Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:21]>ClCCl>[CH2:14]([O:13][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N+:1]([O-:21])=[CH:2][CH:3]=[CH:4]2)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1ccc2ncccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(ccc[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.5 %

Procedure:
To ethyl quinoline-6-carboxylate (3.2 g, 16 mmol) in dichloromethane (120 mL) was added meta-chloroperoxybenzoic acid (4.9 g, 0.024 mol) portionwise. The reaction was stirred at room temperature for 4 hours. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium carbonate (3×30 mL) and brine (2×40 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave the title compound (2.45 g, 71%) as a brown solid. 1H NMR (400 MHz, CDCl3, δ): 8.81-8.79 (d, 1H), 8.62 (s, 2H), 8.35-8.33 (d, 1H), 7.87-7.85 (d, 1H), 7.39 (s, 1H), 4.49-4.44 (q, 2H), 1.47-1.43 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:64]([SH:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:64]([S:71][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Br:1])=[CH:3][N:4]=[CH:5]2)=[CH:10][CH:9]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: Brc1ccc2c(Br)cncc2c1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Brc1cncc2cc(SCc3ccccc3)ccc12
Temperature: 60 °C

Procedure:
To a vial charged with 4,7-dibromoisoquinoline (Pharmabridge, Inc., Doylestown, Pa.) (0.783 g, 2.73 mmol) was added dioxane (10.91 ml), DIEA (0.953 ml, 5.46 mmol), Xantphos (0.316 g, 0.546 mmol), Pd2(dba)3 (0.250 g, 0.273 mmol) and benzyl mercaptan (0.323 ml, 2.73 mmol). The vessel was sealed and heated to 60° C. for 4 hrs affording conversion to desired product as the primary species. The mixture was dried under reduced pressure and the crude material purified with a 40 HP silicycle column (SiliCycle, Inc. Quebec City, Canada) ramping EtOAc in heptane (0 to 25%, then isocratic at 25%, with 10% DCM isocratic throughout) providing product 7-(benzylthio)-4-bromoisoquinoline (0.573 g, 1.735 mmol, 63.6% yield), obtained as an orange solid. m/z (ESI) 330.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=2)[N:3]=1.[CH3:23][NH:24][CH3:25]>CC(O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=3)[N:3]=[C:2]([N:24]([CH3:25])[CH3:23])[N:11]=2)=[CH:15][CH:16]=1
Reactant: CNC
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc(C)cc23)cc1
Solvent: CC(C)O
Product: COc1ccc(N(C)c2nc(N(C)C)nc3ccc(C)cc23)cc1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
A solution of (2-chloro-6-methyl-quinazolin-4-yl)-(4-methoxyphenyl)-methyl-amine (64.4 mg, 0.21 mmol) and dimethylamine (2.0 M in THF, 1.0 mL, 2.0 mmol) in i-PrOH (2 mL) was heated to 100° C. overnight. After cooling to room temperature the reaction was concentrated onto SiO2 and purified by gradient MPLC (SiO2, 0 to 10%, MeOH/CH2Cl2, 20 min). 17.9 mg (26%) of the title compound was obtained: 1H NMR (DMSO-d6) δ 7.17-7.28 (m, 2 H), 7.12-7.16 (m, 2 H), 6.95-7.01 (m, 2 H), 6.51-6.54 (m, 1 H), 3.77 (s, 3 H), 3.44 (s, 3 H), 3.19 (s, 6 H), 1.94 (s, 3 H). HRMS (ES) calcd for C19H23N4O [(M+H)] 323.1866, found 323.1951.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.C[O:15][C:16](=O)[C:17]1[C:22]([I:23])=[C:21]([F:24])[CH:20]=[CH:19][C:18]=1[CH2:25]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:24][C:21]1[C:22]([I:23])=[C:17]2[C:18]([CH2:25][N:9]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:5][CH:6]=3)[C:16]2=[O:15])=[CH:19][CH:20]=1
Reactant: COC(=O)c1c(CBr)ccc(F)c1I
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1c2c(ccc(F)c2I)CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 39.7 %

