Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=O.[C:17]([C:21]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:24][C:22]=1[NH2:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:24][C:22]=1[NH:23][C:3](=[O:5])[C:2]([CH3:1])([CH3:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCCCCCCCCCC(C)(C)C(=O)O
Reactant: CC(C)(C)c1ccc(CCC(CC2CCCCC2)O[Si](C)(C)C(C)(C)C)cc1N
Product: CCCCCCCCCCC(C)(C)C(=O)Nc1cc(CCC(CC2CCCCC2)O[Si](C)(C)C(C)(C)C)ccc1C(C)(C)C

Procedure:
Following a procedure similar to that described in Example 21, but using 2,2-dimethyldodecanoic acid and 2-t-butyl-5-[4-cyclohexyl-3-(t-butyldimethylsilyloxy)butyl]aniline [prepared by a procedure similar to that described in Preparation 11(i)] as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a foam-like material.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([CH:12]([C:33]#[N:34])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:35][O:36][CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O>>[C:33]([CH:12]([C:9]1[CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]([C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH2:39][CH2:38][CH2:37][O:36][CH3:35])=[CH:11][CH:10]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]2[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[Cl:32])=[CH:16][CH:15]=1)#[N:34]
Reactant: COC(=O)c1cc(C(C#N)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)ccc1Br
Reactant: COCCCc1ccccc1B(O)O
Product: COCCCc1ccccc1-c1ccc(C(C#N)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)cc1C(=O)OC

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using methyl 2-bromo-5-(1-cyano-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}ethyl)benzoate from step 3 and [2-(3-methoxypropyl)phenyl]boronic acid from EXAMPLE 3, step 1 as starting materials. Purification by column chromatography on silica gel, eluting with Hex/EtOAc (5 then 10%) afforded the desired compound as a colorless oil.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([CH2:24]O)[CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(OCC)(=O)C>[F:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][Cl:1])[CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: OCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Fc1ccc(CCN2CCC(N3CCc4ccc(CCl)cc43)CC2)cc1
Yield: 94 %

Procedure:
Conc. hydrochloric acid (280 ml) was added to 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxymethylindoline (about 70 g) and the resultant mixture was stirred at 80° C. for a day. Under ice cooling, the reaction solution was neutralized with a conc. aqueous solution of sodium hydroxide followed by addition of ethyl acetate (200 ml). The resulting crystals were collected by filtration and dissolved in ethyl acetate (500 ml) and a 5 N aqueous solution (500 ml) of sodium hydroxide and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (70 g) as a pale yellow powder (yield: 94%).
Reaction SMILES: C[C@@H]1CCCCN1.[C:8]([C:12]1[CH:13]=[C:14]([NH:27][C:28]([NH:30][C@@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@H:34]([O:41][C:42]3[CH:43]=[CH:44][C:45]4[N:46]([C:48]([N:51]5[CH2:56][CH2:55][CH2:54][CH2:53][C@@H:52]5[CH3:57])=[N:49][N:50]=4)[CH:47]=3)[CH2:33][CH2:32]2)=[O:29])[N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][OH:26])[CH:18]=2)[N:16]=1)([CH3:11])([CH3:10])[CH3:9]>>[C:8]([C:12]1[CH:13]=[C:14]([NH:27][C:28]([NH:30][C@@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@H:34]([O:41][C:42]3[CH:43]=[CH:44][C:45]4[N:46]([C:48]([N:51]5[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]5[CH3:57])=[N:49][N:50]=4)[CH:47]=3)[CH2:33][CH2:32]2)=[O:29])[N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][OH:26])[CH:18]=2)[N:16]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Agent: C[C@@H]1CCCCN1
Product: C[C@@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12

