Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:14](=[CH2:19])[C:15]([O:17]C)=[O:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12][CH3:13])=[N:5]2.C([O:24]O)(C)(C)C.CCCCCCCCC.CC(C)([O-])C.[K+]>C1COCC1>[F:1][C:2]1[C:3]([C:14]2([C:15]([OH:17])=[O:16])[CH2:19][O:24]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12][CH3:13])=[N:5]2
Reactant: C=C(C(=O)OC)c1c(F)ccc2ncc(OC)nc12
Reactant: CC(C)(C)OO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCCCCC
Solvent: C1CCOC1
Product: COc1cnc2ccc(F)c(C3(C(=O)O)CO3)c2n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
A solution of methyl 2-[6-fluoro-3-(methyloxy)-5-quinoxalinyl]-2-propenoate (5.45 g, 0.02 mol) (for a preparation, see Example 1(l)) in THF (150 ml) was cooled to 0° C. A 6M solution tert-butyl hydrogen peroxide in nonane (5.2 mL, 0.03 mol) was added dropwise followed by a 1M solution of potassium tert-butoxide (10.39 mL, 0.01 mol). During the addition the temperature was kept at 0° C. The reaction mixture was kept at 0° C. for 16 hours. Another 0.5 equivalent of the 1M solution of potassium tert-butoxide (10.39 mL, 0.01 mol) was added at 0° C. and the reaction mixture was kept for a further 2 hours. The reaction was quenched by addition of a 1M solution of HCl in methanol (20 mL). The reaction mixture was evaporated to dryness. The residue was partially dissolved in methanol. The organic layer was dried over magnesium sulphate, filtered, evaporated under vacuum and chromatographed on silica (required repeated chromatography), eluting with a 0-30% methanol in dichloromethane gradient to afford the product as a white solid (3.22 g, 59%)
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]2[O:7][C:8]([CH3:19])([CH3:18])[C@@H:9]([OH:17])[C@H:10]([NH:11][C:12](=[N:14][C:15]#[N:16])[CH3:13])[C:5]=2[CH:4]=1)#[N:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[C:1]([C:3]1[CH:21]=[CH:20][C:6]2[O:7][C:8]([CH3:18])([CH3:19])[C@@H:9]([O:17][S:23]([CH3:22])(=[O:25])=[O:24])[C@H:10]([NH:11][C:12](=[N:14][C:15]#[N:16])[CH3:13])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1OS(C)(=O)=O
Temperature: 0 °C

Procedure:
17.25 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-[(N-cyano-acetimidoyl)amino]-2H-benzo[b]pyran-3-ol was dissolved in 130 ml of pyridine, and 9.0 of methanesulfonyl chloride was added under stirring and cooling with ice. The mixture was reacted for 4 hours. The reaction mixture was poured into ice water, whereby a solid precipitated. This solid was collected by filtration and recrystallized from ethanol to obtain 28.5 g of 6-cyano-3,4-dihydro-3-methanesulfonyloxy-2,2-dimethyl-trans-4-[(N-cyano-acetimidoyl)amino]-2H-benzo[b]pyran in the form of crystals.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>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.CN(C=O)C.CCN(CC)CC>[F:6][C:7]1[C:8]([C:5]#[C:4][CH2:3][NH:2][CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: C#CCNC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, N-methylpropargyl amine (44.9 mg, 0.65 mmol) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P)4Pd (32 mg) and Cul (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.C(N(CC)CC)C.[Si:46]([O:63][CH2:64][CH2:65][N:66]1[C:70]([NH2:71])=[CH:69][CH:68]=[N:67]1)([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C>[Si:46]([O:63][CH2:64][CH2:65][N:66]1[C:70]([NH:71][C:24]([C:23]2[CH:22]=[N:21][N:18]3[CH:19]=[CH:20][C:15]([N:11]4[CH2:12][CH2:13][CH2:14][C@@H:10]4[C:4]4[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:16][C:17]=23)=[O:26])=[CH:69][CH:68]=[N:67]1)([C:59]([CH3:60])([CH3:61])[CH3:62])([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: CC(C)(C)[Si](OCCn1nccc1N)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)Nc3ccnn3CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (220 mg, 0.616 mmol) in DMF (5 mL) was added dropwise 2,4,6-trichlorobenzoyl chloride (106 μL, 0.677 mmol) and triethylamine (81.0 mg, 0.800 mmol). The reaction was stirred for 2 hours, and 1-(2-(tert-butyldiphenylsilyloxy)ethyl)-1H-pyrazol-5-amine (338 mg, 0.923 mmol) was added to the reaction mixture. The reaction was heated to 60° C. for 3 hours and then cooled to ambient temperature. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography to afford the desired product (201 mg, 46.3% yield). MS (apci) m/z=705.1 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:14](=O)([O-])[O-:15].[K+].[K+]>CO.O>[CH3:14][O:15][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(I)cc(CBr)c1
Agent: [K+]
Solvent: O
Solvent: CO
Product: COCc1cc(I)cc(C(=O)OC)c1
Temperature: 55 °C
Yield: 96.5 %

