Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14]C)[C:9]#[N:10]>ClCCl>[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[C:9]#[N:10]
Reactant: COc1ccc(C#N)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1ccc(O)c(F)c1
Reaction time: 8 h
Yield: 91.2 %

Procedure:
BBr3 (23 mL, 0.242 mol) was added to 3-fluoro-4-methoxy-benzonitrile (24.4 g, 0.16 mol; see step (iii) above) in dichloromethane (200 mL) at −78° C. Stirring was continued at room temperature overnight. Another portion of BBr3 (23 mL, 0.242 mol) was added at −78° C. and stirring was continued at RT for a further 2 days under a nitrogen atmosphere. The reaction mixture was quenched with ice water and extracted with dichloromethane. The organic layer was washed with water and brine, and then dried over sodium sulfate. Solvent evaporation under reduced pressure gave 20 g of the sub-title compound as a solid. This was employed directly in the next step without further purification.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[N:8]1([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[C:22]4[C:23]5[CH2:24][NH:25][CH2:26][CH2:27][C:28]=5[S:29][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(Cl)(=O)C>C(Cl)Cl>[N:8]1([CH:14]2[CH2:15][CH2:16][CH:17]([O:20][C:21]3[C:22]4[C:23]5[CH2:24][N:25]([C:3](=[O:5])[CH3:2])[CH2:26][CH2:27][C:28]=5[S:29][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:18][CH2:19]2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: c1nc(OC2CCC(N3CCOCC3)CC2)c2c3c(sc2n1)CCNC3
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c2C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25.9 %

Procedure:
To a solution of 3-[[4-(morpholin-4-yl)cyclohexyl]oxy]-8-thia-4,6,12-triazatricyclo[7.4.0.0[2,7]]trideca-1(9),2 (7),3,5-tetraene trifluoroacetate (100 mg, crude) in DCM (20 mL) was added TEA (108 mg, 1.07 mmol). The solution was stirred for 10 min at 0° C. under nitrogen. Then acetyl chloride (41.9 mg, 0.53 mmol) was added to the reaction solution at this temperature and the resulting solution was stirred for 1.5 h at room temperature. The reaction was then quenched by the addition of ethanol and concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions (Waters): Column: Xbridge Prep C18, 5 μm, 19*50 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (10% CH3CN up to 35% in 11 min, up to 95% in 1.5 min, down to 10% in 1.5 min); detector: UV 254/220 nm. After concentration in vacuo and lyophilization overnight, the corresponding 1-(3-[[4-(morpholin-4-yl)cyclohexyl]oxy]-8-thia-4,6,12-triazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl)ethan-1-one (22.1 mg) was obtained as a white solid. MS (ES): m/z 417 (M+H)+ and 429 (M+Na)+. 1H NMR (300 MHz, CD3OD): δ 8.54 (1H, s), 5.33-5.23 (1H, m), 4.91 (2H, s), 3.97, 3.90 (2H, t, t), 3.76-3.69 (4H, m), 3.05, 2.95 (2H, t, t), 2.67-2.58 (4H, t), 2.34-2.25 (3H, m), 2.25, 2.23 (3H, s, s), 2.10 (2H, d), 1.74-1.45 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: O=C(O)Cc1cc(Cl)cc(Cl)c1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cc(Cl)cc(Cl)c1

Procedure:
Following General Procedure F′ above, and using 3,5-dichlorophenylacetic acid (from Example C′ above) and L-alanine iso-butyl ester hydrochloride (from Example B′ above), the title compound was prepared as a solid having a melting point of 115′-116° C. The reaction was monitored by tlc on silica gel (Rf=0.40 in 3% methanol/dichloromethane) and purification was by flash chromatography on silica gel using 3% methanol/dichloromethane as the eluant.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:21][C:18]([F:19])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:9][CH:8]([NH2:7])[CH2:11]2)=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccc(C(F)(F)F)cn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CN(c2ccc(C(F)(F)F)cn2)C1
Yield: 92.9 %

Procedure:
D6 (750 mg, 1.28 mM) in dichloromethane (5 ml) was treated with trifluoroacetic acid (5 ml) overnight at ambient temperature. The solution was concentrated and then partitioned between dichloromethane and 2M sodium hydroxide. The dichloromethane solution was washed with brine, dried and concentrated to give the title compound as a colourless solid, (477 mg).
Reaction SMILES: [OH:1][C:2]1([CH2:6][S:7]([NH2:10])(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:21]1([N:27]=[C:28]=S)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.BrN1C(=O)CCC1=O>CN1C(=O)CCC1.C1COCC1.O>[CH:21]1([NH:27][C:28]2[O:1][C:2]3([CH2:6][S:7](=[O:9])(=[O:8])[N:10]=2)[CH2:5][CH2:4][CH2:3]3)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NS(=O)(=O)CC1(O)CCC1
Reactant: S=C=NC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: O=S1(=O)CC2(CCC2)OC(NC2CCCCC2)=N1
Reaction time: 0.67 h

