Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([Cl:12])=[C:4]([C:13]([OH:15])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:22]1([O:28][CH2:29][CH3:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([Cl:12])=[C:4]([C:13]([C:25]2[CH:26]=[CH:27][C:22]([O:28][CH2:29][CH3:30])=[CH:23][CH:24]=2)=[O:15])[CH:3]=1
Reactant: CCOc1ccccc1
Reactant: CC1Cc2c(Cl)c(C(=O)O)cc(Br)c2O1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc(C(=O)c2cc(Br)c3c(c2Cl)CC(C)O3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of compound 88 (2.4 g, 8.23 mmol) in CH2Cl2 (50 mL) were added oxalyl chloride (0.87 mL, 9.88 mmol) and catalytic amounts of DMF at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was evaporated in vacuo and dried under high vacuum. The crude acid chloride was dissolved with CH2Cl2 (45 mL) and cooled to 0° C. To the mixture was added phenetole (1.1 mL, 8.28 mmol) at 0° C. and stirred at 0° C. for 5 min. To the reaction mixture was added AlCl3 (1.1 g, 8.28 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 30 min, warmed up to room temperature and stirred at the temperature for 15 hours. The mixture was poured into ice-water and extracted with CH2Cl2 (50 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 89 was carried on to the next step without further purification (3.15 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]([CH3:17])=[N:15][O:14][N:13]=2)=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:24][OH:25]>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]([CH3:17])=[N:15][O:14][N:13]=2)=[N:24][OH:25])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1nonc1C(=O)Nc1cccc(C#N)c1
Reactant: NO
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Cc1nonc1C(=NO)Nc1cccc(C#N)c1
Yield: 10.8 %

Procedure:
N-(3-Cyanophenyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (25 mg, 0.11 mmol) was suspended in benzene (2 mL) under an atmosphere of nitrogen. Phosphorus pentachloride (25 mg, 0.12 mmol) was added and the solution was heated at reflux for 2.5 hrs. The reaction was then evaporated to dryness. The crude was dissolved in EtOH (1.6 mL) and hydroxylamine (200 μL, 3 mmol, 50% solution in water) was added to the reaction. The crude was purified by preparative LCMS to afford the desired product (2.9 mg). MF═C11H9N5O2; LCMS calculated for C11H9N5O2 (M+H)+: m/z=244.1.
Reaction SMILES: [C:1]([N:5]1[CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17](Br)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:31])([CH3:4])([CH3:3])[CH3:2].[C:32]([NH2:37])(=[O:36])[CH:33]([CH3:35])[CH3:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C(O)(C)(C)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:5]1[CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([NH:37][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1Br)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Reactant: CC(C)C(N)=O
Agent: [Pd]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc2c(cc1NC(=O)C(C)C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Temperature: 100 °C
Yield: 47.4 %

Procedure:
A mixture of 250 mg of 3d, 110 mg of isobutyramide, 230 mg of K3PO4, 15 mg of Pd2 dba3 and 20 mg of di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine in 3 ml of degassed tert-butanol was heated under nitrogen atmosphere for 16 hr at 100° C. The reaction mixture was cooled and diluted with 20 ml of water. The product was extracted into ethyl acetate. The extract was washed with water, dried, concentrated and the product was purified by chromatography over silica gel, using a gradient of heptane/ethyl acetate as eluent, to provide 120 mg of 3f. The sample was crystallized from ethyl acetate; MS-ESI: [M+1] 506.25. NMR (CDCl3) δ 1.18 (d, 6, isoC3H7), 1.58 (s, 9, tertC4H9), 1.89 (m, 2, CH2), 2.44 (m, 1, CH), 2.58 (t, 2, CH2), 3.01 (t, 2, CH2), 3.42 (t, 2, CH2), 3.86 (s, 3, OCH3), 4.50 (t, 2, CH2), 6.70 (s, 1 ArH) and 7.46 (bs, 1, ArH), 7.00, 7.18 and 7.38 (3×m, 3, thiophene-H), 8.08 (bs, 1, NH).
Reaction SMILES: COC1C=C([C@@H](NCCC2(O)CCC3(OCC(C)(C)CO3)CC2)C)C=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([C@@H:48]([N:50]2[CH2:55][CH2:54][C:53]3([CH2:67][CH2:66][C:58]4(OCC(C)(C)C[O:59]4)[CH2:57][CH2:56]3)[O:52][C:51]2=[O:68])[CH3:49])[CH:45]=[CH:46][CH:47]=1>>[CH3:40][O:41][C:42]1[CH:43]=[C:44]([C@@H:48]([N:50]2[CH2:55][CH2:54][C:53]3([CH2:67][CH2:66][C:58](=[O:59])[CH2:57][CH2:56]3)[O:52][C:51]2=[O:68])[CH3:49])[CH:45]=[CH:46][CH:47]=1
Reactant: COc1cccc([C@H](C)N2CCC3(CCC4(CC3)OCC(C)(C)CO4)OC2=O)c1
Agent: COc1cccc([C@H](C)NCCC2(O)CCC3(CC2)OCC(C)(C)CO3)c1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: COc1cccc([C@H](C)N2CCC3(CCC(=O)CC3)OC2=O)c1

