Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10](Cl)[C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:4][CH:3]=1.[NH3:20]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[NH2:20])=[CH:4][CH:3]=1
Reactant: Fc1cccc(Cl)c1C(Cl)=NNc1ccc(Br)cc1
Reactant: N
Solvent: C1CCOC1
Product: NC(=NNc1ccc(Br)cc1)c1c(F)cccc1Cl
Temperature: 2.5 °C
Reaction time: 2.5 h

Procedure:
To a cold solution of N-(4-bromophenyl)-2-chloro-6-fluorobenzenecarbohydrazonoyl chloride (0.070 g, 0.267 mmol) in dry THF was added aq. ammonia. The reaction mass was stirred at 0-5° C. for 2-3 h. The reaction mass was quenched in water, neutralized with dilute acetic acid and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.040 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 6.29 (br s, 2H), 6.80 (d, J=8.4 Hz, 2H), 7.24 (d, J=9.3 Hz, 2H), 7.28-7.50 (m, 3H), 8.33 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:45])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[C:42]([CH3:44])[N:41]=[CH:40][N:39]=2)[CH:33]=1)=O)(C)(C)C>>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:28](=[O:45])[CH2:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[CH:43]=[C:42]([CH3:44])[N:41]=[CH:40][N:39]=4)[CH:33]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (160 mg, 0.5 mmol) and 3-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K41) (187 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (139 mg).
Reaction SMILES: C([O:5][C:6](=[O:70])[CH2:7][C@H:8]([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[C:9]([CH3:61])([CH3:60])[C:10](=[O:59])[C@H:11]([CH3:58])[C@@H:12]([O:49][C:50]([O:52][CH2:53][C:54]([Cl:57])([Cl:56])[Cl:55])=[O:51])[C@@H:13]([CH3:48])[CH2:14][CH2:15][CH2:16]/[C:17](/[CH3:47])=[CH:18]\[CH2:19][C@H:20]([O:39][Si](CC)(CC)CC)/[C:21](/[CH3:38])=[CH:22]/[C:23]1[N:24]=[C:25]([CH2:28][O:29][C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31])[S:26][CH:27]=1)(C)(C)C.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](CC)(CC)CC)(=O)=O.Cl.P([O-])([O-])([O-])=O>C(Cl)Cl.C(OCC)(=O)C>[O:59]=[C:10]([C@H:11]([CH3:58])[C@@H:12]([O:49][C:50]([O:52][CH2:53][C:54]([Cl:55])([Cl:56])[Cl:57])=[O:51])[C@@H:13]([CH3:48])[CH2:14][CH2:15][CH2:16]/[C:17](/[CH3:47])=[CH:18]\[CH2:19][C@H:20]([OH:39])/[C:21](/[CH3:38])=[CH:22]/[C:23]1[N:24]=[C:25]([CH2:28][O:29][C:30]([O:32][CH2:33][C:34]([Cl:35])([Cl:36])[Cl:37])=[O:31])[S:26][CH:27]=1)[C:9]([CH3:61])([CH3:60])[C@@H:8]([O:62][Si:63]([CH2:68][CH3:69])([CH2:64][CH3:65])[CH2:66][CH3:67])[CH2:7][C:6]([OH:70])=[O:5]
Reactant: CC[Si](CC)(CC)O[C@@H](C/C=C(/C)CCC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@H](CC(=O)OC(C)(C)C)O[Si](CC)(CC)CC)/C(C)=C/c1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)O[C@@H](CC(=O)O)C(C)(C)C(=O)[C@H](C)[C@@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)CCC/C(C)=C\C[C@H](O)/C(C)=C/c1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Reaction time: 10 h

Procedure:
A solution of tert-butyl(3S,6R,7S,8S,12Z,15S,16E)-5-oxo-3,15-bis(triethylsilyloxy)-17-(2-(2,2,2-trichloroethoxycarbonyloxymethyl)thiazol-4-yl)-4,4,6,8,12,16-hexamethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-heptadeca-12,16-dienoate (2.86 g) in 12 mL of CH2Cl2 is treated with 2,6-lutidine (0.86 mL) and triethylsilyl trifluoromethanesulfonate (0.98 g) at 0° C. for 30 minutes, then at ambient temperature for 10 hours. The mixture is diluted with 50 mL of ethyl acetate and poured into 20 mL of 1 N HCl. The organic phase is separated, washed with pH 7 phosphate buffer, dried with Na2SO4, filtered, and concentrated. The residue is dissolved in 5 mL of THF and treated with 0.5 mL of 0.1 N HCl in methanol. The reaction is monitored by thin-layer chromatography, with additional aliquots of methanolic HCl being added to achieve complete reaction. When complete, the reaction is poured into 15 mL of pH 7 phosphate buffer and extracted with ethyl acetate. The extract is washed with brine, dried with Na2SO4, filtered, and evaporated. The product is purified by flash chromatography on SiO2 (1:1 hexanes/ethyl acetate).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)[nH]c1ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)[nH]c1ccccc12

