Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[C:13]([N:17]3[CH2:26][C@H:25]4[N:21]([CH2:22][CH2:23][CH2:24]4)[C:20]4[N:27]=[C:28]([NH:31][CH2:32][CH3:33])[N:29]=[CH:30][C:19]=4[C:18]3=[O:34])[CH:14]=[CH:15][CH:16]=2)=[N:8][N:7]=1)(=O)C.[OH-].[Na+].C(OCC)(=O)C>CO>[CH2:32]([NH:31][C:28]1[N:29]=[CH:30][C:19]2[C:18](=[O:34])[N:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:9]4[O:10][C:6]([CH2:5][OH:4])=[N:7][N:8]=4)[CH:12]=3)[CH2:26][C@H:25]3[N:21]([CH2:22][CH2:23][CH2:24]3)[C:20]=2[N:27]=1)[CH3:33]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnc(COC(C)=O)o3)c1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnc(CO)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
(S)-5-[3-(5-Acetoxymethyl-1,3,4-oxadiazol-2-yl)phenyl]-9-ethylamino-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (20.0 mg, 0.0432 mmol) obtained in Step 1 was dissolved in methanol (2 mL), and the mixture was stirred at room temperature for 30 minutes after adding a 1 mol/L aqueous sodium hydroxide solution (2 mL). The mixture was diluted by addition of ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and crystallized from diisopropylether to give the title compound (Compound 48) (6.0 mg, 33%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=3[F:27])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[C:42](=[O:43])[C:41]([C:44](O)=[O:45])=[CH:40][N:39]([CH2:47][CH3:48])[C:38]2=[O:49])=[CH:33][CH:32]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:44]([C:41]4[C:42](=[O:43])[N:37]([C:34]5[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=5)[C:38](=[O:49])[N:39]([CH2:47][CH3:48])[CH:40]=4)=[O:45])=[CH:22][C:21]=3[F:27])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCc1ccccc1
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4cc(OCc5ccccc5)c(OC)cc34)c(F)c2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(7-benzyloxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl]-amide was synthesized using 4-(7-benzyloxy-6-methoxyquinolin-4-yloxy)-3-fluorophenylamine and 3-(4-fluorophenyl)-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid by the method for example 1. mp=142-4° C.; LCMS m/z=651 (M+1); 1H NMR (DMSO) δ: 11.0 (s, 1H), 8.89 (s, 1H), 8.47 (d, 1H, J=5.3 Hz), 7.98, 8.02 (dd, 1H, J=2.3, 13 Hz), 7.50-7.54 (m, 5H), 7.41-7.46 (m, 5H), 7.33-7.38 (m, 3H), 6.48 (d, 1H, J=5 Hz), 5.31 (s, 2H), 4.90 (q, 2H, J=7 Hz), 3.95 (s, 3H), 1.29 (t, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([B:20]4[O:24]C(C)(C)C(C)(C)[O:21]4)=[CH:16][CH:15]=3)[C:10]([CH2:29][CH3:30])=[C:9]([CH3:31])[N:8]=2)=[CH:4][CH:3]=1.F.[F-].[K+].O>CO>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([B:20]([OH:24])[OH:21])=[CH:16][CH:15]=3)[C:10]([CH2:29][CH3:30])=[C:9]([CH3:31])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: F
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
A 18-mL vial was charged with 2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-4-amine (10.3 mg, 0.023 mmol) and potassium hydrogen difluoride (40 mg, 0.5 mmol). Water (0.2 ml) and MeOH (1 ml) were added respectively. The resulting mixture was stirred at rt for 1 hr. Then the volatile material was removed under reduced pressure. The residue was treated with trimethylsilyl chloride (0.1 ml) in a mixture of acetonitrile (1 ml) and water (0.2 ml). After the mixture was stirred at rt for 1 hr, the volatile material was removed the residue was treated with NaHCO3 aq. (5 ml). The precipitate was collected and purified by Preparative TLC plate using 5% of acetone in DCM as mobile phase to give the title compound (2 mg, 23% yield). MW=373.66. 1H NMR (Methanol-d4, 400 MHz) δ 7.87 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.67 (d, J=4.0 Hz, 1H), 6.93 (d, J=4.0 Hz, 1H), 2.67 (q, J=7.6 Hz, 2H), 2.54 (s, 3H), 1.21 (t, J=7.6 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[CH3:26][O:27][C:28](=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35](Cl)=[O:36]>C(Cl)Cl>[CH3:26][O:27][C:28](=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:1][CH:2]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[C:3](=[O:4])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:36]
Reactant: COc1ccc(C(O)C(=O)c2ccccc2)cc1
Reactant: COC(=O)CCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCCCC(=O)OC(C(=O)c1ccccc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a solution of 2-hydroxy-2-(4-methoxyphenyl)-1-phenyl-ethanone (8.2 g, 0.034 mol) prepared in Step 3 and triethylamine (5.21 g, 0.051 mol) in methylene chloride (100 mL) was slowly added a solution of 7-chlorocarbonylheptanoic acid methyl ester (5.64 g, 0.034 mol) in methylene chloride (20 mL). A final reaction solution was stirred at room temperature for 12 hours and then diluted with 200 mL of methylene chloride. The obtained organic layer was washed twice with 100 mL of a saturated sodium bicarbonate solution and then successively washed twice with 100 mL of a brine solution. The obtained organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure, to give 12.90 g (yield: 92%) of octanedioic acid 1-(4-methoxyphenyl)-2-oxo-2-phenylethyl ester methyl ester.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([NH:5][C:6](=[O:16])[C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1ccc(N)cc1
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Ten percent Pd/C (0.1003 g) was added to a solution of N-t-butyl-4-nitrobenzamide (0.7349 g, 3.31 mmol) in ethyl acetate (10 ml), and stirred under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite® bed and the solvent was evaporated. The residue was purified by silica gel chromatography (hexane/ethyl acetate/triethylamine=50/100/1) to give the title compound (0.6156 g; 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[OH:13].C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)(=O)=O.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[O:13][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)c(OCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of methyl 3-hydroxy-4-methoxy benzoate (2.0 g, 11 mmol) in DMF (25 mL) was added cesium carbonate (7.2 g, 22 mmol) and 1,1-dimethylethyl 4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (3.2 g, 11 mmol). The mixture was heated to 70° C. and stirred for 2 h. After cooling to rt, water was added and the resulting aqueous mixture was extracted with ether followed by ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (70% hexanes, 30% ethyl acetate) to provide 3.54 g of 1,1-dimethylethyl 4-[({2-(methyloxy)-5-[(methyloxy)carbonyl]phenyl}oxy)methyl]piperidine-1-carboxylate (9.3 mmol, 85% yield). 1H NMR (400 MHz, CDCl3): δ7.69-7.66 (dd, 1H), 7.52 (d, 1H), 6.88 (d, 1H), 4.15 (br m, 2H), 3.92 (s, 3H), 3.91-3.88 (m, 2H), 3.90 (s, 3H), 2.76 (br m, 2H), 2.06 (m, 1H), 1.88 (br d, 2H), 1.47 (s, 9H), 1.31-1.25 (m, 2H); MS (EI) for C20H29NO6: 402 (MNa+).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]([O:13]C)=O)=[CH:7][N:6]=1)=[O:4].[NH:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17][OH:18]>C(O)C>[OH:18][CH2:17][CH2:16][N:15]([CH2:19][CH2:20][OH:21])[C:11]([C:8]1[CH:7]=[N:6][C:5]([C:3]([N:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17][OH:18])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: COC(=O)c1cnc(C(=O)OC)cn1
Reactant: OCCNCCO
Solvent: CCO
Product: O=C(c1cnc(C(=O)N(CCO)CCO)cn1)N(CCO)CCO
Temperature: 20 °C