Procedure:
A mixture of methyl 3-(bromomethyl)-5-iodobenzoate (400 mg, 1.1 mmol) and potassium carbonate (311 mg, 2.3 mmol) in methanol/tetrathydrofuran (5 mL/5 mL) was heated at 55° C. for 1 hour. After cooling, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. After drying in vacuo, 325 mg (94%) of methyl 3-(methoxymethyl)-5-iodobenzoate was isolated as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[C:7]([Br:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13](N)=[O:14]>>[Br:11][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][C:8]=1[Cl:10])[N:1]=[C:13]([OH:14])[N:12]=[CH:4]2
Reactant: NC(N)=O
Reactant: Nc1cc(Cl)c(Br)cc1C=O
Product: Oc1ncc2cc(Br)c(Cl)cc2n1
Temperature: 180 °C
Reaction time: 5 h

Procedure:
A mixture of 2-amino-5-bromo-4-chlorobenzaldehyde (5 g, 21.46 mmol) and urea (18 g, 300.0 mmol) was stirred at 180° C. for 5 hours. LCMS monitored the reaction was completed. The mixture was cooled to room temperature, washed with water (100 mL×3) and filtered. The filtration cake was dried to get the title compound as a yellow solid (6 g (crude, 100%). MS (ES+) C8H4BrClN2O requires: 258, 260, found: 259, 261 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8](Cl)=[N:9][N:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:9][N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nnc(Cl)s1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1nnc(Sc2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of 5-chloro-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (1.0 g, 5.2 mmol, 1 eq), and K2CO3 (1.44 g, 104 mmol, 2 eq) in CH3CN (50 mL), thiophenol (0.53 mL, 5.2 mmol, 1 eq) is added. The reaction is stirred overnight at room temperature. The reaction is filtered to remove the salts, and the filtrate is washed with CH3CN. The solvents are removed under reduced pressure, and the product is recrystallized from EtOH to give 5-phenylsulfanyl-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (1.03 g, 74%). MS (ESD for C11H10N2O2S2 m/z 267.0 (M+H)+.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14]>C(Cl)Cl>[C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:18]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCC#Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/CCC#Cc1ccccc1
Yield: 83.2 %

Procedure:
5-Phenylpent-4-ynal (3 g) in dry CH2Cl2 (30 ml) was added to a solution of carbethoxymethylenetriphenylphosphorane (10 g) in dry dichloromethane (20 ml), and the mixture was heated at reflux under a nitrogen atmosphere for 5 hours. The solvent was removed under reduced pressure, and the product was purified by chromatography on silica (150 g), eluting with 2:1 hexane:ether to yield ethyl 7-phenylhept-2E-en-6-ynoate (3.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:36])([CH3:35])[C:29]([NH:31][CH2:32][C:33]#[CH:34])=[O:30]>CN(C=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:34]#[C:33][CH2:32][NH:31][C:29](=[O:30])[C:28]([CH3:36])([CH3:35])[CH3:27]
Reactant: C#CCNC(=O)C(C)(C)C
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCC#Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Yield: 57.9 %