Procedure:
The title compound was prepared from (R)-2-methyl piperidine using analogous procedures to those described for the preparation of Intermediate 95e. LCMS (Method 3): Rt 3.63 min, m/z 679 [MH+].
Reaction SMILES: FC(F)(F)S(OC)(=O)=O.[F:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:14][N:15]([CH3:19])[C:16](=S)[CH3:17].[C:24]([O:28][C:29](=[O:42])[NH:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([NH2:40])[CH:38]=2)[CH2:33][CH:32]1[OH:41])([CH3:27])([CH3:26])[CH3:25].N1C=CC=CC=1>C(Cl)Cl>[C:24]([O:28][C:29](=[O:42])[NH:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([N:40]=[C:16]([N:15]([CH2:14][C:13]3[CH:20]=[CH:21][C:22]([F:23])=[C:11]([F:10])[CH:12]=3)[CH3:19])[CH3:17])[CH:38]=2)[CH2:33][CH:32]1[OH:41])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(=S)N(C)Cc1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)NC1c2cc(N)ccc2CC1O
Agent: COS(=O)(=O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=Nc1ccc2c(c1)C(NC(=O)OC(C)(C)C)C(O)C2)N(C)Cc1ccc(F)c(F)c1
Reaction time: 0.5 h
Yield: 298.9 %

Procedure:
Add methyl trifluoromethanesulfonate (0.750 g, 3.49 mmol) to a solution of N-(3,4-difluorobenzyl)-N-methylthioacetamide (0.145 g, 0.736 mmol) in 10 mL of CH2Cl2 at room temperature. Stir the mixture for 30 minutes and remove the solvent under reduced pressure. Then add (6-amino-2-hydroxyindan-1-yl)-carbamic acid t-butyl ester (0.78 g, 2.97 mmol) followed by 5 mL of pyridine. The resulting mixture is stirred for 12 h. After pyridine is evaporated, the residue is purified by column chromatograph (silica gel, 3% MeOH in CH2Cl2) to give 0.98 g of (6-(1-((3,4-difluorobenzyl)-methyl-amino)-ethylideneamino)-2-hydroxyindan-1-yl)-carbamic acid tert-butyl ester as a white solid: MS 446 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[S:17][C:18](=[O:22])N(C)C)C(OC)=O>C[O-].[Na+].CO>[CH3:1][O:2][C:3]([C:4]1[C:18](=[O:22])[S:17][C:11]2[C:10]([C:9]=1[OH:23])=[CH:15][CH:14]=[C:13]([Br:16])[CH:12]=2)=[O:24]
Reactant: COC(=O)C(C(=O)OC)C(=O)c1ccc(Br)cc1SC(=O)N(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Yield: 63.6 %

Procedure:
A mixture of 2-(4-bromo-2-dimethylcarbamoylsulfanyl-benzoyl)-malonic acid dimethyl ester (11.2 g, 26.79 mmol) in 0.5 M NaOMe/MeOH solution (214 mL) was heated to reflux for 6 h. After cooling overnight, the precipitated solid was collected by filtration and rinsed with MeOH followed by ether. The solid was dried in vacuo to provide 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (5.37 g) as a sodium salt. 1H NMR (200 MHz, DMSO-d6): δ (ppm)=7.98 (d, J=8.5 Hz, 1H), 7.50 (d, J=1.9 Hz, 1H), 7.38 (dd, J=8.5, 1.8 Hz, 1H), 3.56 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3Cl)[C:3]=12.CN1C(N)=CC(C2C=CC=CC=2)=N1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Agent: Cn1nc(-c2ccccc2)cc1N
Product: Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 39 was synthesised following similar procedures outlined in Example 1 (Compound 37), starting from Step 2 using 1-methyl-3-phenyl-1H-pyrazol-5-amine instead of 3-(2-chlorophenyl)-1-methyl-1H-pyrazol-5-amine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][CH2:17][CH2:18][O:19][CH3:20]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: COCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCOc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 99.9 %