Procedure:
2-Nitrocarbazole [Mendenhall, G. D.; Smith, P. A. S. Org. Syn. Coll. Vol. 5 1973, 829, the disclosure of which is herein incorporated by reference](structure 14 of Scheme IV, where R1-6 =H, X=NH) (1.0 g, 4.7 mmol) in 50 mL of ethyl acetate was hydrogenated over 10% Pd/C (50 mg) under an atmosphere of hydrogen for 1.5 h at rt giving, after filtration through Celite™, 840 mg (100%) of 2-aminocarbazole. Data for 2-aminocarbazole: 1H NMR (400 MHz, CDCl3) 7.94 (d, J=9.0, 1H), 7.83 (d, J=8.0, 1H), 7.80 (br s, 1H), 7.35 (m, 2H), 7.15 (dd, J=8.2, 1H), 6.67 (d, J=1.8, 1H), 6.58 (dd, J=9.0, 1.8, 1H), 3.73 (br s, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:14][CH2:15][S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10](B(O)O)=[C:6]2[C:5](=[O:36])[N:4]([CH3:37])[C:3]1=[O:38].Br[C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[C:43]#[N:44].[OH-].[Ba+2].[OH-].O>C(OC(C)=O)CCC.C(Cl)Cl>[CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:14][CH2:15][S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]([C:40]3[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=3)[C:43]#[N:44])=[C:6]2[C:5](=[O:36])[N:4]([CH3:37])[C:3]1=[O:38]
Reactant: Cn1c(=O)c2c(B(O)O)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Reactant: N#Cc1cccc(Br)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCCCOC(C)=O
Solvent: O
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A suspension comprising 1,3-dimethyl-2,4-dioxo-6-(2-(tritylthio)ethyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-ylboronic acid (Intermediate F) (300 mg, 0.571 mmol), 3-bromobenzonitrile (104 mg, 0.571 mmol) and barium hydroxide (196 mg, 1.142 mmol) in n-BuOAc (5710 μL) was treated with Pd-118 (18.61 mg, 0.029 mmol) and the mixture was heated to 80° C. Water (247 μL, 13.70 mmol) was added at 80° C. and the suspension was stirred rapidly for 90 minutes. After cooling to RT, the mixture was allowed to stand at RT overnight. The mixture was diluted with DCM (50 ml) and washed with water (50 ml). The layers were separated and the aqueous portion was extracted with DCM (3×30 ml). The organics were combined and dried over MgSO4, filtered and concentrated. Purification of the crude product by trituration with EtOAc/iso-hexane afforded the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[N:16]([CH3:18])[C:15](=[O:19])[N:14]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9]2[C:17]3[N:16]([CH3:18])[C:15](=[O:19])[N:14]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)[C:13]=3[CH:12]=[CH:11][CH:10]=2)[C:29](=[O:31])[CH3:30])=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2c(=O)n(C)c3c(Nc4ccc(Cl)cc4)cccc32)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(Cn2c(=O)n(C)c3c(N(C(C)=O)c4ccc(Cl)cc4)cccc32)cc1
Temperature: 120 °C

Procedure:
A mixture of 4-[(4-chlorophenyl)amino]-1-(4-methoxybenzyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.393 g, 1.0 mmol), pyridine (0.1 ml) and acetic anhydride (10 ml) was heated at 120° C. for 4 days. The mixture was evaporated in vacuo. The residue was diluted with ethyl acetate (50 ml), washed with saturated sodium bicarbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was flash chromatographed eluting with 40-50% ethyl acetate/hexanes to give N-(4-chlorophenyl)-N-[1-(4-methoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl]acetamide (0.388 g, quant.) as an oil.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:18])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[NH:10][C:9](=[O:15])[C:8]([CH3:16])=[C:7]2[CH3:17])[CH:2]=[CH2:3].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:19][CH2:3][CH:2]1[O:18][C:5]2=[C:6]3[C:11](=[C:12]([CH3:14])[CH:13]=[C:4]2[CH2:1]1)[NH:10][C:9](=[O:15])[C:8]([CH3:16])=[C:7]3[CH3:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCc1cc(C)c2[nH]c(=O)c(C)c(C)c2c1O
Solvent: ClC(Cl)Cl
Product: Cc1c(C)c2c3c(cc(C)c2[nH]c1=O)CC(CBr)O3
Temperature: 100 °C
Yield: 79.1 %

