Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:19])[CH3:18]>CN(C=O)C>[CH:17]([O:9][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=1)([CH3:19])[CH3:18]
Reactant: CC(C)Br
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(CO)c1
Temperature: 90 °C

Procedure:
To a mixture of 3-(hydroxymethyl)phenol (10 g) and potassium carbonate (27.2 g) in DMF (100 ml) was added 2-bromo-propane (14.8 g), the reaction was heated to 90° C. overnight. The reaction mixture was filtered and the filtrate was concentrated and purified by chromatography on silica gel, eluting with petrol:ethyl acetate=5:1.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][N:13]=2)[CH2:8]1.[CH:24]#[C:25][CH3:26]>ClCCl.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:24]#[C:25][CH3:26])=[CH:14][N:13]=2)[CH2:8]1
Reactant: Clc1ccc(CNC2CCN(c3ccc(I)cn3)C2)c(Cl)c1
Reactant: C#CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Reaction time: 8 h

Procedure:
Dissolve (2,4-dichlorobenzyl)-[1-(5-iodopyridin-2-yl)-pyrrolidin-3-yl]-amine hydrochloride (130 mg, 0.27 mmol) in dichloromethane (10 mL) and triethylamine (10 mL). Add trans-dichlorobis(triphenylphosphine)palladium (II) (10 mg, 0.014 mmol) and copper(I) iodide (3 mg, 0.016 mmol). Bubble propyne into the mixture for 1 min. Stir the mixture overnight, filter it through a pad of Celite®, concentrate and chromatograph on silica gel, eluting with 10:90 to 1:1 ethyl acetate:hexanes, to give the title compound as a residue. Dissolve the residue in methanol, add 1 N HCl in methanol (1 mL). Concentrate and dry in vacuum oven at 60° C. to give the title compound as its hydrochloride salt as a light yellow solid (95 mg, 89%). δ 1H NMR (400 MHz, MeOH-d4) δ 8.03 (d, 1H, J=1.6 Hz), 7.84 (d, 1H, J=8.8 Hz), 7.69-7.68 (m, 2H), 7.49 (dd, 1H, J=8.0, 2.2 Hz), 6.95 (d, 1H, J=9.6 Hz), 4.53-4.45 (m, 2H), 4.28-4.23 (m, 1H), 4.10-4.06 (m, 1H), 3.90-3.83 (m, 2H), 3.72-3.66 (m, 1H), 2.73-2.65 (m, 1H), 2.50-2.41 (m, 1H), 2.03 (s, 3H), MS (ES): m/z=360 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][Mg]Br.O.[Cl-].[NH4+]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([OH:14])([CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.05 mmol) in diethyl ether (20 mL) at −25 to −30° C. was added methyl magnesium bromide (3M in diethyl ether, 3.35 mL, 10.05 mmol) dropwise under argon. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. Water (20 mL) was then added dropwise, followed by saturated ammonium chloride (20 mL) and the ether layer was separated. The aqueous phase was further extracted with ether (50 mL) and the combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (2.09 g, 97%). 1H NMR (CDCl3, 300 MHz): 3.76-3.62 (m, 2H), 3.30-3.13 (m, 2H), 2.48-2.39 (m, 1H), 1.57-1.51 (m, 4H), 1.46 (s, 9H), 1.27 (s, 3H).
Reaction SMILES: NC(N)=S.[CH3:5][N:6]([CH3:19])[S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[OH:18])(=[O:9])=[O:8].[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[S:30]>>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([NH:17][C:29]([NH:28][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=2[F:20])=[S:30])=[C:11]([OH:18])[C:10]=1[S:7]([N:6]([CH3:19])[CH3:5])(=[O:9])=[O:8]
Reactant: Fc1cccc(N=C=S)c1F
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=S
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(F)c2F)c1O
Yield: 55.3 %

