Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:32])([CH3:31])[CH2:4][O:5][CH2:6][C:7]1[NH:8][C:9]([CH3:30])=[C:10]([C:26]([O:28][CH3:29])=[O:27])[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[Cl:25])[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].CN(C)/[CH:35]=[N:36]/[N:37]=[CH:38]/N(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:25][C:19]1[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:18]=1[CH:11]1[C:10]([C:26]([O:28][CH3:29])=[O:27])=[C:9]([CH3:30])[NH:8][C:7]([CH2:6][O:5][CH2:4][C:3]([OH:32])([CH3:31])[CH2:2][N:1]2[CH:38]=[N:37][N:36]=[CH:35]2)=[C:12]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C1=C(COCC(C)(O)CN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: CN(C)/C=N/N=C/N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(COCC(C)(O)Cn2cnnc2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 65.1 %

Procedure:
A solution of 1-amino-3-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2-hydroxy-2-methylpropane (0.25 g), N,N-dimethylformamide azine (0.21 g) and para-toluenesulphonic acid (10 mg) in toluene (10 ml) was heated under reflux for 1.5 hours and then partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with water, dried over Na2SO4 and evaporated. The residue was purified by chromatography on SiO2 (5 g) using dichloromethane plus 0-5% methanol as the eluant. Appropriate fractions were combined and evaporated and the residue triturated with ether. The resulting solid was collected, washed with ether and dried to give the title compound (0.18 g), m.p. 172°-176° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>C1(C)C=CC=CC=1.O.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:20][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([C:28]([F:39])([F:38])[F:27])[CH:34]=3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1oc(-c2ccc(-c3cccc(C(F)(F)F)c3)cc2)nc1CCN1CCCC1
Yield: 64.9 %

Procedure:
To a stirred solution of 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole (100 mg, 0.299 mmol), sodium carbonate (94.9 mg, 0.895 mmol) and 3-Trifluoromethylbenzene boronic acid (284 mg, 1.49 mmol) in toluene (5 mL), water (1 mL) and ethanol (1.5 mL) under nitrogen was added Tetrakis(triphenylphosphine) palladium (0) (34.5 mg, 0.030 mmol). The reaction was then heated to reflux for 48 h. The reaction was allowed to cool and bound to a SCX-2 cartridge (5 g). The cartridge was washed with one cartridge volume of dimethylformamide and two volumes of methanol. The product was eluted using 2M ammonia in methanol. The ammonia/methanol solution was evaporated on a Genevac® HT4. The sample was further purified by prep-LCMS. The resulting acetonitrile/water fractions were combined and evaporated using a Genevac® HT4 to give 77.7 mg of a colourless oil (65%). MS (m/e): 401.2 (M+1)
Reaction SMILES: [Tl].[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:4]=1[C:5]([OH:7])=[O:6].Cl[CH2:14][N:15]1[C:19](=[O:20])[CH:18]([CH2:21][CH2:22][CH3:23])[NH:17][S:16]1(=[O:25])=[O:24]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:4]=1[C:5]([O:7][CH2:14][N:15]1[C:19](=[O:20])[CH:18]([CH2:21][CH2:22][CH3:23])[NH:17][S:16]1(=[O:24])=[O:25])=[O:6]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: CCCC1NS(=O)(=O)N(CCl)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Tl]
Solvent: CN(C)C=O
Product: CCCC1NS(=O)(=O)N(COC(=O)c2c(Cl)cccc2Cl)C1=O
Yield: 28.5 %

