Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:27][CH3:28])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:29]=[CH:30][N:31](C)C)#[N:2].[CH:34]1(N)[CH2:37][CH2:36][CH2:35]1.ClCCl.CO>CO>[CH:34]1([NH:2][C:1]2[C:3]3[C:4](=[CH:5][C:6]([O:11][CH2:12][C:13]4[CH:14]=[C:15]([S:19]([CH2:27][CH3:28])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:16]=[CH:17][CH:18]=4)=[C:7]([O:9][CH3:10])[CH:8]=3)[N:29]=[CH:30][N:31]=2)[CH2:37][CH2:36][CH2:35]1
Reactant: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Reactant: NC1CCC1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc3ncnc(NC4CCC4)c3cc2OC)c1
Yield: 91 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-ethylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (50 mg, 0.11 mmol) with cyclobutylamine (9.1 mg, 0.13 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 91% yield (48 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:4]=1[CH2:5][N:6]([C:42]1[S:46][N:45]=[CH:44][N:43]=1)[S:7]([C:10]1[N:15]=[C:14]2[N:16](C(OC(C)(C)C)=O)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=3[C:29]3[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=3)[C:13]2=[CH:12][CH:11]=1)(=[O:9])=[O:8].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:4]=1[CH2:5][N:6]([C:42]1[S:46][N:45]=[CH:44][N:43]=1)[S:7]([C:10]1[N:15]=[C:14]2[NH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=3[C:29]3[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=3)[C:13]2=[CH:12][CH:11]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)cn(C(=O)OC(C)(C)C)c3n2)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)c[nH]c3n2)c(OC)c1
Reaction time: 3 h
Yield: 89.4 %

Procedure:
A 50-mL round-bottom flask was charged with tert-butyl 6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (469 mg, 0.621 mmol) and THF (4 mL) to give a clear solution. Tetra-n-butylammonium fluoride (1M in THF) (3103 μl, 3.10 mmol) was added in one portion. The mixture was stirred for 3 h, then diluted with EtOAc. The organic solution was washed with a saturated aq. ammonium chloride solution, washed with water (2×), washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (10 to 60% EtOAc/Heptane) to give N-(2,4-dimethoxybenzyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-6-sulfonamide (363.86 mg, 0.555 mmol, 89% yield) as an off-white foam. 1H NMR (400 MHz, DMSO-d6) δ=12.68 (s, 1 H), 8.36 (s, 1 H), 8.09 (s, 1 H), 7.98-7.87 (m, 2 H), 7.83-7.79 (m, 1 H), 7.73 (d, J=8.3 Hz, 1 H), 7.43-7.36 (m, 2 H), 6.98 (s, 1 H), 6.46-6.31 (m, 3 H), 5.18 (s, 2 H), 3.70 (s, 3 H), 3.69 (s, 3 H), 3.26 (s, 3 H). m/z (ESI) 656.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](O)=[O:25])=[CH:18][CH:17]=1.S(Cl)(Cl)=O.[C:31]([NH2:34])(=[O:33])[CH3:32]>CO>[C:31]([NH:34][C:24](=[O:25])[CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:21][CH:20]=1)(=[O:33])[CH3:32]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)O)cc1
Reactant: CC(N)=O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CC(=O)NC(=O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 100 °C
Yield: 32.3 %

Procedure:
To 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionic acid (1.50 g, 4.27 mmol) obtained in Example 17 was added thionyl chloride (2.0 ml), and the mixture was stirred under heating for 1 hr at 100° C. Excess thionyl chloride was evaporated under reduced pressure and acetamide (504 mg, 8.54 mmol) was added to the obtained residue. The mixture was stirred under heating for 1 hr at 120° C. Methanol (5 ml) was added, and the reaction mixture was stirred for 10 min and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=1:1) to give the title compound (541 mg, yield 32%) as a white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[CH3:15][CH:14]([NH:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1)[CH3:16]
Reactant: CC(C)N
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Product: CC(C)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 1A starting with 4-fluoro-2-(trifluoromethyl)benzonitrile and isopropyl amine: MS (ES) m/z 229 (M+1).
Reaction SMILES: Cl.Cl.[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[CH2:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH:4]1[N:12]1[CH2:13][CH2:14][N:15]([C:28]([C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:22]3[N:21]=[C:20]([C:19]([F:34])([F:18])[F:35])[O:24][N:23]=3)[CH:26]=2)=[O:29])[CH2:16][CH2:17]1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: c1ccc2c(c1)CC(N1CCNCC1)C2
Agent: Cl
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(C2Cc3ccccc3C2)CC1
Yield: 39 %

