Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]([NH2:25])[C:14]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][C:16]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26]C(O)=O.C(OC=C(C#N)C#N)C.CO.C(Cl)Cl>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH2:19][CH:17]([C:16]3[CH:15]=[C:14]4[C:13](=[CH:12][C:11]=32)[N:25]=[CH:26][N:20]4[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCNc1cc2c(cc1N)C1CC2CN(C(=O)OC(C)(C)C)C1
Reactant: CC(=O)O
Agent: CCOC=C(C#N)C#N
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CCCCn1cnc2cc3c(cc21)C1CC3CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
4-Butylamino-5-amino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (440 mg, 1.27 mmol) was dissolved in ethanol (20 mL) and HOAc (2 mL) and treated with ethoxymethylenemalononitrile (186 mg, 1.52 mmol). The resulting mixture was warmed to 60° C. and stirred 18 hours. The reaction was cooled, concentrated, treated with H2O and saturated aqueous Na2CO3 solution then extracted with ethyl acetate (3×50 mL) and dried (Na2SO4). After filtration and concentration, the residue was chromatographed to provide a yellow oil. (400 mg, 89%). (TLC 5% methanol/CH2Cl2 (NH3) Rf 0.70).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]3)[O:11][C:10]2=[O:21])[CH:5]=[CH:6][C:7]=1I.[O:22]=[S:23]1(=[O:45])[CH2:28][CH:27]=[C:26](C2C(F)=CC(N3C[C@H](CN)OC3=O)=CC=2F)C[CH2:24]1.[F-].[K+].C(OCC)(=O)C>CN1CCCC1=O.[Cu]I.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>[O:45]=[S:23]1(=[O:22])[CH2:24][CH:26]=[C:27]([C:7]2[CH:6]=[CH:5][C:4]([N:9]3[CH2:13][C@H:12]([CH2:14][N:15]4[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]4)[O:11][C:10]3=[O:21])=[CH:3][C:2]=2[F:1])[CH2:28]1
Reactant: NC[C@H]1CN(c2cc(F)c(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: Cc1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cn(C[C@H]2CN(c3ccc(C4=CCS(=O)(=O)C4)c(F)c3)C(=O)O2)nn1
Temperature: 40 °C
Reaction time: 120 h
Yield: 10.2 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-[4-methyl-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (Intermediate 13) (200 mg, 0.50 mmol) and copper (I) iodide (39 mg, 0.20 mmol) were dissolved in dry 1-methyl-2-pyrrolidinone (2 ml) and the reaction mixture placed under an atmosphere of argon. TetrakiS(triphenylphosphine)palladium(0) (35 mg, 0.05 mmol) was added, followed by a solution of tributyl(1,1-dioxo-2,5-dihydrothien-3-yl)stannane [Bew, Sean P.; Sweeney, J. B., Synthesis (1994), (7), p698] (263 mg, 0.65 mmol) in 1-methyl-2-pyrrolidinone (2 ml) and the reaction mixture stirred for 5 days at 40° C. Aqueous potassium fluoride 1M (150 ml) and ethyl acetate (150 ml) were added and the insoluble materials filtered off. The ethyl acetate layer was separated, dried over magnesium sulphate, filtered then concentrated in vacuo onto Isolute HM-N (2 g). Purification by chromatography on silica gel with 1.5% methanol in dichloromethane gave 20 mg (10%) of the desired compound.
Reaction SMILES: B([O-])[O-].IC1C2C(=NC=NC=2N)N([C@H]2CC[C@@H](N3CCN(C)CC3)CC2)N=1.[NH2:28][C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([CH:55]3[CH2:60][CH2:59][CH:58]([N:61]4[CH2:66][CH2:65][N:64]([CH3:67])[CH2:63][CH2:62]4)[CH2:57][CH2:56]3)[N:36]=[C:37]([C:38]3[CH:43]=[CH:42][C:41]([NH:44][C:45]4[S:46][C:47]5C=C(Cl)[CH:51]=[CH:50][C:48]=5[N:49]=4)=[CH:40][CH:39]=3)[C:30]=12>>[NH2:28][C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C@H:55]3[CH2:60][CH2:59][C@@H:58]([N:61]4[CH2:66][CH2:65][N:64]([CH3:67])[CH2:63][CH2:62]4)[CH2:57][CH2:56]3)[N:36]=[C:37]([C:38]3[CH:39]=[CH:40][C:41]([NH:44][C:45]4[S:46][CH:47]=[C:48]([CH2:50][CH3:51])[N:49]=4)=[CH:42][CH:43]=3)[C:30]=12
Reactant: CN1CCN(C2CCC(n3nc(-c4ccc(Nc5nc6ccc(Cl)cc6s5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: [O-]B[O-]
Product: CCc1csc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)n1