Procedure:
A mixture of 4-trifluoromethoxy-benzyl amine (0.763 mL, 5.0 mmol), 2-bromomethyl-5-fluoro-6-iodo-benzoic acid methyl ester (1.49 g, 4.0 mmol), and K2CO3 (0.828 g, 1 mmol) in toluene (7 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 6-fluoro-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.717 g, 40%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.18 (s, 2H), 4.79 (s, 2H), 7.14-7.38 (m, 6H). GC-MS: m/z 451 (M)+, 366 (M−85)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH:31]1([NH2:35])[CH2:34][CH2:33][CH2:32]1>ClCCl>[CH:31]1([NH:35][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[N:10][N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH2:34][CH2:33][CH2:32]1
Reactant: NC1CCC1
Reactant: Fc1ccc(-c2nn3c(c2-c2ccnc(Cl)n2)CCCC3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(-c2nn3c(c2-c2ccnc(NC4CCC4)n2)CCCC3)cc1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
A mixture of 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (i.e. the product of Step B) (200 mg, 0.54 mmol), triethylamine (55 mg, 0.54 mmol) and cyclobutylamine (5.0 mL) was stirred at 65° C. for 18 h. The reaction mixture was diluted with dichloromethane (50 mL) and treated with silica gel (20.0 g). The silica gel suspension was concentrated under reduced pressure to leave a mixture of silica gel and crude product, which was purified by silica gel chromatography using a gradient of ethyl acetate/hexanes (1:9 to 1:0) as eluant to give 70 mg of the title product, a compound of the present invention, as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH:10]([CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.Cl.[CH3:31][O:32][NH:33][CH3:34]>C(Cl)Cl>[CH3:31][O:32][N:33]([CH3:34])[C:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH:10]1[CH3:17])=[O:16]
Reactant: CNOC
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-3-methylpiperidine-4-carboxylic acid (3.00 g, 12.3 mmol) in CH2Cl2 (200 mL) was added di(1H-imidazol-1-yl)methanone (2.19 g, 13.6 mmol) portionwise. After the bubbling ceased (−60 minutes), N-methoxymethanamine hydrochloride (1.32 g, 13.6 mmol) was added in one portion. The mixture was allowed to stir overnight at ambient temperature, then was washed with water, 1N HCl, and saturated sodium bicarbonate. The organic layer was dried, filtered, and concentrated to give the desired product (2.29 g, 64.8% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CON
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Yield: 72.3 %

Procedure:
Following a procedure analogous to Example 45, from the carboxylic acid (6b, 276 mg, 1.00 mmol) of Example 9 or 16 and (S)-tert-butyl 2-((aminooxy)methyl)piperidine-1-carboxylate (300 mg) described in Reference Example 23, 353.3 mg of the title compound was afforded (yield 72%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:5]=[C:4]([NH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[N:3]=1.[NH3:27]>CC(O)C.O1CCOCC1>[NH2:27][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:5]=[C:4]([NH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[N:3]=1
Reactant: Cc1cc(C)c(Nc2nc(Cl)nc(Nc3ccc(C#N)cc3)n2)c(C)c1
Reactant: N
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Cc1cc(C)c(Nc2nc(N)nc(Nc3ccc(C#N)cc3)n2)c(C)c1
Yield: 66.1 %