Procedure:
Under inert gas, 200 mg of (1-hydroxycyclobutyl)methanesulfonamide were dissolved in 2.5 ml of NMP, and admixed at −10° C. with 0.61 ml of a 2 N solution of sodium bis(trimethylsilyl)amide in THF and, after stirring for 5 minutes, with a solution of 0.19 ml of cyclohexyl isothiocyanate in 0.5 ml of NMP. After stirring at constant temperature for 40 minutes, 215 mg of N-bromosuccinimide were added in 4 portions within 5 minutes, and the reaction solution was stirred for a further 15 minutes. The reaction mixture was diluted with 60 ml of water and extracted twice with 20 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC. After lyophilization of the product-containing fractions, the product (114.7 mg) was thus obtained with a molecular weight of 272.4 g/mol (C12H20N2O3S); MS (ESI): m/e=273 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[F:30][C:29]([F:32])([F:31])[C:26]1[CH:27]=[CH:28][C:23]([O:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:13](=[O:14])[N:2]([C:3]3[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=3[C:5](=[O:6])[NH2:7])[CH3:1])=[CH:17][CH:18]=2)=[N:24][CH:25]=1
Reactant: CNc1ccccc1C(N)=O
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccccc1C(N)=O

Procedure:
The title product was prepared from 2-(methylamino)benzamide and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (57%, light yellow oil). HPLC-MS m/z=454.2 (M+Na), Rt: 3.66 min.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].ClC1[C:25](Cl)=[N:26][CH:27]=[C:28](C=1)[C:29]([OH:31])=O.N1CC[C@@H](O)C1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:1][C:2]1[C:3]([N:26]2[CH2:27][CH2:28][C@@H:29]([OH:31])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Cl)c1
Agent: O[C@@H]1CCNC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Cl)c1

Procedure:
A mixture of 5,6-dichloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (prepared from 5,6-dichloronicotinic acid in an analogous fashion to that described in Stage 6.2, 1.5 g, 4.27 mmol) and (R)-pyrrolidin-3-ol (447 mg, 5.13 mmol), iPrOH (10 mL) and DIPEA (1.104 g, 8.54 mmol) were subjected to MW irradiation at 140° C. for 60 min. The RM was quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered and the filtrate was evaporated off under reduced pressure to afford the title compound as a beige powder. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.85-1.97 (m, 2H) 3.59 (d, J=12 Hz, 1H) 3.7-3.8 (m, 1H) 3.8-3.95 (m, 2H) 4.35-4.40 (m, 1H) 5.00 (s, 1H) 7.35 (d, J=2 Hz, 2H) 7.86 (d, J=2 Hz, 2H) 8.17 (s, 1H) 8.66 (s, 1H) 10.22 (s, 1H).
Reaction SMILES: C(O[K])(C)(C)C.[CH2:7]([O:9][C:10]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([C:20]([O:22]CC)=O)[CH2:15]1)=[O:11])[CH3:8].CCO>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10]([C:12]1[CH2:13][N:14]2[CH2:15][CH:16]([C:20]=1[OH:22])[CH2:17][CH2:18][CH2:19]2)=[O:11])[CH3:8]
Reactant: CCOC(=O)CCN1CCCC(C(=O)OCC)C1
Agent: CC(C)(C)O[K]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(O)C2CCCN(C1)C2
Yield: 40.1 %