Procedure:
The boronate intermediate (0.15 g, 0.45 mmol) was coupled with cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.182 g, 0.41 mmol) using the procedure for Suzuki coupling described in the preparation of N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-6-chloro-1,3-benzothiazol-2-amine. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 7.0-8.0 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-ethyl-1,3-thiazol-2-amine as an off-white powder (0.069 g, 0.133 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 7.05 min; MS (MH)+ 518.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:13]2[C:18]([CH2:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:21][CH3:22])[C:5]([CH3:12])=[C:6]2[C:10]([CH3:11])=[CH:9][NH:8][C:7]=12.[OH-].[Na+]>CO.[Pd]>[CH2:21]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH2:19][CH3:20])[C:13]=1[C:4]1[C:5]([CH3:12])=[C:6]2[C:10]([CH3:11])=[CH:9][NH:8][C:7]2=[CH:2][N:3]=1)[CH3:22]
Reactant: CCc1cccc(CC)c1-c1nc(Cl)c2[nH]cc(C)c2c1C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cccc(CC)c1-c1ncc2[nH]cc(C)c2c1C

Procedure:
The titled compound is prepared from 7-chloro-5-(2,6-diethyl-phenyl)-3,4-dimethyl-1H-pyrrolo[2,3-c]pyridine (Example 7) by catalytic hydrogenation (10% Pd on carbon in MeOH with addition of 15% of 10 M NaOH) at 50 psi. 1H NMR: (CDCl3) 10.2 (1H, br), 8.85 (1H, s), 7.3 (1H, t, J=7.8 Hz), 7.20 (2H, d, J=7.8 Hz), 6.7 (1H, s), 2.50 (3H, s), 2.36 (3H, s), 2.29 (4H, q, J=7.0 Hz), 1.04 (6H, t, J=7.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.Cl[C:17]1[N:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][N:21]([S:27]([NH:30][C:31]1[S:35][N:34]=[CH:33][N:32]=1)(=[O:29])=[O:28])[CH2:22]2>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:17]1[N:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][N:21]([S:27]([NH:30][C:31]1[S:35][N:34]=[CH:33][N:32]=1)(=[O:29])=[O:28])[CH2:22]2
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: O=S(=O)(Nc1ncns1)N1CCc2c(ccnc2Cl)C1
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2c1CCN(S(=O)(=O)Nc1ncns1)C2