Procedure:
Following the general procedure for thiourea formation outlined in example 12, N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (500 mg, 2 mmol) and 2,3-difluorophenylisothiocyanate (342 mg, 2 mmol) were coupled to form the desired thiourea (467 mg, 54%). EI-MS m/z 422.2 (M+).
Reaction SMILES: [O:1]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Br:18]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:18][C:2]1[O:1][C:10]2[CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccoc2CC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2cc(Br)oc2CC1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4,5,7,8-tetrahydrofuro[3,2-d]azepine-6-carboxylate (0.21 mmol) in chloroform (0.5 mL) and acetic acid (0.5 mL) is treated with N-bromosuccinimide (0.21 mmol) at RT. After 1 hour, the reaction is poured over saturated aqueous NaHCO3, and extracted with ethyl acetate (2×5 mL). The organic layers are washed with brine, dried, and purified by silica chromatography (20% ethyl acetate/hexanes) to give tert-butyl 2-bromo-4,5,7,8-tetrahydrofuro[3,2-d]azepine-6-carboxylate.
Reaction SMILES: [CH3:1][CH:2]([CH3:35])[C@H:3]([NH:11][CH2:12][CH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[O:25][C:26]=2[CH3:27])[CH2:15]1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:36](=[O:39])([O-])[O-:37].[Na+].[Na+]>C(Cl)Cl>[CH3:21][O:20][C:16]1[CH:17]=[CH:18][C:19]([O:37][C:36]([N:11]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])[CH2:15]2)[C@@H:3]([CH:2]([CH3:35])[CH3:1])[C:4]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:5])=[O:39])=[CH:14][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(-c2nc(CO[C@@H]3CCC[C@H](CCN[C@H](C(=O)OC(C)(C)C)C(C)C)C3)c(C)o2)c1
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(OC(=O)N(CC[C@H]2CCC[C@@H](OCc3nc(-c4cccc(C)c4)oc3C)C2)[C@H](C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
130 mg of tert-butyl (S)-3-methyl-2-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyl]ethylamino}butyrate are dissolved in 1 ml of methylene chloride, 2 ml of a sat. sodium carbonate solution are added and the mixture is cooled to 0° C., an excess of the acid chloride is then added and the mixture is stirred at RT for 1 h. The entire reaction solution is applied to a kieselguhr cartridge and the cartridge is washed with 20 ml of methylene chloride. The solvent is removed under reduced pressure. This gives 0.1 g of tert-butyl (S)-2-((4-methoxyphenoxycarbonyl)-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}amino)-3-methylbutyrate.
Reaction SMILES: Br[C:2]1[C:3]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:4][N:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[C:6]=1[NH2:7].[CH3:21]B1OBOBO1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:17]([C:3]1[C:2]([CH3:21])=[C:6]([NH2:7])[N:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:4]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CB1OBOBO1
Reactant: COc1cccc(C)c1-n1nc(C(C)(C)C)c(Br)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C)c1-n1nc(C(C)(C)C)c(C)c1N
Temperature: 155 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of 4-bromo-3-tert-butyl-1-(2-methoxy-6-methylphenyl)-1H-pyrazol-5-amine (2.6 g, 7.68 mmol) in DMF (15 mL) was added methylboroxine (6.66 mL, 46.08 mmol), [1,1′-bis(diphenylphosphino)-butane]palladium (II) dichloride (481.97 mg, 0.80 mmol), and potassium carbonate (3.3 g, 23.04 mmol). The reaction mixture was stirred for 18 h at 155° C. The reaction was diluted with water (100 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 90% hexane/EtOAc, to afford the product (1.7 g, 77%) as a pure white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.24 (s, 9H), 1.96 (s, 3H), 1.99 (s, 3H), 3.71 (s, 3H), 4.25 (s, 2H), 6.85 (d, 1H), 6.94 (d, 1H), 7.23-7.29 (m, 1H). ES-MS m/z 274.2 (MH+); HPLC RT (min.) 1.78.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:10]1([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C(Cl)Cl>[O:16]([C:10]1[CH:11]=[CH:12][C:13]([C:3](=[O:4])[CH2:2][Br:1])=[CH:14][CH:15]=1)[C:17]1[CH:18]=[CH:19][C:20]([C:3](=[O:4])[CH2:2][Br:1])=[CH:21][CH:22]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)CBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1ccc(Oc2ccc(C(=O)CBr)cc2)cc1
Temperature: -15 °C
Reaction time: 0.05 h
Yield: 66.8 %