Procedure:
A solution of 500 mg of 2,5-dimethoxycarbonylpyrazine and 0.48 cm3 of diethanolamine in 3 cm3 of ethanol is heated to a temperature in the region of the reflux temperature for 3 hours. The reaction mixture is cooled to 20° C. and the white solid formed is then filtered off and washed with 2 cm3 of ethanol. 600 mg of N,N,N′,N′-tetrakis(2-hydroxyethyl)pyrazine-2,5-dicarboxamide are thus obtained in the form of a white solid melting at 143° C. [1H NMR spectrum (250 MHz, (CD3)2SO-d6, at a temperature of 403 K, δ in ppm): from 3.50 to 3.80 (mt, 16H: 4×NCH2CH2O); 4.32 (mt, 4H: 4×OH); 8.76 (s, 2H: ═CH at 3 and ═CH at 6)].
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][N:14]([C@@H:22]([CH3:38])[C:23](=[O:37])[NH:24][C@H:25]1[CH2:31][O:30][C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[NH:27][C:26]1=[O:36])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[CH2:39]([N:41]1[C:49]2[C:44](=[C:45]([CH2:50]O)[CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42]1)[CH3:40].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:39]([N:41]1[C:49]2[C:44](=[C:45]([CH2:50][N:27]3[C:26](=[O:36])[C@@H:25]([NH:24][C:23](=[O:37])[C@@H:22]([N:14]([CH3:13])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19])[CH3:38])[CH2:31][O:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]3=4)[CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42]1)[CH3:40]
Reactant: C[C@@H](C(=O)N[C@H]1COc2ccccc2NC1=O)N(C)C(=O)OC(C)(C)C
Reactant: CCn1ccc2c(CO)cccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCn1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc4ccccc43)cccc21
Reaction time: 60 h
Yield: 51 %