Procedure:
The title compound is prepared from 9-{2-[(S)-1-(3-methoxy-phenyl)-ethylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 3-[(S)-1-(3-methoxy-phenyl)-ethyl]-12,12-dimethyl-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained thereafter is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound as well. Yield: 41% of theory; LC (method 6): tR=1.11 min; Mass spectrum (ESI+): m/z=318 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][CH:44]([CH2:47][CH2:48][O:49][Si](C(C)C)(C(C)C)C(C)C)[CH2:43][CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][CH:44]([CH2:47][CH2:48][OH:49])[CH2:43][CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(CCO[Si](C(C)C)(C(C)C)C(C)C)CC5)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(CCO)CC5)n4c3)c3ccccc32)cc1

Procedure:
A solution of Intermediate 66d (207 mg, 0.253 mmol) and TBAF (1M in THF, 0.303 mL, 0.303 mmol) in THF (4 mL) was stirred at RT for 2.25 h. The mixture was diluted with water and extracted with DCM (4×15 mL). The combined organic extracts were dried and concentrated in vacuo. The residue was purified by FCC, using 0-15% MeOH in DCM, to give the product. This was further purified by HPLC (C18 X-select column, 30-98% MeCN in H2O, 0.1% formic acid) to give the title compound as an off-white powder after freeze-drying (114 mg, 68%). LCMS (Method 5): Rt 4.29 min, m/z 663.3 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.38-1.51 (4H, m), 1.57-1.68 (1H, m), 1.72-1.97 (4H, m), 1.99-2.16 (2H, m), 2.36 (3H, s), 2.85-2.95 (2H, m), 3.30-3.52 (4H, m, under water signal), 4.38 (1H, s), 4.77-4.85 (1H, m), 5.55 (1H, t, J 4.3), 6.32 (1H, s), 7.09 (1H, d, J 8.6), 7.16 (1H, dd, J 9.9, 2.2), 7.26-7.40 (8H, m), 7.61 (1H, d, J 9.9), 7.65 (1H, d, J 1.4), 8.06 (1H, s).
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]2[N:22]=[C:21]([NH2:23])[C:20]([NH2:24])=[C:19]([NH2:25])[N:18]=2)=[N:9]1.[C:30](Cl)(=[O:37])[O:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34]>N1C=CC=CC=1>[NH2:25][C:19]1[C:20]([NH:24][C:30](=[O:37])[O:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:21]([NH2:23])[N:22]=[C:17]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:8]([CH2:7][C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[F:4])[N:9]=2)[N:18]=1
Reactant: CC(C)(C)COC(=O)Cl
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1N
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)COC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N

