Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[S:4][C:3]=1[C:12]([NH2:14])=[O:13].C[Si]([N:19]=[C:20]=[O:21])(C)C>>[NH2:19][C:20]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[S:4][C:3]=1[C:12]([NH2:14])=[O:13])=[O:21]
Reactant: C[Si](C)(C)N=C=O
Reactant: NC(=O)c1sc(-c2ccsc2)cc1N
Product: NC(=O)Nc1cc(-c2ccsc2)sc1C(N)=O

Procedure:
Prepared by the method of Example 1 from 3-amino-5-(3-thienyl)-2-thiophenecarboxamide and trimethylsilylisocyanate.
Reaction SMILES: [OH:1][C:2]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:23]([F:26])([F:25])[F:24])([OH:22])[C:18]([F:21])([F:20])[F:19])[CH:12]=1)([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:22][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]([C:3]([F:6])([F:5])[F:4])([O:1][S:35]([CH3:34])(=[O:37])=[O:36])[C:7]([F:10])([F:9])[F:8])[CH:12]=1)([C:18]([F:19])([F:20])[F:21])[C:23]([F:24])([F:25])[F:26])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: OC(c1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1)(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(c1cccc(C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F)c1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
4.1 g (10 mmol) of 1,3-bis-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoroethyl)-benzene were dissolved in 50 ml of methylene chloride, and 2.5 g (25 mmol) of triethylamine were added. 3.64 g (25 mmol) of methanesulfonyl chloride were then added dropwise. The mixture was stirred for 8 hours at room temperature, separated off from the precipitated salt and evaporated down. 5.6 g of 1,3-bis-(1-methanesulfonyloxy-1-trifluoromethyl-2,2,2-trifluoro-ethyl)-benzene were obtained (colorless crystals, m.p.: 125° C. [from diisopropyl diether]).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH3:12][C:13]1[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([CH3:22])[C:14]=1[CH:15]=[O:16]>C(C(C)=O)C>[CH2:2]([O:21][C:19]1[CH:18]=[C:17]([CH3:22])[C:14]([CH:15]=[O:16])=[C:13]([CH3:12])[CH:20]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Cc1cc(O)cc(C)c1C=O
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCOc1cc(C)c(C=O)c(C)c1
Reaction time: 20 h
Yield: 91.1 %

Procedure:
1-Iodobutane (9.2 g; 50 mmole) and potassium carbonate (6.9 g; 50 mmole) were added to a solution of 2,6-dimethyl-4-hydroxybenzaldehyde (7.5 g; 50 mmole) in methyl ethyl ketone (150 ml). The mixture was heated under reflux with stirring for 20 hours and then evaporated to dryness. The residue was dissolved in dichloromethane and washed with water, then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 4-butoxy-2,6-dimethylbenzaldehyde (9.4 g; 92.0%). The product was obtained as a yellow oil and was characterized by its proton magnetic resonance spectrum, the details of which are recorded in Table 2 below.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:29])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:21]=[N:22][NH:23][C:24]=3[Si](C)(C)C)[CH:15]=2)[CH:10]([CH3:30])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+]>Cl.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:29])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:21]=[N:22][NH:23][CH:24]=3)[CH:15]=2)[CH:10]([CH3:30])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CCC1(C)c1cccc(-c2nn[nH]c2[Si](C)(C)C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1CN(Cc2ccccc2)CCC1(C)c1cccc(-c2c[nH]nn2)c1
Yield: 95 %

Procedure:
A solution of 1-benzyl-3,4-dimethyl-4-(3-(5-(trimethylsilyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine (Example 1, 6.5 g, 15.8 mmol) in 2 N HCl/methanol (1:1, 100 mL) was heated at reflux overnight. After allowing to cool, the reaction mixture was adjusted to pH 10 using saturated aqueous sodium hydrogencarbonate solution (ca. 250 mL). The aqueous mixture was extracted with ethyl acetate (3×100 mL) and the combined extracts were washed with water (150 mL), followed by brine (150 mL) before drying over MgSO4. The organic solution was filtered and the mother liquor concentrated in vacuo to provide the title compound as a cream solid (5.2 g, 95%).
Reaction SMILES: Br[CH:2]1[CH2:16][CH2:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]1=O.[C:18]([NH2:26])(=[S:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>C(O)CC>[CH2:13]([NH:12][C:10]([NH:9][C:7]1[S:8][C:4]2[C:3]3[N:26]=[C:18]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[S:25][C:2]=3[CH2:16][CH2:15][C:5]=2[N:6]=1)=[O:11])[CH3:14]
Reactant: CCNC(=O)Nc1nc2c(s1)C(=O)C(Br)CC2
Reactant: NC(=S)c1cccnc1
Solvent: CCCO
Product: CCNC(=O)Nc1nc2c(s1)-c1nc(-c3cccnc3)sc1CC2
Temperature: 105 °C
Yield: 35.4 %