Procedure:
A mixture of 5.0 g of 3-bromophenol, 7.99 g of potassium carbonate and 3.77 g of 1-chloro-3-methoxypropane in 90 ml of dimethylformamide is stirred at 100° C. for 4.5 hours. The reaction mixture is clarified by filtration and the filtrate is evaporated in vacuo. The residue is taken up in 100 ml of tert-butyl methyl ether, and the organic phase is washed once each wit 50 ml of 1N NaOH, 50 ml of water and 50 ml of brine. The organic phase is dried with sodium sulphate, filtered and evaporated. 7.08 g of the title compound are obtained as an orange oil. Rt=4.91.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=2)[C:10]=1[Br:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:26][CH:27]=[CH:28][CH2:29]Cl.CC(O)=O>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]([CH2:29][CH:28]=[CH:27][Cl:26])[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=2)[C:10]=1[Br:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClC=CCCl
Reactant: COC(=O)c1ccc2c(Br)c(NC(=O)OC(C)(C)C)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(Br)c(N(CC=CCl)C(=O)OC(C)(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
A stirred solution of bromide 148 (1.05 g, 2.76 mmol) in dry DMF (8 mL) was treated at 0° C. with NaH (132 mg, 60% in oil, 3.30 mmol). The resulting suspension was warmed to room temperature for 30 min, then cooled to 0° C. and treated with 1,3-dichloropropene (0.80 mL, 8.7 mmol, mixed isomers). The mixture was stirred at room temperature for a further 4 h then poured into dilute aqueous AcOH and exacted with EtOAc (×2). The combined organic layers were washed with dilute aqueous NaHCO3 and water (×2), dried, and concentrated to dryness under reduced pressure at 100° C. The residue was chromatographed on silica gel, eluting with CH2Cl2/EtOAc (19:1) to give methyl 2-[(tert-butoxycarbonyl)(3-chloro-2-propen-1-yl)amino]-1-bromo-6-naphthoate (149) (1.19 g, 95%) as a gum; 1H NMR [(CD3)2SO] (mixture of rotamers and E and Z forms) δ 8.73 (s, 1H), 8.34 (d, J=8.9 z, 1H), 8.16 (d, J=8.9 Hz, 1H), 7.63, 7.58 (2 d, J=8.7 Hz, 1H), 8.25, 8.24 (2 d, J=8.6 Hz, 1H), 6.45-6.31 (m, 1H), 6.20-6.00 (m, 1H), 4.58-4.48, 4.43-4.21, 4.16-4.00 (3 m, 2H), 3.95 (s, 3H), 1.50, 1.27 (2 s, 9H). HRMS (FAB) calcd. for C20H2279Br35ClNO4 (MH+) m/z 454.0421, found 454.0410.
Reaction SMILES: [F:1][C:2]([F:24])([CH2:8][CH2:9][CH2:10][C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[C:3]([O:5]CC)=[O:4].[OH-].[K+:26].O>CO>[F:1][C:2]([F:24])([CH2:8][CH2:9][CH2:10][C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:19])([F:18])[C:14]([F:15])([F:16])[F:17])[C:3]([O-:5])=[O:4].[K+:26]
Reactant: CCOC(=O)C(F)(F)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])C(F)(F)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 97.5 %

Procedure:
Potassium 2,2,6,6,7,7,8,8,9,9,9-undecafluorononanoate (69.2 g, 98% yield, formula above, H6-C9K) was prepared from ethyl 2,2,6,6,7,7,8,8,9,9,9-undecafluorononanoate (69.1 g, 0.18 mol), potassium hydroxide (10.5 g, 0.188 mol), water (150 mL) and methanol (150 mL) according to the procedure of Example 7.
Reaction SMILES: CO[CH2:3][CH2:4]OC.C(S(C1N(C2C=CC=CC=2)N=NN=1)(=O)=O)C.[CH2:23]([CH:26]1[CH2:30][CH2:29][CH:28]([CH:31]2[CH2:36][CH2:35][CH:34]([CH:37]=O)[CH2:33][CH2:32]2)[CH2:27]1)[CH2:24][CH3:25].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:37](/[CH:34]1[CH2:35][CH2:36][CH:31]([CH:28]2[CH2:29][CH2:30][CH:26]([CH2:23][CH2:24][CH3:25])[CH2:27]2)[CH2:32][CH2:33]1)=[CH:3]\[CH3:4]
Reactant: CCCC1CCC(C2CCC(C=O)CC2)C1
Reactant: COCCOC
Agent: CCS(=O)(=O)c1nnnn1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C/C=C/C1CCC(C2CCC(CCC)C2)CC1
Temperature: -70 °C