Procedure:
Bromoacetyl chloride (2.22 ml, 22 mmol) was added dropwise during 15 min with stirring at −15° C. to a mixture of aluminum chloride (6.0 g, 44.8 mmol) in methylene dichloride (40 ml). The reaction mixture was stirred at −15° C. for an additional 3 min. Diphenyl ether (1.87 g, 11.0 mmol) was added during 30 min with stirring at −15° C. and the reaction mixture was allowed to warm to room temperature and then stirred for 3 h. It was then poured into a mixture of concentrated hydrochloric acid and crushed ice and extracted with methylene dichloride (2×50 ml). The combined organic extracts were washed with 2% aqueous sodium hydrogen carbonate and water and dried over Na2SO4. Evaporation of the solvent under reduced pressure gave desired product 50 3.03 g (67%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].[C:22]1([C@H:28]([NH2:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([NH:30][C@@H:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:29])=[O:13])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C(F)(F)F
Product: C[C@@H](NC(=O)CN(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1)c1ccccc1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)glycine and (1R)-1-phenylethanamine: MS (APCI) m/z 402 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[S:10])[NH2:9])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:14][C:15](=O)[C:16]([OH:18])=[O:17].Cl>O.CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:10][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(=O)CBr
Reactant: NC(=S)c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1csc(-c2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Hydroxybenzenecarbothioamide (1.53 g, 10 mmol) and potassium hydroxide (1.50 g, 26.8 mmol) were dissolved in a mixture of 60 ml of water and 15 ml of methanol. A solution of bromopyruvic acid (1.67 g, 10 mmol) in 10 ml of methanol was added dropwise at room temperature. The resulting mixture was heated to reflux for 1.5 h, cooled to room temperature, poured into 100 ml of water and adjusted with 0.2N HCl solution to pH2. The mixture was placed in a refrigerator for 15 h. The title compound was obtained by filtration as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.82 (d, 2H), 7.78 (d, 2H), 8.37 (s, 1H), 10.05 (s, 1H), 13.00 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([O:11][CH2:12][CH:13]2[CH2:15][O:14]2)=[C:6](C(=O)C)[CH:7]=1.C1C=C(Cl)C=[C:19]([C:24]([O:26]O)=[O:25])C=1>C(Cl)Cl>[C:24]([O:26][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([F:16])[C:5]=1[O:11][CH2:12][CH:13]1[CH2:15][O:14]1)(=[O:25])[CH3:19]
Reactant: CC(=O)c1cc(Br)cc(F)c1OCC1CO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)Oc1cc(Br)cc(F)c1OCC1CO1
Yield: 189.4 %

Procedure:
A solution of 1-[5-bromo-3-fluoro-2-(oxiran-2-ylmethoxy)phenyl]ethanone (1.3 g, 4.5 mmol) and m-CPBA (4.0 g, 18 mmol) in DCM (25 ml) was heated at reflux. After 22 h more m-CPBA (2.7 g, 12 mmol) was added and the mixture was heated at reflux for another 22 h and then brought to ambient temperature. The solid was filtered off and rinsed. The resulting filtrate was washed with sodium bicarbonate (saturated), brine and further dried (Na2SO4) and evaporated to dryness to give the crude title compound (2.6 g). MS m/z (rel. intensity, 70 eV) 305 (M+, 5), 304 (M+, 6), 263 (97), 262 (bp), 206 (49), 57 (65).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14])([O-])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[NH:8][C:7]3=[O:14])=[CH:18][CH:17]=1
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2cc(Oc3ccc(F)cc3)ccc21
Reaction time: 3 h
Yield: 18.6 %