Procedure:
A suspension of N-(6-bromo-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-N′-ethylurea (25 mg, 0.079 mmol) and thionicotinamide (11 mg, 0.079 mmol) in n-propanol (0.4 mL) was heated to about 105° C. for about 16 hrs. The reaction mixture was concentrated in vacuo and the residual crude material was purified by preparative HPLC. 10 mg (36%) pure product was isolated.
Reaction SMILES: O.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([CH:18]=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][CH:21]([NH2:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=1[O:33][CH3:34].C([O:43]C1C=CC=CC=1C(C=O)=O)C1C=CC=CC=1>CS(C)=O>[CH3:20][CH:21]([N:35]=[C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:18]=1)=[O:43])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=1[O:33][CH3:34]
Reactant: O=CC(=O)c1ccccc1OCc1ccccc1
Reactant: COc1ccc(CC(C)N)c(OC)c1OC
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CC(C)N=C(OCc2ccccc2)C(=O)c2ccccc2)c(OC)c1OC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
10.3 g of 2-benzyloxyphenylglyoxal hydrate are dissolved in 5 ml of dimethylsulfoxide. 7.6 g of α-methyl-2,3,4-trimethoxyphenethylamine are dissolved in 6 ml of dimethylsulfoxide, and the solution is added to the 2-benzyloxyphenylglyoxal solution under ice-cooling. The mixture is stirred at 20° C. for 2 hours, whereby a solution of α-(α-methyl-2,3,4-trimethoxyphenethylimino)-2-benzyloxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:6]2[NH:7][CH:8]=[N:9][C:10](=O)[C:5]=2[CH:4]=1)[CH3:2].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:10]1[N:9]=[CH:8][NH:7][C:6]2=[N:12][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=12
Reactant: CCc1cc2c(=O)nc[nH]c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1cc2c(Cl)nc[nH]c-2n1
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of 3.35 g (20.5 mmol) of 1,7-dihydro-6-ethyl-4H-pyrrolo[2,3-d]pyrimidin-4-one in 187 mL of phosphorous oxychloride was heated to reflux for 4 hours. The reaction was cooled to ambient temperature and concentrated under vacuum. The residue was dissolved in 100 mL of methylene chloride and poured onto 100 g of ice. The mixture was neutralized to pH 7 by the addition of powdered potassium carbonate. After an additional 200 mL of methylene chloride and 200 mL of water were added, some solids remained and were removed by filtration. The solids were shown to be desired product by thin layer chromatography (silica, 19:1 methylene chloride-methanol). The solids were combined with the organic phase and concentrated to 4.0 g of brown residue. The residue was purified by flash chromatography (200 g of silica, 19:1 methylene chloride-methanol) to provide 2.50 g (67%) of 4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine as a white solid. nmr (500 MHz, dmso-d6) δ1.27 (t, J=7.5 Hz, 3H), 2.76 (q, J=7.5 Hz, 2H), 6.30 (s, 1H), 8.48 (s, 1H), 12.41 (s, 1H)
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][C:11]([O:13]C)=[CH:12][C:6]=2[CH:5]=1)(=[O:3])N.Br.C(O)(=[O:18])C>>[OH:13][C:11]1[CH:10]=[CH:9][C:7]2[S:8][C:4]([C:1]([OH:3])=[O:18])=[CH:5][C:6]=2[CH:12]=1
Reactant: COc1ccc2sc(C(N)=O)cc2c1
Reactant: CC(=O)O
Agent: Br
Product: O=C(O)c1cc2cc(O)ccc2s1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of 2-Carbamoyl-5-methoxybenzo[b]thiophene (2.0 g), acetic acid (5 ml) and 48% hydrobromic acid (20 ml) was stirred for 16 hours at 110° C., and the mixture was poured into the ice-water. The resulting precipitate was collected by filtration, and dried to give 5-Hydroxybenzo[b]thiophene-2-carboxylic acid (1.66 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#[N:12].Cl[CH2:14][CH2:15][CH2:16]Cl>CS(C)=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([C:11]#[N:12])[CH2:16][CH2:15][CH2:14]1
Reactant: N#CCc1ccccc1F
Reactant: ClCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC1(c2ccccc2F)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
Slowly add NaH (922 mg, 23.0 mmol) to a solution of (2-fluorophenyl)-acetonitrile (1.27 mL, 9.95 mmol) in DMSO (40.0 mL). Stir the mixture at RT for 30 mins then add via cannula a solution of 1,3-dichloropropane (0.95 mL, 10.0 mmol) in DMSO (20 mL). After addition is complete stir at 75° C. for 5 h. Pour mixture over ice (60 g) and extract with Et2O (3×50 mL). Combine the organic solutions and wash with brine (50 mL), dry filter and concentrate. Purify the material by flash chromatography (using a linear gradient of 100% hexanes to 35% EtOAc/hexanes) to give the title compound (1.4 g, 80%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.32 (m, 1H), 7.25 (dt, 1H, J=1.9, 8.0), 7.16 (dt, 1H, J=0.9, 7.5), 7.09 (ddd, 1H, J=1.2, 8.1, 10.7), 2.86 (m, 2H), 2.69 (m, 2H), 2.50 (m, 1H), 2.05 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=O)(C)(C)C.[CH3:16][C:17]1[CH:22]=[CH:21][C:20](C(N)C2C=CC=CC=2)=[CH:19][CH:18]=1.[CH2:31]=[CH:32]C1C=CC=CC=1.[CH2:39]=CC1C=CC(C=C)=CC=1.[ClH:49].N1(C(OC(C)(C)C)=O)CCC[C@H]1C(O)=O.CC1C=CC(C(N)C2C=CC=CC=2)=CC=1.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.Cl.FC(F)(F)C(O)=O>ClCCl.C(N(C(C)C)CC)(C)C.C(N(CC)CC)C>[NH:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([CH:15]([NH2:8])[C:14]2[CH:13]=[CH:9][CH:10]=[CH:32][CH:31]=2)=[CH:19][CH:18]=1.[CH2:16]=[CH:17][C:10]1[CH:9]=[CH:13][CH:14]=[CH:15][CH:39]=1.[CH2:21]=[CH:22][C:17]1[CH:15]=[CH:14][C:13]([CH:9]=[CH2:10])=[CH:19][CH:18]=1.[ClH:49]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: C=Cc1ccc(C=C)cc1
Agent: Cc1ccc(C(N)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(O)[C@@H]1CCCN1

