Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:17]([CH2:18][S:19][C:20]2[CH2:24][C:23]([CH3:26])([CH3:25])[O:22][N:21]=2)=[C:16]([C:27]([F:30])([F:29])[F:28])[N:15]([CH:31]([F:33])[F:32])[N:14]=1.[OH2:34]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[C:17]([CH2:18][S:19]([C:20]2[CH2:24][C:23]([CH3:25])([CH3:26])[O:22][N:21]=2)(=[O:9])=[O:34])=[C:16]([C:27]([F:28])([F:29])[F:30])[N:15]([CH:31]([F:32])[F:33])[N:14]=1
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(SCc2c(Cl)nn(C(F)F)c2C(F)(F)F)=NO1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(S(=O)(=O)Cc2c(Cl)nn(C(F)F)c2C(F)(F)F)=NO1
Reaction time: 1 h
Yield: 79.7 %

Procedure:
1.1 g of m-chloroperbenzoic acid (purity: 70%, 6.4 mmoles) was added, with ice-cooling, to a solution of 0.54 g (1.5 mmoles) of 3-(3-chloro-1-difluoromethyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 20 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting solid was washed, with n-hexane to obtain 0.47 g (yield: 79.7%) of 3-(3-chloro-1-difluoromethyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 136.0 to 137.0° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2SC=CN=2)=[CH:4][CH2:3]1.FC(F)(F)S(O[C:37]1[C:38]2[CH:39]=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=[CH:42][C:43]=2C(C)(C)C[CH:46]=1)(=O)=O>>[CH3:30][C:2]1([CH3:1])[C:11]2[CH:6]=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:9][C:10]=2[C:5]([C:25]2[CH:42]=[CH:43][C:38]([CH3:39])=[CH:37][CH:46]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67), 200.0 mg (0.42 mmol) of ethyl 4-[(5-triflouromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 113.8 mg (0.835 mmol) of zinc chloride and 4-methylphenyllithium (prepared by adding 40.4 mg (0.42 ml, 0.63 mmol) of n-butyllithium (1.5 M solution in hexane) to a cold solution (-78° C.) of 108.0 mg (0.63 mmol) of 4-bromotoluene in 1.0 ml of THF).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.C(N(CC)CC)C.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[NH:39]([C:40]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)Nc2ccccc2)cc13
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a stirred solution of 3-hydroxy-N-(tert-butyloxycarbonyl)morphinan (9 mg, 0.026 mmol) and triethylamine (10 μL, 0.04 mmol) in dry dichloromethane (0.3 mL) was added phenyl isocyanate (4 μL, 0.045 mmol) and the mixture was stirred for 1 h. After starting material disappeared on TLC, solvent was removed and column chromatography gave 11 mg (90%) of the title compound: 1H NMR (300 MHz, CDCl3) δ7.4 (2H, d); 7.3 (2H, t); 7.1 (3H, m); 6.9 (2H, m); 4.3 (1H, m); 3.8 (1H, m); 3.1 (1H, d. d.); 2.4˜2.8 (2H, m); 2.3 (1H, m); 1.3 (9H, s); 1.0˜1.7 (10H, m).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH2:32]([C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1)[CH3:33]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:43][S:40]([C:37]3[CH:36]=[CH:35][C:34]([CH2:32][CH3:33])=[CH:39][CH:38]=3)(=[O:41])=[O:42])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: CCc1ccc(S(N)(=O)=O)cc1
Product: CCc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-ethylbenzenesulfonamide: 1H-NMR (CDCl3) δ 7.77 (2H, d, J=8.4 Hz), 7.47-7.23 (11H, m), 6.39 (1H, br.s), 3.52-3.45 (2H, m), 2.86 (2H, t, J=6.7 Hz), 2.71 (2H, q, J=7.7 Hz), 2.33 (3H, s), 2.25 (3H, s), 1.25 (3H, t, J=7.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][N:13]([C:24](Cl)=[O:25])[CH2:12]2)[CH3:10])=[N:6][CH:7]=1.CCN(CC)CC.[CH2:34]1[NH:39][CH2:38][CH2:37][N:36]2[C:40](=[O:43])[CH2:41][CH2:42][CH:35]12>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][N:13]([C:24]([N:39]3[CH2:38][CH2:37][N:36]4[C:40](=[O:43])[CH2:41][CH2:42][CH:35]4[CH2:34]3)=[O:25])[CH2:12]2)[CH3:10])=[N:6][CH:7]=1
Reactant: CC(Oc1ccc(Cl)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C1CCC2CNCCN12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Cl)cn1)C1CN(C(=O)N2CCN3C(=O)CCC3C2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 25 %