Procedure:
DME (1,2-dimethoxyethane; 80 ml) and 5-(ethylsulfonyl)-1-phenyl-1H-tetrazole (4.62 g) were added to 4-(3-propylcyclopentyl)cyclohexanecarboaldehyde (3.29 g) obtained in the second step in Example 3, in a reaction vessel under an atmosphere of nitrogen, and the mixture was cooled to −70° C., and then KHMDS (Potassium Hexamethyldisilazide; 20%, in a THF solution) (23.9 ml) was added dropwise. The reaction solution was warmed to room temperature, and was extracted with diethyl ether after the addition of water (50 ml) The resulting organic layer was washed with water and dried over anhydrous sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane=1/9 by volume) and then purified by means of a preparative HPLC system, Model PLC-561 made by GL Sciences Inc. to give (E)-1-(prop-1-enyl)-4-(3-propylcyclopentyl)cyclohexane (2.0 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH2:16]([O:23][CH2:24][C@H:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:33]([O:32][C:30](=[O:31])[NH:29][C@H:25]([C:26](=[O:27])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:24][O:23][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:34])([CH3:36])[CH3:35]
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(F)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine (550 mg, 2.7 mmol), (S)-3-benzyloxy-2-tertbutoxycarbonylaminopropionic acid (880 mg, 3.0 mmol), HOAt (410 mg, 3.0 mmol), 4-methylmorpholine (0.65 mL, 5.9 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (580 mg, 3.0 mmol) in DCM (13 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(S)-2-benzyloxy-1-(4-fluoro-2-phenylaminophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester as a red oil (1.1 g, 83%).
Reaction SMILES: C([C:5]1[C:13]2[N:12]=[C:11]([CH:14]([F:16])[F:15])[N:10]([C:17]3[N:22]=[C:21]([N:23]4[CH2:27][CH2:26][CH2:25][CH:24]4[CH2:28][OH:29])[CH:20]=[C:19]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:18]=3)[C:9]=2[C:8](C)=[C:7](C)[C:6]=1O[SiH3])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH2:58]>C1COCC1>[F:15][CH:14]([F:16])[C:11]1[N:10]([C:17]2[N:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[CH2:28][OH:29])[CH:20]=[C:19]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:18]=2)[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:58])[C:13]=2[N:12]=1
Reactant: O
Reactant: Cc1c(O[SiH3])c(C(C)(C)C)c2nc(C(F)F)n(-c3nc(N4CCOCC4)cc(N4CCCC4CO)n3)c2c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCC1CCCN1c1cc(N2CCOCC2)nc(-n2c(C(F)F)nc3c(O)cccc32)n1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
213 mg (0.38 mmol) of 2-(4-tert-butyldimethyl-silyloxy-2-difluoromethylbenzimidazol-1-yl)-4-(2-hydroxymethylpyrrolidin-1-yl)-6-morpholinopyrimidine dissolved in anhydrous THF (7 ml) was added with tetra-n-butylammoniumfluoride (0.4 ml, 1M THF solution) at room temperature and stirred for 30 minutes. The reaction solution was added with water, extracted several times with ethyl acetate, washed with saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was removed under the reduced pressure and the residue was purified by silica gel column chromatography (n-hexane ethyl acetate=1:4) to obtain 101 mg (yield: 60%) of the titled compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH:31]1(B(O)O)[CH2:34][CH2:33][CH2:32]1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:31]1([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)C1CCC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C2CCC2)CC1
Yield: 14 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), cyclobutylboronic acid (commercially available), copper(II) acetate and pyridine using chloroform as solvent and stirring under reflux for 6 days, to give the desired product as a light brown foam (14%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:14](O)=[O:15])=O)=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>C(O)C>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:14](=[O:15])[NH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)C2=C(C(=O)O)CCCC2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2n[nH]c(=O)c3c2CCCC3)cc1

