Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[C:45]([F:46])=[CH:44][C:43]([F:47])=[C:42]2[C:37]=1[CH:38]=[C:39](OS(C(F)(F)F)(=O)=O)[N:40]=[CH:41]2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:39]4[N:40]=[CH:41][C:42]5[C:37]([CH:38]=4)=[C:36]([Cl:35])[C:45]([F:46])=[CH:44][C:43]=5[F:47])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Oc1cc2c(Cl)c(F)cc(F)c2cn1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5c(Cl)c(F)cc(F)c5cn4)c3)cn2)CC1
Temperature: 100 °C

Procedure:
To a solution of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (18.3 mg, 0.0391 mmol), trifluoromethanesulfonic acid 5-chloro-6,8-difluoroisoquinolin-3-yl ester (0.0326 mmol), and Pd(PPh3)4 (2.51 mg, 0.00215 mmol) in 1,4-dioxane (0.90 ml) in a sealable microwave tube was added a solution of Cs2CO3 (21.4 mg, 0.0651 mmol) in H2O (0.30 ml). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 100° C. for 30 min. The reaction mixture was diluted with EtOAc (40 ml), washed with water (2×20 ml) and brine (20 ml), and dried over MgSO4. After concentration in vacuo, a brown oil was obtained. It was then purified by prep. TLC eluting with 4% MeOH/CH2Cl2 to give the title compound as a brown oil. 1H NMR (400 MHz, CDCl3): δ=1.49 (s, 9H), 1.94-2.05 (m, 2H), 2.16-2.24 (m, 2H), 2.87-2.98 (m, 2H), 4.24-4.38 (m, 3H), 6.45 (brs, 2H), 7.18 (t, J=9.6 Hz, 1H), 7.68 (d, J=0.8 Hz, 1H), 7.79 (d, J=0.8 Hz, 1H), 7.99 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.34 (m, 1H), 9.53 (d, J=1.2 Hz, 1H). MS(ES+): m/z=540.92/542.87 (100/86) [MH+]. HPLC: tR=3.15 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][Si](C)(C)C.O.[CH3:7][N:8]([CH3:33])[C:9]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:17])[CH2:11][CH2:10]1>CC(CC)=O>[ClH:1].[CH3:33][N:8]([CH3:7])[C:9]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[O:17])[CH2:13][CH2:14]1
Reactant: C[Si](C)(C)Cl
Agent: COc1ccc(NC(=O)CC2CCC(c3ccccc3)(N(C)C)CC2)cc1
Solvent: CCC(C)=O
Solvent: O
Product: Cl

Procedure:
Chlorotrimethylsilane (0.097 ml) and water (7 μl) were added to a solution of the less polar diastereoisomer of 2-(4-dimethylamino-4-phenyl-cyclohexyl)-N-(4-methoxy-phenyl)-acetamide (255 mg, 0.7 mmol) in ethyl methyl ketone (2 ml). The hydrochloride was extracted as an oil with hexane and isolated in a quantitative yield.
Reaction SMILES: NC1C=CC(B(O)O)=CC=1.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.FC(F)(F)S(O[Si:25]([CH3:28])([CH3:27])[CH3:26])(=O)=O>C(N(CC)CC)C>[CH3:26][Si:25]([CH3:28])([CH3:27])[N:16]([Si:25]([CH3:28])([CH3:27])[CH3:26])[C:15]1[CH:17]=[CH:18][C:12]([Br:11])=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Nc1ccc(Br)cc1
Agent: Nc1ccc(B(O)O)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N(c1ccc(Br)cc1)[Si](C)(C)C
Yield: 65 %

Procedure:
4-Aminophenylboronic acid by Grignard reaction on N,N-bis(trimethylsilyl)-4-bromoaniline 10.0 g (58.1 mmol) of 4-bromoaniline were dissolved in 200 ml of triethylamine and admixed with 25 ml (130 mmol) of trimethylsilyl trifluoromethanesulfonate. The mixture was heated to reflux for 8 h. The reaction mixture was concentrated and the crude product distilled under high vacuum. 11.9 g (37.8 mmol, 65%) of N,N-bis(trimethylsilyl)-4-bromoaniline were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH3:7])=[CH:4][CH:3]=1.[CH3:15][Mg]I.Cl>C(OCC)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]([C:11]#[N:12])[C:9]#[N:10])([CH3:15])[CH3:7])=[CH:13][CH:14]=1
Reactant: C[Mg]I
Reactant: CC(=C(C#N)C#N)c1ccc(Cl)cc1
Agent: [Cu]I
Agent: Cl
Solvent: CCOCC
Product: CC(C)(c1ccc(Cl)cc1)C(C#N)C#N
Yield: 69 %