Procedure:
This compound was synthesized from 1-(2,3-dihydro-1H-inden-2-yl)piperazine dihydrochloride and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (100 mg, yield 39%). 1H NMR (400 MHz, MeOD) δ 8.27-8.24 (m, 1H), 8.18 (m, 1H), 7.72-7.71 (m, 2H), 7.20-7.16 (m, 2H), 7.14-7.11 (m, 2H), 3.87 (m, 2H), 3.55 (m, 2H), 3.26-3.20 (m, 1H), 3.17-3.12 (m, 2H), 2.93-2.87 (dd, J=15.1 Hz, 8.5 Hz, 2H), 2.73 (m, 2H), 2.60 (m, 2H). MS (ESI) m/z: Calculated for C23H21F3N4O2: 442.16. found: 443.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH-:5].[Li+].Cl[Si:8]([CH:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([CH3:18])=[C:12]1[CH3:19])([CH3:10])[CH3:9]>CCCCC>[CH3:1][O:2][CH2:3][CH2:4][NH:5][Si:8]([CH:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([CH3:18])=[C:12]1[CH3:19])([CH3:9])[CH3:10]
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Reactant: COCC[NH-]
Agent: [Li+]
Solvent: CCCCC
Product: COCCN[Si](C)(C)C1C(C)=C(C)C(C)=C1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.00 g (24.67 mmol) of lithium methoxyethylamide were added a little at a time at 0° C. to a solution of 5.30 g (24.70 mmol) of (chlorodimethylsilyl)tetramethylcyclopentadiene in 40 ml of dry pentane and the mixture was stirred for 16 hours at room temperature. The pale yellow reaction solution was filtered to remove the precipitated lithium chloride and the pentane was removed under an oil pump vacuum. Subsequent distillation of the remaining oil gave [(methoxyethylamino)dimethylsilyl]tetramethylcyclopentadiene in the form of a hydrolysis-sensitive, greenish yellow oil. Yield: 5.26 g (76%); boiling point: 70-77° C./10-2 torr.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8].C(N(C(C)C)C(C)C)C.[CH3:60][C:61]1([CH3:68])[CH2:65][C:64](=[O:66])[O:63][C:62]1=[O:67]>O1CCOCC1>[CH3:41][O:40][C:38]([C:37]1[CH:42]=[CH:43][C:34]([CH2:33][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([NH:25][C:23]([C:22]3[C:21]4[CH2:44][CH2:45][CH2:46][CH2:47][C:20]=4[S:19][C:18]=3[NH:17][C:15]([C:14]3[CH:13]=[C:12]([CH:50]=[CH:49][CH:48]=3)[CH2:11][N:5]([CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[CH2:4][CH2:3][N:2]([CH3:1])[C:64](=[O:66])[CH2:65][C:61]([CH3:68])([CH3:60])[C:62]([OH:63])=[O:67])=[O:16])=[O:24])=[CH:31][CH:30]=2)=[CH:35][CH:36]=1)=[O:39]
Reactant: CCC(CC)N(CCNC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Reactant: CC1(C)CC(=O)OC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCC(CC)N(CCN(C)C(=O)CC(C)(C)C(=O)O)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a mixture of 200 mg of methyl 4-[2-(4-{[(2-{[3-({[2-(methylamino)ethyl](pentan-3-yl)amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 48 mg of N-ethyl-N-isopropylpropan-2-amine and 4 mL of dioxane was added 44 mg of 3,3-dimethyldihydrofuran-2,5-dione, followed by stirring overnight at 65° C. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, thereby obtaining 200 mg of 4-[(2-{[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl](pentan-3-yl)amino}ethyl)(methyl)amino]-2,2-dimethyl-4-oxobutanoic acid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=5[O:28][CH2:29][CH:30]5[CH2:31][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:37])[CH2:35][CH2:34]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Reactant: O=C(Cl)C1CC1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)C5CC5)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A151) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH2:6].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1.C([BH3-])#N.[Na+]>CO>[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH:6][CH2:15][C:11]1[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cccnc1
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](C)NCc1cccnc1
Temperature: 25 °C