Procedure:
DEAD 40% w/w (359 mg, 376 μl, 826 μmol, Eq: 3) was added to a mixture of tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)propan-2-yl)carbamate (100 mg, 275 μmol, Eq: 1.00), (1-ethyl-1H-indol-4-yl)methanol (48.2 mg, 275 μmol, Eq: 1.00) and polymer-bound Ph3P (500 mg, 275 μmol, Eq: 1.00) in THF (10 mL). After 2.5 d., additional portions of (1-ethyl-1H-indol-4-yl)methanol (48.2 mg, 275 μmol, Eq: 1.00), polymer-bound Ph3P (1 eq) and DEAD (1 eq), were added. After 1 d, the mixture was filtered and the filter cake washed with MeOH and THF. The filtrate was concentrated and the residue was purified by preparative TLC to afford tert-butyl (S)-1-((S)-5-((l-ethyl-1H-indol-4-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (73 mg, 51%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=O)=[CH:5][CH:4]=1)=[O:2].Cl.[NH2:13][OH:14].N1C=CC=CC=1>C(O)C>[CH:1]([C:3]1[S:7][C:6]([C:8](=[N:13][OH:14])[O:10][CH3:11])=[CH:5][CH:4]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COC(=NO)c1ccc(C=O)s1
Yield: 72 %

Procedure:
A solution of methyl 5-formyl-2-thiophenecarboxylate, prepared according to Example 10, (6.26 g, 36.78 mmoles), hydroxylamine hydrochloride (3.07 g, 44.14 mmoles) and pyridine (3.49 g, 44.14 imoles) in 200 ml of ethanol was refluxed for 2 hours. The ethanol was removed in vacuo, the residue dissolved in ether and washed with water. The organic layer was dried (magnesium sulfate) and evaporated to a yellow solid. Trituration with a small amount of ether furnished the title compound as a white solid (4.93 g, 72%), m.p. 164-7° C. Oxime Z:E ratio:(82:18).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:9]1=[O:20])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:27][C:26]3[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=3)=[CH:17][CH:18]=2)[C:9]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(O)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(OCc3ccc(F)cc3)cc2)C1=O

Procedure:
In an analogous manner to that described in Example 2c), the alkylation of the (S)-[1-(4-hydroxy-phenyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester with 4-fluorobenzylbromide in presence of potassium carbonate yields the title compound as a white solid; MS: m/e=401 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:16])=[C:11]([CH:15]=2)[C:12]([NH2:14])=[O:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:17]1[CH:22]=[C:21]2[C:23]([CH:26]=O)=[CH:24][S:25][C:20]2=[CH:19][CH:18]=1>>[O:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:15]=[C:11]3[C:10](=[CH:9][CH:8]=2)[N:16]=[C:26]([C:23]2[C:21]4[CH:22]=[CH:17][CH:18]=[CH:19][C:20]=4[S:25][CH:24]=2)[NH:14][C:12]3=[O:13])[CH2:2][CH2:3]1
Reactant: O=Cc1csc2ccccc12
Reactant: NC(=O)c1cc(N2CCOCC2)ccc1N
Product: O=c1[nH]c(-c2csc3ccccc23)nc2ccc(N3CCOCC3)cc12

Procedure:
Compound 31 was synthesized from 5-morpholinyl-2-aminobenzamide (13) (1.6 g, 7.3 mmol) and thianaphthene-3-carboxaldehyde (16) (1.2 g, 7.3 mmol): yield 1.6 g (60%); brown crystals; mp>300° C.; 1H NMR (DMSO-d6) δ 2.47 (4H, t, J=4.7 Hz, CH2NCH2), 3.75 (4H, t, J=4.7 Hz, CH2OCH2), 7.44-7.59 (4H, m, 4×ArH), 7.67-7.72 (1H, m, 1×ArH), 8.03-8.07 (1H, m, 1×ArH), 8.67 (1H, s, 1×ArH), 8.96-9.00 (1H, m, 1×ArH), 12.31 (1H, br s, NH) ppm; MS (ESI) m/z 363; Anal. (C20H17N3O2S): C, H, N.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][N:12](CC2C=CC=CC=2)[CH2:11][CH:10]1[CH:22]=[CH2:23])C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[ClH:1].[CH2:22]([CH:10]1[CH2:11][NH:12][CH2:13][CH2:14][NH:9]1)[CH3:23]
Reactant: C=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CCC1CNCCN1
Reaction time: 12 h

