=8.4 Hz, 2H), 7.14 (d, J=8.2 Hz, 1H), 7.25 (br d, J=8.4 Hz, 2H), 7.31 (dd, J=1.9 and 8.2 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.996 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@@H:16]3[CH2:20][C@@H:19]([OH:21])[CH2:18][N:17]3C(OC(C)(C)C)=O)=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1>Cl>[F:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C@@H:16]3[CH2:20][C@@H:19]([OH:21])[CH2:18][NH:17]3)=[O:15])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
Step (b) (2S,4R)-tert-butyl 2-(4-(4-fluorophenoxy)phenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate was combined with hydrogen chloride (4N in dioxane, 20 mL) and the mixture was stirred at ambient temperature for 1 hour and then quenched with saturated sodium bicarbonate (aq., 100 mL). This mixture was extracted with ethyl acetate (30 mL) and the extract was washed with deionized water (30 mL) and then brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with ethyl acetate to give (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-hydroxypyrrolidine-2-carboxamide (1.47 g, 4.65 mmol, 51% yield) as an off-white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].C([O:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)(=O)C>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:25][CH2:24][CH2:23][CH2:22][OH:21])[CH:10]=1)=[O:8]
Reactant: O=C(Nc1nccs1)c1c[nH]c2ccccc12
Reactant: CC(=O)OCCCCBr
Product: O=C(Nc1nccs1)c1cn(CCCCO)c2ccccc12

Procedure:
The title compound was prepared using 1H-indole-3-carboxylic acid thiazol-2-ylamide and 4-bromobutyl acetate as R5X.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16](#[N:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.[I:24]I>O1CCCC1>[I:24][C:22]1[C:17]([C:16]#[N:23])=[CH:18][N:19]=[CH:20][CH:21]=1
Reactant: N#Cc1cccnc1
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cnccc1I
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2,2,6,6-tetramethyl-piperidine (42.3 g, 0.3 mol) in 2 L of tetrahydrofuran was added butyllithium (120 mL, 2.5 M, 0.3 mol) at −78° C. under N2 atmosphere. The mixture was stirred for 1 hour before a solution of nicotinonitrile (26 g, 0.25 mol) in 500 mL of tetrahydrofuran was slowly added, and the resulting mixture was stirred for 0.5 hour at −78° C. Then I2 (76.2 g, 0.3 mol) in 500 mL of tetrahydrofuran was added in a dropwise manner. After stirring for 2 hours, the mixture was quenched with 500 mL of ice-water. Tetrahydrofuran was removed under reduced pressure and the aqueous phase was extracted with ether. The organic phase was washed with brine, citric acid, brine, aqueous Na2S2O3 and brine again. After being dried over Na2SO4, the organic phase was concentrated and purified by using column chromatography on silica gel (petroleum ether:ethyl acetate, 10:1) to obtain the title compound.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.C(N(CCC)CCC)CC.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: Oc1nc(COc2ccccc2)nc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCN(CCC)CCC
Product: Clc1nc(COc2ccccc2)nc2ccccc12
Temperature: 110 °C

Procedure:
To a solution of 4-hydroxy-2-phenoxymethylquinazoline (2 g, 7.93 mmol) in phosphorus oxychloride (10 mL) is added tripropylamine (3.02 mL, 15.8 mmol) and the reaction mixture is heated for 30 minutes at 110° C. The excess phosphorus oxychloride is evaporated in vacuo, the residue is poured on ice cold aqueous NaHCO3 and extracted with ethyl acetate. The organic layer is washed with brine, dried, filtered and evaporated. The resulting residue is purified on flash chromatography (SiO2, hexane/AcOEt gradient) to give 4-chloro-2-phenoxymethylquinazoline.
Reaction SMILES: CON(C)[C:4](=[O:6])[CH3:5].[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[CH2:12][Mg]Br>CCOCC>[Br:8][C:9]1[CH:10]=[C:11]([CH2:12][C:4]([CH3:5])=[O:6])[CH:15]=[CH:16][CH:17]=1
Reactant: Br[Mg]Cc1cccc(Br)c1
Reactant: CON(C)C(C)=O
Solvent: CCOCC
Product: CC(=O)Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-methoxy-N-methylacetamide (10 g, 0.10 mol) in 200 mL of ether at 0° C. was added 3-bromobenzylmagnesium bromide (0.25 M, 200 mL, 50 mmol). After stirring at 0° C. for 2 h, the reaction mixture was partitioned between hexane and saturated aqueous ammonium chloride. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (500 MHz, CD3OD): δ 7.5-7.1 (m, 4H), 3.78 (s, 2H), 2.19 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([NH2:13])[C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1.[O-:14][C:15]#[N:16].[Na+]>O>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][C:8]=1[O:9][CH3:10])[CH2:2][NH:13][C:15]([NH2:16])=[O:14]
Reactant: COc1ccc(CN)cc1OC
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(CNC(N)=O)cc1OC
Reaction time: 8 h