Procedure:
First, 1.00 g of (4-chloro-α-methylbenzylidene)malononitrile of the formula: was dissolved in 20 ml of diethyl ether, to which a catalytic amount of copper (I) iodide was added, and while stirring under ice cooling, a solution of methyl magnesium iodide in diethyl ether (prepared from 0.30 g of magnesium, 10 ml of diethyl ether, and 0.86 ml of methyl iodide) was added dropwise, followed by stirring for 30 minutes under ice cooling. Then, 10% hydrochloric acid was added to the reaction mixture, which was extracted with ethyl ether. The organic layer was successively washed with 10% hydrochloric acid, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.74 g of (1-(4-chlorophenyl)-1-methylethyl)malononitrile (the intermediate (2)).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:34][CH:35]([C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=2)[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[CH:28]1([CH2:34][CH:35]([C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=2)[C:36]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
A solution of triphenylphosphine (416 mg, 1.58 mmol) in methylene chloride (8 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (281 mg, 1.58 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acid (290 mg, 0.93 mmol) in methylene chloride (5 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (233 mg, 2.32 mmol), and the resulting suspension was stirred for 20 h at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and, concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 to 1/1 hexanes/ethyl acetate) afforded 3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (337 mg, 92%) as an amorphous solid: EI-HRMS m/e calcd for C19H24N2O3S2 (M+) 392.1228, found 392.1230.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20](O)=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][CH:30]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:29][CH:30]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:31]([OH:36])[C:32]([F:33])([F:34])[F:35])=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:29][CH:30]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:31](=[O:36])[C:32]([F:34])([F:35])[F:33])=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccncc2)ncc(NC(=O)OCc2ccccc2)c1=O
Reactant: NC(Cc1ccccc1)C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2ccncc2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(=O)C(F)(F)F
Product: O=C(Cn1c(-c2ccncc2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(O)C(F)(F)F

Procedure:
2-[5-Benzyloxycarbonylamino-6-oxo-2-(4-pyridyl)-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)acetamide was synthesized in the same manner as in Example 1. That is, [5-benzyloxycarbonylamino-6-oxo-2-(4-pyridyl)-1,6-dihydro-1-pyrimidinyl]acetic acid (title compound in Reference Example 18, 2.66 g, 6.57 mmol) was treated with 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol (title compound in Reference Example 1, 1.51 g, 6.89 mmol), WSCI hydrochloride (1.51 g, 7.88 mmol) and HOBT (1.77 g, 13.1 mmol) in DMF (25 mL) to give 3.59 g (94%) of the target compound as pale-yellow crystals.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:9]=[O:10])[CH2:3][CH2:2]1.OOS([O-])=O.[K+].[CH3:24][OH:25]>>[CH3:24][O:25][C:9](=[O:10])[C:8]1[CH:11]=[CH:12][C:13]([O:14][CH:15]([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH:7]=1
Reactant: CO
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Agent: O=S([O-])OO
Agent: [K+]
Product: COC(=O)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 57.5 °C
Yield: 52 %