Procedure:
Peptides described in this invention are prepared starting from t-butyloxycarbonyl-proline linked to MBHA resin (Boc-Pro-MBHA) which is also commercially available. Boc-Pro-MBHA resin is treated with anhydrous trifluoroacetic acid (TFA) or 25% to 75% mixture of TFA in dichloromethane (TFA-DCM) to deprotect the amino group, and the resulting salt neutralized using 5% to 20% triethylamine in DCM (TEA-DCM) or 5% to 20% diisoproylethylamine in DCM (DIEA-DCM) to furnish H2N-Pro-MBHA resin.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+].[OH-].[Na+]>ClCCl.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)[S:24]([CH3:23])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(NCc2ccncc2)c(F)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1ccncc1)c1ccc(F)cc1F

Procedure:
A 4.7 g. portion of 4-(2,4-difluorophenylaminomethyl)pyridine was dissolved in 15 ml. of chloroform, and 4.1 g. of potassium carbonate was added, followed by 2.3 ml. of methanesulfonyl chloride. The mixture was stirred under reflux overnight, and then for several days at ambient temperature. It was then diluted with 20 ml. of dichloromethane and 20 ml. of aqueous sodium bicarbonate, and 5 ml. of 2N sodium hydroxide was added. The organic phase was then washed with aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in dichloromethane and chromatographed over silica gel, to obtain 0.5 g. of impure product, which was triturated with diethyl ether to obtain 0.29 g. of the desired product, m.p. 101°-105°.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9](Cl)[CH:8]=[C:7]2[C:3]=1[C:4]([C:12]([OH:14])=[O:13])=[CH:5][NH:6]2.N1[C:23]2[C:18](=CC=CC=2)[CH:17]=C1>>[CH:23]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]([C:12]([OH:14])=[O:13])=[CH:5][NH:6]3)[CH2:18][CH2:17]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(O)c1c[nH]c2cc(Cl)cc(Cl)c12
Product: O=C(O)c1c[nH]c2cccc(C3CC3)c12