Procedure:
The title compound was prepared in a manner analogous to Example 1, except that (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid was used in place of (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid and 5-chloro-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2,6-naphthyridine-2(1H)-sulfonamide (Intermediate V) was used in place of 5-bromo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide. [M+H]+=472.0 1H NMR (400 MHz, Acetone-d6) δ ppm: 8.41 (d, J=5.1 Hz, 1H), 8.25 (s, 1H), 7.35-7.44 (m, 3H), 7.20 (d, J=5.1 Hz, 1H), 4.26-4.51 (m, 2H), 3.89 (s, 3H), 3.43-3.56 (m, 1H), 3.15-3.26 (m, 1H), 2.82-2.93 (m., 1H), 2.40-2.56 (m, 1H)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:13]=[CH:12][O:11][C:10]=2[CH3:14])O1.Br[C:17]1[N:22]=[C:21]([N:23]2[CH2:28][C@H:27]([CH3:29])[O:26][C@H:25]([CH3:30])[CH2:24]2)[CH:20]=[CH:19][CH:18]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:30][C@H:25]1[O:26][C@@H:27]([CH3:29])[CH2:28][N:23]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:9]3[CH:13]=[CH:12][O:11][C:10]=3[CH3:14])[N:22]=2)[CH2:24]1
Reactant: C[C@@H]1CN(c2cccc(Br)n2)C[C@H](C)O1
Reactant: Cc1occc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1occc1-c1cccc(N2C[C@@H](C)O[C@@H](C)C2)n1
Temperature: 100 °C

Procedure:
4,4,5,5-Tetramethyl-2-(2-methyl-3-furanyl)-1,3,2-dioxaborolane (412 mg, 1.980 mmol) was added to a solution of cis-4-(6-bromo-2-pyridinyl)-2,6-dimethylmorpholine (537 mg, 1.980 mmol) in a mixture of 1,4-dioxane (15 mL), water (2.500 mL) and sodium carbonate (420 mg, 3.96 mmol). The solution was degassed using argon gas and then charged with tetrakis(triphenylphosphine)palladium(0) (229 mg, 0.198 mmol). After addition, the reaction mixture was stirred and heated in the microwave at 100° C. for 1 hour. Crude LC/MS showed starting material and desired product so tetrakis(triphenylphosphine) palladium(0) (229 mg, 0.198 mmol), sodium carbonate (420 mg, 3.96 mmol) and 4,4,5,5-tetramethyl-2-(2-methyl-3-furanyl)-1,3,2-dioxaborolane (412 mg, 1.980 mmol) were added to the reaction mixture which was then stirred and heated at 100° C. in the microwave for 1 hour. Crude LC/MS showed desired product and no starting material can be seen. The reaction mixture was washed with ethyl acetate (200 mL), water (100 mL), filtered and then evaporated to dryness. The residue was dissolved in dichloromethane (˜5 ml) and purified on silica by a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-50% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a colourless oil (270 mg, 0.942 mmol, 47.6% yield). LC/MS [M+H]+=273.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CS(=O)(=O)c1ccc(-c2ccccc2-c2ccc(C(F)(F)F)cc2)cc1
Yield: 77.7 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 4.0 g (13 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene (Example 4, Step 2) was reacted with 3.8 g (20 mmol) of 4-(trifluoromethyl)phenylboronic acid (Step 1). Purification by silica gel chromatography (Waters Prep-500A) with ethyl acetate/hexane (1:3) and subsequent recrystallization from ethyl acetate/hexane gave 3.80 g (77%) of 1-[4-(trifluoromethyl)phenyl]-2-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 172.8°-173.5° C.; NMR (CDCl3) δ 3.06 (s, 3H), 7.23 (d, J=8 Hz, 2H), 7.33 (d, J=9 Hz, 2H), 7.41-7.46 (m, 2H), 7.48-7.54 (m, 4H), 7.81 (d, J=9 Hz, 2H). MS (ES): m/e 383 (M+Li); HRMS Calc'd for C20H15F3O2S: 376.0745. Found: 376.0766.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[C:14]2[N:15]=[C:16]([CH2:26][CH2:27][CH3:28])[N:17]([CH2:18][C:19]3([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:13]=2[C:12]([CH3:29])=[C:11]([CH3:30])[N:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO.C(O)C>[NH2:8][C:9]1[C:14]2[N:15]=[C:16]([CH2:26][CH2:27][CH3:28])[N:17]([CH2:18][C:19]3([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:13]=2[C:12]([CH3:29])=[C:11]([CH3:30])[N:10]=1
Reactant: CCCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(C)c(C)c2n1CC1(O)CCCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CC1(O)CCCCC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 63.8 %