Procedure:
Prepared in analogy to Example 2 with 100 mg (0.29 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine trihydrochloride from Example 8A, 5 ml of pyridine and 43 mg (0.29 mmol) of neopentyl chlorocarbonate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][C@H:8]([CH2:12][C@H:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C[C@@H](C(N1[C@H](C)[C@H](C2C=CC=CC=2)OC1=O)=O)C[C@@H](C)CCCCC)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[CH2:7][C@H:8]([CH2:12][C@@H:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: CCCCC[C@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Product: CCCCC[C@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O

Procedure:
A procedure similar to that used for compound 157 was used except that ester 165 (8.42 g, 18.89 mmol) was used as a reactant to give 166 as an oil (5.81 g). The material was used directly in the next step. MS (APCI) m/z 285 (M−1, 100%).
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]([F:30])([F:29])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:19]=1)[CH:9]([CH3:15])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[F:29][C:17]([F:30])([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:19]=1)[CH2:16][NH:8][CH:9]([CH3:15])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11]
Reactant: CCCCOc1cccc(C(F)(F)CN(C(=O)OC(C)(C)C)C(C)C(=O)N(C)C)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCOc1cccc(C(F)(F)CNC(C)C(=O)N(C)C)c1
Reaction time: 8 h

Procedure:
84 mg (0.196 mmol) of 2-[N-tert-butoxycarbonyl-2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylpropanamide are dissolved in 3 mL of DCM and 0.49 mL (1.96 mmmol; 10 eq) of a 4M HCl solution in dioxane are added. After 8 hours, further 10 eq (0.49 mL) of 4M HCl 1 dioxane are added and the mixture is stirred overnight. Further 5 eq (0.245 mL) of 4M HCl in dioxane are the added and the mixture stirred for further 24 hours. The solution is evaporated, the white residue suspended in diethyl ether and then evaporated twice. The residue is flash-chromatographed on silica gel (DCM/MeOH 1/1 as an eluant followed by MeOH/conc. NH3 95/5). and the free base 2-[2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylpropanamide is isolated as a pale yellow fluid. The compound is dissolved in DCM (3 mL) and 4M HCl in dioxane is added to bring the solution to pH 2. The mixture is stirred for 10 minutes and then evaporated. The white residue is taken up with ether and evaporated twice. 45 mg (49%) of 2-[2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylpropanamide, hydrochloride (Example 2-1) are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[CH:7]=[C:8]3[NH:31][CH:30]=[N:29][C:9]3=[CH:10][C:11]=2[C:12]=1[N:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)C=O)#[N:2].C(=O)([O-])[O-].[K+].[K+]>CO>[O:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:13][C:12]2[C:11]3[CH:10]=[C:9]4[N:29]=[CH:30][N:31]=[C:8]4[CH2:7][C:6]=3[N:5]=[CH:4][C:3]=2[C:1]#[N:2])=[CH:17][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1cnc2cc3[nH]cnc3cc2c1N(C=O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1cnc2c(c1Nc1ccc(Oc3ccccc3)cc1)C=C1N=CN=C1C2
Yield: 70 %

Procedure:
A suspension of 211.8 mg (0.52 mmol) of 7-cyano-3H-imidazo[4,5-g]quinolin-8-yl(4-phenoxyphenyl)formamide and 288.9 mg (2.09 mmol) of potassium carbonate in 15 mL of methanol is refluxed for 2.5 hours. The solution is concentrated and the residue is diluted with water followed by neutralization to pH 7–8 with acetic acid. The precipitate is collected by filtration and washed with water and dried in vacuo, giving a deep yellow solid. The solid is purified by flash chromatography (elution with a gradient of 98:2 to 90:10 methylene chloride/methanol) yields 137.4 mg (70.0%) of the final product as a yellow solid, mp>270° C.
Reaction SMILES: C(OC([NH:8][C:9]([NH:26]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[ClH:34].[N+:23]([C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:26])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2[N+](=O)[O-])c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N=C(N)Nc1cccc(-c2ncccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-nitropyridin-2-yl)phenyl)guanidine (200 mg) in dichloromethane (2 ml) was added 4N hydrogen chloride in 1,4-dioxane (2 ml), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the.precipitate was collected by filtration and dried under reduced pressure to give 3-(3-nitropyridin-2-yl)phenylguanidine dihydrochloride (127 mg).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[N:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>N1C=CC=CC=1.Cl>[CH:1]1([C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ncc([N+](=O)[O-])cn1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])cn1)C1CCCCC1
Yield: 64.4 %