Procedure:
Part A: To a solution of D-alanine methyl ester hydrochloride (6.0 grams) in methanol (25 mL) is added 1.1 equivalents of 3-Pyridinecarboxaldehyde. The solution is stirred at room temperature for several hours and then the solvent removed by rotary evaporation. The resulting imine is redissolved in acetic acid (10 mL) and methanol (2 mL), and sodium cyanoborohydride (1.5 equivalents) is added in several portions over 10 minutes. The mixture is then stirred for 16 hours and then concentrated by rotary evaporation. The resulting residue is partitioned between ethyl acetate and aqueous sodium carbonate (10%). The organic layer is dried over magnesium sulfate, filtered and concentrated to yield the desired N-3-picolyl-D-alanine methyl ester.
Reaction SMILES: Cl.C([O:6][CH:7](OCCCC)[C@H:8]([CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:41])[NH2:40])[NH:9][C:10](=[O:34])[C@H:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:12][C:13](=[O:29])[C@H:14]([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[NH:15][C:16](=[O:23])[C@@H:17]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18]1)CCC.O1CCN(C(S(O)(=O)=O)C)CC1.C(N=C=NCCCN(C)C)C>O1CCOCC1>[NH:18]1[C:19](=[O:22])[CH2:20][CH2:21][C@H:17]1[C:16]([NH:15][C@H:14]([C:13]([NH:12][C@H:11]([C:10]([NH:9][C@H:8]([CH:7]=[O:6])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:40])[NH2:41])=[O:34])[CH2:30][CH:31]([CH3:32])[CH3:33])=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])=[O:23]
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H]1CCC(=O)N1
Agent: CC(N1CCOCC1)S(=O)(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@H](C=O)CCCNC(=N)N
Temperature: 37 °C
Reaction time: 24 h

Procedure:
270 mg of L-pyroglutamyl-L-lysyl-L-leucyl-L-argininal dibutyl acetal hydrochloride obtained in Example 1(c) was suspended in a mixed solution of 78 ml of 0.1M morpholinoethanesulfonic acid and 78 ml of dioxane. To this suspension, with its pH adjusted to 5.0, were added 30 ml of CM-Biogel® A (100-200 meshes) (a product of Bio-Rad Lab.) and then portionwise 3 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide for a period of one hour under stirring. The resulting solution was further stirred at 37° C. for 24 hours. After the completion of the reaction, the obtained resin was washed with water and hydrolyzed with a 0.2M sodium citrate buffer solution of pH 2.5 at 40° C. for 70 hours. There was obtained 30 ml of pyroglutamyl-lysyl-leucyl-argininal-CM-Biogel® A.
Reaction SMILES: N1CCCCC1.[S:7]1[CH2:11][C:10](=[O:12])[NH:9][C:8]1=[O:13].[F:14][C:15]([F:41])([F:40])[O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[C:25]1[C:34]([CH3:35])=[CH:33][C:32]2[C:31]([CH3:37])([CH3:36])[CH2:30][CH2:29][C:28]([CH3:39])([CH3:38])[C:27]=2[CH:26]=1>C1(C)C=CC=CC=1.O.C(O)(=O)C>[CH3:35][C:34]1[C:25]([C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][C:17]=2[O:16][C:15]([F:14])([F:41])[F:40])[CH:21]=[C:11]2[S:7][C:8](=[O:13])[NH:9][C:10]2=[O:12])=[CH:26][C:27]2[C:28]([CH3:39])([CH3:38])[CH2:29][CH2:30][C:31]([CH3:36])([CH3:37])[C:32]=2[CH:33]=1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1cc2c(cc1-c1cc(C=O)ccc1OC(F)(F)F)C(C)(C)CCC2(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(cc1-c1cc(C=C3SC(=O)NC3=O)ccc1OC(F)(F)F)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.4 %