Procedure:
The thallium salt of 2,6-dichlorobenzoic acid (0.96 g; 2.43 mmol, prepared from 0.46 g of 2,6-dichlorobenzoic acid and 0.605 g of TlOC2H5 in ethanol ) was added to a solution of 2-chloromethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g; 2.21 mmol) in DMF (10 ml) containing tetrabutylammonium bromide (70 mg; 0.22 mmol). The mixture was allowed to react at 50° C. for 15 hours and at 100° C. for an additional hour, and then cooled. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (25%-30% ethyl acetate in hexane) to afford 0.24 g (29%) of 2-(2,6-dichlorophenylcarbonyloxymethyl)-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar=2,6-Cl2 -phenyl; R1 =H; R2 =propyl; R3 =H) as a solid, m.p.95°-97° C.
Reaction SMILES: C(OC[N:9]1[C:13]2[N:14]=[C:15]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][CH:36]4[CH2:39][N:38]([CH2:40][CH2:41][F:42])[CH2:37]4)=[CH:31][C:30]=3[O:43][CH3:44])[N:16]=[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=3)[C:12]=2[CH:11]=[CH:10]1)(=O)C(C)(C)C.NN.O>[Pd].CO>[NH2:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][C:17]1[C:12]2[CH:11]=[CH:10][NH:9][C:13]=2[N:14]=[C:15]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][CH:36]3[CH2:39][N:38]([CH2:40][CH2:41][F:42])[CH2:37]3)=[CH:31][C:30]=2[O:43][CH3:44])[N:16]=1
Reactant: COc1cc(NC2CN(CCF)C2)ccc1Nc1nc(Oc2cccc([N+](=O)[O-])c2)c2ccn(COC(=O)C(C)(C)C)c2n1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc(NC2CN(CCF)C2)ccc1Nc1nc(Oc2cccc(N)c2)c2cc[nH]c2n1
Temperature: 25 °C
Yield: 31 %

Procedure:
A mixture of (2-(4-(1-(2-fluoroethyl)azetidin-3-ylamino)-2-methoxyphenylamino)-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (530 mg, 0.87 mmol), NH2NH2.H2O (98%, 2.5 mL), Pd/C (110 mg), a magnetite, and MeOH (10 mL) was stirred at reflux temperature overnight. The mixture was cooled to room temperature, and was filtered through diatomaceous earth, washing with MeOH (20 mL). The filtrate was concentrated under reduced pressure. NaHCO3(aq) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were concentrated under reduced pressure. The crude material was purified by column chromatography (DCM/MeOH=40/1 as elution) to give the title compound (125 mg, yield 31%, M+H+=464.2) as a white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:15]([C:17]([NH:19][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)=[O:18])[N:16]=2)=[CH:8][CH:7]=1)(=O)C.[OH-].[Na+]>>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:14]2[NH:13][C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][OH:4])=[CH:11][CH:10]=3)=[N:16][C:15]=2[C:17]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:18])=[CH:30][CH:29]=1
Reactant: CC(=O)OCc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(Cl)cc3)[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1nccs1)c1nc(-c2ccc(CO)cc2)[nH]c1-c1ccc(Cl)cc1

Procedure:
2-(4-Acetoxymethylphenyl)-5-(4-chlorophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide obtained in Example 222 is hydrolyzed with aqueous sodium hydroxide solution to give the objective 5-(4-chlorophenyl)-2-(4-hydroxymethylphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]1([CH:16]([CH3:18])[CH3:17])[O:13][C:12](=[O:14])[CH:11]=[C:10]([OH:15])[CH2:9]1.[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32][C:11]1[C:12](=[O:14])[O:13][C:8]([CH2:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)([CH:16]([CH3:18])[CH3:17])[CH2:9][C:10]=1[OH:15])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: CC(C)C1(CCc2ccco2)CC(O)=CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccco3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16a using 6-(2-furan-2-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (Example E-17; 1 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.1 mmol), potassium carbonate (4 mmol) in DMF (5 mL), mp 64-110° C. MS (APCI): 457 (M−H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:11]([CH3:21])[C:12]=2[S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-:33][Si](C)(C)C)(C)C>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]>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][C:12]2[N:11]([CH3:21])[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([NH2:33])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(Br)cc2)c1Sc1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li+]
Product: Cn1c(-c2ccccn2)nc(-c2ccc(N)cc2)c1Sc1ccc(Cl)cc1
Temperature: 75 °C