Procedure:
A suspension of tert-BuOK (505 mg, 4.5 mmol) in anhydrous toluene (4.5 mL) was refluxed (1 h) and then an anhydrous toluene solution (1.5 mL) of 15a (386 mg, 1.5 mmol) was added (20 min) and the reaction mixture was refluxed for an additional 3 h, and then cooled. EtOH (2 mL) was added, and the reaction was filtered (Celite pad) and concentrated in vacuo. The residue was purified by PTLC (5% MeOH—CHCl3) to give 4 (127 mg, 40%) as a yellow oil: Rf 0.21 (5% MeOH—CHCl3); IR (neat) 2932, 2857, 1656, 1292, 1207 cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.25 (t, J=7.1 Hz, 3H, CH2CH3), 1.55-1.64 (m, 2H, C(7)H2), 1.65-1.73 (m, 1H), C(6)HH′), 1.84-1.86 (m, 1H, C(6)HH′), 2.19 (br s, 1H, C(5)H), 2.89 (d, J=13.0 Hz, 1H), C(9)HH′), 2.90-2.96 (m, 2H, C(8)H2), 2.96 (d, J=13.0 Hz, 1H, C(9)HH′), 3.24 (d, J=16.8 Hz, 1H, C(2)HH′), 3.73 (d, J=16.8 Hz, 1H, C(2)HH′), 4.17 (q, J=7.1 Hz, 2H, CH2CH3), 11.83 (br s, 1H, C(4)OH), the 1H NMR assignments were consistent with the COSY spectrum; 13C NMR (CDCl3, 150 MHz) 14.2 (CH2CH3), 19.1 (C(7)), 26.6 (C(6)), 32.2 (C(5)), 49.5 (C(2)), 51.4 (C(9)), 55.2 (C(8)), 60.2 (CH2CH3), 99.3 (C(3)), 170.6 (C(O)), 172.1 (C(4) ppm, the assignments were consistent with the DEPT, HMQC and HMBC spectra; MS (+CI) 212 [M+1]+; Mr (+CI) 212.128 08 [M+1]+ (calcd for C11H18NO3 212.128 67). Anal. (C11H17NO3): C, H, N.
Reaction SMILES: C[O:2][C:3](=[O:43])[C@@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[C:33]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[CH3:6][CH:5]([CH3:7])[C@H:4]([NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[C:33]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:3]([OH:43])=[O:2]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(N5CCOCC5)c4c3C)cc2)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc3)cc2)oc2cccc(N3CCOCC3)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 96 %

Procedure:
To 160 mg of (S)-3-methyl-2-{4′-[(3-methyl-4-morpholin-4-yl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid methyl ester was added 1 mL of THF and 3 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature for 4 days. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried under vacuum to give 150 mg of (S)-3-methyl-2-{4′-[(3-methyl-4-morpholin-4-yl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid, obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=14.1, 6.8 Hz, 6 H) 2.0 (dd, J=12.1, 6.8 Hz, 1 H) 2.8 (s, 3 H) 3.0 (m, 4 H) 3.5 (m, 1 H) 3.8 (m, 4 H) 7.0 (d, J=7.8 Hz, 1 H) 7.4 (d, J=8.3 Hz, 1 H) 7.4 (m, 1 H) 7.8 (d, J=8.6 Hz, 2 H) 7.8 (m, 4 H) 8.0 (d, J=9.1 Hz, 3 H) 10.5 (s, 1 H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[OH:13])[NH:9][C:8](=[O:14])[CH2:7]2)(=O)[CH3:2].[N:15]1C=CC=CC=1.O>CN(C)C=O>[CH3:2][C:1]1[C:4]2[CH:5]=[C:6]3[CH2:7][C:8](=[O:14])[NH:9][C:10]3=[CH:11][C:12]=2[O:13][N:15]=1
Reactant: c1ccncc1
Reactant: CC(=O)c1cc2c(cc1O)NC(=O)C2
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc2cc3c(cc12)CC(=O)N3
Yield: 64.9 %

Procedure:
A mixture of the oxime acetate formed in step c (4.48 g, 18.0 mmol) and pyridine (14.6 mL, 180 mmol) in dimethylformamide (DMF) (660 mL) was heated at 125°-130° C. for 4 hours. The cooled reaction mixture was poured over water and extracted with EtOAc (4 times). The combined organic layer was washed with water and brine and dried (MgSO4), filtered, and concentrated. Purification by silica gel flash chromatography (50% EtOAc/hexanes→100% EtOAc) gave the title compound (2.20 g, 65%) as a pale yellow-orange solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[CH3:22])=[O:4].[CH2:24]([NH:26][CH3:27])[CH3:25]>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:22])[CH:10]=1)[N:7]=[C:6]([N:26]([CH2:24][CH3:25])[CH3:27])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1c(Cl)nc2c(C)cc(Cl)cc2c1-c1ccccc1
Reactant: CCNC
Product: CCN(C)c1nc2c(C)cc(Cl)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 40 step D from 2,6-dichloro-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 40 step C) and ethyl-methyl-amine. Yellow foam. MS (ESI): 355.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:13][NH:14]C(=O)OC(C)(C)C)#[N:2].[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:14][CH2:13][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(F)(F)F)c1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(CN)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl {[2-cyano-3-(trifluoromethyl)phenyl]methyl}carbamate (0.190 g, 0.63 mmol) was dissolved in dichloromethane (4 ml) and treated with trifluoroacetic acid (4 ml). The mixture was stirred at room temperature for 1 hr and then evaporated. The residue was twice taken up in dichloromethane and evaporated again to give crude 2-(aminomethyl)-6-(trifluoromethyl)benzonitrile trifluoroacetate which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1>CO>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H]1CCCN1
Reaction time: 12 h