Procedure:
A mixture of 4-[[4-chloro-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]-amino]benzonitrile (*A9c) (0.00137 mol) and NH3 in 1,4-dioxane (0.5 M; 0.00548 mol) was heated in a pressure vessel at 100° C. for 6 days. The solvent was evaporated and the residue was dissolved in CH2Cl2, washed with a saturated aqueous NaHCO3 solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0, 99/1 and 98/2). The desired fractions were collected and the solvent was evaporated. The residue was recrystallized from toluene. The precipitate was filtered and dried, yielding 0.29 g (61.4%) of 4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]-benzonitrile. b) As an alternative for the preparation of this compound, a mixture of 4-[[4-chloro-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile (0.0230 mol) in NH3 in 2-propanol (2.0 M; 60 ml) and NH3 in 1,4-dioxane (0.5 M; 20 ml) was heated at 95° C. for 21 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate, washed with 1 N NaOH, water and brine, dried, filtered and the filtrate was evaporated. The residue was recrystallized with acetonitrile, yielding 5.25 g (66.1%) of 4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13](Cl)=[O:14])[N:7]2[CH3:12].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([C@H:33]3[CH2:38][CH2:37][C@H:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=23)=[CH:19][C:18]=1[OH:46].C(N(CC)C(C)C)(C)C>ClCCl>[OH:46][C:18]1[CH:19]=[C:20]([C:23]2[N:24]=[C:25]([C@H:33]3[CH2:38][CH2:37][C@H:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=23)[CH:21]=[CH:22][C:17]=1[NH:16][C:13]([C:6]1[N:7]([CH3:12])[C:8]2[C:4]([CH:5]=1)=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=2)=[O:14]
Reactant: Cc1nccn2c1c(-c1ccc(N)c(O)c1)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Reactant: COc1cccc2c1cc(C(=O)Cl)n2C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc2c1cc(C(=O)Nc1ccc(-c3nc([C@H]4CC[C@H](N5CCN(C)CC5)CC4)n4ccnc(C)c34)cc1O)n2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere 4-methoxy-1-methyl-1H-indole-2-carbonyl chloride (described in example 2g) (0.048 mmol, 10.64 mg) was added to a solution of 2-amino-5-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenol (116 mg impure material) and N,N-diisopropylethylamine (0.145 mmol, 24 μl) in dichloromethane at 0° C. The mixture was stirred at room temperature for one hour. Purification by column chromatography (silica gel; gradient of dichloromethane to dichloromethane/methanol 5/1) followed by purification with HPLC (column: X-bridge; eluens acetonitrile/methanol/water with constant 0.003M trifluoroacetic acid). Proper fractions were collected and basified with aqueous sodium carbonate, extracted with dichloromethane, organic layer dried (Na2SO4) and concentrated in vacuo to give N-(2-hydroxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (7 mg)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C=O.[CH2:18](N(CC)CC)C>[Ni].CO>[CH3:18][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CCN(CC)CC
Agent: [Ni]
Agent: C=O
Solvent: CO
Product: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 127 °C
Reaction time: 0.25 h
Yield: 91.8 %

Procedure:
A 2.5 liter shaker reactor was charged with 2,6-di-t-butylphenol (52 g, 0.25 m), formaldehyde (21 g of 37% aq. solution, 0.25 m), triethylamine (30 g, 0.3 m) and methyl alcohol (200 ml). The mixture was heated at 127° C. for 2 hrs. under a nitrogen blanket with agitation. The mixture was hydrogenated at 160° C. in the presence of nickel catalyst (5 g) and 300 psig of H2. Absorption of hydrogen ceased after 15 minutes. The product, after filtering to remove the catalyst, was distilled to recover methyl alcohol, triethylamine and crude DBPC which was distilled at 128° C./6-8 mm Hg to give 51 g (93 mole % yield) of DBPC. Analysis of DBPC by GC was 97% DBPC and 2.8% 2,6-di-t-butylphenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])=[CH:4][C:3]=1[CH2:32]Br.C[N+]1([O-])CC[O:38]CC1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])=[CH:4][C:3]=1[CH:32]=[O:38]
Reactant: CC(=O)OC[C@H]1OC(O)(c2ccc(Cl)c(CBr)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CC(=O)OC[C@H]1OC(O)(c2ccc(Cl)c(C=O)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-chloro-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-bromomethyl-benzene (2.0 g) in acetonitrile (20 mL) is added N-methylmorpholine-N-oxide (0.47 g). The resulting solution is stirred at ambient temperature for 2 h before more N-methylmorpholine-N-oxide (0.20 g) is added. After stirring at ambient temperature overnight, the solvent is removed under reduced pressure and the residue is filtered over silica gel eluting with dichloromethane.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CC[CH2:11][CH2:10]1>>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH2:10][CH3:11]
Reactant: C1CCOC1
Reactant: O=Cc1ccccc1
Product: CCC(=O)c1ccccc1
Temperature: 180 °C
Reaction time: 14 h
Yield: 45 %

