Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1.[S].C1[S:23](=O)(=O)CCC1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([SH:23])[NH:11][C:12]=2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:7]=1
Reactant: O=S1(=O)CCCC1
Reactant: Clc1ccc(-c2nc[nH]c2-c2cccs2)cc1
Agent: [S]
Solvent: CN(C)C=O
Solvent: O
Product: Sc1nc(-c2ccc(Cl)cc2)c(-c2cccs2)[nH]1
Temperature: 200 °C

Procedure:
A mixture of 9.4 g of 4-(4-chlorophenyl)-5-(2-thienyl)-1H-imidazole, 2 g of sulfur, and 50 ml of tetramethylene sulfone was stirred under nitrogen and heated to 200° C. for 8 hrs. It was cooled, poured into water, filtered and washed well with water to give 11.5 g. This was dissolved in dimethylformamide and chromatographed on a column 6 cm diameter by 125 cm long of alumina (Woelm neutral activity grade 1) using dimethylformamide to elute. A yield of 5.6 g was obtained as the dimethylformamide adduct. A sample was dried by heating under a high vacuum, m.p. 274.5°-276° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[C:22]([C:23]#[N:24])=[CH:21][CH:20]=[CH:19][N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:17]1[C:22]([C:23]#[N:24])=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1ncccc1C#N
Yield: 28.9 %

Procedure:
The title compound (0.66 g) was prepared from (S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.55 g) and 2-chloro-3-cyanopyridine (1.0 g) according to the method of D28.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][NH:25][C:26](=[O:31])[C:27]([O:29]C)=O)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C1C=CC=CC=1.[NH3:32].CO>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][NH:25][C:26]([C:27]([NH2:32])=[O:29])=[O:31])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)C(=O)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: N
Solvent: CO
Product: NC(=O)C(=O)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 17 h
Yield: 93 %

Procedure:
A suspension of methyl N-[2-(3,4-dibenzyloxyphenyl)ethyl]oxamate (5.0 g, 11.9 mmol) in methanol (100 mL) contained in a Fischer-Porter pressure vessel under argon was cooled to -78° C. Ammonia (ca. 60 mL) was condensed into the vessel, the vessel was sealed and allowed to come to room temperature. The suspension was allowed to stir at room temperature under a pressure of approximately 60 psi for 17 h. The mixture was cooled to -78° C., the vessel was opened and the vigorously stirred suspension was allowed to come to room temperature under a stream of argon. After 1.5 h, the solvent was removed in vacuo and the solid was triturated with 20% methylene chloride/ether to provide a white solid (4.5 g, 93%): m.p. 187° C.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(O)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C)C.S(=O)(=O)(O)O>O>[C:1]1([C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(O)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: CC=C(c1ccccc1)c1ccccc1
Yield: 49.4 %

Procedure:
A mixture of 1,1-diphenyl-1-propanol (64 g, 0.30 mol), isopropanol (300 ml) and a 5 N solution of sulphuric acid (150 ml) was heated at reflux temperature for 18 h. The reaction mixture was cooled, diluted with water (600 ml) and extracted with toluene (3×150 ml). The combined organic phases was dried (Na2SO4) and the solvent was evaporated in vacuo to give a solid residue which was triturated with iso-octane. The solid was collected by filtration to give 28.8 g (49%) of 1,1-diphenyl-1-propene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5](O)=[O:6].[CH3:24][N:25]([CH3:40])[C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][CH:30]=[C:31]2[S:36]([NH2:39])(=[O:38])=[O:37]>>[Br:23][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Br:1])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:21])[CH3:22])[CH:13]=1)[C:5]([C:30]1[CH:29]=[CH:28][C:27]2[C:32](=[CH:33][CH:34]=[CH:35][C:26]=2[N:25]([CH3:24])[CH3:40])[C:31]=1[S:36]([NH2:39])(=[O:38])=[O:37])=[O:6]
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Reactant: CN(C)c1cccc2c(S(N)(=O)=O)cccc12
Product: CC(C)c1cc(Oc2c(Br)cc(C(=O)c3ccc4c(N(C)C)cccc4c3S(N)(=O)=O)cc2Br)ccc1O
Yield: 34.5 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol) was coupled with 5-dimethylamino-1-naphthalenesulphonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 8 mg (34%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=1)[S:11]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12].[OH-].[Na+]>CO>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:10]([S:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:31])=[O:2])=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCc1ccc(CN(CCCCCCC(=O)OC)S(=O)(=O)c2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1ccc(CN(CCCCCCC(=O)O)S(=O)(=O)c2cccnc2)cc1