Procedure:
2-{4-(4-Bromophenyl)-5-[(4-chlorophenyl)thio]-1-methyl-1H-imidazol-2-yl}pyridine (Example 15, 300 mg, 0.57 mmol), Pd(dba)2 (19 mg, 0.03 mmol), and biphenyl-PCy2 (11.5 mg, 0.03 mmol) were charged into a flask that was flushed with nitrogen. Toluene (2.2 mL) was added, followed by LiHMDS (1M in PhMe, 2 mL, 2 mmol). After heating at 75° C. overnight, the reaction was quenched with aqueous NH4Cl and diluted with EtOAc. The organic layer was washed with water and brine. The volatiles were evaporated and the residue was purified by reverse phase HPLC to afford the title compound. 1H NMR (500 MHz, (CD3OD): 8.58 (broads, 1H), 8.18 (broad s, 1H), 7.98 (t, 1H), 8.27 (d, 2H), 7.68 (d, 2H), 7.46 (broad s, 7.07 (d, 2H), 6.78 (d, 2H), 3.98 (s, 3H). LCMS: m/z 393 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][N:5]=[C:4]([CH3:7])[CH:3]=1.[Cl-].[Li+].C([Mg+])(C)C.[Cl-].Cl[C:16]1[N:21]=[C:20]2[C:22]([C:25]([F:37])([F:36])[C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[CH:31][CH:30]=[CH:29]4)=[N:23][O:24][C:19]2=[CH:18][CH:17]=1.CC(N(C)C)=O>C1COCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2].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]>[F:37][C:25]([F:36])([C:22]1[C:20]2=[N:21][C:16]([C:2]3[S:6][N:5]=[C:4]([CH3:7])[CH:3]=3)=[CH:17][CH:18]=[C:19]2[O:24][N:23]=1)[C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][CH:30]=[CH:29]2
Reactant: FC(F)(c1ccc2ncccc2c1)c1noc2ccc(Cl)nc12
Reactant: Cc1cc(Br)sn1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2ccc3onc(C(F)(F)c4ccc5ncccc5c4)c3n2)sn1
Temperature: -40 °C
Yield: 3.5 %

Procedure:
To a solution of 5-bromo-3-methylisothiazole (0.19 g, 1.1 mmol) in anhydrous THF (3 mL) was added isopropylmagnesium lithium chloride (1.0 M in THF, 1.5 mL, 1.5 mmol) at −40° C. The mixture was stirred at −40° C. for twenty minutes followed by the addition of zinc chloride (0.5 M in THF, 3.1 mL, 1.6 mmol). The mixture was brought to room temperature and stirred for thirty minutes followed by the addition of Q-Phos (0.12 g, 0.17 mmol), Pd2(dba)3 (0.097 g, 0.110 mmol), 6-((5-chloroisoxazolo[4,5-b]pyridin-3-yl)difluoromethyl)quinoline (0.10 g, 0.30 mmol), and anhydrous dimethylacetamide (3.5 mL). The mixture was stirred at 50° C. for ninety minutes then was diluted with ethyl acetate and washed with water. Organic extracts were dried over magnesium sulfate and purified by MPLC (eluted with a gradient of 10 to 50% ethyl acetate in hexanes), then purified by HPLC (eluted with a gradient of 15 to 90% acetonitrile in water) to afford the product as a white solid (4.2 mg, 3%). MS m/z=395.2 [M+1]+Calc'd for C23H15F2N3O: 394.4.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:35][CH:36]([C:40]2[CH:45]=[CH:44][C:43]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH:42][CH:41]=2)[C:37]([OH:39])=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[S:52][CH:53]=[CH:54][N:55]=1>C(Cl)Cl>[CH:28]1([CH2:35][CH:36]([C:40]2[CH:45]=[CH:44][C:43]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH:42][CH:41]=2)[C:37]([NH:50][C:51]2[S:52][CH:53]=[CH:54][N:55]=2)=[O:39])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A solution of triphenylphosphine (116 mg, 0.44 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (78 mg, 0.44 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acid (72 mg, 0.22 mmol) in methylene chloride (2 mL). The clear solution was stirred for 10 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 (66 mg, 0.66 mmol), and the resulting suspension was stirred for 20 h at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (30 mL) and a 1N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×10 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×20 mL) and a saturated aqueous sodium chloride solution (1×30 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-cycloheptyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (68 mg, 76%) as an amorphous solid: EI-HRMS m/e calcd for C20H26N2O3S2 (M+) 406.1426, found 406.1424.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14]Br)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1.Cl>>[OH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([O:31][CH2:14][CH2:13][CH2:12][NH:11][C:8]2[C:9](=[O:10])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6](=[O:23])(=[O:22])[C:7]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(C)(C)N1C(=O)C(NCCCBr)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Product: CC(C)(C)N1C(=O)C(NCCCOC(=O)c2ccc(O)cc2)=C(c2ccccc2)S1(=O)=O
Yield: 21 %