Procedure:
To a solution of Example 29B (140 mg, 0.28 mmol.) in methanol (2 mL) was added hydrogen chloride in dioxane (0.5 mL, 2.000 mmol) and stirred for 12 hr. The solvent was removed under reduced pressure and the residue recrystallized from methanol:diethyl ether to provide the title compound as a hydrogen chloride salt. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 1.68-1.79 (m, 1H) 1.87-2.01 (m, 2H) 2.03-2.12 (m, 1H) 3.14-3.28 (m, 2H) 3.81 (s, 3H) 3.93-4.06 (m, 1H) 4.47 (d, J=6.44 Hz, 2H) 7.14 (d, J=9.16 Hz, 1H) 7.45-7.50 (m, 2H) 7.63 (d, J=2.71 Hz, 1H) 9.29 (d, J=4.41 Hz, 2H); MS (DCI) m/z 408 (M+H)+. Anal. calcd for C20H26ClN3O2S.2 HCl.1.0 H2O: C, 48.15; H, 6.06; N, 8.42. Found: C, 48.00; H, 6.04; N, 8.27.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.OC1C=C([O:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])(=[O:23])=[O:22])C=CC=1.C(C1C=C(C=CC=1)CO)#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[S:21]([OH:23])(=[O:22])=[O:20]
Reactant: O=S(=O)(Oc1cccc(O)c1)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N#Cc1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(O)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 194.7 %

Procedure:
Diethyl azodicarboxylate (174 mg, 1.0 mmol) was added to a solution of 2-chlorobenzenesulfonic acid 3-hydroxyphenyl ester (285 mg, 1.0 mmol), as prepared in the preceding step, 3-cyanobenzyl alcohol (133 mg, 1.0 mmol)(Yoon et al., J. Org. Chem. 38:2786-2792 (1973)), and triphenylphosphine (263 mg, 1.0 mmol) in tetrahydrofuran (10 mL) at 0° C. The mixture was stirred at 0° C. for 2 hours and at room temperature for 3 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×30 mL). The organic phase was washed with saturated NaHCO3 (2×30 mL), brine (2×30 mL) and dried over Na2SO4. The solvent was removed in vacuo the residue was purified by flash column chromatography (2:1 ethyl acetate:hexane) to give the title compound as a pale yellow oil (375 mg, 93%). 1H-NMR (300 MHz, CDCl3) δ 5.02 (s, 2 H), 6.78 (m, 2 H), 6.85 (dd, 1H, J=4.2, 1.3 Hz), 7.20 (t, 1H, J=8.2 Hz), 7.38 (t, 1H, J=5.8 Hz), 7.51 (t, 1H, J=7.7 Hz), 7.59-7.68 (m, 5 H) and 7.93 (dd, 1 H, J=4.0, 0.7 Hz).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Br[C:11]1[CH:39]=[C:38]([N+:40]([O-:42])=[O:41])[CH:37]=[C:36]([Br:43])[C:12]=1[CH2:13][N:14]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34]C)=[CH:29][CH:28]=1)[C:15]([NH:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])=[O:16]>CN(C=O)C.[Cu]I>[Br:43][C:36]1[CH:37]=[C:38]([N+:40]([O-:42])=[O:41])[CH:39]=[C:11]2[C:12]=1[CH2:13][N:14]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[C:15](=[O:16])[N:17]2[C:18]1[C:19]([Cl:25])=[CH:20][CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: CCOc1ccc(CN(Cc2c(Br)cc([N+](=O)[O-])cc2Br)C(=O)Nc2c(Cl)cccc2Cl)cc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(Br)cc([N+](=O)[O-])cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 130 °C

Procedure:
Diisopropylethylamine (1.78 g, 13.8 mmol) and CuI (2.63 g, 13.8 mmol) was added to N-(2,6-dibromo-4-nitrobenzyl)-N′-(2,6-dichlorophenyl)-N-(4-ethoxybenzyl)urea (4.25 g, 6.88 mmol) in DMF (150 mL). After evacuating and flushing three times with argon, the reaction mixture was heated to 130° C. for 3 h, cooled to rt, and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography on Biotage 40M columns, eluting with 80:20 hexanes-acetone to yield 5-bromo-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-7-nitro-3,4-dihydroquinazolin-2(1H)-one. Mass spectrum (ESI) 536.0 (M+1).
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][S:13][C:12]3=[N:15][CH:16]=[C:17]([C:18]([OH:20])=O)[N:11]23)=[CH:6][CH:5]=1)#[N:3].[C:21]1([S:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>>[ClH:1].[C:21]1([S:27][CH2:28][CH2:29][NH:30][C:18]([C:17]2[N:11]3[C:12]([S:13][CH2:14][CH:10]3[C:7]3[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][CH:8]=3)=[N:15][CH:16]=2)=[O:20])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCSc1ccccc1
Reactant: N#Cc1ccc(C2CSc3ncc(C(=O)O)n32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C2CSc3ncc(C(=O)NCCSc4ccccc4)n32)cc1
Reaction time: 0.25 h