Procedure:
To a stirred solution of (3SR,4RS)-3-[(RS)-1-(5-chloro-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl chloride (22 mg, 0.051 mmol) in CH2Cl2 (3 mL) were added Et3N (0.015 ml, 0.11 mmol) and hexahydro-pyrrolo[1,2-a]pyrazin-6-one (commercially available) (9 mg, 0.064 mmol). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, EtOAc) to yield 7 mg (25%) the title compound as light yellow oil. ES-MS m/e: 539.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:15][N:16]=[C:17]=[O:18]>C(N(CC)CC)C.C1C=CC=CC=1>[CH3:15][NH:16][C:17](=[O:18])[O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])=[CH:7][CH:8]=1
Reactant: COC(COc1ccc(O)cc1)OC
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CNC(=O)Oc1ccc(OCC(OC)OC)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-(2,2-Dimethoxyethoxy)phenol (5.0 grams) and benzene were charged into a glass reaction vessel equipped with a mechanical stirrer. Methyl isocyanate (3.5 ml) and 4 drops of triethylamine were then added, and the reaction mixture was stirred at room temperature for a period of about 6 hours. After this time the reaction mixture was filtered, and the filtrate was concentrated to 10 ml by partially stripping the solvent under reduced pressure. Cyclohexane (10 ml) was then added to the concentrate, resulting in the formation of a precipitate. The precipitate was recovered by filtration to yield the desired product O-[4-(2,2-dimethoxyethoxy)phenyl] N-methylcarbamate as a slightly pink solid melting at 79° to 81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:39])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:35])([CH3:34])[C:31](=[O:33])[CH3:32])=[CH:26][C:25]=3[O:36][CH2:37][CH3:38])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[O:42]=[S:43]1(=[O:55])[CH2:48][CH2:47][CH:46]([N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH2:45][CH2:44]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:39])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:52]3[CH2:53][CH2:54][N:49]([CH:46]4[CH2:45][CH2:44][S:43](=[O:42])(=[O:55])[CH2:48][CH2:47]4)[CH2:50][CH2:51]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:35])([CH3:34])[C:31](=[O:33])[CH3:32])=[CH:26][C:25]=3[O:36][CH2:37][CH3:38])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCC(N2CCNCC2)CC1
Reactant: CCOc1cc(C(C)(C)C(C)=O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C(C)=O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCS(=O)(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(1,1-dimethyl-2-oxo-propyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-piperazine dihydrochloride (example 22) to give the title product as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C40H49N4O5SCl2 [(M+H)+] 767.2795, observed 767.2790.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[C:7]([Cl:14])=[N:8][C:9]([Cl:13])=[N:10][C:11]=1Cl.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].[K].O.Cl>CS(C)=O>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:11]2[C:6]([O:5][C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=3[O:2][CH3:1])=[C:7]([Cl:14])[N:8]=[C:9]([Cl:13])[N:10]=2)(=[O:30])=[O:31])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1ccccc1Oc1c(Cl)nc(Cl)nc1Cl
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: [K]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Oc1c(Cl)nc(Cl)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
5-(2-Methoxyphenoxy)-2,4,6-trichloropyrimidine (4) (4.8 g; 15.6 mmol) was dissolved in dimethyl sulfoxide (45 ml). Potassium 4-t-butylbenzenesulfonamide (8.0 g; 32 mmol) was added to the mixture while being cooled on ice, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water, made acidic with hydrochloric acid, and extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was recrystallized from ether, to thereby obtain 4.9 g (yield: 65%) of the title compound as colorless needles.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:2]=1.[N:21]1([CH2:26][CH2:27][O:28][C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[NH:34][C:33]([CH:38]=O)=[CH:32]3)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[CH:38][C:33]2[NH:34][C:35]3[C:31]([CH:32]=2)=[CH:30][C:29]([O:28][CH2:27][CH2:26][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:37][CH:36]=3)(=[O:10])=[O:9])[CH:2]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3cccnc3)ccc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: O=C1Nc2ccc(S(=O)(=O)Nc3cccnc3)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid pyridin-3-ylamide was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH3:19])[C:12]2=[N:11][C:10]=1[C:20]([OH:22])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:20]([C:10]2[N:11]=[C:12]3[N:18]([CH3:19])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:22])=[CH:26][CH:25]=1
Reactant: CN1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Reaction time: 3 h
Yield: 76.7 %