Procedure:
The title compound was prepared as described for Example 5 from 2-tert-butyl-4-[(3-bromopropyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-hydroxybenzoic acid with a reaction time of 1.5 h. The reaction mixture was acidified with HCl (1N) and extracted with EtOAc. The organic layers were combined and evaporated to dryness. The residue was triturated in MeOH, the solvent was decanted and the residue was purified by silica gel column chromatography (Horizons Biotage) using 50% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.028 g, 21%). 1H NMR (500 MHz CD3CN): δ 7.80 (d, 2H), δ 7.62 (bs, 1H), 7.56-7.48 (m, 2H), 7.56-7.42 (m, 3H), 5.93 (t, 1H), 4.09 (t, 2H), 3.08-3.03 (m, 2H), 1.76-1.68 (m, 1H); 13C NMR (125 MHz CD3CN): δ 166.5, 160.6, 159.8, 135.2, 132.2, 131.8, 129.9, 128.9, 125.0, 122.2, 115.5, 107.4, 62.2, 61.1, 41.1, 28.4, 27.1; Mass Spectrum: M+H+ 459.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:33](Cl)=[O:34])=[CH:27][CH:26]=1>O1CCOCC1.O>[NH:1]([C:33]([O:32][CH2:31][C:28]1[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=1)=[O:34])[C@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
To a solution of Tyr(3-tBu)-OMe (41.4 g, 0.165 mol) in 1,4-dioxane (170 ml) and H2O (170 ml), under cooling with ice, sodium carbonate (26.2 g, 0.247 mol) was added and then Z—Cl (24.7 ml 0.173 mol) was further added over 25 min., followed by stirring for 2.5 hours at room temperature. The reaction mixture was mixed with water, extracted with chloroform, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus precipitated crystals were collected by filtration, washed with n-hexane and dried to give Z-Tyr(3-t-Bu)-OMe (54.7 g, 86%).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([F:11])[CH:3]=1.Cl.[C:13]1(Cl)[C:19](=O)C(Cl)=C(Cl)[C:15](=O)[C:14]=1Cl.C(=O)/C=C/C.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([O:9][CH3:10])=[C:6]2[C:7]=1[N:8]=[C:14]([CH3:15])[CH:13]=[CH:19]2
Reactant: COc1cc(N)c(Br)cc1F
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: C/C=C/C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1c(F)cc(Br)c2nc(C)ccc12
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To 6-bromo-4-fluoro-3-methoxyaniline (7.0 g, 32 mmol) was added conc. HCl (10 ml) followed by p-chloranil (7.80 g, 32 mmol), then nbutanol (10 ml) was added and the whole mix heated up to reflux, with stirring. A solution of crotonaldehyde (2.7 g 38.4 mmol) in nbutanol (5 ml), was added slowly over 0.5 h, and reflux continued for a further 0.5 h. The reaction mixture was allowed to cool, and the basified to pH14 using 50% NaOH solution. The reaction mixture was diluted with water (200 ml) and extracted with dichloromethane (3×100 ml). The combined organic extracts were dried over Na2SO4 and evaporated in vacuo to give a dark oil which was chromatographed on silica gel (˜200 g) eluting from 20% ethyl acetate in hexane to give the title compound as a brown oil (2.97 g, 34%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C@@H:10]([NH:22]C(=O)OC(C)(C)C)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=1)#[N:9]>C(Cl)Cl>[NH2:22][C@@H:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=1)[C:8]#[N:9]
Reactant: CC(C)Oc1ccc(C[C@@H](C#N)NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(C[C@H](N)C#N)cc1
Reaction time: 1 h
Yield: 111.8 %

