Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[C:9]([O:13][C:14]([C@@:16]1([CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[C:9]([O:13][C:14]([C@@:16]1([CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:38])([CH3:37])[CH3:39])([CH3:35])[CH3:34])[CH:20]([CH3:1])[C:19](=[O:21])[N:18]([C@@H:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH3:23])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)[N-]C(C)C
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)CC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
A 1.8 M solution of lithium diisopropylamide in tetrahydrofuran (3.10 mL) was added dropwise to a solution of (3S)-3-[2-(tert-butyldimethylsilyloxy)ethyl]-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (2.24 g, 5.00 mmol) in tetrahydrofuran (20 mL) in a nitrogen atmosphere at −72° C. over five minutes. After stirring at the same temperature for 10 minutes, methyl iodide (0.34 mL, 5.50 mmol) was added. The mixture was stirred at the same temperature for 15 minutes and then heated to −10° C. over 10 minutes. Thereafter, a 10% citric acid aqueous solution (5 mL) was added. The reaction solution was poured into a mixture of ethyl acetate (100 mL) and 10% citric acid solution (50 mL), followed by extraction with ethyl acetate (200 mL). The organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The resulting dark brown residue was used for the next reaction without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=2[CH2:6][CH2:5]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](O)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:17][O:16][C:13]1[C:14](=[O:15])[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:1][C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:10][CH2:9][C:8]=2[C:11](=[O:20])[C:12]=1[O:18][CH3:19]
Reactant: COc1cc(O)cc(OC)c1
Reactant: COC1=C(OC)C(=O)C2=C(CCC(CCO)CC2)C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3cc(OC)cc(OC)c3)CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
To a solution of 7-(2-hydroxyethyl)-2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo[a]cycloheptene-1,4-dione (103 mg), 3,5-dimethoxyphenol (168 mg) and triphenylphosphine (125 mg) in THF (2 ml) was added a solution of diethyl azodicarboxylate (81 mg) in THF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hr and then concentrated in vacuo. The residue was purified by alumina column chromatography(ethyl acetate:hexane=1:4) and then with recrystallization from ethyl acetate-hexane to obtain the entitled compound (108 mg).
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(O)=O.S(=O)(=O)(O)O.[NH:24]=[N+]=[N-]>C(Cl)CCl>[NH2:24][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(C2CCCc3cncn32)cc1
Reactant: [N-]=[N+]=N
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: Nc1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 2.42 g of 5-p-carboxyphenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in 100 ml of ethylene dichloride is treated with 6 ml of concentrated sulfuric acid. The reaction mixture is heated to 40° and 6 ml of hydrazoic acid (2M in ethylene dichloride) is added dropwise. When gas evolution has ceased, the reaction is evaporated. The residue is redissolved in water and adjusted to pH 10. The aqueous phase is extracted with methylene chloride (3×30 ml). The organic extracts are dried over potassium carbonate and evaporated to yield the title compound (a).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]=[CH:12][CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:15]1([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C(C=Cc1ccccc1)=CCCOCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OCCCCCCc1ccccc1
Yield: 88 %

Procedure:
The whole of this 1-benzyloxy-6-phenyl-3,5-hexadiene was then treated with hydrogen in the presence of 250 mg of 5% w/w palladium-on-carbon in 40 ml ethanol at room temperature for 15 hours, the catalyst was removed by filtration and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.14 g (yield 88%) of 6-phenylhexanol as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>C(#N)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2([CH2:3][CH2:2][N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)[O:8][CH2:7][CH2:6][O:5]2)=[CH:10][CH:11]=1
Reactant: ClCCC1(c2ccc(Cl)cc2)OCCO1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: Clc1ccc(C2(CCn3ccnc3)OCCO2)cc1