Procedure:
A mixture of 6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.393 g, 1.30 mmol) and 4-fluorobenzylamine (0.163 g, 1.30 mmol) in acetonitrile (15 ml) was treated at 25° C. with triethylamine (0.42 ml, 2.5 mmol) followed by benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (0.662 g, 1.49 mmol). After 3 h, the reaction mixture was diluted with ethyl acetate, washed successively with 0.1 N hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystallization of the residual solid from ethyl acetate gave 0.407 g (76% yield) of the title amide as white cubes; mp 189-191° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.02 (3H, s, NCH3), 3.70 (2H, t, J=9 Hz, CH2), 4.15 (2H, t, J=9 Hz, CH2), 4.50 (2H, d, J=5.6 Hz, NCH2), 5.11 (2H, s, OCH2), 7.0 (2H, m, aromatics), 7.24 (2H, m, aromatics), 7.3-7.45 (SH, m, aromatics), 7.71 (1H, broad t, NH). Anal. Calcd for C22H21FN4O3: C, 64.69; H, 5.18; N, 13.71. Found: C, 64.41; H, 5.10; N, 13.72.
Reaction SMILES: C(O)(=O)C.[CH2:5]1[CH2:12][CH2:11][NH:10][C:8](=[S:9])[CH2:7][CH2:6]1.[Br:13][CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](O)=[O:16]>CCOCC>[Br-:13].[OH:16][C:15]1[N+:10]2[CH2:11][CH2:12][CH2:5][CH2:6][CH2:7][C:8]=2[S:9][C:14]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: S=C1CCCCCN1
Solvent: CC(=O)O
Solvent: CCOCC
Product: Oc1c(-c2ccccc2)sc2[n+]1CCCCC2
Product: [Br-]
Yield: 86 %

Procedure:
An acetic acid (50 ml.) solution of ω-thiocaprolactam (6.5 g., 0.05 mole) and α-bromophenylacetic acid (10.8 g., 0.05 mole) was heated on a steam bath for 1/2 hour. The solution was first cooled and diluted with ether. Upon scratching solid which precipitated was collected. The crude material was recrystallized from acetonitrile. The purified material weighed 14 g. (86% yield) and melted at 172°-175° C.
Reaction SMILES: C([N:20]([CH2:34][CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[O:45][C:46]3[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=3[N:48]=2)=[CH:40][CH:39]=1)[CH2:21][CH2:22][O:23][CH2:24][C:25]#[C:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.[ClH:56]>C(Cl)Cl.CCO.CO>[ClH:56].[O:45]1[C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[N:48]=[C:44]1[C:41]1[CH:42]=[CH:43][C:38]([CH2:37][O:36][CH2:35][CH2:34][NH:20][CH2:21][CH2:22][O:23][CH2:24][C:25]#[C:26][C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1
Reactant: Cc1ccc(C#CCOCCN(CCOCc2ccc(-c3nc4ccccc4o3)cc2)C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: Cc1ccc(C#CCOCCNCCOCc2ccc(-c3nc4ccccc4o3)cc2)cc1

Procedure:
N-trityl-N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-[3-(4-methylphenyl)-2-propynyloxy]ethanamine (600 mg) is dissolved in a solution of CH2Cl2 (10 ml) and EtOH (10 ml) and is treated with a solution of EtOH/HCl until acidic by pH paper. The solution is concentrated in vacuo, then purified by column chromatography using 5% MeOH/CH2Cl2. The residue is isolated, dissolved in methanol and acidified with acidic methanol. The solution is concentrated to obtain N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-[3-(4-methylphenyl)prop-2-ynyloxy]ethanamine hydrochloride (m.p. 161°-162° C.).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=C(N)C=1NC.C1N=CN([C:18]([N:20]2[CH:24]=[N:23][CH:22]=[CH:21]2)=O)C=1.C1C[O:28]CC1>>[F:1][C:2]1[C:21]2[N:20]([CH3:18])[C:24](=[O:28])[NH:23][C:22]=2[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C1CCOC1
Reactant: CNc1c(N)ccc(OC)c1F
Reactant: O=C(n1ccnc1)n1ccnc1
Product: COc1ccc2[nH]c(=O)n(C)c2c1F