Procedure:
873 g of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde (3.61 mol) were dissolved in MeOH (4.4 L), then solid Oxone® (1.86 Kg, 6.06 mol) was added portion-wise in 1 hour, and the solution was stirred and warmed to 55 to 60° C. for 2 hours. The solvent was concentrated under vacuum to 1.6 L and water (7 L) was added. The resulting heterogeneous solution was stirred at 50 to 55° C., then toluene (3 L) was added, and the biphasic mixture vigorously stirred. Aqueous phase was discharged and the organic one was washed with water (3 L). The solvent was concentrated under vacuum to 2 to 3 volumes, and the obtained solution warmed to 80 to 90° C. n-Heptane (5.5 L) was slowly added. The mixture was cooled to −10° C., and the suspension was stirred at −10° C. over-night. The solid was filtered on a Buchner funnel and washed with n-heptane (1 L). The obtained yellow solid was dried under vacuum at room temperature. (yield 52%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.CO[CH:22]1[CH:27]([O:28][CH3:29])[CH:26]([O:30][CH3:31])[CH2:25][NH:24][CH2:23]1.[C:32](=O)([O-])[O-:33].[Na+].[Na+].[I-].[K+]>CC(C)CC(=O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:24]2[CH2:23][CH2:22][C:27]([O:28][CH3:29])([O:33][CH3:32])[CH:26]([O:30][CH3:31])[CH2:25]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: O=C([O-])[O-]
Reactant: COC1CNCC(OC)C1OC
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: COC1CN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCC1(OC)OC

Procedure:
A mixture of 56.2 parts of 1,1'-(4-chlorobutylidene) bis[4-fluorobenzene], 31.5 parts of 3,4,5-trimethoxypiperidine, 42.5 parts of sodium carbonate, 1 part of potassium iodide and 960 parts of 4-methyl-2-pentanone was stirred and refluxed for 18 hours. The reaction mixture was cooled, filtered and the filtrate was evaporated, yielding 82.5 parts of 1-[4,4-bis(4-fluorophenyl)butyl]-3,4,4-trimethoxypiperidine as a residue (intermediate 66).
Reaction SMILES: COC1C=CC(CN2C(=O)[CH:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]3([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])C2=O)=CC=1.O.[NH2:28]N.[CH2:30]([OH:32])C>>[CH3:30][O:32][C:15]1[CH:14]=[CH:11][C:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:28])=[CH:17][CH:16]=1
Reactant: NN
Reactant: CCCCCCC12C=CC=CC1C(=O)N(Cc1ccc(OC)cc1)C2=O
Reactant: CCO
Solvent: O
Product: COc1ccc(CCCCCCN)cc1

Procedure:
N-(4-methoxybenzyl)-1-hexyl phthalimide (19.9 g, 60 mmol) was dissolved in ethanol (300 ml) and hydrazine monohydrate (8.9 g, 0.11 mol) was added. The mixture was refluxed for 3 hours, filtered, the residue washed with ethanol and the filtrate evaporated. The residue was taken up in diethyl ether, filtered and the residue washed well with ether. Evaporation of the filtrate gave a yellow oil which was purified by distillation to give a clear oil bp 108-110° C., 0.02 mbar.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH2:12]Br)[O:11][CH2:10][CH2:9][O:8]2)=[CH:3][CH:2]=1.[OH:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH2:12][O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[O:11][CH2:10][CH2:9][O:8]2)=[CH:3][CH:2]=1
Reactant: Oc1cccnc1
Reactant: BrCC1(c2ccc(-c3ccccc3)cc2)OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: c1ccc(-c2ccc(C3(COc4cccnc4)OCCO3)cc2)cc1

Procedure:
A mixture of 2-([1,1'-bipheny]-4-yl)-2-(bromomethyl)-1,3-dioxolane (16 g.), 3-hydroxypyridine (5.7 g.) and potassium carbonate (9 g.) were refluxed with stirring in N,N-dimethylacetamide (75 ml.) for 18 hours. After refluxing, the mixture was allowed to cool and was thereafter poured into water (150 ml.). The resultant aqueous solution was extracted twice with ether. The combined ether fractions were washed once with 5% aqueous sodium hydroxide and 4 times with water. The washed ether fractions were then dried, filtered and the solvent evaporated to yield 3-[[2-([1,1'-biphenyl]-4-yl)-1,3-dioxolan-2-yl]methoxy]pyridine as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2([C:19]#[N:20])[CH:16]3[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)[CH:6]=[CH:7][CH:8]=1)[CH3:2].[NH4+:21].[Cl-:22].C[Al](C)C>C1(C)C=CC=CC=1>[ClH:22].[CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2([C:19](=[NH:21])[NH2:20])[CH:10]3[CH2:18][CH:14]4[CH2:13][CH:12]([CH2:17][CH:16]2[CH2:15]4)[CH2:11]3)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCc1cccc(C2(C#N)C3CC4CC(C3)CC2C4)c1
Reactant: [Cl-]
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCc1cccc(C2(C(=N)N)C3CC4CC(C3)CC2C4)c1
Product: Cl
Temperature: 25 °C
Yield: 55.8 %