Procedure:
Into a stainless steel autoclave with a glass liner was placed 1.5 g. of the 3-methyl-2-aminopyridyl aldimine of benzaldehyde, 75 ml of tetrahydrofuran and 0.2 g. of RhCl(PPh3)3. The autoclave was flushed with ethylene, to remove any air, then pressurized with ethylene to 150 psi, followed by heating to 180 degrees C. for 14 hours. Upon cooling the resulting dark red liquid was concentrated to one-fourth its original volume and stirred with moist silica gel in 20 ml of CH2Cl2 for 1 hour. Solvent was removed on the rotary evaporator and the product propiophenone was obtained by heating the silica gel at 130 degrees and 50 mm and collecting the distillate. The yield of propiophenone, as a clear oil, was 0.45 g., 45% yield based on starting aldimine and 1800% yield based on the rhodium catalyst.
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[CH2:5]([O:7][C:8]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[O:10][N:9]=1)[CH3:6].C([O-])(O)=O.[Na+]>CCO>[CH2:5]([O:7][C:8]1[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH2:1][CH3:2])=[O:15])[O:10][N:9]=1)[CH3:6]
Reactant: CCOc1noc(C(=O)O)c1C
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1onc(OCC)c1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
Acetyl chloride (25 mL, 0.35 mol) was added to EtOH (250 mL) at 0° C. and the solution was stirred at 0° C. for 20 min. A solution of 3-ethoxy-4-methylisoxazole-5-carboxylic acid (WO95/12587,A1) (18 g, 0.10 mol) in EtOH (20 ml) was added and the resulting mixture was boiled under reflux for 4 h. The mixture was cooled, added NaHCO3 (200 mL) and extracted with diethylether (3×300 mL). The organic extracts were dried (MgSO4) and concentrated in vacuo to afford crude title compound (18 g, 86%).
Reaction SMILES: [Br:1]Br.[C:3]1([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH4+].[Cl-]>CN(C=O)C>[C:3]1([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[C:14]([Br:1])=[CH:13]2)(=[O:11])=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: BrBr
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(F)ccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.5 %

Procedure:
Bromine (0.187 mL, 3.632 mmol) was added dropwise to a room temperature solution of 1-benzenesulfonyl-5-fluoro-1H-indole (1.0 g, 3.632 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 5 hours. A saturated solution of NH4Cl was added, and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with water and with brine; dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 95/5) to give 0.676 g (53% yield) of 1-benzenesulfonyl-3-bromo-5-fluoro-1H-indole as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[CH:14]=[C:13]([O:16][CH3:17])[N:12]=[CH:11][C:10]=3[CH:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1>[Pd].C(O)C>[CH:1]1([N:7]2[C:15]3[CH:14]=[C:13]([O:16][CH3:17])[N:12]=[CH:11][C:10]=3[CH:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc2c(ccn2C2C=CCCC2)cn1
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(ccn2C2CCCCC2)cn1
Yield: 94.6 %