Procedure:
A mixture of 2-(2-chloroethyl)-2-(4-chlorophenyl)-1,3-dioxolane (from 2.03 g of β,p-dichloropropiophenone as in Preparation 3) and imidazole (3.5 g) in acetonitrile (5 ml) were heated at 100° for 24 hours and the solvent removed. After addition of water (30 ml) and ether (30 ml) and shaking, a white solid separated and was collected by filtration. Washing with water, ether and drying in air gave 1-[2-(2-(4-chlorophenyl)-1,3-dioxolan-2-yl]ethyl]imidazole. Further product was obtained by separation of the ether layer, washing, drying (MgSO4) and concentrating.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[NH:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:26]C(O)=O.C(N=C=NC(C)C)(C)C.CN(C=[O:50])C>>[C:33]([O:32][C:30](=[O:31])[NH:24][CH2:25][C:26](=[O:50])[NH:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1nc(N)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CN(C)C=O
Agent: CC(C)N=C=NC(C)C
Product: Cc1nc(NC(=O)CNC(=O)OC(C)(C)C)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine (0.12 g, 0.37 mmol), Boc-βAla-OH (0.18 g, 0.93 mmol), 1,3-diisopropylcarbodiimide (0.07 mL, 0.45 mmol) and 4-N,N-dimethylaminopyridine (36 mg, 0.3 mmol) in of dry DMF (2 mL) was stirred at room temperature for 24 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organics were combined and washed with brine, filtered, and dried on MgSO4. The solvent was evaporated to give brown residue, which was purified by SiO2 chromatography (1:1 EtOAc/PE) to afford ({4-Methyl-5-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-thiazol-2-ylcarbamoyl}-methyl)-carbamic acid tert-butyl ester as light yellow solid. Anal. RP-HPLC: tR=19.5 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity >93%). 1H-NMR (DMSO-d6) δ: 1.11 (s, 9H, CH3), 2.54 (s, 3H, CH3), 3.62 (m, 2H, CH2), 5.38 (m, 2H, CH2), 7.06 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.46 (m, 1H, Ph-H), 7.72 (m, 1H, Ph-H), 8.15 (m, 1H, Ph-H), 8.45 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 8.77 (s, 1H, NH). A solution of this material (97 mg, 0.19 mmol) in dioxane (5 mL) was treated with CF3COOH (1 ml). After stirring at room temperature for 22 h, the reaction mixture was evaporated and purified by preparative RP-HPLC (0-60% MeCN in 0.1% aq CF3COOH over 40 min, 9 mL/min) to afford the titled compound (34 mg) as a light yellow solid. Anal. RP-HPLC: tR=14.0 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity >93%). 1H-NMR (CD3OD) δ: 2.64 (s, 3H, CH3), 3.30 (m, 2H, CH2), 3.33 (m, 2H, CH2), 7.14 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.52 (t, 1H, J=8.2 Hz, Ph-H), 7.63 (m, 1H, Ph-H), 7.96 (m, 1H, Ph-H), 8.46 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 8.88 (s, 1H, NH). MS (ESI+) m/z 400.6 (C17H17N7O3S requires 399.4).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[CH:4]=[O:5].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[OH:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[C:7]([O:12][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: C1=COCCC1
Reactant: Cc1c(O)cc(C=O)c(O)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1c(OC2CCCCO2)cc(C=O)c(O)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
2,5-Dihydroxy-3,4-dimethyl-benzaldehyde (2.0 g) was dissolved in dichloromethane (50 mL) and 3,4-dihydro-2H-pyran (1.5 g) was added followed by addition of p-toluenesulfonic acid monohydrate (200 mg). The solution was stirred at room temperature for 1 hour and quenched by adding sodium bicarbonate solution (1 mL). Then the dichloromethane solution was dried over MgSO4 and concentrated. The residue was purified by silica gel column eluting with hexane and ethyl acetate (8:2) to give 1.5 g of 2-hydroxy-3,4-dimethyl-5-(tetrahydro-pyran-2-yloxy)-benzaldehyde product.
Reaction SMILES: [N:1]12[CH2:11][CH2:10][CH2:9][NH:8][CH:7]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]2.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([N:8]1[CH2:9][CH2:10][CH2:11][N:1]2[CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1=CN2CCCNC2CCC1
Reactant: BrCc1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCCN3CCCCCC32)cc1
Reaction time: 0.17 h
Yield: 127.9 %

Procedure:
A mixture of 34.0 g (0.2 mol) 1,8-diazabicylo[5.4.0]undecene and 200 mL toluene was mixed with 34.2 g (0.2 mol) benzyl bromide. An insoluble oil formed and then changed to a white solid as the temperature rose to 57° C. over 10 minutes. After 4 hours, the solid was filtered and dried to provide 62.5 g of 8-benzyl-1,8-diazabicyclo[5.4.0]undecane (the 8-benzyl salt of DBU, which was soluble in water). NaBH4 solution (1.58 g, 5.1 mmol, 4.4M NaBH4 in 14M NaOH solution, obtained from Alfa Aesar, Ward Hill, Mass.) was diluted with 10 mL water. Then, 15 mL t-butyl methyl ether (t-BuOMe) was added to the diluted solution, and the resulting mixture was magnetically stirred and cooled to 3° C. To the cooled mixture was added 3.23 g of the 8-benzyl salt of DBU prepared as described above. After 2 hours, the resulting cold mixture was phase split, the resulting aqueous layer was extracted with t-BuOMe, and the resulting t-BuOMe solutions were combined, dried, and stripped to yield 0.86 g of a product (photolatent catalyst mixture). Gas-liquid chromatographic (GLC) analysis of the product indicated that it contained 39 percent 8-benzyl-1,8-diazabicyclo[5.4.0]undecane (GLC area response with a thermal conductivity detector; identified by gas chromatography/mass spectrometry (GC/MS) analysis), 13 percent of N-3-benzylaminopropylazepine (identified by GC/MS and nuclear magnetic resonance (NMR) analysis), and 48 percent of what was believed to be N-(3-benzylaminopropyl)azepin-2-one (GC/MS mass of 262).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=O)=O)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([SH:12])=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Sc1ccc(-c2cnco2)cc1
Reaction time: 0.33 h
Yield: 89.4 %