Procedure:
To a solution of toluene (50 mL) containing piperidine (0.84 mL, 8.53 mmol) and acetic acid (0.84 mL) was added 2,4-thiazolidinedione (3.3 g, 28.43 mmol) and 4-trifluoromethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehyde (11.1 g, 28.43 mmol). The reaction mixture was heated at reflux with continuous removal of water using a Dean-Stark water separator. After 12 hours at reflux 25 mL of toluene was removed by distillation and the solution was cooled to room temperature. The yellow solid was collected and taken up in ethanol (40 ml). After stirring at room temperature for 15 minutes, the pale yellow solid was collected and washed with a minimum of ethanol, dried under vacuum to give 6.6 g of 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione. The organic layers were combined and evaporated. Further crystallization from ethanol afforded an additional 2.0 g to give a total of 8.6 g (61%) of product. 1H NMR (300 MHz; DMSO-d6): 1.21 (s, 6H); 1.27 (s, 6H); 1.65 (s, 4H); 2.04 (s, 3H); 7.08 (s, 1H); 7.26 (s, 1H); 7.62 (m, 2H); 7.70 (dd, J1=8.0 Hz, J2=1.5 Hz, 1H); 7.86 (s, 1H); 12.5 (s, 1H).
Reaction SMILES: N#N.[Li+].[Br-].[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([CH2:18][OH:19])[N:15]([CH2:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29](Cl)[CH:30]=3)[C:25]([CH3:34])([CH3:33])[CH2:24]2)=[O:22])[CH2:14][C@H:13]1[CH3:35])=[O:11])([CH3:8])([CH3:7])[CH3:6].[Br-].[CH2:37]([Zn+])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1.CN1C(=O)CCC1.CO.C(N1C=CN(C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C.C1COCC1>[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([CH2:18][OH:19])[N:15]([CH2:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:30]=3)[C:25]([CH3:34])([CH3:33])[CH2:24]2)=[O:22])[CH2:14][C@H:13]1[CH3:35])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: [Zn+]Cc1ccccc1
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ccc(Cl)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Agent: CC(C)n1ccn(C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: N#N
Agent: [Br-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ccc(Cc4ccccc4)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 12.7 %

Procedure:
To a degassed (N2) solution of LiBr (20 mg, 0.2 mmol) and (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium (II) dichloride (1.0 mg, 0.14 mmol) in anhydrous THF/NMP (1:1, 0.48 mL) was added a solution of (2R,5R)-4-[2-(6-chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (65 mg, 0.14 mmol), THF (0.1 mL) and benzylzinc bromide (575 μL, 0.30 mmol). The reaction was stirred for 18 h and diluted with MeOH then loaded onto a SCX column eluting with MeOH and then 2.0 M ammonia-MeOH to release the amine. The solvent was removed in vacuo, to give the title compound (9.0 mg, 12%) as a colourless oil. 1H NMR (Me-d3-OD): 8.03 (1H, s), 7.33-7.03 (6H, m), 6.96 (1H, d), 4.15 (1H, d), 4.10-3.93 (5H, m), 3.76 (1H, dd), 3.67 (1H, d), 3.59-3.49 (2H, m), 2.93-2.83 (2H, m), 2.65 (1H, dd), 1.48 (9H, s), 1.35 (6H, s), 1.23 (3H, d).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[N:5][CH:4]=1.Cl.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1.C(N(CC)CC)C>CS(C)=O.O>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[C:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)=[N:5][CH:4]=[C:3]2[CH2:2][N:40]1[CH2:41][CH2:42][N:37]([C:34]2[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:36][CH:35]=2)[CH2:38][CH2:39]1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(N2CCN(Cc3cnc(Cc4ccc(OC)c(OC)c4)c4cc(OC)c(OC)cc34)CC2)cc1
Yield: 80 %

Procedure:
A mixture of 1.16 g of 4-chloromethyl-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]isoquinoline, 0.8 g of 1-(para-methoxyphenyl)piperazine hydrochloride, and 1.3 ml of triethylamine in 10 ml dimethylsulfoxide was heated at 80° for one hour under argon. The cooled solution was then diluted with water and extracted with methylene chloride. The organic layer was washed with sodium bicarbonate solution, dried over sodium sulfate, charcoaled, and evaporated. The residue was crystallized from ethanol to give 1.3 g of 6,7-dimethoxy-1-{(3,4-dimethoxyphenyl)methyl}-4-([4-(4-methoxyphenyl)-1-piperazinyl]methyl)isoquinoline as a yellow solid, mp 176°-177°. Recrystallization from ethanol provided the analytical sample, mp 176°-177°.
Reaction SMILES: C([O:4][C@@H:5]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[OH:16])[CH2:6][Br:7])(=O)C.Cl>CO>[Br:7][CH2:6][C@@H:5]([OH:4])[CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[OH:16]
Reactant: CC(=O)O[C@H](CBr)Cc1cc(F)ccc1O
Agent: Cl
Solvent: CO
Product: Oc1ccc(F)cc1C[C@H](O)CBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.1 %