Procedure:
Cyclohexanoyl chloride (1.05 g, 7.14 mmol) was added dropwise to a stirred suspension of 2-amino-5-nitropyrimidine (1.0 g, 7.14 mmol) in pyridine (10 ml) and the reaction was heated at reflux for 4 hours under an inert atmosphere. The reaction mixture was cooled then stirred in 2N hydrochloric acid (100 ml) and extracted with ethyl acetate. Crystallisation from ethyl acetate/hexane, yielded 2-(N-cyclohexanoyl)amino-5-nitropyrimidine (1.15 g, 64% yield) as a beige solid:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:16]1[C@@H:21]([CH3:22])[CH2:20][C:19]([CH3:23])=[CH:18][CH2:17]1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[Pd]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:16]1[CH2:17][CH2:18][C@H:19]([CH3:23])[CH2:20][C@@H:21]1[CH3:22])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=CC[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@@H](C)C1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CC[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
A mixture of (S)-4-benzyl-3-((1S,6S)-4,6-dimethylcyclohex-3-enecarbonyl)oxazolidin-2-one (6 g, 19.1 mmol) and 10% Pd/C (500 mg) in EtOH (50 mL) under a H2 atmosphere (1 atm) was stirred at room temperature overnight. The reaction mixture was filtered through a pad of diatomaceous earth and concentrated to give a 3:1 mixture of diastereomers, which were separated by preparative chiral column chromatography (Chiralcel OD-H (20 cm×250 cm; semi prep): Retention time: 24 min, 33 min (major) (80:20 heptane:ethanol)), providing (S)-4-benzyl-3-((1S,2S,4S)-2,4-dimethylcyclohexanecarbonyl)oxazolidin-2-one (2.3 g, 38%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)N[C:32](=[O:37])/C/2=C\C1NC=CC=1OC)#C.IC1C=CC(O)=CC=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][C:25]=2[O:37][CH3:32])=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Reactant: C#Cc1ccc2c(c1)/C(=C/c1[nH]ccc1OC)C(=O)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Oc1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(C#Cc3ccc(O)cc3)cc21

Procedure:
This compound was also prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (75 mg, 0.28 mmol) (from Example 93) was coupled with 4-iodophenol (75 mg, 0.34 mmol) (Aldrich) using CuI (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (14 mg, 0.020 mmol) (Aldrich) as catalyst in 1 mL DMF and 1 mL triethylamine at 70° C. for 14 hours to give (Z)-1,3-dihydro-5-(4-hydroxyphenyl) ethynyl-3-[(3-methoxy-1H-pyrrol-2-yl)-methylene]-2H-indol-2-one as a yellow powder. (Yield 62 mg, 62%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:13][N:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].CO.C(Cl)(Cl)Cl>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][N:12]=1)([CH3:10])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(N(Cc2ccccc2)Cc2ccccc2)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(N)cn1
Reaction time: 16 h

Procedure:
To a solution of 42 (700 mg, 1.6 mmol) in methanol (30 mL) was added 20% Pd(OH)2 (1.25 g) and hydrogenated at 50 psi for 16 h. The reaction mixture was filtered through a pad of Celite and the filtrate was evaporated. The crude compound was purified by silica gel column chromatography (100-200 mesh, eluting with 5% MeOH/CHCl3) to obtain A4-13 (250 mg, 61%) as a white solid. Rf: 0.3 (10% MeOH/CHCl3), (m/z): 252 [MH]+; 1H NMR (400 MHz, DMSO-d6): δ 7.81 (1H, d, J=2.8 Hz), 7.08 (1H, d, J=8.4 Hz), 6.99 (1H, br s), 6.89 (1H, dd, J=2.4, 8.4 Hz), 5.11 (2H, br s), 1.45 (6H, s), 1.34 (9H, s).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[K].Cl[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+:19]([O-])=O>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]2[O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:9])[NH:19][C:13]=2[CH:14]=1
Reactant: O=Cc1ccccc1O
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [K]
Product: O=C1Nc2cc(Cl)ccc2Oc2ccccc21