Procedure:
To a solution of 4-oxazol-5-yl-benzenesulfonyl chloride (1 g) in THF (20 ml) was added triphenylphosphine (4.3 g). After stirring at RT for 10 minutes water (2 ml) was added and the reaction was stirred for a further 20 minutes. The reaction was evaporated under reduced pressure and the residue dissolved in EtOAc. The EtOAc solution was extracted with 1M NaOH (×3), the basic extractions were combined, the pH adjusted to 3 using 1M HCl and then re-extracted with EtOAc (×3). The EtOAc fractions were combined and washed with brine, dried (MgSO4) and evaporated under reduced pressure to give the subtitle compound as a green solid (0.65 g).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][OH:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:14](OCC)=[CH2:15]>O1CCCC1.C([O-])(=O)C.[Hg+]>[CH:14]([O:13][CH2:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)=[CH2:15]
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Reactant: C=COCC
Agent: CC(=O)[O-]
Agent: [Hg+]
Solvent: C1CCOC1
Product: C=COCCC12CC3CC(CC(C3)C1)C2

Procedure:
36 g (0.2 mol) of 1-admantaneethanol and 72 g (1.0 mol) ethyl vinyl ether were put into a round bottom flask to be dissolved in 100 mL tetrahydrofuran (THF), followed by adding 5 mol % of mercury acetate. Thereafter, the reaction product was reacted for approximately 12 hours under a reflux condition.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:60][C:61]([F:65])([F:64])[CH2:62]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[O:25][CH2:62][C:61]([F:65])([F:64])[F:60])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(Cl)c1
Reactant: OCC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OCC(F)(F)F)C4CC4)c23)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.6 %

Procedure:
To a solution of [9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (120 mg, 0.26 mmol), 1,1′-(azodicarbonyl)dipiperdine (131 mg, 0.52 mmol) in tetrahydrofuran (5.0 mL) was added tri(n-butyl)phosphine (0.130 mL, 0.52 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2,2-trifluoroethanol (0.189 mL, 2.58 mmol) was added to the reaction mixture. The mixture was stirred at 60° C. for 5 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-25% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (77.4 mg, 0.155 mmol, 60%) as colorless crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([CH:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH2:21]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=O)=[CH:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30].CS(C)(=O)=O>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([CH:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH2:21]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[S:30])=[CH:2]1
Reactant: O=C1Nc2ccccc2C1(c1c[nH]c2ccccc12)C1CNc2ccccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: CS(C)(=O)=O
Solvent: O
Product: S=C1Nc2ccccc2C1(c1c[nH]c2ccccc12)C1CNc2ccccc21

Procedure:
3-(1H-indol-3-yl)-3,3′-biindolin-2-one (728 mg, 2 mmol), crystalline P2S5.2 C5H5N (228 mg, 0.6 mmol) and dimethylsulfone (3.05 g) were heated (165-170° C.) for 20 min. The melt was allowed to cool and then heated in water for 10 min. The solid formed was collected, 766 mg (94%), mp>260° C. 1H NMR (300 MHz, DMSO-d6) δ 7.09-7.15 (m, 2H), 7.18-7.20 (m, 5H), 7.24-7.30 (m, 7H), 13.00 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ 72.7 (s), 111.2 (d), 124.4 (d), 126.5 (d), 127.5 (d), 128.6 (s), 128.7 (s), 129.0 (d), 129.1 (d), 129.1 (d), 139.2 (s), 143.0 (s), 143.5 (s), 145.3 (s, 2C), 208.4 (s). Elemental analysis calcd for C24H17N3S; C, 75.96; H, 4.51; N, 11.07. Found C, 76.10; H, 4.46; N, 11.00.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5](=[O:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:28][CH3:29])[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH:25]([CH3:27])[CH3:26])[CH:16]=3)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:28]([N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:24][CH:25]([CH3:27])[CH3:26])[CH:16]=2)[C:21]([C:22]#[N:23])=[C:13]1[C:10]1[CH:11]=[CH:12][C:7]([N:6]2[CH2:2][CH2:3][O:4][C:5]2=[O:30])=[CH:8][CH:9]=1)[CH3:29]
Reactant: CCn1c(-c2ccc(NC(=O)OCCCl)cc2)c(C#N)c2ccc(OC(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(-c2ccc(N3CCOC3=O)cc2)c(C#N)c2ccc(OC(C)C)cc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a solution of [4-(3-cyano-1-ethyl-6-isopropoxy-1H-indol-2-yl)-phenyl]-carbamic acid 2-chloro-ethyl ester (30 mg, 0.07 mmol) in DMF (1 mL) is added aqueous K2CO3 (10 mg) and then stirred at 50° C. for 18 h. The reaction mixture is poured into cold water and the precipitate collected by filtration and washed with hexane and dried in vacuo to afford the title compound (21 mg, 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([C:18]3[S:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[N:20][C:19]=3[CH3:33])=[O:17])[CH2:11]2)=[CH:6][C:3]=1[C:4]#[N:5].C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([C:18]3[S:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=4)=[N:20][C:19]=3[CH3:33])=[O:17])[CH2:11]2)=[CH:6][C:3]=1[C:4]1[NH:40][N:39]=[N:38][N:5]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc([C@H]2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1C#N
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1ccc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1-c1nnn[nH]1
Yield: 46 %