Procedure:
Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (212 mg, 0.5 mmol) and 2,2-dimethyl-N-prop-2-ynyl-propionamide (139 mg, 1 mmol) (prepared by following the procedure described in Org. Lett. 2004, 6, 3593) in DMF/triethylamine (5:1, 6 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1 to 7:3 gradient) to obtain 7-chloro-6-[3-(2,2-dimethyl-propionylamino)-prop-1-ynyl]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (120 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)[C:10]([F:13])([F:12])[F:11].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+]>>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:26]([CH2:25][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[C:27]([O:36][CH3:37])[CH:28]=1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(COc2ccc(C(C)C(O)(c3cnc(C)cn3)C(F)(F)F)c(Cl)c2)c(OC)c1

Procedure:
In analogy to Example 1, step 7, 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 1, step 6) was reacted with methyl 4-(bromomethyl)-3-methoxy-benzoate and potassium carbonate to give the title compound as a colorless waxy solid. MS (m/e, ISP neg. ion)=523.1 [M−H+].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl[C:16]1[C:17]2[C:22]([N:23]=[C:24]3[C:29]=1[CH:28]=[CH:27][CH:26]=[CH:25]3)=[CH:21][CH:20]=[CH:19][CH:18]=2>Cl.CO>[CH:18]1[C:17]2[C:22](=[N:23][C:24]3[C:29]([C:16]=2[NH:12][C:11]2[CH:13]=[CH:14][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:9][CH:10]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[CH:20][CH:19]=1
Reactant: Clc1c2ccccc2nc2ccccc12
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: Cl
Solvent: CO
Product: CN1CCN(c2ccc(Nc3c4ccccc4nc4ccccc34)cc2)CC1
Reaction time: 0.5 h
Yield: 12 %

Procedure:
0.191 g (1.0 mmol) of 4-(4-methylpiperazin-1-yl)aniline, 2.5 ml of methanol and a few drops of concentrated hydrochloric acid were mixed and heated under reflux. The 9-chloroacridine (1-1,5 equivalents) and 2.5 ml methanol were mixed separately and added to the reaction mixture in small portions. After 30 min of stirring, two drops of concentrated hydrochloric acid were added, and heating was continued for 2 h. The reaction mixture was then evaporated to dryness and purified by chromatography (silica gel column; gradient from 100% methylene chloride to 90% methylene chloride and 10% methanol; when 4-(4-methylpiperazin-1-yl)aniline eluted from the column, the eluent was changed to methylene chloride:methanol:triethylamine 94:5:1). A final amount of 0.126 g (34%, overall yield 12%) of the title compound in pure form was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][C:44]=1[O:45][CH3:46])[CH2:41][NH:40][CH2:39][CH2:38]2>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:40]1[CH2:39][CH2:38][C:37]2[C:42](=[CH:43][C:44]([O:45][CH3:46])=[C:35]([O:34][CH3:33])[CH:36]=2)[CH2:41]1)=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: COc1cc2c(cc1OC)CN(C(=O)[C@@H]1C[C@H](NCc3ccc(F)cc3F)CN1Cc1ccccc1)CC2
Yield: 5 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline instead of 2-piperazin-1-yl-benzonitrile, to the title compound (3.5 mg, 5.0%) as light yellow oil. MS m/e=522.4 [M+H]+.
Reaction SMILES: ClC1C=CC=CC=1.[C:8]([N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2)#[N:9].BrN1C(=[O:31])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O>[C:8]([N:10]1[C:11]2[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=2[CH:13]([OH:31])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2)#[N:9]
Reactant: N#CN1c2ccccc2CCc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Solvent: O
Product: N#CN1c2ccccc2CC(O)c2ccccc21
Temperature: 87.5 °C
Yield: 52.2 %