Procedure:
60 ml of 5n HCl were added at room temperature within 45 min to a solution of 49.5 ml (300 mM) of 90% veratrylamine and 20.40 g (307 mM) of 98% sodium cyanate in 500 ml of water. After stirring overnight the crystals were collected: 52.66 g (83.5%) of urea with a melting point of 172-3° C. (sublimation 157° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:45](=[O:55])[N:46]([CH2:51][CH2:52][CH2:53][CH3:54])[CH2:47][CH2:48][CH2:49][CH3:50])=[N:4][N:5]([C:8]2[CH:32]=[CH:31][C:11]([C:12]([NH:14][S:15]([C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25]4)=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[O:13])=[CH:10][C:9]=2[C:33]([N:35]2[CH2:44][CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36]2)=[O:34])[C:6]=1[CH3:7].[NH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>>[CH2:47]([N:46]([CH2:51][CH2:52][CH2:53][CH3:54])[C:45]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:32]=[CH:31][C:11]([C:12](=[O:13])[NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]4[C:26](=[CH:25][C:24]([C:28]([N:56]5[CH2:61][CH2:60][O:59][CH2:58][CH2:57]5)=[O:29])=[CH:23][CH:22]=4)[CH:27]=3)(=[O:16])=[O:17])=[CH:10][C:9]=2[C:33]([N:35]2[CH2:44][CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36]2)=[O:34])[N:4]=1)=[O:55])[CH2:48][CH2:49][CH3:50]
Reactant: C1COCCN1
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(C(=O)O)cc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(C(=O)N5CCOCC5)cc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 23.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 12B of Example 12, 7-(N-(4-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoyl)sulfamoyl)-2-naphthoic acid (Intermediate 46A 12 mg, 0.015 mmol) and morpholine (4 mg, 0.046 mmol) were converted to the title compound (3 mg, 20%). 1H NMR (1:1 CD3OD:CDCl3, 2:1 mixture of amide rotamers) δ 8.67 (s, 1H), 8.21 (d, J=8.3 Hz, 1H), 8.14 (dd, J=8.7, 1.5 Hz, 1H), 8.11 (d, J=1.7 Hz, 1H), 8.06 (s, 1H), 7.98 (t, J=7.6 Hz, 2H), 7.60 (d, J=8.3 Hz, 1H), 7.44-7.42 (m, 1H), 7.19-7.09 (m, 3.5H), 6.89 (d, J=7.2 Hz, 0.5H), 4.83 (br s, 1H), 4.50 (s, 1H), 4.36 (br s, 1H), 3.79 (br s, 4H), 3.68 (br s, 3H), 3.54 (br s, 3H), 3.45 (s, 1H), 3.00 (br s, 1.5H), 2.83 (br s, 1.5H), 2.29 (s, 2H), 2.24 (s, 1H), 1.50-1.44 (m, 1H), 1.40-1.35 (m, 2H), 1.32-1.16 (m, 4H), 1.12-0.99 (m, 2H), 0.92-0.86 (m, 3H), 0.75 (t, J=7.4 Hz, 2H), 0.68 (t, J=7.4 Hz, 1H); MS(ESI+) m/z 853.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:34]=[CH:35][N:36]([CH:38]([CH3:40])[CH3:39])[CH:37]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:34]=[CH:35][N:36]([CH:38]([CH3:39])[CH3:40])[CH:37]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2ccc(-c3cn(C(C)C)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1nc2ccc(-c3cn(C(C)C)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-ethoxy-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.