Procedure:
A solution of 7-((4-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-heptanoic acid methyl ester prepared of Example 1, Step B (0.040 g, 0.158 mmol), in 2 mL MeOH and 0.5 mL 2N NaOH was stirred at room temperature overnight. The mixture was quenched with 2N HCl and was diluted with CH2Cl2. The organic layer was washed with 1N HCl and water, dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (2% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2) to afford the title compound (42 mg). 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.77 (d, 1H), 8.08 (d, 1H), 7.48 (dd, 1H), 7.09 (m, 4H), 4.32 (s, 2H), 3.12 (s, 2H), 2.55 (t, 2H), 2.25 (t, 2H), 1.12-1.58 (m, 12H), 0.88 (t, 3H); MS 431 (M−1).
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[C:6]([OH:21])[CH:5]=1)[CH3:2].Cl.CN(C)[CH2:27][CH2:28][CH2:29]N=C=NCC.C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>CN(C=O)C>[CH2:29]([O:13][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[C:8](=[O:9])[C:7]1[CH:19]=[CH:20][C:4]([N:3]([CH2:1][CH3:2])[CH2:22][CH3:23])=[CH:5][C:6]=1[OH:21])[C:28]#[CH:27]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(O)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOC(=O)c1ccccc1C(=O)c1ccc(N(CC)CC)cc1O

Procedure:
A solution of 200 mmol 2-(4-diethylamino-2-hydroxybenzoyl)benzoic acid, 500 mmol propargylic alcohol, 220 mmol 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), and 500 mmol N-ethyldiisopropylamine in 600 mL DMF is stirred at room temperature for 2 h. 1 L of ethyl acetate is added and the solution extracted with 1 L water. The organic layer is separated, dried (Na2SO4), and the solvent evaporated. The crude product is purified via FC (n-hexane/EtOAC 2:1) yielding 2-(4-diethylamino-2-hydroxybenzoyl)benzoic acid prop-2-ynyl ester. MS (EI): 374 (18%, M+Na+), 352 (100%, M+H+), 296 (17%). UV (EtOH): λmax=356 nm (ε=31'648).
Reaction SMILES: N[CH2:2][C:3]1([OH:31])[C:12]2[C:7](=[C:8]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.N([O-])=O.[Na+].C(Cl)Cl>CC(O)=O.O>[Si:14]([O:13][C:8]1[C:7]2[CH2:6][CH2:5][CH2:4][C:3](=[O:31])[CH2:2][C:12]=2[CH:11]=[CH:10][CH:9]=1)([C:27]([CH3:30])([CH3:28])[CH3:29])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2(O)CN)(c1ccccc1)c1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1cccc2c1CCCC(=O)C2)(c1ccccc1)c1ccccc1
Reaction time: 2.5 h
Yield: 37.8 %

Procedure:
To a solution of 1-aminomethyl-5-(tert-butyldiphenyl-silyloxy)-1,2,3,4-tetrahydronaphthalen-1-ol (34.5 g) in 20% AcOH (700 ml) was added NaNO2 (7.18 g) in water (60 ml) at 5° C. The mixture was stirred at the same temperature for 2.5 hours. After addition of CH2Cl2 (70 ml), the mixture was stirred for 30 minutes. The reaction mixture was extracted with EtOAc. The organic layer was washed with water and then brine. It was dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane-EtOAc 10:1) to give 1-(tert-butyldiphenylsilyloxy)-6,7,8, 9-tetrahydro-5H-benzocyclohepten-6-one (12.52 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)=[CH:6][C:5]([C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.C1(=O)NC(=O)CC1>CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:1][C:2]1[C:7]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:11])([CH3:12])[O:9]2)=[CH:6][C:5]([C:17]([F:19])([F:18])[F:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(F)(F)F)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(c2cc(C(F)(F)F)ccc2CBr)OC1(C)C
Temperature: 25 °C
Yield: 98.6 %