Procedure:
The starting material 8-chloro-10,11-dihydro-dibenz[b,f][1,4]oxazepin-11-one was prepared according to the procedures reported in Coyne et al (J. Med. Chem., 1967, 10:541). Briefly, this entailed coupling potassium salicylaldehyde with 2,5-dichloronitrobenzene, followed by oxidation to carboxylic acid, reduction of nitro, and finally ring closure, to yield the desired 8-chloro starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10](OCC)OCC)=[CH:4][CH:3]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:8][CH:9]=[CH:10][C:6]=2[CH:7]=1
Reactant: CCOC(COc1ccc(Cl)cc1)OCC
Solvent: c1ccccc1
Product: Clc1ccc2occc2c1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1-chloro-4-(2,2-diethoxyethoxy)benzene (45 g, 184 mmol,) in benzene (200 mL) was added polyphosphoric acid (25 g, 221 mmol) with stirring for 2.5 h at 90° C. in an oil bath. The reaction mixture was cooled to room temperature and decanted from the polyphosphoric acid. The solvent was removed under vacuum. The residue was applied onto a silica gel column with 1% ethyl acetate in petroleum ether to afford 5-chlorobenzofuran as colorless oil (14.0 g, crude).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH:12]=[O:13])=[C:7]([O:14][CH3:15])[CH:6]=[CH:5]2.[CH3:16][O:17][C:18]1[CH:19]=[C:20](OB(O)O)[CH:21]=[CH:22][CH:23]=1>>[CH3:15][O:14][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[CH:23]=3)[CH:3]=2)[C:8]=1[CH:12]=[O:13]
Reactant: COc1ccc2cc(Br)ccc2c1C=O
Reactant: COc1cccc(OB(O)O)c1
Product: COc1cccc(-c2ccc3c(C=O)c(OC)ccc3c2)c1
Yield: 86 %

Procedure:
The compound is prepared by the reaction of 6-bromo-2-methoxy-1-naphthaldehyde (2 g, 7.55 mmol, 1 eq) with 3-methoxyphenylboric acid (1.3 g, 8.30 mmol, 1.1 eq) according to method A. Purification by column chromatography with hexane/ethyl acetate 1/1 as the eluent yielded the desired compound in a yield of 86%, 1.9 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+].[CH3:22][O:23][C:24](=[O:27])[CH2:25]Cl>O>[CH3:22][O:23][C:24](=[O:27])[CH2:25][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 6 h

Procedure:
300 g of 3-nitrophenol are added to 800 ml of DMF. Then 240 g of sodium carbonate are added portionwise. Subsequently 270 g of chloroacetic acid methylester is added at 22° C. Then the mixture is stirred at 85° C. for six hours. After being cooled down to 25° C. it is given to 3 kg of water and 1 kg of ice. The resulting suspension is filtered off. The filter cake is washed with 300 g of water and dried in vacuum. Yield: 407 g.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[C:20]([CH3:44])=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]([CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[N:24]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23][CH2:22]4)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[C:20]([CH3:44])=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]([CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[N:24]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:23][CH2:22]4)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CCOC(=O)CCCC1c2ccc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)c(C)c2CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(-c2noc(-c3cnc(OC(C)C)c(Cl)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2CCCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
Ethanol (1 ml) and 2M sodium hydroxide (1 ml) were added to 1,1-dimethylethyl 6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-[4-(ethyloxy)-4-oxobutyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 30; 100 mg, 0.17 mmol) and the mixture stirred at room temperature for 3 hours. The ethanol was evaporated and the residue acidified with glacial acetic acid. The mixture was extracted with ethyl acetate (2×2 ml). The combined extracts were dried and evaporated. The residue was triturated with iso-hexane to give the title compound (51 mg) as a colourless glassy solid.