Procedure:
6-Allyl-5-hydroxy-3,4,8-trimethylcarbostyril (1.01 g, 4.16 mmol) was dissolved in chloroform (50 ml). To the obtained solution, N-bromosuccinimide (888 mg, 4.99 mmol) was added. The mixture was refluxed with in a bath of 100° C. for 1.5 hours. The reaction mixture was cooled, washed with saturated aqueous NaCl solution and dried. The solvent was distilled off under reduced pressure. The residue was recrystallized from chloroform--ether to obtain 1.06 g of the title compound as yellow needles (79.8%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[O:3].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:12]=1[CH2:13][OH:14].N1C=CC=CC=1>ClCCl>[OH:14][CH2:13][C:12]1[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]=1[NH:10][C:2](=[O:3])[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)COC(=O)Cl
Reactant: Cc1cccc(N)c1CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)COC(=O)Nc1cccc(C)c1CO
Yield: 35.1 %

Procedure:
Starting from methoxycarbonylmethyl chloroformate (11.7 g), 2-amino-6-methylbenzyl alcohol (10.5 g) and pyridine (6.2 ml) in dichloromethane (230 ml), 6.8 g (20%) of the title compound, m.p. 70-74° C., are obtained according to the procedure indicated in Example C1, after chromatography on silica gel (eluent: ethyl acetate/petroleum ether 50/70=1:1) and crystallization from diisopropyl ether.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5](Br)=[CH:4][CH:3]=1.[Cu][C:11]#[N:12]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]#[N:12])=[C:6]([CH3:8])[N:7]=1
Reactant: N#C[Cu]
Reactant: Cc1nc(N)ccc1Br
Solvent: CN(C)C=O
Product: Cc1nc(N)ccc1C#N
Yield: 84.2 %

Procedure:
A mixture of 6-amino-3-bromo-2-methyl-pyridine (20 g, 0.107 mol) and copper (I) cyanide (11.0 g, 0.123 mol) in DMF (25 mL) was heated to reflux for 4 h. The DMF was evaporated in vacuo and the residue was partitioned between ethyl acetate and 10% sodium cyanide solution. The organic layer was washed with 10% sodium cyanide solution and brine, dried (Na2SO4) and evaporate in vacuo to a brown solid. This was dissolved in a minimum amount of ethyl acetate and the product was precipitated by adding hexane. The mixture was filtered to give the title compound (12 g, 85%) as a brown powder:
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:29][CH:27]([C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:26][CH:25]=2)[CH3:28])=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Reactant: CC(N)c1ccc(C(F)(F)F)cc1
Product: CCCCCCCCC#Cc1ccc(CNC(C)c2ccc(C(F)(F)F)cc2)cc1
Yield: 54 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-dec-1-ynylbenzaldehyde and 1-[4-(trifluoromethyl)phenyl]ethanamine gave the title compound as a colorless oil (54%). M+(ESI): 416.2. HPLC (Condition A), Rt: 4.67 min (HPLC purity: 87.6%).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][N:7]([CH2:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C:17]4[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=4)[CH:12]=3)[CH2:6][CH2:5]2)[O:3]C1.Cl.[OH-].[Na+]>C1COCC1>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([C:13]2[CH:12]=[C:11]([CH2:10][N:7]3[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]3)[CH:16]=[CH:15][N:14]=2)[CH:18]=[C:19]([O:27][CH3:28])[C:20]=1[O:25][CH3:26]
Reactant: COc1cc(-c2cc(CN3CCC4(CC3)OCCO4)ccn2)cc(OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone ethylene ketal (19.0 g) in THF (200 mL) was added 1 M hydrochloric acid (200 mL). The mixture was stirred at 90° C. overnight, then neutralized with 2 M sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residual oil was applied to a column of silica gel using chloroform-methanol (40:1) as an eluent. Fractions containing the product were collected and evaporated to give the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.[Cl-].[Li+].C(=O)([O-])[O-].[K+].[K+].[CH:34]1[C:39](O)=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41]>ClCCl.C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[CH2:1]([O:8][CH2:9][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:11][O:12][C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:41])[CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)COCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cccc(OC[C@H](COCc2ccccc2)NC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To t-butyl (1R)-2-(benzyloxy)-1-(hydroxymethyl)ethylcarbamate (3.23 g) obtained in Step 1 were added dichloromethane (40 ml), methanesulfonyl chloride (1.07 ml) and triethylamine (3.20 ml), and the mixture was stirred at 0° C. for 3 hrs. The reaction mixture was diluted with dichloromethane and, after washing with water, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated to give a crude product. To this crude product were added dimethylformamide (30 ml) and lithium chloride (2.4 g), and the mixture was stirred overnight at 40° C. The solvent was evaporated, and the residue was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to give a crude product. To this crude product were added dimethylformamide (20 ml), potassium carbonate (2.4 g) and m-cresol (1.47 ml), and the mixture was stirred overnight at 90° C. The mixture was diluted with ethyl acetate and, after washing with water, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained crude product was purified by silica gel chromatography (ethyl acetate-hexane) to give t-butyl (1S)-2-(benzyloxy)-1-[(3-methylphenoxy)methyl]ethylcarbamate (1.5 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][C:5]=2[N:4]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)[N:3]=1>CCO.C1COCC1.[Pd]>[CH3:1][C:2]1[C:10]2[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][C:5]=2[N:4]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: CCOC(=O)c1cc(/C=C/c2ccccc2)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CCc2ccccc2)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Reaction time: 8 h
Yield: 85.1 %