Procedure:
10.3 g of 2-(4-amino-benzoyl)-cyclohex-1-enecarboxylic acid (42 mmol) were dissolved in 45 mL ethanol, 2.7 g (54 mmol) hydrazine hydrate was added and the mixture was heated under reflux for 30 hours. Precipitation of the product already started several hours after heating. After cooling in the refrigerator overnight the precipitated product was filtered and washed with cold ethanol.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][S:12][C:13]1[N:18]=[C:17]([NH:19][S:20]([N:23]2[CH2:26][CH2:25][CH2:24]2)(=[O:22])=[O:21])[CH:16]=[C:15]([O:27][CH3:28])[N:14]=1.ClC1C=C(OC)N=C(SCC2C=CC=C(F)C=2F)N=1.[CH3:48][O:49][C:50]1[CH:57]=[CH:56][C:53]([CH2:54]Cl)=[CH:52][CH:51]=1.[I-].[K+]>CN(C=O)C>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][S:12][C:13]1[N:18]=[C:17]([N:19]([CH2:54][C:53]2[CH:56]=[CH:57][C:50]([O:49][CH3:48])=[CH:51][CH:52]=2)[S:20]([N:23]2[CH2:24][CH2:25][CH2:26]2)(=[O:22])=[O:21])[CH:16]=[C:15]([O:27][CH3:28])[N:14]=1
Reactant: COc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Reactant: COc1ccc(CCl)cc1
Agent: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2cc(OC)nc(SCc3cccc(F)c3F)n2)S(=O)(=O)N2CCC2)cc1
Temperature: 0 °C

Procedure:
60% Sodium hydride (0.42 g) was added to a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]azetidine-1-sulfonamide (the product of Example 35) (3.82 g) in anhydrous DMF (38 ml) stirred at 0° C. under nitrogen. The reaction mixture was stirred for a further 15 min when 4-methoxybenzylchloride (2.98 g) was added dropwise over one min followed by potassium iodide (1.66 g). After stirring at room temperature for 18 h. the reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was separated and further extracted with EtOAc (2×). The combined organic extracts were washed with H2O, dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using EtOAc/iso-hexane (2:8) as eluent. The product was further purified by flash column chromatography on silica gel using DCM/isohexane (6:4) as eluent to give the subtitle product as a white solid. Yield: 2.4 g.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[NH:5][C:6](=[O:25])[CH:7]([C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)[CH:8]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[OH:9].[OH-].[Na+]>CO>[CH2:23]1[O:22][C:19]2[CH:20]=[CH:21][C:16]([CH:7]([CH:8]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[OH:9])[C:6]([NH:5][C@H:4]([C:3]([OH:36])=[O:2])[CH2:26][C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][CH:28]=3)=[O:25])=[CH:17][C:18]=2[O:24]1
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(c1ccc2c(c1)OCO2)C(O)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(c1ccc2c(c1)OCO2)C(O)C1CCCCC1
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of N-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophan methyl ester (160 mg) in MeOH (2 ml) was added 1M aqueous sodium hydroxide solution (1 ml) at room temperature. After being stirred for 1 hours at the same temperature, the mixture was concentrated in vacuo. The residue was dissolved in 1N hydrochloric acid (5 ml) and ethyl acetate (10 ml) and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give N-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophan (150 mg).
Reaction SMILES: [CH2:1]([N:4](C)[CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:33])[C:14]=2[NH:18][C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([F:31])[CH:22]=2)[C:9]1=[O:34])[CH3:7])C=C.C(Cl)Cl.CN1C(=O)CC(=O)N(C)C1=O>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>[F:31][C:23]1[CH:22]=[C:21]([CH2:20][C:19]([NH:18][C:14]2[C:13]([CH3:33])=[CH:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[CH:17][N:8]([C@H:6]([CH3:7])[CH2:5][NH:4][CH3:1])[C:9]3=[O:34])=[O:32])[CH:26]=[CH:25][C:24]=1[C:27]([F:30])([F:28])[F:29]
Reactant: C=CCN(C)C[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C)ccc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: CNC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C)ccc2c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (R)—N-(2-(1-(allyl(methyl)amino)propan-2-yl)-6-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamide (56 mg, 0.00011 mol) in methylene chloride (2.5 mL, 0.039 mol) was added to 1,3-dimethylbarbituric acid (60 mg, 0.0004 mol) and tetrakis(triphenylphosphine)palladium(0) (1 mg, 0.000001 mol) under argon. The mixture was stirred at room temperature for 4 hours, purified via flash chromatography and then by reverse phase preparative HPLC to afford the desired product as a white solid.