Procedure:
190 ml of chlorobenzene and 25 g of (I) are loaded into a 500 ml pyrex round-bottom flask, under nitrogen. Afterwards, 21.2 g of N-bromosuccinimide and 2.2 g of dibenzoylperoxide are added and the mixture is heated to 85-90° C., keeping this temperature for 1.5 hours. 150 ml of water and 5 g of PEG 6000 are added, heating to 85°-90° C. for 2 hours. After decanting at 60° C., water is removed and the organic phase is washed with further water (2×100 ml). Chlorobenzene is evaporated off under vacuum at 5 mm/Hg and the residue is taken up with 50 ml of ethyl acetate. The mixture is cooled to 0° C. for 2 hours, filtered and dried at 60° C. for 4 hours, to obtain 14 g of (VI), m.p. 111-112° C., with good purity.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>C(#N)C.O>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(C)(Oc1ccc(Cl)cn1)C(=O)O
Temperature: 50 °C

Procedure:
A mixture of ethyl 2-methyl-2-(5-chloro-2-pyridyloxy)propionate and sodium hydroxide (0.85 g, 21 mmol) in 15 mL of acetonitrile and 15 mL of water was heated at 50° C. overnight. The volatile materials were removed by concentrating on a rotary evaporator, and the residue was partitioned between 2 M hydrochloric acid (100 mL) and ether (100 mL). The organic layer was separated and washed with water (2×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.02 (d, 1H), 7.65 (dd, 1H), 6.77 (d, 1H), 1.62 (s, 6H). LC-MS: m/e 216 (M+H)+ (2.33 min).
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[CH2:13]([OH:16])[C:14]#[CH:15]>C(OCC)C>[OH:16][CH2:13][C:14]1[CH:15]=[C:3]2[N:1]([C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[N:2]=1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Reactant: C#CCO
Solvent: CCOCC
Product: O=c1[nH]c2ccccc2c2cc(CO)nn12
Temperature: 25 °C
Yield: 55.3 %

Procedure:
2.0 g (0.0126 mole) of 3-diazooxindole is dissolved in 22 ml of propargyl alcohol (0.378 mole) and refluxed under nitrogen for 3 hours. The reaction mixture is cooled to room temperature and diluted with 10 volumes of ethyl ether. The solid is filtered, washed with ethyl ether and dried to give 2.0 of product (75% direct yield). Recrystallization from methanol gives 1.5 g of title compound, m.p. 286°-288° (sl. dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1[CH3:8].[Li]CCCC.C(NCC)C.[CH3:19][N:20]([CH:22]=O)[CH3:21]>C1COCC1>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:7][C:4]1[CH:5]=[CH:6][N:1]=[C:2]([CH3:8])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1ccnc(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCNCC
Product: Cc1cc(C=CN(C)C)ccn1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
11.05 g 2,4-Lutidine (0.1 mol) were dissolved in 50 ml THF. The solution was cooled and stirred, maintaining the temperature at between −70 to −50° C. 81.25 ml nBuLi (0.13 mol) was added over 0.25 hour. The dark red solution was stirred for a further 0.5 hour, then 15.14 ml diethylamine (0.145 mol) was added in one portion producing an orange suspension. After a 0.5 hour, 15.5 ml DMF (0.2 mol) was added. The brown-red solution was stirred for 1 hour then quenched with 50 ml 50% saturated aqueous ammonium chloride solution. Upon warming to ambient temperature, the reaction mixture was extracted with tert. butyl methyl ether (TBME) (3×100 ml), and the combined organic phases were washed with 50 ml H2O, dried over Na2SO4, filtered and concentrated under reduced pressure (45° C./450-20 mbar) providing an orange-red oil (14.8 g, 91%) which was sufficiently pure (Gas Liquid Chromatography (GLC) 98 area %) to be used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][N:5]([CH:14]([CH3:16])[CH3:15])[C:4]=2[N:3]=1.C[O:18][C:19](=[O:31])[C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[C:22]([NH2:30])[CH:21]=1>>[CH:14]([N:5]1[C:4]2[N:3]=[C:2]([NH:30][C:22]3[CH:21]=[C:20]([CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=3)[C:19]([OH:31])=[O:18])[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Cl)nc21
Reactant: COC(=O)c1cc(N)cc(S(C)(=O)=O)c1
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(C(=O)O)cc(S(C)(=O)=O)c3)nc21