Procedure:
3-fluoro-4-methoxy-N2-methylbenzene-1,2-diamine (7-3, 1.09 g, 6.40 mmol) was dissolved in anhydrous THF (15 ml) and treated with CDI (1.25 g, 7.69 mmol, 1.2 eq). The resulting orange solution was stirred at reflux for 6 h, then cooled to 23 deg C. The remaining dark reaction mixture was partitioned between EtOAc (2×40 ml) and water (45 ml). The combined organic layers were dried over Na2SO4 and concentrated. The crude mixture was purified via flash column chromatography (SiO2: 100% Hex to 50:50 Hex:EtOAc), affording the title compound, 7-fluoro-6-methoxy-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (7-4), as a maroon oil. 1H NMR (500 MHz, CDCl3) δ 7.11 (s, 1H), 6.68-6.74 (m, 2H), 3.89 (s, 3H), 3.60 (s, 3H). LRMS m/z: Calc'd for C9H9FN2O2(M+H) 197.2, found 196.9.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[C:18]([OH:23])(=[O:22])[C:19]([CH3:21])=[O:20].[OH-].[K+]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]=[CH:21][C:19](=[O:20])[C:18]([OH:23])=[O:22])=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)C(=O)O
Reactant: CCOc1cccc(-c2ccc(C=O)cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOc1cccc(-c2ccc(C=CC(=O)C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 42 %

Procedure:
To a mixture of 3′-ethoxy-biphenyl-4-carbaldehyde (4.6 g, 20.1 mmol) prepared in Step 1 and pyruvic acid (1.7 mL, 24.1 mmol) in methanol (15.0 mL), was slowly added a solution of potassium hydroxide (2.0 g, 36.2 mmol) in methanol (15.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 7 hours and then filtered. The resulting solid was diluted with a 1N hydrochloric acid solution and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 2.5 g of the titled compound as a brown liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:17][CH:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>ClCCl.C(Cl)(Cl)Cl>[Cl:17][CH:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1)=[O:20]
Reactant: N#Cc1ccc(N)cn1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)C(Cl)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 5-amino-2-cyanopyridine (0.500 g, 4.2 mmol) in dry dichloromethane (20 mL) was added triethylamine (0.637 g, 6.3 mmol) and the mixture was stirred at 0° C. α-Chloro phenylacetyl chloride (0.952 g, 5.04 mmol) was added dropwise to the mixture, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with chloroform (100 mL) and washed with water (150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel and ethyl acetate (20%) in petroleum ether as an eluent) to obtain the title compound.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:14]=[CH:13][C:11](O)=[CH:10][C:9]=1[OH:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:15][C:9]1[CH:10]=[C:11]([O:4][CH2:1][C:8]2[CH:14]=[CH:13][CH:11]=[CH:10][CH:9]=2)[CH:13]=[CH:14][C:8]=1[Br:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Br)c(O)c1
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 7.5 °C
Reaction time: 8 h
Yield: 199 %

Procedure:
106.6 g (0.771 mol, 3 eq) of potassium carbonate (325 mesh) are added to a solution of 50.1 g (0.257 mol, 1 eq) of 4-bromoresorcinol at 97% in 500 ml of acetone. The reaction medium is cooled to 5-10° C. and 75 ml (0.630 mol, 2.45 eq) of benzyl bromide are added dropwise. The reaction medium is stirred at ambient temperature overnight and is then heated at 50° C. for 2 hours. The solvent is evaporated off and the residue is then taken up with a water/ethyl acetate mixture. The aqueous phase is extracted with ethyl acetate, and the organic phases are combined, washed with a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated. The residue (114.34 g) is chromatographed on silica gel (600 g), elution being carried out with 90/10 heptane/dichloromethane. 94.4 g of 2,4-bis(benzyloxy)-1-bromobenzene are obtained in the form of white crystals. Yield=99%.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].CCN(C(C)C)C(C)C>C(#N)C.CO>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:25][C@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC#N
Product: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Temperature: 85 °C
Reaction time: 72 h
Yield: 34.5 %

Procedure:
A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (316 mg, 0.851 mmol) and cis-tert-butyl 2-aminocyclohexylcarbamate (365 mg, 1.703 mmol) and DIPEA (0.743 mL, 4.26 mmol) in ACN (2 mL) was stirred at 85° C. for 3 d. The resulting crude material was reconstituted in MeOH (1 mL) and purified by preparative HPLC. The fractions were collected and stripped to dryness via rotary evaporation to yield the title compound (161 mg, 34%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.35 (br s, 10H), 1.58 (br s, 2H), 1.76 (br s, 2H), 3.71-3.90 (m, 11H), 4.33 (br s, 2H), 4.51 (br s, 2H), 6.43-6.72 (m, 3H), 6.87 (br s, 1H), 7.07 (br s, 1H). [M+H] calc'd for C27H34ClFN4O5, 549. found, 549.