Procedure:
Trifluoroacetic acid (1 mL, 10 mmol) was added to a solution of the (S)-tert-butyl 1-cyano-2-(4-isopropoxyphenyl)ethylcarbamate (40 mg) in methylene chloride (2 mL). After stirring for 1 h., the reaction was concentrated under reduced pressure to give the crude product (2S)-2-amino-3-(4-isopropoxyphenyl)propanenitrile (30 mg, 90%).
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])(C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C(Cl)Cl>C1COCC1>[OH:6][C@@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN([C@@H]1c2ccccc2C[C@H]1O[Si](C)(C)C(C)(C)C)S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN([C@@H]1c2ccccc2C[C@H]1O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[(1R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1-yl]-N-methyl-methanesulphonamide (0.53 g) is dissolved in 5 mL THF, combined with Bu4NF (5 mL of a 1 N solution in THF) and stirred for 2 h at RT. After the reaction is complete the reaction mixture is freed from the solvent. After the addition of CH2Cl2 it is extracted with HCl (aqu., 1 N). The organic phase is dried on MgSO4. After elimination of the solvent the mixture is purified by normal phase chromatography (CH2Cl2, MeOH). The product-containing fractions are combined and freed from the solvent using the rotary evaporator.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]4[C:28]5[C:27]([NH2:29])=[N:26][CH:25]=[N:24][C:23]=5[N:22]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:21]=4)=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:36](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]4[C:28]5[C:27]([NH2:29])=[N:26][CH:25]=[N:24][C:23]=5[N:22]([CH:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH:21]=4)=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(CC(=O)N2CCc3cc(-c4cn(C5CCNCC5)c5ncnc(N)c45)ccc32)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4cn(C5CCN(C)CC5)c5ncnc(N)c45)ccc32)c1
Yield: 43.1 %

Procedure:
To a solution of 5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(4-piperidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (97 mg, 0.193 mmol) in DMF (3 mL) was added cesium carbonate (188 mg, 0.578 mmol) then iodomethane (0.013 mL, 0.212 mmol). After 2 hr the reaction was filtered and the filtrate was concentrated and then loaded on to a 10 g SNAP column. Elution with 0 to 10% MeOH in DCM gradient provided 5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(1-methyl-4-piperidinyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-amine (40 mg, 43.2% yield) as a white solid. LC-MS (ES) m/z=481.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH2:11]([NH:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)[CH3:12]>>[CH3:10][S:9][C:4]1[N:5]=[C:6]([N:13]([CH2:11][CH3:12])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH:7]=[C:2]([N:13]([CH2:11][CH3:12])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[N:3]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CCNc1cccc(O)c1
Product: CCN(c1cccc(O)c1)c1cc(N(CC)c2cccc(O)c2)nc(SC)n1
Yield: 43 %

Procedure:
This compound was obtained (yield 43%) based on the method described in Production Example 2B using 4,6-dichloro-2-methylthio-pyrimidine instead of the 4,6-dichloro-2-ethylpyrimidine, and using 3-ethylaminophenol instead of the 3-aminophenol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([O:10][C:11]1[C:12](=O)[C:13](=[O:18])[C:14]=1[O:15]CC)[CH3:9]>CCO>[CH2:8]([O:10][C:11]1[C:14](=[O:15])[C:13](=[O:18])[C:12]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:9]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1ccccn1
Solvent: CCO
Product: CCOc1c(Nc2ccccn2)c(=O)c1=O
Yield: 29.5 %

Procedure:
2-Aminopyridine (630 mg, 6.7 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (1.0 mL, 6.7 mmol) in EtOH (10 mL). The mixture was heated to reflux for 2.5 h, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (800 mL hexanes/EtOAc 3:1, 1.5 L hexanes/EtOAc 1:1) to give 431 mg (29%) of the title compound as a yellow powder.