Procedure:
A mixture of 1-{[4-(dibenzylamino)-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl]methyl}cyclohexanol (1.50 g, 3.02 mmol), ammonium formate (2.84 g, 45.0 mmol), and 10% palladium on carbon (1.50 g) in methanol (60 mL) and ethanol (120 mL) was heated at 85° C. for 2 h. More ammonium formate (1.00 g) was added and heating was continued of 3 h, then the reaction mixture was stirred overnight at rt. The mixture was filtered through CELITE filter agent and the filtrate was concentrated in vacuo. The crude product was purified using HPFC (gradient elution with 10-40% CMA/chloroform). The appropriate fractions were concentrated and the resulting solid was triturated with acetonitrile. A solid was isolated by filtration and dried at 100° C. under vacuum to provide 1-[(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclohexanol as a white powder (0.61 g, 64%), mp 214.0-216.0° C. Anal. Calcd for C18H28N4O C, 68.32; H, 8.92; N, 17.71. Found: C, 68.06; H, 8.65; N, 17.45
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1
Product: Fc1ccc(CNc2nc(-n3cncn3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[O:21][C:22]=1[CH3:23]>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)[O:21][C:22]=3[CH3:23])=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: Cc1oc(-c2cccs2)nc1CCl
Product: Cc1oc(-c2cccs2)nc1COc1ccc(CCCn2ccnc2)cc1
Yield: 84 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-5-methyl-2-(2-thienyl)oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-methyl-2-(2-thienyl)oxazole. The yield was 84%. Recrystallization from acetone-isopropyl ether gave colorless prisms, mp 102-103° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12]Br>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][Br:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: Cc1ccc(C(C)(C)C)cc1
Product: CC(C)(C)c1ccc(CBr)cc1

Procedure:
In another known process in which a Cu salt is likewise used, i.e. Cu(NO3)2, p-tert.butyltoluene is the starting material, which is first reacted with an approximately equivalent amount of bromine to give p-tert.butylbenzyl bromide which is then boiled for a prolonged period of time in combination with a Cu(NO3)2 solution. p-tert.Butylbenzaldehyde is obtained in this manner in a yield of about 42% of the theory (cf. J. Chem. Soc., 1935, page 1848).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][NH:14]1.N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:22][C:21]3[NH:20][CH:19]=[C:18]4[C:17]=3[CH2:16][CH2:15][NH:14][C:13]4=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 6-chloro-1,3-dihydro-indol-2-one (33.5 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 equivalent) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[CH:16][CH:17]=[N:18][C:11]=3[N:10]=[C:9]2[C@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])=[CH:4][CH:3]=1.[C-:29]#[N:30].[Na+]>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.[Cu]I>[C:29]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[CH:16][CH:17]=[N:18][C:11]=3[N:10]=[C:9]2[C@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH3:20])=[CH:4][CH:3]=1)#[N:30]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nc2ncccc2c(=O)n1-c1ccc(I)cc1
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: C[C@@H](NC(=O)OC(C)(C)C)c1nc2ncccc2c(=O)n1-c1ccc(C#N)cc1
Temperature: 70 °C
Yield: 88.5 %

Procedure:
Compound 15 (2.02 g, 4.10 mmol), prepared as described in Section 7.11, was combined with (Ph3P)4Pd (439 mg, 0.38 mmol), CuI (157 mg, 0.82 mmol) and NaCN (406 mg, 8.29 mmol) in a 25 mL pear shaped flask equipped with a reflux condenser. The mixture was evacuated under high vacuum and backfilled with dry N2 three times. Acetonitrile (6 mL) was then added and the resulting suspension heated to 70° C. for 30 min. at which point TLC and HPLC analysis indicated near complete consumption of 15. The mixture was diluted with EtOAc (100 mL) and filtered through a pad of celite. The filtrate was washed with saturated NaHCO3 (100 mL). The aqueous wash was extracted with additional EtOAc (2×50 mL). The combined extracts were dried over Na2SO4 and concentrated. Purification of the residue by silica gel chromatography (50×400 mm column; 80% EtOAc/hexanes to 100% EtOAc) gave 16 (1.42 g, 89%; purity 96% AUC; 92% e.e. by chiral HPLC analysis). Rf=0.35 (80% EtOAc/hexanes).
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][C:45](Cl)=[O:46]>N1C=CC=CC=1>[CH3:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][C:45]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7]1)=[O:46]
Reactant: COCCOCCOCC(=O)Cl
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COCCOCCOCC(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Reaction time: 18 h
Yield: 19.8 %