Procedure:
6-Methyl-3-(trifluoromethyl)phenylboronic acid pinacol ester (24b, 3.0 g, 10 mmol) and 60 ml CCl4 were placed in 500 ml round-bottom flask. NBS (1.9, 10.5 mmol, 1.05 eq) and AIBN (0.02 g, 0.14 mmol, 0.014 eq) were added and the reaction mixture was refluxed for 4.5 h in the presence of 75 W incandescent bulb. After 4.5 h the solution was cooled down to room temperature allowing the succinimide to precipitate out. The solid was filtered off. The solvent was removed and oily product was collected. The crude product was purified by triturating with hexane which resulted in 80% pure product (25b, 3.6 g, 95% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:65]=[CH:64][C:53]2[NH:54][C:55]([CH:57]([NH2:63])[CH2:58][C:59]([F:62])([F:61])[F:60])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:65]=[CH:64][C:53]2[NH:54][C:55]([CH:57]([NH:63][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][C:59]([F:61])([F:60])[F:62])=[N:56][C:52]=2[CH:51]=1
Reactant: NC(CC(F)(F)F)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(C(=O)NC(CC(F)(F)F)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 52 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and 1-(5-chloro-1H-benzimidazol-2-yl)-3,3,3-trifluoropropylamine in tetrahydrofuran. Yield: 52%; Rf value: 0.50 (silica gel; dichloromethane/ethanol=9:1); C23H22ClF3N4O2 (478.90); mass spectrum: (M+H)+=479/481 (chlorine isotope).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CNCCC1C=CC=CC=1.Cl[C:21]1[N:26]=[N:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]([F:44])([F:43])[F:42])=[O:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH2:8]([NH:9][C:21]1[N:26]=[N:25][C:24]([N:27]2[CH2:28][CH2:29][N:30]([C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]([F:42])([F:44])[F:43])=[O:34])[CH2:31][CH2:32]2)=[CH:23][CH:22]=1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Reactant: NCCc1ccccc1
Agent: CNCCc1ccccc1
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(NCCc3ccccc3)nn2)CC1

Procedure:
Following the procedure set forth above in Example 1, only making variations using 2-phenylethylamine to replace N-methyl-2-phenylethylamine to react with [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (11.8 mg, 15% yield). 1H NMR (CDCl3, 400 MHz) δ 7.74, 7.62-7.68, 7.52-7.57, 7.33-7.37, 7.28-7.32, 7.40-7.46, 6.83, 6.18, 3.95, 3.68-3.70, 3.30-3.50, 2.96. MS (ES+) m/z 456.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.Cl.O>[Fe].C(O)C>[Br:11][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)cnc1N
Yield: 50.4 %

Procedure:
A mixture of 2-amino-5-bromo-3-nitropyridine (62.2 g, 285 mmol), iron powder (171 g, 3.06 mol), concentrated hydrochloric acid (2.85 ml), water (60 ml) and ethanol (230 ml) was refluxed for 2 h, filtered whilst warm, the solids washed twice with ethanol (2×150 ml) and the combined ethanol solutions were evaporated to dryness. The crude solid was recrystallized from water, using decolourising charcoal, filtered whilst warm, the solids washed twice with warm ethanol (2×100 ml), the ethanol evaporated off and the precipitate was filtered off, washed with water (3×75 ml) and dried to afford the title compound (27 g, 50%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([Br:42])[C:38]2=[N:43][C:35]3=[C:36](Br)[N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[C:25]([F:46])=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CN(C=O)C.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>[Br:42][C:39]1[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]([N:13]2[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]4[C:25]([F:46])=[CH:26][CH:27]=[CH:28][C:29]=4[C:30]4[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=4)[CH2:48][CH2:49]2)=[C:11]([C@H:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH3:10])=[O:8])[C:40]=1[CH3:41]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1c(F)cccc1-c1cccc-3c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1c(F)cccc1-c1cccc-3c1
Temperature: 40 °C
Yield: 59.4 %