Procedure:
To a solution of (1S)-2-bromo-1-(5-fluoro-2-hydroxybenzyl)ethyl acetate (3.57 g, 12.2 mmol) in methanol was added hydrogen chloride (1.0 M in diethylether, 49 ml) and the reaction mixture was allowed to stir at room temperature for 12 h. The solvent was removed in vacuo and purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) afforded 2.95 g (97%) of (S)-2-(3-bromo-2-hydroxy-propyl)-4-fluoro-phenol as a colorless oil. HRMS ESI m/e 246.9761 [M−H]+; Calc'd 246.9755. [α]D25=+8.2° (c 0.71% in methanol).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1>Br>[CH3:16][CH:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1)[CH3:15]
Reactant: COc1ccc(CCCCNC(C)C)cc1
Agent: Br
Product: CC(C)NCCCCc1ccc(O)cc1
Yield: 53.4 %

Procedure:
4-[4-methoxyphenyl]-N-(1-methylethyl)butylamine (10 g) was added to 48% hydrobromic acid solution (70 ml) and the mixture was refluxed for 3 hours. The residual hydrobromic hydrogen acid was distilled off in vacuo and the residue was made alkaline with 10% sodium carbonate solution. The product was filtered, washed with water and dried to give 5.0 g of 4-[4-(1-methylethyl)aminobutyl]phenol. Mass spectrum and gas chromatography confirmed the identity and purity (93.5%) of the product.
Reaction SMILES: C[Si]([C:5]#[C:6][N:7]1[C:12]([OH:13])=[C:11]2[CH:14]=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[N:16]=[C:10]2[N:9]=[CH:8]1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:6]([N:7]1[C:12]([OH:13])=[C:11]2[CH:14]=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])[N:16]=[C:10]2[N:9]=[CH:8]1)#[CH:5]
Reactant: CC(C)(C)C(=O)Nc1cc2c(O)n(C#C[Si](C)(C)C)cnc-2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cn1cnc2nc(NC(=O)C(C)(C)C)cc-2c1O
Reaction time: 0.08 h

Procedure:
To a solution of 1.5 g of 3-trimethylsilylethynyl-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine in 100 mL of anhydrous tetrahydrofuran cooled to 0° C. are added under nitrogen 4.75 mL of 1M tetrabutylammonium fluoride in anhydrous tetrahydrofuran. After 5 minutes, the reaction mixture is allowed to attain room temperature and is then stirred for 2 hours. The solvent is removed under reduced pressure and the residue purified by chromatography over silica gel to yield 3-ethynyl-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH4+]=[S:14]>CO>[C:1]([N:5]1[CH2:10][CH2:9][CH:8]([C:11](=[S:14])[NH2:12])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1CCC(C#N)CC1
Solvent: CO
Product: CC(C)(C)N1CCC(C(N)=S)CC1
Yield: 13 %

Procedure:
The 1-tert-butylpiperidine-4-carbonitrile (0.900 g, 5.41 mmol, (prepared as described in WO2008/1017461, Compound XXIV), ammonium sulfide (20 wt % in water, 3.69 mL, 10.8 mmol) and MeOH (9.0 mL) were heated in a CEM® microwave at about 120° C. for about 2 h (250 psi maximum pressure, 10 min ramp, 300 max watts). The mixture was concentrated under a stream of air and the resulting material was purified by flash chromatography on silica gel using DCM/MeOH with 3% NH4OH (8:2) as an eluent to give the title compound (0.140 g, 13%): LC/MS (Table 1, Method a) Rt=0.44 min; MS m/z: 201.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:9]([C:11]3[C:15]4=[N:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=[C:14]4[N:13](C(OC(C)(C)C)=O)[CH:12]=3)=[CH:10][C:3]=12>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:32])=[O:33])[C:9]([C:11]3[C:15]4=[N:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=[C:14]4[NH:13][CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2[nH]cc(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2nc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.8 %

Procedure:
Dissolve bisazaindole 27 (0.28 g, 0.48 mmol) in TFA at 50%/CH2Cl2 (8.0 mL) and stir at room temperature for 5 h. The reaction medium is concentrated under vacuum, and the residue is dissolved in EtOAc (100 mL), washed with saturated NaHCO3 (3×), dried (MgSO4) and concentrated, to give 28 (0.222 g, 96%) as an amorphous solid: TLC (EtOAc at 40%/heptane) Rf=0.05.