Procedure:
The carboxylic acid from Step D, Example 1 (20.0 mg, 0.0625 mmol), 2-aminoethyl phenyl sulfide (9.6 mg, 0.0625 mmol), EDC hydrochloride (14.4 mg, 0.0751 mmol), HOBT (10.1 mg, 0.0751 mmol), and N,N-diisopropylethylamine (0.044 mL, 0.250 mmol) were stirred in dry, degassed DMF (1 mL) at 25° C. for 16 hours. The crude product was purified by preparative HPLC using a gradient of 5%-95% acetonitrile/0.1% TFA; 95%-5%/0.1% aqueous TFA over 15 min. The title compound was isolated after conversion to the HCl salt. MS (es) m+1=407. 1H-NMR (CD3OD): δ7.77 (s, 1H); 7.74 (d, 2H, J=8.3 Hz); 7.25-7.33 (m, 6H); 7.18 (t, 2H, J=7.2 Hz); 6.44 (bd, 1H, J=8.6 Hz); 4.77 (dd, 1H, J=11.8, 8.9 Hz); 3.91 (d, 1H, J=11.8 Hz), 3.40 (ddd, 2H, J=13.6, 6.8, 4.3 Hz); 3.00 (t, 2H, J=6.8 Hz).
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([CH2:11][C:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:15]3[CH:33]=[C:34]([O:39]C)[C:35]([O:37]C)=[CH:36][C:14]=3[N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>ClCCl>[CH:5]1([CH2:11][C:12]2[N:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][CH:23]=3)[C:15]3[CH:33]=[C:34]([OH:39])[C:35]([OH:37])=[CH:36][C:14]=3[N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1cc2nc(CC3CCCCC3)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1ccccc1-c1ccc(Cn2c(CC3CCCCC3)nc3cc(O)c(O)cc32)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.29 ml (3 mmol) of boron tribromide is added dropwise to a suspension of 242 mg (0.5 mmol) of 4'-[(2-cyclohexylmethyl-5,6-dimethoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid in 25 ml of dichloromethane at -5° C. When the addition is complete, the cooling bath is removed and the mixture is stirred at ambient temperature for 5 hours. 20 ml of methanol are then added while the mixture is cooled with ice, then the reaction mixture is evaporated to dryness and the residue is suspended in 10 ml of water while stirring. The crude product precipitated is filtered off under suction, washed with a further 10 ml of water, dried and chromatographed over a silica gel column (eluting agent: dichloromethane/ethanol=9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:15])[CH2:13]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:10][O:11][C:12](=[O:15])[CH2:13][NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CNCc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 4-chloro-benzylamine (1 eq.) in MeCN was added bromo-acetic acid methyl ester (1 eq.), K2CO3 (1.5 eq.) and KI (0.1 eq.). The reaction was stirred for 15 h at 20° C. The crude was concentrated under reduced pressure then partitioned between water and EtOAc. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 8/2) to afford (4-chloro-benzylamino)-acetic acid methyl ester.
Reaction SMILES: [N:1]([CH2:4][CH:5]([O:8][CH3:9])[O:6][CH3:7])=[C:2]=[S:3].[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH2:18])=[CH:13][CH:12]=1>O1CCCC1>[CH3:7][O:6][CH:5]([O:8][CH3:9])[CH2:4][NH:1][C:2]([NH:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=1)=[S:3]
Reactant: COC(CN=C=S)OC
Reactant: NCc1ccc(F)cc1
Solvent: C1CCOC1
Product: COC(CNC(=S)NCc1ccc(F)cc1)OC
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of 4.8 parts of 1-isothiocyanato-2,2-dimethoxyethane, 4.2 parts of 4-fluorobenzenemethanamine and 90 parts of tetrahydrofuran was stirred overnight. The reaction mixture was evaporated, yielding 8.9 parts (99%) of N-(2,2-dimethoxyethyl)-N'-[(4-fluorophenyl)methyl]thiourea (188).