Procedure:
Methyl(2S)-2-(tert-butoxy)-2-[(22S)-5,8-dibromo-19-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (0.13 g, 0.16 mmol, 1.0 equiv) and ammonium formate (0.101 g, 1.6 mmol, 10.0 equiv) were dissolved in DMF (3.19 mL). To this solution was added tetrakis (0.018 g, 0.016 mmol, 0.1 equiv). The mixture was heated at 40° C. overnight. Then it was diluted with ethyl acetate, washed by NaHCO3, dried over MgSO4, concentrated and purified by flash column (24 g, 0-100% EtOAc[2% TEA]/Hex) to afford the product (70 mg, 59.6%). LCMS (ESI, M+1): 736.3.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:3].C(N(CC)CC)C.[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18]>C(#N)C>[Si:21]([NH:3][CH:2]([CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(N)c1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(N[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of racemic α-methyl-benzenemethanamine (24.2 g, 0.2 mol) and triethylamine (42 mL, 0.30 mol) in acetonitrile (400 mL) in a flame-dried flask under nitrogen was added dropwise t-butylchlorodiphenylsilane (47 mL, 0.18 mol). The mixture was stirred at room temperature for 3 hours and then filtered to remove the insoluble white precipitate (triethylamine hydrochloride). After removal of the solvent in vacuo, the crude product was taken up in ether and washed sequentially with H2O, saturated NaHCO3 solution and brine. The solution was dried (Na2SO4 /K2CO3) and concentrated to leave a clear oil which was distilled under high vacuum. The major fraction consisting of the pure title compound (30.5 g, 47%) distilled from 160° to 165° C. at about 0.4 mm Hg.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:21][C:3]1=2.[SH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38]>>[C:37]([CH2:36][CH2:35][S:34][CH:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:21][C:3]1=2)([OH:39])=[O:38]
Reactant: O=C(O)CCS
Reactant: OC1c2ccc(-c3nnn[nH]3)cc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Product: O=C(O)CCSC1c2ccc(-c3nnn[nH]3)cc2COc2ccc(OCc3ccc4ccccc4n3)cc21

Procedure:
11-Hydroxy-2-(quinolin-2-yl)methoxy-8-(tetrazol-5-yl)-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:4][CH2:3]1.C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[O:28]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][NH:10][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH2:6][CH2:7]1
Reactant: COCCCN(CCN1CCS(=O)(=O)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCCCNCCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-N-(3-methoxypropyl)-2-nitrobenzenesulfonamide (0.510 g, 1.17 mmol) and thiophenol (0.387 g, 3.51 mmol) were combined in dry acetonitrile (10 mL). Potassium carbonate (0.647 g, 4.68 mmol) was added and the mixture was stirred at rt for 18 h. The mixture was diluted with ethyl acetate and filtered to remove unwanted solids. The crude filtrate was concentrated in vacuo, redissolved in methanol, and loaded onto a strong cation exchange resin cartridge to capture the desired product. Undesired materials were eluted from the cartridge with methanol, and then the desired material was released from the resin by elution with 2M ammonia in methanol. Concentration in vacuo gave a yellow oil (0.255 g, 87% yield). No further purification was performed and the mixture was carried forward to the next step. LCMS: m/z 251 (M+H+), 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.77 (quin, J=6.53 Hz, 2H) 2.13 (br. s., 2H) 2.62-2.68 (m, 2H) 2.68-2.75 (m, 4H) 2.93-3.11 (m, 8H) 3.32 (s, 3H) 3.44 (t, J=6.15 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1F)[C:14]#[N:15].C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:14]#[N:15]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)c(Cl)c1
Temperature: 100 °C
Yield: 94.8 %