Procedure:
A solution of 2-(3-ethylphenyl)-2-adamantanecarbonitrile (265 mg, 1 mmol) and NH4Cl (107 mg, 2 mmol) in dry toluene (5 mL) under argon was treated dropwise with 2-M trimethylaluminium in toluene (1.0 mL, 2 mmol), refluxed for 12 h, cooled to room temperature and purified directly by chromatography [SiO2; EtOAc—MeOH (9:1)] to give the title compound (178 mg, 56%) as a white solid: mp >300° C.; IR νmax (Nujol)/cm−1 2921, 2855, 1669, 1454, 1377, 1089, 798, 744 and 704; NMR δH (400 MHz, DMSO-d6) 1.18 (3H, t, J 8.0 Hz), 1.55-1.69 (7H, m), 1.83 (5H, s), 2.60 (2H, q, J 8.0 Hz), 3.15 (2H, s), 7.10-7.17 (1H, m), 7.27-7.38 (3H, m) and 8.88 (4H, br s); Anal. Calcd for C19H27ClN2.0.35 H2O: C, 70.18; H, 8.59; N, 8.61. Found: C, 70.25; H, 8.41; N, 8.46.
Reaction SMILES: [Br:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Br:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([CH2:20]Cl)[C:14]=1[CH3:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:20][C:15]1[C:14]([CH3:22])=[C:13]([Br:12])[C:18]([CH3:19])=[CH:17][N:16]=1
Reactant: Cc1cnc(CCl)c(C)c1Br
Reactant: Nc1nc(Br)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(Cn2cnc3c(Br)nc(N)nc32)c(C)c1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
A mixture of 6-bromo-9H-purin-2-ylamine (2.4 g, 11 mmol), 4-bromo-2-chloromethyl-3,5-dimethyl pyridine (3.5 g, 15 mmol), K2CO3 (2.07 g, 15 mmol) and DMF (50 mL) was stirred at 50° C. for 2 h. Work-up and flash chromatography gave the title compound as a white solid (2.6 g, 56%). HPLC Rt: 5.415 min. 1H-NMR (CDCl3): δ 8.17 (s, 1H), 7.88 (s, 1H), 5.38 (s, 2H), 5.05 (s, 2H), 2.51 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]3)=[N:33][CH:34]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1.ClCCl>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@@H:11]3[CH2:12][C:13](=[O:16])[NH:14][CH2:15]3)[CH3:10])=[N:7][C:2]([C:29]3[CH:30]=[CH:31][C:32]([N:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]4)=[N:33][CH:34]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reaction time: 1.5 h

Procedure:
(R)-4-((R)-1-((6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (150 mg, 0.51 mmol), tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (277.37 mg, 0.71 mmol), potassium phosphate tribasic (324 mg, 0.1.53 mmol), Bis[di-tert-butyl(4 dimethylaminophenyl)phosphine]dichloropalladium(II) (11.92 mg, 0.017 mmol) were combined in water (0.72 ml) and 1,4-Dioxane (9 ml). The reaction was stirred at 100 C for 90 mins. The reaction was diluted with dichloromethane, washed with water, dried, filtered and concentrated. Residues were purified by silica gel column chromatography to yield the title compound as a free base.
Reaction SMILES: C(OC(N1C[CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.[F:31][C:32]1[CH:38]=CC(N)=C[CH:33]=1.C(N1CCC(N)C1)(OC(C)(C)C)=O>>[F:31][C:32]1[CH:38]=[CH:9][C:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])=[CH:11][CH:33]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Agent: CC(C)(C)OC(=O)N1CCC(N)C1
Product: O=C(Nc1ccc(F)cc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 4-fluoroaniline of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 353 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.) 10.11 (1H, s) 9.90 (1H, s) 8.01 (1H, d, J=5.42 Hz) 7.88 (1H, d, J=5.42 Hz) 7.64 (2H, dd, J=9.13, 5.08 Hz) 7.49 (1H, d, J=5.42 Hz) 7.30 (1H, dd, J=3.25, 2.66 Hz) 7.16 (2H, t, J=8.93 Hz) 6.82 (1H, d, J=5.47 Hz) 6.43 (1H, dd, J=3.49, 1.93 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][N:12]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][O:9]2)=[CH:4][C:3]=1[F:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[F:32].CCN(C(C)C)C(C)C>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:9][CH2:10][CH2:11][N:12]([CH2:14][C@H:15]([O:20][C:30](=[O:31])[NH:29][C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([F:32])[CH:25]=3)[C:16]([F:17])([F:18])[F:19])[CH2:13]2)=[CH:4][C:3]=1[F:21]
Reactant: O[C@@H](CN1CCO[C@H](c2ccc(Cl)c(F)c2)C1)C(F)(F)F
Reactant: O=C=Nc1ccc(Cl)c(F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: O=C(Nc1ccc(Cl)c(F)c1)O[C@@H](CN1CCO[C@H](c2ccc(Cl)c(F)c2)C1)C(F)(F)F
Temperature: 60 °C
Reaction time: 5 h
Yield: 119.6 %