Procedure:
(see, e.g., WO2013039988A1). To a suspension of 10% Pd/C (70 mg) in EtOH (5 mL) was added 52 (186 mg, 0.38 mmol) dissolved in THF (1.5 mL). The suspension was stirred under an atmosphere of hydrogen (ca. 1 atm, balloon) overnight. The suspension was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to provide the title compound (159 mg, 84%) as a light brown oil. Crude was used in the next reaction without further purification. 1H NMR (500 MHz, CDCl3) δ 7.44 (s, 1H), 7.36-7.31 (m, 3H), 7.31-7.26 (m, 3H), 7.26-7.22 (m, 2H), 7.19 (t, J=7.0 Hz, 1H), 7.09 (t, J=7.4 Hz, 1H), 7.00 (d, J=7.9 Hz, 2H), 6.95 (d, J=8.5 Hz, 2H), 5.67 (s, 2H), 4.49 (q, J=7.1 Hz, 2H), 3.35-3.27 (m, 2H), 3.24-3.17 (m, 2H), 2.73 (s, 3H), 1.47 (t, J=7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.85, 161.09, 157.08, 156.78, 152.23, 141.30, 140.97, 133.36, 132.21, 129.72, 129.55, 128.49, 128.41, 126.04, 123.30, 118.95, 118.80, 117.33, 109.68, 61.83, 49.83, 39.82, 35.23, 16.31, 14.30. ESI MS: m/z 516.9 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH:24][CH:25]4[CH2:27][CH2:26]4)[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1)=[N+]=[N-].CP(C)C.O>C1COCC1>[NH2:1][CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:13])([CH3:14])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH:24][CH:25]4[CH2:27][CH2:26]4)[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1
Reactant: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@@H](CN)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Reaction time: 8 h
Yield: 92 %