Procedure:
Mix 4-hydroxy-benzaldehyde (0.86 g, 7.07 mmol), 3-chloro-4-fluoro-benzonitrile (1.00 g, 6.43 mmol), cesium carbonate (3.14 g, 9.64 mmol) and dimethylacetamide (30 mL) in a flask. Heat to 100° C. for 4 hrs. Let cool to room temperature (rt) and pour into water (200 mL). After trituration, filter the solid formed and dry on a vacuum pump to obtain the product (1.57 g, 95%). 1H NMR (DMSO-d6) 9.96 (s, 1H), 8.29 (d, J=1.8 Hz, 1H), 7.97 (d, J=8.6 Hz, 2H), 7.89 (dd, J=1.8 Hz, 8.6 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.23 (d, J=8.6 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:41]S(C2C=CC=CC=2)(=O)=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]([CH2:28][CH2:29][NH:30][C:31](=[O:40])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38]C)=[O:37])[O:13][C:14](=[O:27])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:26])[NH:22][CH2:23][C:24]#[CH:25])[CH:8]=[CH:7]2.[OH-].[Na+]>CO>[Br:1][C:2]1[C:3]([OH:41])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]([CH2:28][CH2:29][NH:30][C:31](=[O:40])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[O:13][C:14](=[O:27])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:26])[NH:22][CH2:23][C:24]#[CH:25])[CH:8]=[CH:7]2
Reactant: C#CCNC(=O)CCCCCNC(=O)OC(CCNC(=O)CCCCC(=O)OC)c1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCNC(=O)CCCCCNC(=O)OC(CCNC(=O)CCCCC(=O)O)c1ccc2ccc(O)c(Br)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
To a stirred solution of methyl 14-(8-bromo-7-(phenylsulfonyloxy)quinolin-2-yl)-5,12,18-trioxo-13-oxa-4,11,17-triazatricos-1-yn-23-oate (20 mg, 0.026 mmol) in MeOH (500 uL), were added 0.4 N NaOH (500 uL), and the reaction mixture was stirred for 4 h at room temperature. Methanol was removed in vacuo, and remaining mixture was loaded onto a TOYOPEARL SuperQ-650M packed column pre-washed with 0.2 N NaOH. After washing the column with CH3CN/H2O (1:1) twice, the loaded compound was eluted with AcOH/CH3CN/H2O (5:50:45). After remove the CH3CN in vacuo, the remaining mixture was lyophilized overnight to dryness. The residue was dissolved in MeOH/CH3Cl, transferred to a new vial and evaporated to give a yellow gum (15 mg, 0.024 mmol, 92%) and was used for next step without further purification. MS-ESI (m/z): [M+H]+ calculated for C28H36BrN4O7, 619.2 (79Br) and 621.2 (81Br); found 619.3 (79Br) and 621.3 (81Br).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](#[N:12])[CH:9]([CH3:11])[CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:10][C:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:11])[C:8]#[N:12]
Reactant: Fc1ccccc1
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C#N)c1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 50.4 %

Procedure:
To a solution of fluorobenzene (5.85 mL, 62.4 mmol) in 100 mL of anhydrous toluene was added isobutyronitrile (22.5 mL, 250 mmol) followed by 200 mL (100 mmol) of a 0.5 M solution of KHMDS in toluene. The reaction was stirred at 80° C. for 24 hours. The reaction was then allowed to cool to room temperature, diluted with diethyl ether, and washed with water and brine. The organic fraction was then dried over sodium sulfate and concentrated under reduced pressure. The product was purified by flash chromatography using an ethyl acetate/hexanes gradient to yield 4.57 g (50%) of the objective compound as a brown oil. MS: (ESI, Pos) m/z 168.0 (M+23) 1H NMR (500 MHz, CDCl3): δ (ppm) 7.48 (d, 2H), 7.39 (t, 2H), 7.31 (t, 1H), 1.73 (s, 6H).