Procedure:
At room temperature, concentrated hydrochloric acid (6 ml) and palladium hydroxide (1.1 g) were added to solution (600 ml) of 1,4-dibenzyl-2-ethenylpiperazine (10.9 g)in ethanol, followed by stirring for 12 hours under a hydrogen gas stream of 1 atmospheric pressure. The catalyst was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was solidified using methylene chloride—diethyl ether, followed by washing with diethyl ether. The resulting solid was dried under reduced pressure, whereby the title compound (6.516 g) was obtained as a brown solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:15][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: COc1ccc(CO)cc1C#N
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CCl)cc1C#N
Yield: 89.9 %

Procedure:
To a solution of 5-hydroxymethyl-2-methoxy-benzonitrile (500 mg, 3.064 mmol) in toluene (10 mL) cooled to 0° C. was added thionyl chloride (338 μL, 4.596 mmol). The reaction mixture was heated at reflux for 3 h. The reaction mixture was concentrated in vacuo to afford 5-chloromethyl-2-methoxy-benzonitrile as a white solid (500 mg, 90%). The product was used without firther purification.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:11]1[N:16]2[N:17]=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:15]2[N:14]=[C:13]([CH3:34])[CH:12]=1.[H-].[Na+]>C1COCC1>[C:1]([N:5]1[CH2:8][CH:7]([O:9][C:11]2[N:16]3[N:17]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[C:19]([C:20]4[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=4)=[C:15]3[N:14]=[C:13]([CH3:34])[CH:12]=2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reactant: CC(C)(C)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(OC2CN(C(C)(C)C)C2)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butylazetidin-3-ol (24 mg, 0.19 mmol) and 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (I-3A-4b; 36 mg, 0.093 mmol) in THF (1 ml) was added NaH (60% dispersion in oil, 9.3 mg, 0.23 mmol). After stirring for 1 hour, the reaction was quenched with water, extracted from saturated aqueous NaHCO3 with ethyl acetate, the combined organic layers were dried (MgSO4), concentrated and purified on a Biotage™ Flash 12M column using 0–5% methanol in methylene chloride as eluant to afford 9A-1 (26 mg, 59%) as a colorless solid: +ESI MS (M+1) 481.4; 1H NMR (400 MHz, CD2Cl2) δ 7.50–7.36 (m, 6H), 7.24 (d, J=8.7 Hz, 2H), 5.99 (s, 1H), 5.10–5.02 (m, 1H), 3.76–3.70 (br m, 2H), 3.49–3.43 (br m, 2H), 2.60 (s, 3H), 1.00 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:16][CH2:17][C:4]=2[CH:3]=1)[C:15]1[N:11]([CH:12]=[N:13][CH:14]=1)[CH2:10][CH2:9]3.[CH3:18][N:19](C)C=O>[C-]#N.[Zn+2].[C-]#N.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:14]1[N:13]=[CH:12][N:11]2[CH2:10][CH2:9][C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:18]#[N:19])=[CH:3][C:4]=4[CH2:17][O:16]3)[C:15]=12
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)COC21CCn2cncc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Product: N#Cc1ccc2c(c1)COC21CCn2cncc21
Temperature: 120 °C