Procedure:
Starting from 2-chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (4.8 g; 0.05 mmol) and 3-amino-5-(methylsulfonyl)-benzoic acid methyl ester (5.5 g; 0.024 mmol), 6.4 g (15.27 mmol; 77% yield) of white powder were obtained.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][CH:37]=[C:36]2[CH2:42][C:43](O)=[O:44]>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:43](=[O:44])[CH2:42][C:36]4[C:35]5[C:39](=[CH:40][CH:41]=[C:33]([F:32])[CH:34]=5)[NH:38][CH:37]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: Cl
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)Cc3c[nH]c4ccc(F)cc34)C[C@H]21
Yield: 34.1 %

Procedure:
By working in accordance with the operating method of Example 4, starting from 0.8 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride and 0.39 g of (5-fluoro-3-indolyl)acetic acid, 0.36 g of (3aS,4S,7aS)-7,7-diphenyl-2-[(5-fluoro-3-indolyl)acetyl]-4-(2-methoxyphenyl)perhydroisoindol-4-ol is obtained in the form of white crystals which melt with decomposition at 170° C.
Reaction SMILES: COC(=O)NC1([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH:17]2[C:21]2[NH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[C:37]([C:42]6[NH:43][C:44]([CH:47]7[CH2:51][CH2:50][CH2:49][N:48]7[C:52](=[O:62])[CH:53]([NH:57][C:58]([O:60][CH3:61])=[O:59])[CH:54]([CH3:56])[CH3:55])=[N:45][CH:46]=6)[CH:38]=5)[CH:33]=4)=[CH:28][CH:27]=3)=[CH:24][N:25]=2)=[O:15])CC2C(=CC=CC=2)C1.N[C:65]1(C(O)=O)[CH2:73][C:72]2[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=2)[CH2:66]1>>[CH3:61][O:60][C:58](=[O:59])[NH:57][C:73]1([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH:17]2[C:21]2[NH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[C:37]([C:42]6[NH:43][C:44]([CH:47]7[CH2:51][CH2:50][CH2:49][N:48]7[C:52](=[O:62])[CH:53]([NH:57][C:58]([O:60][CH3:61])=[O:59])[CH:54]([CH3:56])[CH3:55])=[N:45][CH:46]=6)[CH:38]=5)[CH:33]=4)=[CH:28][CH:27]=3)=[CH:24][N:25]=2)=[O:15])[C:72]2[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=2)[CH2:66][CH2:65]1
Reactant: NC1(C(=O)O)Cc2ccccc2C1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C6(NC(=O)OC)Cc7ccccc7C6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C6(NC(=O)OC)CCc7ccccc76)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 38 %

Procedure:
[1-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-indan-1-yl]-carbamic acid methyl ester (0.13 g, 38%) was prepared following the procedure for [2-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-indan-2-yl]-carbamic acid methyl ester, substituting 1-Amino-indan-1-carboxylic acid for 2-Amino-indan-2-carboxylic acid. LCMS-ESI+: calc'd for C49H52N8O6: 848.40 (M+); Found: 849.91 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[O:22]1[CH2:27][CH2:26][CH:25]([C:28](Cl)=[O:29])[CH2:24][CH2:23]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH:21][C:28]([CH:25]2[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)=[O:29])=[CH:17][CH:16]=1
Reactant: O=C(Cl)C1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)C2CCOCC2)nn1
Yield: 91 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (280 mg, 1 mmol) was converted, using tetrahydro-2H-pyran-4-carbonyl chloride instead of methoxyacetyl chloride, to the title compound (360 mg, 91%) which was obtained as a white solid. MS: m/e=395.1 [M+H]+.