Procedure:
Compound 4 was converted into the target indole acid using a similar procedure to Example 42.
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[OH:32])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1>>[CH2:1]([S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH:20]2[O:32][CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCSCc3ccccc3)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCSCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-benzylsulphanyl-propoxy)-phenyl]-3-hydroxy-piperidine-1-carboxylate with 2-bromomethyl-naphthalene there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzylsulphanyl-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless resin; MS: 598 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14](=[O:33])[N:13]1[CH:9]([CH2:10][CH:11]([O:34][C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][N:36]=3)[CH2:12]1)[C:8](=[O:45])[NH:7]2)=[O:5])C.C1COCC1.CO.O.[OH-].[Li+]>O>[C:29]([O:28][C:26]([NH:25][CH:15]1[C:14](=[O:33])[N:13]2[CH:9]([CH2:10][CH:11]([O:34][C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][N:36]=3)[CH2:12]2)[C:8](=[O:45])[NH:7][C:6]2([C:4]([OH:5])=[O:3])[CH:23]([CH2:24]2)[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)C12CC1C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(Oc3nccc4ccccc34)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid ethyl ester (1.10 g, 1.77 mmol) was dissolved in the mixed solvent system; THF (18 mL), methanol (8 mL), and water (2 mL). Powdered lithium hydroxide hydrate (744 mg, 17.7 mmol) was added. The light yellow slurry was stirred at rt under N2 for 24 h, and then concentrated in vacuo. The residue was partitioned between ether and water. The ether phase was discarded, and the aqueous phase was treated with 4N HCl until the pH was 4. This acidic solution was extracted with ether four times. The combined ether extracts were dried (MgSO4) and concentrated in vacuo to give 0.95 g (90%) of 14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid as a white solid: 1H NMR (300 MHz, CD3Cl3) δ 1.30 (s, 9H), 1.34–1.46 (m, 4H), 1.52–1.68 (m, 2H), 1.84 (m, 2H), 2.08–2.58 (m, 6H), 2.78–2.87 (m, 1H), 4.07 (m, 1H), 4.32 (d, J=11.3 Hz, 1H), 4.41 (m, 1H), 4.79 (t, J=7.3 Hz, 1H), 5.14 (t, J=9.5 Hz, 1H), 5.23 (d, J=7.3 Hz, 1H), 5.60 (q, J=8.8 Hz, 1H), 5.86 (s, 1H), 7.08 (s, 1H), 7.22 (d, J=6.2 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.94 (d, J=5.9 Hz, 1H), 8.17 (s, J=8.4 Hz, 1H). LC-MS (Method A, retention time: 3.32 min), MS m/z 593 (M++1)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][NH:16]3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1.[H-].[Na+]>CN(C=O)C>[Cl:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([N:16]2[C:17]3[C:13](=[CH:12][CH:11]=[C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH:18]=3)[CH:14]=[CH:15]2)[CH:25]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3cc[nH]c3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(-c2ccc3ccn(-c4cc(Cl)ncn4)c3c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.7 %

Procedure:
6-(3-Nitrophenyl)-1H-indole (2 g, 8.39 mmol) and 4,6-dichloropyrimidine (1.25 g, 8.39 mmol) were dissolved in DMF (20 mL) and sodium hydride (60% in mineral oil, 671 mg, 16.78 mmol) was added at 0° C. 1 hour later, ice was added to the reaction solution and the mixture solution was added to ice water. The mixture solution was stirred at room temperature for 12 hours. Thus prepared solid was filtered, washed with water, and dried in the air. 1-(6-Chloropyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (2.61 g) was yielded as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH3:10][C:11](=[CH2:13])[CH3:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]([CH3:13])([CH3:12])[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: C=C(C)C
Product: COc1ccc(OC(C)(C)C)cc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
To a 300 cc stainless steel stirred autoclave may be added 124 g (1.0 mol) 4-methoxyphenol and 10 g of XN-1010, a cation exchange resin bearing sulfonic acid groups supplied by Rohm and Haas Co. The system may be charged with 56 g (1.0 mol) isobutylene and the mixture stirred 5 hours at 20° C. Resin may be removed by filtration and unreacted phenol may be removed by washing the filtrate with an aqueous solution of 10% sodium hydroxide. The organic material may be washed with water to remove caustic and dried with magnesium sulfate to afford t-butyl 4-methoxyphenyl ether in a yield of about 70%.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([NH2:8])[O:6][CH:7]=1.[F:11][C:12]1[CH:25]=[CH:24][C:23]2[O:22][C:21]3[C:16](=[CH:17][C:18]([F:26])=[CH:19][CH:20]=3)[CH:15]([C:27](O)=[O:28])[C:14]=2[CH:13]=1>>[F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([NH:8][C:27]([CH:15]2[C:16]3[CH:17]=[C:18]([F:26])[CH:19]=[CH:20][C:21]=3[O:22][C:23]3[C:14]2=[CH:13][C:12]([F:11])=[CH:25][CH:24]=3)=[O:28])[O:6][CH:7]=1
Reactant: O=C(O)C1c2cc(F)ccc2Oc2ccc(F)cc21
Reactant: Nc1nc(C(F)(F)F)co1
Product: O=C(Nc1nc(C(F)(F)F)co1)C1c2cc(F)ccc2Oc2ccc(F)cc21