Procedure:
A mixture of 5-Nitro-isoindole-1,3-dione (177 g, 0.904 mol), 4-fluoro-phenol (128 g, 1.13 mol), K2CO3 (419 g, 3 mol) and DMF (2 l) was refluxed with stirring for 3 h before the mixture was poured into water (12 l) with stirring. The precipitate formed was isolated by vacuum filtration, washed with water (8 l) and dried in vacuo at 70° C. to give the title compound as a tan powder (43.2 g); 1H NMR (CDCl3) δ=7.79 (d, 1 H), 7.57 (br s, 1 H), 7.01 to 7.29 (m, 6 H).
Reaction SMILES: Br[C:2]1[CH:42]=[CH:41][C:5]2[NH:6][C:7]([C@@H:9]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:10][C:11](=[O:32])[NH:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:8][C:4]=2[CH:3]=1.[Cl:43][C:44]1[CH:49]=[C:48]([C:50]#[N:51])[CH:47]=[CH:46][C:45]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:43][C:44]1[CH:49]=[C:48]([C:50]#[N:51])[CH:47]=[CH:46][C:45]=1[C:2]1[CH:42]=[CH:41][C:5]2[NH:6][C:7]([C@@H:9]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:10][C:11](=[O:32])[NH:12][C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc2cc(Br)ccc2[nH]1
Reactant: N#Cc1ccc(B(O)O)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc2cc(-c3ccc(C#N)cc3Cl)ccc2[nH]1
Temperature: 120 °C
Yield: 47.1 %

Procedure:
A mixture of (S)-tert-butyl (1-(5-bromo-1H-benzo[d]imidazol-2-yl)-3-oxo-3-(tritylamino)propyl)carbamate (Preparation 14, 87 mg, 0.14 mmol), 2-chloro-4-cyanophenylboronic acid (34 mg, 0.19 mmol) and aqueous sodium carbonate solution (2M, 150 μL, 0.30 mmol) in 1,2-dimethoxyethane (0.95 mL) was sparged with argon three times, then tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.007 mmol) was added. The reaction mixture was heated under microwave irradiation at 120° C. for 60 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulphate, and concentrated in vacuo to give the crude product. The residue was purified using silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the title compound (45 mg, 48%) as a pale tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:27])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[NH:23])[CH2:16][CH2:17][C:12]=3[C:11]([C:28]([F:31])([F:30])[F:29])=[N:10]2)=[CH:5][CH:4]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:26][N:24]([CH3:25])[C:22](=[N:23][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:21][CH2:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][C:12]2[C:11]([C:28]([F:31])([F:29])[F:30])=[N:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:13]=2[C:14]1=[O:27]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC(=N)N(C)C)CC3)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC(=NS(C)(=O)=O)N(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
5-[1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-N,N-dimethyl-pentanamidine (0.050 g, 0.114 mmol) was dissolved in methylene chloride (10 mL). Methanesulfonyl chloride (0.1 mL, excess) and triethylamine (0.3, excess) were added to the reaction. The reaction was stirred at rt overnight, concentrated, and purified by flash chromatography using 0–100% ethyl acetate/hexanes as the eluent followed by a methanol flush. Further purification by reverse phase HPLC and freeze-drying afforded the title compound (0.120 g, 74%): 1H NMR (CHCl3) δ 7.44 (d, j=8.7 Hz, 2H), 6.95 (d, j=8.8 Hz, 2H), 3.84 (s, 3H), 3.69 (t, j=7.0 Hz, 2H), 3.52 (t, j=6.3 Hz, 2H), 3.03 (s, 3H), 3.00(s, 3H), 2.99 (s, 3H), 3.14–2.98 (m, 2H), 2.89 (t, j=7.7 Hz, 2H), 1.75–1.62 (m, 2H) ppm; Mass Spec 516.3(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][CH2:10][C:11](Cl)=[O:12]>ClCCl.O>[Cl:8][CH2:9][CH2:10][C:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)CCCl
Solvent: O
Solvent: ClCCl
Product: O=C(CCCl)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of aniline (40 g, 0.429 mol) in dichloromethane (500 mL) cooled at 0° C., was added 3-chloropropanoyl chloride (49.1 mL, 0.515 mol) drop wise with constant stirring. Reaction mass was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane (4×500 mL). The combined organic layer was washed with saturated sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 7.58-7.56 (d, J=8 Hz, 2H), 7.30-7.26 (t, J=8 Hz, 2H), 7.05-7.01 (t, J=7.6 Hz, 1H), 3.88-3.85 (t, J=6.4 Hz, 2H), 2.82-2.81 (t, J=6.0 Hz, 2H). MS (M+1): 184.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[N:14][C:13]=1[CH2:18][NH2:19].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH2:18][C:13]2[N:14]=[CH:15][CH:16]=[CH:17][N:12]=2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: NCc1ncccn1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ncccn1)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a flask was charged with 4-bromo-2-fluorobenzoic acid (180 mg, 0.821 mmol), pyrimidin-2-ylmethanamine (89.6 mg, 0.821 mmol), DIEA (0.358 mL, 2.05 mmol) in DMF (3 mL), and to the resulting solution was added PyBOP (513 mg, 0.915 mmol) and the resulting mixture was stirred at room temperature overnight, then was concentrated under reduced pressure and the residue was diluted with EtOAc (20 mL), washed with water (3×10 mL), brine (10 mL) and dried (Na2SO4), concentrated and the residue was purified by flash chromatography on silica gel eluted with gradient EtOAc/heptane (0-100%) and 4-bromo-2-fluoro-N-(pyrimidin-2-ylmethyl)benzamide (74.5 mg, 29.3%) was obtained as light color solid. LCMS (m/z): 310.0/312.0 (MH+), 0.64 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([CH:21]([S:30][CH2:31][CH2:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[S:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1>CO.[OH-].[Li+].O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([CH:21]([S:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[S:30][CH2:31][CH2:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCCSC(SCCC(=O)N(C)C)c1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)C(=O)CCSC(SCCCC(=O)O)c1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.3 %