Procedure:
The compound of step 1 (5.6 g, 24.5 mmol) and palladium on charcoal (1.12 g, 10%) were stirred in ethanol (160 ml) under a hydrogen atmosphere for 3 h. The catalyst was filtered off and the solvent removed in vacuo to give 5.34 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)=[O:18].[Cl:26][C:27]([Cl:32])([Cl:31])[C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Cl:26][C:27]([Cl:32])([Cl:31])[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:17](=[O:18])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)=[O:29]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ccc(C(=O)c2ccc(N)c(C(=O)c3cccc(Cl)c3)c2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)c2ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c3cccc(Cl)c3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Intermediate 20 (0.0085 mol) was added at 5° C. to DCM (30 ml) under N2 flow, trichloro-acetyl chloride (0.01 mol) then triethylamine (0.01 mol) were added dropwise. The mixture was brought to room temperature, stirred at room temperature for 3 hours, poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated, yielding 4.2 g (quantitative) of 2,2,2-trichloro-N-[2-(3-chlorobenzoyl)-4-(4-methylbenzoyl)phenyl]-acetamide (intermediate 21).
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.[NH4+].[Cl-].C1[CH2:21][O:20][CH2:19]C1>>[Br:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:9]([CH:10]=[CH:19][O:20][CH3:21])[CH:8]=1
Reactant: C1CCOC1
Reactant: O=Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: COC=Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of (methoxymethyl)triphosphonium chloride (5.56 g, 16.21 mmol) in dry THF (13 mL) under inter atmosphere was added dropwise at 0° C. a solution of nBuLi in dry THF (22 mL, 21.62 mmol). The reaction mixture was stirred at room temperature for 1 h. Then, a solution of 3-bromobenzaldehyde (2.0 g; 10.81 mmol) in dry THF (20 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 h. A saturated solution of NH4Cl was added and the crude product was extracted with EtOAc (2 times) and the organic layer was washed with water, then with a saturated solution of NaCl, dried over MgSO4 and concentrated. The final product was purified by silica gel chromatography using 10 to 15% EtOAc/cyclohexane as eluent to give III-a as yellow oil in 66% yield. 1H NMR (300 MHz, CDCl3) δ 7.79 (s, J=1.5 Hz, 1H), 7.48-7.24 (m, 5H), 7.20-7.12 (m, 2H), 7.06 (d, J=13.0 Hz, 1H), 6.19 (d, J=7.0 Hz, 1H), 5.75 (d, J=13.0 Hz, 1H), 5.17 (d, J=7.0 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:25][S:26]([O:11][C@H:10]([C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:28])=[O:27]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccncc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccncc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of (R)-2-(tert-butyldimethylsilyloxy)-1-(pyridin-4-yl)ethanol (80 mg, 0.316 mmol), triethylamine (97 μL, 0.695 mmol) and 4-(dimethylamino)pyridine (3.85 mg, 0.032 mmol) in DCM was added methanesulfonyl chloride (36.8 μL, 0.474 mmol) at 0° C. The reaction was stirred at 0° C. for 20 min, then at room temperature overnight. The mixture was washed with a NaHCO3 solution, water and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give the title compound without further purification. LCMS m/z=332.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([CH2:26][CH2:27][C:28](=[O:34])[N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:24]([CH3:35])[NH:23][C:22]=1[CH:36]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:36][C:22]4[NH:23][C:24]([CH3:35])=[C:25]([CH2:26][CH2:27][C:28](=[O:34])[N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1CCC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.1 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3,5-dimethyl-4-(3-oxo-3-pyrrolidin-1-yl-propyl)-1H-pyrrole-2-carbaldehyde (64.6 mg, 0.26 mmol) and piperidine (3 drops) in ethanol was stirred at room temperature under nitrogen for 2 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 65 mg (51%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.18 (br s, 1H, NH), 11.61 (br s, 1H, NH), 9.13 (brs, 1H), 8.26 (s, 1H), 7.70 (dd, J=2.4 & 6.9 Hz, 1H), 7.31-7.42 (m, 3H), 3.25 (m, 4H, 2×CH2), 2.63 (t, J=7.5 Hz, 2H, CH2), 2.35 (m, 2H, CH2), 2.31 (s, 3H, CH3), 2.12 (s, 3H, CH3), 1.76 (m, 4H, 2×CH2). MS 509 [M++1].