Procedure:
(S)-3-((R)-2-(4-chloro-3-fluorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol (338 mg, 1.03 mmol) was combined with 1-chloro-2-fluoro-4-isocyanatobenzene (212 mg, 1.24 mmol) in 4 mL of dichloromethane. DIPEA (160 mg, 1.24 mmol) was added. The reaction tube was sealed and reaction mixture stirred at 60° C. for 5 h. TLC indicated complete consumption of the starting material. The mixture was evaporated and the residue was extracted with ether/hexanes (1:2 ratio) and water. The organic layer was washed with brine and dried. Solvents were evaporated and the residue was purified by ISCO flash column chromatography (0% to 25% ethyl acetate in hexanes gradient). The desired fraction was concentrated and dissolved in ether/hexanes (1:2 ratio) and treated with 1N HCl in ether. Solvents were evaporated the residue was triturated with ether/hexanes (1:2 ratio) and the clear top layer solution was decanted. The resultant white solid residue was dried under heated vacuum to provide (4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(R)-2-(4-chloro-3-fluoro-phenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochloride as a white solid (330 mg). (M+H)+=499 m/e.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][O-:12].[Na+].[CH3:14][OH:15]>ClCCl>[CH3:11][O:12][C:14](=[O:15])[NH:10][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:9]
Reactant: CO
Reactant: C[O-]
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N[C@@H](C)c1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
17.2 g (105 mmol) CDT are added to a mixture of 20.0 g (100 mmol) (S)-1-(4-bromophenyl)-ethylamine and 17.6 mL (125 mmol) TEA in 300 mL dichloromethane at 0° C. Stirring is continued for 15 min at 5° C. After that time, the solvent is removed in vacuo and taken up in 50 mL methanol. 33.4 mL (180 mmol) sodium methoxide in methanol (30%) are added and stirring is continued for 48 h at rt. After that time, the solvent is removed in vacuo, the residue is taken up in ethyl acetate and washed with sat. KHSO4-solution (2×) and water. The organic layer is dried over magnesium sulphate and the solvent is removed by evaporation.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]([Cu])#[N:13].O>CN(C)C=O.Cl.[Fe](Cl)Cl>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: N#C[Cu]
Reactant: O=C1CCc2cc(Br)ccc21
Agent: Cl[Fe]Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)CCC2=O

Procedure:
9.5 g of 5-bromo-1-indanone and 4.93 g of CuCN are suspended in 10 ml of dimethylformamide and boiled under reflux for 4 hours. A solution of 18 g of iron(II) chloride in 5 ml of concentrated hydrochloric acid with 30 ml of water are added dropwise to the cooled, dark-brown viscous suspension while stirring, and the mixture is then stirred at 70° C. for 30 minutes. The reaction mixture is extracted by shaking three times with 50 ml of toluene, and the combined organic phases are extracted by shaking with 50 ml of 2N hydrochloric acid and 50 ml of 2N sodium hydroxide solution and then washed with water until neutral. The toluene extract is dried over magnesium sulfate and concentrated in vacuo, and the residue is recrystallized from n-heptane. 1-oxoindane-5-carbonitrile is obtained with a melting point of 123-125° C.