Procedure:
7-[(3aS,4R,6R,6aR)-6-(Azidomethyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (4.683 g, 12.55 mmol) was dissolved in THF (23 ml) and trimethylphosphane (1M in THF) (25 ml, 25.1 mmol) was added at r.t. under N2 and the reaction stirred overnight. Water (2.25 ml) was added and the reaction was left for 15 mins. The solvents were removed in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 100% DCM to 20% 2M NH3 in MeOH:80% DCM as eluent to give the product as pale yellow viscous oil (3.964 g, 92%): MS (ESI+) for C18H25N5O2 m/z 344.5 [M+H]+, 366.0 [M+Na]+; LC purity 100% (UV), 100% (ELS) (ret. time, 0.21 and 0.44 min); 1H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 7.25 (d, J=3.63 Hz, 1H), 6.70 (br. s., 1H), 5.03 (dt, J=12.06, 6.27 Hz, 1H), 4.92-4.99 (m, 1H), 4.55 (dd, J=7.25, 5.99 Hz, 1H), 2.82-2.93 (m, 2H), 2.72-2.82 (m, 1H), 2.39 (dt, J=12.65, 6.52 Hz, 1H), 2.23-2.28 (m, 1H), 2.03 (q, J=12.14 Hz, 1H), 1.56 (s, 3H), 1.31 (s, 3H), 0.82-0.93 (m, 2H), 0.60-0.71 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([C:13]#[N:14])[CH2:11][C:10](=C)[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH2:15]>C(Cl)Cl.C(#N)C>[F:1][C:2]1[C:3]([C:8]2([C:13]#[N:14])[CH2:11][C:10](=[O:15])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1CC(C#N)(c2ncccc2F)C1
Reactant: O
Solvent: ClCCl
Solvent: CC#N
Product: N#CC1(c2ncccc2F)CC(=O)C1
Temperature: 15 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a mixture of 1-(3-fluoropyridin-2-yl)-3-methylenecyclobutanecarbonitrile (272 g, 1.45 mol) and RuCl3.H2O (9.0 g, 0.044 mol) in DCM (1 L), acetonitrile (1 L), and water (1.5 L) mixture was added solid NaIO4 (1235 g, 5.8 mol) portionwise at 10-30° C. Upon the completion of addition, the reaction was stirred 1 h at 15° C. and overnight at rt. The solid precipitate was filtered off and washed with DCM (2×1000 mL). The organic layer was washed with water (2×500 mL) and brine (500 mL), dried over Na2SO4, and concentrated to provide a crude title compound as a dark solid (238 g, 86.3%). LRMS (M+H+) m/z 191.1.
Reaction SMILES: [C:1]1([C@@H:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C@@H:8]2[C:13](OC)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]1([C@@H:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C@@H:8]2[CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H]1CCC=C[C@H]1c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OC[C@H]1CCC=C[C@H]1c1ccccc1
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
A solution of 300 mg (1.38 mmol) of 1(R)-phenyl-2(S)-carbomethoxy-cyclohex-5-ene (from Step A) in 30 mL of CH2Cl2 at 0° C. was treated with 2.3 mL of 1.5 M diisobutylaluminum hydride solution in toluene. After stirring for 30 minutes the reaction was quenched with 50 mL of sat'd sodium potassium tartrate solution, diluted with 100 mL of ether and stirred at rt for 20 h. The layers were separated and the organic layer was washed with 75 mL of H2O , dried over MgSO4 and concentrated in vacuo. Flash chromatography on 100 g of silica gel using 5-25% v/v EtOAc/hexanes as the eluant afforded 185 mg (72%) of the title compound as an oil. 1H NMR (CDCl3, 500 MHz) δ 7.23-7.34 (m, 5H), 5.95-5.97 (m, 1H), 5.77-5.79 (m, 1H),3.66 (s, 1H), 3.23-3.32 (m, 2H), 2.14-2.25 (m, 3H),1.51-1.62 (m, 3H) ppm.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:4].[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O.C(=O)(O)[O-].[Na+]>C1COCC1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:33]2[CH2:34][CH2:35][N:30]([C:25]3[N:24]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:31][CH2:32]2)[S:7][C:8]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CN1CCN(c2ncccn2)CC1)Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
Compound 262 (300 mg, 0.860 mmol) was dissolved in THF (5.0 mL), and 1-(2-pyrimidinyl)piperazine (0.370 mL, 2.58 mmol) was added thereto, followed by stirring at room temperature for 16 hours. Further, 1-(2-pyrimidinyl)piperazine (0.370 mL, 2.58 mmol) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. Water and aqueous saturated sodium bicarbonate solution were added to the reaction mixture, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (hexane:ethyl acetate=1:2) to afford the entitled Compound 278 (345 mg, 84%) as pale yellow crystals.
Reaction SMILES: C(O[C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.[CH:21]([NH2:24])([CH3:23])[CH3:22].C([BH3-])#N.[Na+]>C(Cl)CCl.CO.[Ti](Cl)(Cl)(Cl)Cl>[Br:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[C:4](=[O:20])[N:24]([CH:21]([CH3:23])[CH3:22])[CH:12]2[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)N
Reactant: CCOC(=O)c1ccc(Br)cc1C(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CC(C)N1C(=O)c2ccc(Br)cc2C1c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-Benzoyl-4-bromo-benzoic acid ethyl ester (50 mg; 0.15 mmol) is dissolved in ethylene dichloride (1 ml) and treated with 1 mol/l Titanium(IV)chloride solution (150 μl; 0.15 mmol) and cooled down to 0° C. Isopropylamine (13 μl; 0.15 mmol) is added and stirred for 2 hours at ambient temperature and 16 hours at 80° C. A 6.5 mol/l solution of sodium cyano borohydride in methanol (140 μl; 0.90 mmol) is added and stirred for 3 days followed by another portion of sodium cyano borohydride in methanol and 16 hours at 50° C.