Procedure:
(R)-2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzonitrile (262 mg, 0.56 mmol) was dissolved in toluene (5 mL). Trimethyltin azide (230 mg, 1.12 mmol) was added and the mixture heated at reflux for 24 h. The mixture was diluted with diethyl ether (100 mL) and washed with 0.1 N HCl (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 7.5% methanol/chloroform (0.5% ammonium hydroxide modifier). The product fractions were combined and concentrated under reduced pressure. The resultant oil was taken up in 100 mL ethyl acetate and extracted with 0.1 N HCl (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 132 mg (46%) of the desired {3-[4-methyl-3-(1H-tetrazol-5-yl)-phenyl]-piperidin-1-yl}-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanone as a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18]Br)=[C:8]2[C:13]([Cl:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].CO.[C:22]([O-])(O)=[O:23].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18][O:23][CH3:22])=[C:8]2[C:13]([Cl:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1CBr
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1COC
Temperature: 70 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of compound 16A (31 mg, 0.09 mmol) in 1:1 MeOH:CH2Cl2 (2 mL) was added NaHCO3 (30 mg, 0.36 mmol). The reaction was kept at room temperature for 3 h, heated to 70° C. for 1 h, cooled to room temperature, concentrated to dryness, redissolved in CH2Cl2 and filtered. The filtrate was concentrated to give compound 17A as a yellow solid (26 mg, 98%).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:53])[N:23]([C:27]2[C:32]([CH3:33])=[CH:31][C:30]([N:34]3[CH2:38][C@H:37]([CH2:39][N:40]4C(=O)C5C(=CC=CC=5)C4=O)[O:36][C:35]3=[O:51])=[CH:29][C:28]=2[CH3:52])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN.O.ClCCl>C(O)C>[NH2:40][CH2:39][C@@H:37]1[O:36][C:35](=[O:51])[N:34]([C:30]2[CH:29]=[C:28]([CH3:52])[C:27]([N:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:22]3=[O:53])=[C:32]([CH3:33])[CH:31]=2)[CH2:38]1
Reactant: Cc1cc(N2C[C@H](CN3C(=O)c4ccccc4C3=O)OC2=O)cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: CN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(N2C[C@H](CN)OC2=O)cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Temperature: 52.5 °C

Procedure:
130 g (179 mmol) of the compound from Example 67A are dissolved in 650 ml of ethanol, 193 ml (2.68 mol) of a 40% strength aqueous methanamine solution are added and the mixture is heated at 50-55° C. for one hour. After cooling to room temperature, water and dichloromethane are added, the phases are separated and the organic phase is dried over sodium sulphate. After filtration, the mixture is evaporated to dryness under reduced pressure. The residue (117 g, 89% of theory) is reacted further without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:9][C:10]1[N:11]=[C:12]([N:4]2[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]2)[CH:13]=[CH:14][CH:15]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Brc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(c2cccc(Br)n2)C[C@H](C)O1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
cis-2,6-Dimethylmorpholine (0.535 g, 4.64 mmol) was added to a suspension of 2,6-dibromopyridine (1 g, 4.22 mmol) and potassium carbonate (1.750 g, 12.66 mmol) in anhydrous acetonitrile (35 mL). After addition, the reaction mixture was stirred at 120° C. overnight. Crude LC/MS showed starting material and desired product so cis-2,6-dimethylmorpholine (185 mg, 1.61 mmol) was added to the reaction mixture which was then stirred at 120° C. overnight. Crude LC/MS showed desired product can be seen and no starting material left, so the reaction mixture was diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-100% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a colourless oil (705 mg, 2.340 mmol, 55.4% yield). LC/MS [M+H]+=271/273.