Procedure:
To a solution of 7-chloro-2-[5-{[2-(dimethylcarbamoyl)ethylthio](3-methoxycarbonylpropylthio)methyl}-benzofuran-2-yl]quinoline (0.49 g) in methanol (5 ml), 1N aqueous lithium hydroxide (1.32 ml) was added at ambient temperature under nitrogen atmosphere. After being stirred for 15 hours at ambient temperature, the resulting mixture was concentrated under reduced pressure to give a syrup. The syrup was dissolved in water, washed with diethyl ether, adjusted to pH 4 with diluted aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol. The fractions containing object compound were combined and concentrated in reduced pressure to give a syrup of 7-chloro-2-[5-{(3-carboxypropylthio)[2-(dimethylcarbamoyl)ethylthio]methyl}benzofuran-2-yl]quinoline (0.35 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.O.[NH2:17]N.Cl.Cl.NN>C(O)CO>[NH:1]([C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:13])[F:14])[CH:8]=[CH:7][C:5]=2[N:6]=1)[NH2:17]
Reactant: NN
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Agent: Cl
Solvent: OCCO
Solvent: O
Product: NNc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 140 °C
Yield: 90.3 %

Procedure:
To a suspension of 93.6 g of 2-amino-6-trifluoromethoxybenzothiazole in 420 cm3 of ethylene glycol under a stream of nitrogen are added 48 g of hydrazine hydrate and 42 g of hydrazine dihydrochloride. The mixture is heated for 2 hours at 140° C. After cooling, the precipitate is filtered off and triturated with a water/diethyl ether mixture (1/1 by volume). 89.9 g of 2-hydrazino-6-trifluoromethoxybenzothiazole are thus obtained, melting at 208° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=O)[N:7]=1.S(Cl)([Cl:13])=O>>[CH3:1][S:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([Cl:13])=[O:10])[N:7]=1
Reactant: CSc1nc(C(=O)O)cs1
Reactant: O=S(Cl)Cl
Product: CSc1nc(C(=O)Cl)cs1
Temperature: 25 °C

Procedure:
2-(Methylthio)-1,3-thiazole-4-carboxylic acid (Intermediate 11; 1.0 g) in thionyl chloride (10 ml) was heated to reflux for 30 min. The solution was cooled to room temperature and concentrated in vacuo. The residue was washed with anhydrous THF and concentrated to yield a black solid which was dried and stored cold under nitrogen (1.2 g). NMR (CDCl3): 2.76 (s, 3H), 8.32 (s, 1H).