Procedure:
To a solution of 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-one dihydrochloride (399 mg, 0.92 mmol) in pyridine (10 ml) was added triethylamine (0.31 ml, 2.2 mmol) and 2-(2-(2-methoxyethoxy)ethoxy)acetyl chloride (197 mg, 1 mmol). The mixture was stirred for 18 hours, evaporated to dryness, the residue dissolved in dichloromethane, and purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (95 mg).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH:15]([CH3:18])[CH2:16][NH2:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC>C1(C)C=CC=CC=1>[CH3:18][CH:15]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:17][CH2:16]1
Reactant: CC(CN)c1ccccc1
Reactant: O=Cc1ccccc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC1CNC(c2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 78 %

Procedure:
4 Å molecular sieve (10 g) was added to a solution of 1.06 g (10.0 mmol) of benzaldehyde and 1.35 g (10.0 mmol) of 2-phenylpropylamine in toluene (45 ml) and the mixture was refluxed for 4 h. After cooling to RT the mixture was filtered through diatomaceous earth and the filtrate was concentrated to small volume under vacuum. The residue was dissolved in TFA (90 ml) and the solution was heated at 120° C. for 20 h. Then it was concentrated to small volume under vacuum and made alkaline with a 2N aqueous NaOH solution. It was then extracted with EE. The organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 7:3) of the residue produced 1.74 g (7.8 mmol, 78%) of 4-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=O)[C@H:10]2[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=[S:33])[C@H:10]2[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@H]2F)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)[C@H]2F)CC1
Temperature: 60 °C
Yield: 150.1 %

Procedure:
4-(S)-(1-Ethoxycarbonylcyclopropyl)-3-(S)-fluoro-1-[1-(S)-phenylethyl]-2-pyrrolidone (6.86 g, 21.48 mmol) was dissolved in dry toluene (100 ml), and the solution was mixed with Lawesson's reagent (5.21 g, 12.89 mmol) and heated at 60° C. for 30 minutes. After cooling, toluene was evaporated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=4:1, to thereby obtain 6.49 g (90.1%) of the title compound as a light yellow oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:3]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:28][C@H:29]1[CH2:34][O:33][CH2:32][CH2:31][NH:30]1>CC(O)CC.C(Cl)Cl>[CH3:28][C@H:29]1[CH2:34][O:33][CH2:32][CH2:31][N:30]1[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:3]=1
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Reactant: C[C@H]1COCCN1
Agent: Cl
Solvent: CCC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@@H]2C)nc2[nH]cnc12
Temperature: 175 °C
Reaction time: 48 h
Yield: 65.7 %

Procedure:
2-Chloro-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (712 mg, 2.81 mmol), diisopropylethylamine (0.98 mL, 5.61 mmol), and (S)-3-methylmorpholin hydrochloride (579 mg, 4.21 mmol) were stirred in 2-butanol (3 mL) in a closed 5 mL microwave tube under argon at 50° C., until all ingredients were dissolved. The reaction was then stirred at 175° C. for 48 hours. The organic layer was diluted with 200 mL of CH2Cl2 and washed with brine. Drying over Na2SO4, filtering and concentration under reduced pressure gave a residue, which was purified by column chromatography (40 g SiO2, CH2Cl2/EtOH/aq NH3 in a gradient from 100/0/0.1 to 90/10/0.1) to give the product as a solid (588 mg, 66%).