Procedure:
The title compound, white solid, m.p. 259° C. and MS: m/e=397.1 (M+H+), is prepared in accordance with the general method of example 3c from 4-trifluoromethyl-oxazol-2-ylamine and 2,7-difluoro-9H-xanthene-9-carboxylic acid (CAS:[188028-26-4]).
Reaction SMILES: C=O.[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:14][CH2:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[N:17]=2)=[C:8]([CH2:10][C:11]([NH2:13])=[O:12])[CH:9]=1.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:14][CH2:15][C:16]2[C:21]([C:22]([F:24])([F:25])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[N:17]=2)=[C:8]([CH2:10][C:11]([NH2:13])=[O:12])[CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1cc(F)ccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccc(F)cc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
Formaldehyde (37 wt. % in H2O; 29 μL, 0.39 mmol) was added to a suspension of 2-(5-fluoro-2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (9) (0.065 g, 0.13 mmol) in MeOH (8 mL) under an atmosphere of nitrogen. The resulting mixture was stirred for 10 minutes at room temperature then sodium triacetoxyborohydride (0.110 g, 0.518 mmol) was added in one portion and stirring continued for 3 hours The volatiles were removed in vacuo, then the residue was partitioned between EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. The volatiles were removed under reduced pressure to yield the title compound 10 as an off-white solid (58 mg, 87%); 1H NMR (400 MHz, d6-DMSO) δ 10.13 (s, 1H), 8.65 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.49 (s, 1H), 7.22-7.16 (m, 3H), 7.08 (dd, J=10.2, 2.8 Hz, 1H), 7.04-6.95 (m, 2H), 3.50 (s, 2H), 3.12-3.04 (m, 2H), 3.04-2.95 (m, 2H), 2.87 (d, J=11.3 Hz, 2H), 2.46-2.36 (m, 1H), 2.20 (s, 3H), 2.02-1.92 (m, 2H), 1.76-1.58 (m, 4H). LCMS-A: rt 4.867 min; m/z 516 [M+H]+.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([F:24])[CH:13]=1)([O:3][CH2:4][C:5]1C=CC=CC=1)=[O:2].CC(C)([O-])C.[Li+].ClC[C@@H](O)[CH2:34][N:35]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Cl-].[NH4+]>C(OCC)(=O)C.CS(C)=O>[CH2:43]([N:35]([CH2:34][C@@H:4]1[O:3][C:1](=[O:2])[N:11]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:14]([F:24])[CH:13]=2)[CH2:5]1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Reactant: O=C(Nc1ccc(N2CCOCC2)c(F)c1)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Temperature: -30 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
N-carbobenzoxy-3-fluoro-4-morpholinylaniline (0.33 g, 1 mmol) was added to 8 mL of dimethyl sulfoxide. The solution was cooled to −30° C. under the protection of nitrogen flow and then 50 mmol of lithium tert-butoxide was added. The mixture was stirred at −30° C.˜−20° C. for 2 hours. (S)-1-chloro-3-(dibenzylamino)propan-2-ol (1.45 g, 5 mmol) was added and then the solution was heated slowly to 60° C. and stirred for 2 hours. After the solution was cooled down, saturated ammonium chloride solution and ethyl acetate were added to separate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to provide 280 mg white solid with 59% yield. HPLC: 99.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]#[N:19])=[C:6]([C:8]2[CH:13]=[C:12]([O:14]C)[N:11]=[CH:10][C:9]=2[C:16]#[N:17])[CH:7]=1.Cl.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]#[N:19])=[C:6]([C:8]2[C:9]([C:16]#[N:17])=[CH:10][NH:11][C:12](=[O:14])[CH:13]=2)[CH:7]=1
Reactant: COc1cc(-c2cc(Cl)ccc2C#N)c(C#N)cn1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1C#N

Procedure:
414 mg (purity 94%, 1.14 mmol) of 4-(5-chloro-2-cyanophenyl)-6-methoxypyridin-3-carbonitrile and pyridinium hydrochloride were reacted according to General Method 3A. Yield: 312 mg (purity 91%, 77% of theory)