Procedure:
To a degassed solution of 31.2 mmol of 5-bromo-5′,6′-dihydro-3H-spiro[2-benzofuran-1,7′-pyrrolo[1,2-c]imidazole]] in 90 ml of N,N-dimethylformamide are added 62.4 mmol of zinc(II) cyanide and 1.25 mmol of [1,1′-bis(diphenylphosphino)ferrocene]-dichloro palladium. The mixture is heated at 120° C. for 16 h. The mixture is poured into ice water and extracted with ethyl acetate. The combined organics are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO2 60 F) followed by crystallization from diethyl ether to afford the title compound as a beige solid. Rf=0.33 (dichloromethane-2M ammonia in ethanol 95:5); Rt=4.62 (gradient II).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH2:14][CH2:15]OC)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[I:18][Si](C)(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH2:14][CH2:15][I:18])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCCc1cc(C(=O)OC)cc(Br)c1C
Reactant: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)c(C)c(CCCI)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a chloroform (0.1 M) solution of methyl 3-bromo-5-(3-methoxypropyl)-4-methylbenzoate (1 eq.) from the previous step was added iodotrimethylsilane (10 eq.). The resulting red solution was stirred at RT in darkness for 18 h. The reaction was quenched with methanol before the volatiles were removed in vacuo. The resulting residue was then taken up in ether, washed sequentially with 10% aq. HCl, 1 N aq. NaOH, water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→3:7 (v/v) Hex:EtOAc) afforded the title compound as an orange oil.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=3[I:22])=[N:8]2)=[C:4]([NH2:23])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:34][CH2:35][CH2:36][C:37]#[CH:38])(=O)=O>CN(C=O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=3[I:22])[N:8]2[CH2:38][CH2:37][CH2:36][C:35]#[CH:34])=[C:4]([NH2:23])[N:3]=1
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc(I)c(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc(OC)c(OC)cc2I)nc2c(N)nc(F)nc21

Procedure:
A solution of 2-fluoro-8-(2-iodo-4,5-dimethoxy-benzyl)adenine (12 mg, 0.028 mmol), Cs2CO3 (9 mg, 0.028 mmol), pent-4-ynyl tosylate (8.6 mg, 7 L, 0.036 mmol) in anhydrous DMF (80 L) was stirred at 50° C. for 1 h. Following solvent removal, the product (13.7 mg, 99%) was collected through silica gel column purification (CHCl3:EtOAc:hexanes:i-PrOH at 20:10:20:1). 1H NMR (400 MHz, CDCl3) 7.27 (s, 1H), 6.65 (s, 1H), 5.94 (bs, 2H), 4.29 (s, 2H), 4.13 (t, J=7.3 Hz, 2H), 3.87 (s, 3H), 3.73 (s, 3H), 2.26-2.22 (m, 2H), 2.00 (t, J=2.6 Hz, 1H), 1.97-1.90 (m, 2H); 13C NMR (100 MHz, CDCl3) 156.5, 153.2, 151.3, 150.0, 149.1, 130.9, 121.9, 112.6, 88.5, 82.5, 70.0, 56.4, 56.2, 42.6, 39.2, 28.4, 16.1; MS m/z 496.2 (M+H)+. HPLC: (a) 99.9% (60% water-40% acetonitrile); (b) 96.8% (35% to 55% acetonitrile).
Reaction SMILES: [Na+].[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([C:15]3[C:16]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:14])=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:31]([O-:33])=O.CS(O)(=O)=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:63]([N:70]([CH3:81])[C:71](=[O:80])[C@H:72]([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[NH2:73])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>ClCCl.C(N(CC)CC)C>[CH2:63]([N:70]([CH3:81])[C:71](=[O:80])[C@@H:72]([NH:73][C:31]([C:4]1[N:3]([CH3:2])[C:11]2[C:6]([CH:5]=1)=[CH:7][C:8]([NH:12][C:13]([C:15]1[C:16]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14])=[CH:9][CH:10]=2)=[O:33])[C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1)[C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1
Reactant: CN(Cc1ccccc1)C(=O)[C@@H](N)c1ccccc1
Reactant: Cn1c(C(=O)[O-])cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1C)c1ccccc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
1-Methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid sodium salt (16.0 g), from step (d) alternative A, methanesulfonic acid (2.24 mL), 1-hydroxybenzotriazole hydrate (5.32 g) and N-[3-(dimethylamino)propyl-N′-ethylcarbodimide hydrochloride (8.66 g) were combined in dichloromethane (384 mL) at 0-5° C. and the mixture stirred for 1 hour. Triethylamine (4.78 ml mL) was added followed by a slurry of (S)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloride (11.1 g), from step (e), in dichloromethane (48 mL) was added slowly, maintaining 0-5° C. The resulting slurry was allowed to warm to room temperature overnight. Further triethylamine (2.4 mL) was added at 0° C. After approximately 2 hours, the mixture was twice washed with saturated aqueous sodium hydrogen carbonate (2×200 mL), once washed with 0.5M aqueous hydrochloric acid solution (200 mL) and once washed with demineralized water (200 mL) adjusting to pH=6 with aqueous sodium hydrogen carbonate solution, providing a dichloromethane solution of (S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide.