Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12](C3CCCCO3)[CH:11]=[N:10][C:9]=2[C:8]2=[N:20][N:21]=[CH:22][N:7]2[C:6]1=[O:23])[CH:2]([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:5]1[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[C:8]2=[N:20][N:21]=[CH:22][N:7]2[C:6]1=[O:23])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(=O)n2cnnc2c2ncn(C3CCCCO3)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1c(=O)n2cnnc2c2nc[nH]c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-isobutyl-7-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-i]purin-5-one (20 mg, 0.06 mmol) in methylene chloride (0.8 mL) was added TFA (0.1 mL, 1 mmol) dropwise. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated to give the crude product which was used for next step without further purification. LCMS calculated for C10H13N6O (M+H): 233.1. found: 233.1.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Li][CH3:14].[NH4+].[Cl-]>C(OCC)C>[OH:1][C:2]1([CH3:14])[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)C1CCC(C)(O)CC1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution of ethyl 4-oxocyclohexanecarboxylate (4.00 g, 23.5 mmol) in diethyl ether (80 mL) was added MeLi (37.6 mL, 1M in diethyl ether) at −60° C. under nitrogen atmosphere. The reaction mixture was stirred at −60° C. for 30 min. Saturated aqueous NH4Cl (50 mL) was added and the resulting mixture was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (150 mL) and water (150 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=10:1) to afford ethyl 4-hydroxy-4-methylcyclohexanecarboxylate (1.8 g, 41% yield) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[N:4][N:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[CH:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Brc1cnn(-c2ccccn2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cnn(-c3ccccn3)c2)c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(4bromo-1H-pyrazol-1-yl)pyridine (0.669 g, 3.0 mmol), 3-methoxyphenylboronic acid (0.453 g, 3.0 mmol) and potassium carbonate (0.828 g, 6.0 mmol) in a mixture of ethyleneglycol dimethyl ether (20 mL) and H2O (4 mL) were degassed by argon bubbling for 15 min., then tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) was added and degassing continued a further 15 min. The resulting solution was stirred at 70° C. for 14 h, whereupon H2O (30 mL) was added, then extracted with EtOAc (3×30 mL) and the combined extracts washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo, and the crude residue was chromatographed on silica gel eluting with EtOAc:hexane (1:4) afford a white solid which was recrystallized from EtOAc/Hexane to give 2-[4(3-methoxyphenyl)-1H-pyrazol-1-yl]pyridine. MP=89-90° C. 1H NMR (CD3Cl, 300 MHz) δ 8.84 (s, 1H), 8.45 (dd, 1H), 8.03 (s, 1H), 8.02 (d, 1H), 7.84 (dd, 1H), 7.34 (t, 1H), 7.23˜7.15 (m, 3H), 6.84 (dd, 1H) 3.87 (s, 3H). MS (ESI) 252.1 (M++H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>CC(O)C>[Br:1][C:2]1[N:3]=[C:4]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([CH:16]3[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]3)=[CH:20][CH:21]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CN1CCC(c2ccc(Nc3nc(Br)cn4ccnc34)cc2)CC1
Yield: 57.5 %

Procedure:
A solution of 6,8-dibromoimidazo[1,2-a]pyrazine (500 mg, 1.8 mmol), 4-(1-methylpiperidin-4-yl)benzenamine (376 mg, 1.98 mmol) and CSA (356 mg, 1.53 mmol) in iPrOH (30 mL) was stirred at 90° C. overnight. The solvent was evaporated. The residue was dissolved in DCM (30 mL), NaHCO3 solution (10 mL) was added to adjust pH=8. The organic layer was dried over Na2SO4 and evaporated. The residue was purified through a silica-gel column (ethyl acetate:petroleum ether=1:1) to afford the desired product as a yellow solid (400 mg, 58% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][CH:10]1[CH2:12][CH2:11]1.FC(F)(F)C(NC1C=CC=CC=1)=O>>[CH:10]1([CH2:9][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:11]1
Reactant: BrCC1CC1
Reactant: Nc1ccccc1
Agent: O=C(Nc1ccccc1)C(F)(F)F
Product: c1ccc(NCC2CC2)cc1

Procedure:
N-(Cyclopropylmethyl)aniline [NMR (200 MHz, DMSO-d6): δ 0.21 (m, 2H); 0.51 (m, 2H); 1.01 (m, 1H); 3.63 (d, J=7.3 Hz, 1H); 3.80 (br s, 1H); 5.78 (br s, 1H); 7.18 (t, J=7.2 Hz, 1H); 7.25 (d, J=7.8 Hz, 2H); 7.42 (t, J=7.3 Hz, 2H)] was prepared from aniline and (bromomethyl)cyclopropane via trifluoroacetanilide using the general method described by Hodge (Harland, P. A.; Hodge, P; Maughan, W.; Wildsmith, E. Synthesis, 1984, 941.).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:2].[CH2:28]([C@H:30]1[O:32][CH2:31]1)Cl>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:28][C@H:30]4[CH2:31][O:32]4)=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:27]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1O
Reactant: ClC[C@@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@H]1CO1
Reaction time: 24 h
Yield: 74.8 %

Procedure:
To a solution of 4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (500 mg, 1.36 mmol) in isopropanol (15 mL) and 3 N aq. NaOH (6 mL), (S)-epichlorohydrine (378 mg, 4.09 mmol) is added. The orange solution is stirred at rt for 24 h before another portion of (S)-epichlorohydrine is added. Stirring is continued for 24 h, the mixture is diluted with EA, washed with sat. aq. NaHCO3-solution, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give diethyl-{4-[3-((R)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridin-2-yl}-amine (430 mg) as a yellow oil; LC-MS: tR=0.96 min; [M+1]+=423.21.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].C(Cl)CCl.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][N:23]([CH3:52])[C@@H:24]1[CH2:31][N:30]2[C:32]3[CH:33]=[C:34]([C:45](O)=[O:46])[CH:35]=[CH:36][C:37]=3[C:38]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:29]2[C:28]2[CH:48]=[CH:49][CH:50]=[CH:51][C:27]=2[O:26][CH2:25]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:21][CH2:22][N:23]([C@@H:24]1[CH2:31][N:30]2[C:32]3[CH:33]=[C:34]([C:45]([NH:8][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])=[O:46])[CH:35]=[CH:36][C:37]=3[C:38]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:29]2[C:28]2[CH:48]=[CH:49][CH:50]=[CH:51][C:27]=2[O:26][CH2:25]1)[CH3:52])([CH3:16])([CH3:14])[CH3:15]
Reactant: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Reactant: NS(=O)(=O)CCCCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)CCCCl)cc3n2C1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
3-chloropropane-1-sulfonamide (1.8 eq), DMAP (2.9 eq) and EDC (1.8 eq), were added to a solution of (7R)-7-[{2-[(tert-butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (prepared as described in Example 1, Step 7) (0.025 M) in DCM. The reaction was stirred under N2 at 40° C. for 2 h, before being allowed to cool. Volatiles were removed in vacuo to leave the crude product as a yellow gum which could be taken on without further purification. (ES+) m/z 687 (M+H)+; 689 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:24])=[C:7]([C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:23])[C:21]=2[OH:22])=[O:16])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])=[O:4].C(N(CC)CC)C.[CH3:32][CH2:33][S:34][C:35](Cl)=[O:36]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:24])=[C:7]([C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:23])[C:21]=2[O:22][C:35]([S:34][CH2:33][CH3:32])=[O:36])=[O:16])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])=[O:4]
Reactant: CCSC(=O)Cl
Reactant: COC(=O)c1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(C(=O)OC)c2C)cnn1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.1 %

Procedure:
5-Hydroxy-1-methylpyrazol-4-yl 3-(methoxycarbonyl)-2-methyl-4-(methylsulfonyl)phenyl ketone (290 mg, 0.82 mmol) was dissolved in dry tetrahydrofuran (15 mL), and triethylamine (166 mg, 1.64 mmol) was added thereto. A solution (4 mL) of 96% S-ethyl chlorothiolformate (107 mg) dissolved in dry tetrahydrofuran was added thereto little by little under cooling with ice water. The reaction mixture was stirred for 90 minutes while the reaction temperature was allowed to warm to room temperature. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:4) to obtain the desired product as an amorphous solid (202 mg, 0.46 mmol) (yield: 56%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([NH2:26])=[CH:23][C:24]=3[CH2:25][C@H:14]12)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][C:24]=3[CH2:25][C@H:14]12)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2c3ccc(N)cc3C[C@@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]2c3ccc(NS(C)(=O)=O)cc3C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylsulfonyl chloride (42 μL) is added to a solution of cis-7-amino-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridine-1-carboxylic acid tert-butyl ester (160 mg) and triethylamine (76 μL) in dichloromethane (3 mL) at room temperature. The solution is stirred for 1 h at room temperature and then aqueous NaHCO3 solution is added. The mixture is stirred vigorously for 20 min and then extracted with dichloromethane. The combined extract is concentrated and the residue is chromatographed (cyclohexane/ethyl acetate 7:3→1:9) to give the title compound. Yield: 120 mg (59% of theory); LC (method 1): tR=3.80 min; Mass spectrum (ESI+): m/z=365 [M−H]+.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]([CH2:15][CH:16]1[CH2:18][O:17]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].S(=O)(=O)(O)[OH:20].[Cl-].[Na+]>O1CCCC1>[OH:17][CH2:18][C@H:16]1[O:20][C@@H:2]([CH2:3][OH:1])[CH2:4][N:5]([S:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:15]1
Reactant: O=S(=O)(c1ccccc1)N(CC1CO1)CC1CO1
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1C[C@@H](CO)O[C@@H](CO)C1
Reaction time: 72 h
Yield: 25 %

Procedure:
Tetrahydrofuran (60 mL) was added to chirally-enriched N,N-bis(2-oxiranylmethyl)benzenesulfonamide (from step (i) above; 14.8 g, 55 mmol), followed by dilute sulfuric acid (15 mL of 1 M), and the mixture stirred for 3 days. Solid sodium chloride (11 g) was added and the mixture stirred for 1 hour. The organic phase was separated and concentrated under reduced pressure to give crude product (22.4 g). The material was purified by column chromatography over silica, eluting with dichloromethane:ethanol (19:1), to give the title compound (4 g, 25%) and an impure fraction that was a 2:1 mixture of cis- and trans- isomers (8 g, 75%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([Br:32])[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:40])[CH3:39])=O)(C)(C)C.[Cl:41]CCl>Cl>[ClH:41].[Br:32][C:29]1[C:28](=[O:33])[N:27]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:12][CH2:13][NH:8][C:9]([CH3:40])([CH3:39])[CH2:10]4)=[CH:15][N:16]=3)[N:22]=[CH:23][C:24]=2[C:30]=1[CH3:31]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)ncc12
Reactant: ClCCl
Agent: Cl
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCNC(C)(C)C4)cn3)ncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.051 g, 0.083 mmol) was dissolved in dichloromethane (3 mL) to which 2 N HCl (2 mL) was added and the resulting mixture was stirred at room temperature for 2 hours. This mixture was concentrated and allowed to sit for 10 days, it was then dissolved in 2 N HCl (2 mL) and stirred at room temperature for 5 hours. The solvent was removed to give 6-bromo-8-cyclopentyl-2-[5-(3,3-dimethyl-piperazin-1-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.035 g, 71.4%). 1H NMR δ (400 MHz, DMSO-d6) 9.32 (s, 2H), 8.98 (s, 1H), 8.04 (d, J=2.7 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.26 (m, 1H), 5.89 (m, 2H), 3.34 (m, 2H), 3.23 (m, 4H), 2.58 (s, 3H), 2.14 (m, 2H), 1.91 (m, 2H), 1.77 (m, 2H), 1.57 (m, 2H), 1.38 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH2:13](I)[CH:14]=[CH2:15]>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:15][CH:14]=[CH2:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C=CCI
Reactant: Clc1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCn1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.3 g: 8.5 mmol) in dry THF (30 ml) was added sodium hydride (1.0 g, 0.25 mmol, 60% dispersion in mineral oil). After stirring at ambient temperature for 1 hour, allyl iodide (0.93 ml, 10 mmol) was added and stirring continued for 48 hours. The mixture was concentrated in vacuo, triturated in hot ethyl acetate, and filtered. The filtrate was concentrated in vacuo to give an orange solid residue. The solid was triturated in CH2Cl2 and filtered to afford 4-chloro-7-allyl-pyrrolo[2,3-d]pyrimidine as a light yellow powder (0.58 g, 36%): TS-MS: 194 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[C:11]([C:10]1[C:3]2[C:2]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:23][CH2:22]3)=[N:7][CH:6]=[N:5][C:4]=2[N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=1)#[N:12]
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c2c(Cl)ncnc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cc(C#N)c2c(N3CCC(NC(=O)c4ccccc4)CC3)ncnc21
Reaction time: 0.75 h

Procedure:
4-chloro-7-({[2-(trimethylsilyl)ethyl]oxy}methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile D43 (100 mg) and N-4-piperidinylbenzamide (86 mg, 0.42 mmol, commercially available from e.g. Fluorochem, Alfa Aesar and Apollo) were dissolved in NMP and then N,N-diisopropylethylamine was added dropwise. The reaction mixture was carried out in the microwave at 120° C. for 45 minutes. The reaction mixture was poured onto water extracted with EtOAc (2×60 ml). Organic layers were washed water (3×20 ml), brine (30 ml), dried (MgSO4), filtered and solvent removed. Crude product obtained was purified by flash chromatography on silica gel eluting with Pet Eth/EtOAc 3/1-2/1 to give the desired product D44 in 69 mg. LCMS [MH+] 477.2@1.80 min (5 min run)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:3]=1[CH:4]=O.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:3]=1[CH:4]=[N:17][OH:18]
Reactant: NO
Reactant: O=Cc1c(Cl)cccc1-c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1c(Cl)cccc1-c1ccncc1
Reaction time: 8 h
Yield: 98.7 %

Procedure:
2-Chloro-6-(4-pyridyl)benzaldehyde (80 mg, 0.37 mmol) was dissolved in pyridine (2 mL) at room temperature. Hydroxylamine hydrochloride (26 mg, 0.38 mmol) was added and the mixture was allowed to stir overnight. The mixture was then concentrated under reduced pressure to obtain 2-chloro-6-(4-pyridyl)benzaldoxime (85 mg, 99% yield). MW=233 confirmed by LC-MS, tr=8.36 min (Method Y) MH+=231–235
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[N:37][NH:38]3)O1>>[NH:38]1[C:39]2[C:35](=[C:34]([C:2]3[N:3]=[C:4]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:8][C:6]=4[N:7]=3)[CH:42]=[CH:41][CH:40]=2)[CH:36]=[N:37]1
Reactant: CS(=O)(=O)CCCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CS(=O)(=O)CCCNCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(3-methanesulfonyl-propyl)-amine was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification by column chromatography yielded 384. NMR: CDCl3: 1.99-2.05 (2 H, m, CH2), 2.80 (2 H, t, J 7.2, CH2), 2.81 (3 H, s, Me), 3.10-3.13 (2 H, m, CH2), 3.85-3.88 (4 H, m, CH2), 4.01-4.06 (6 H, m), 7.45 (1 H, s, Ar), 7.50 (1 H, apparent triplet, J 8.2, Ar), 7.61 (1 H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5, Ar) and 9.03 (1 H, s, Ar). MS: (ESI+): MH+ 487.20
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:19]O)[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:45]I>C(Cl)Cl>[CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][I:45])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])[CH3:3]
Reactant: II
Reactant: CC(C)(C)OC(=O)CC[C@H](CO)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H](CI)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of crude 1,1-dimethylethyl (4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-hydroxypentanoate (23.8 g, 82.4 mmol), triphenylphosphine (32.42 g, 123.6 mmol) and imidazole (8.41 g, 123.6 mmol) in 515 mL anhydrous CH2Cl2 under N2 at 0° C. was added iodine over 15 min portionwise. The ice bath was removed and the reaction was allowed to warm to room temperature and stirred over 30 minutes. The reaction was quenched with 200 mL H2O. The aqueous layer was extracted with diethyl ether (2×150 mL). The combined organic layers were washed with sat. aq. Na2SO3 solution (2×25 mL) and brine (25 mL), dried over MgSO4, and concentrated in vacuo. Purification of the residue by silica gel chromatography (Analogix IF280, 5%-50% EtOAc/Hex) afforded the title compound as a white solid (25.34 g, 77%). ESMS [M+H]+=400.4.
Reaction SMILES: C(OC(=O)[CH:7]([C:19]#[N:20])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([O:17][CH3:18])[CH:9]=1)(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O>>[CH3:18][O:17][C:10]1[CH:9]=[C:8]([CH2:7][C:19]#[N:20])[CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15]
Reactant: COc1cc(C(C#N)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
Into a 1-neck round-bottom flask, Cyano-(3-methoxy-4-nitro-phenyl)-acetic acid tert-butyl ester (12.80 g, 43.79 mmol), Methylene chloride (50 g, 600 mmol), and Trifluoroacetic Acid (20 mL, 200 mmol) were added and stirred at room temperature overnight. The solvent was removed under vacuum. The residual TFA was co-evaporated with DCM three times to give brown oil. The reaction was partitioned with saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc as eluant. The collected fractions afforded as a light brown solid. The solid was triturated with Et2O to give (3-Methoxy-4-nitro-phenyl)-acetonitrile as a light yellow solid (5.20 g, 61%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[C:18]3[N:19]=[C:20](Cl)[N:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[O:13])[CH:4]=[CH:3][CH:2]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[NH:34]C(C2C3N=C(ON4C5C=CC=CC=5N=N4)N=CC=3SC=2)=O)C=CC=1.N[C@@H]1CCCC[C@@H]1N>O1CCOCC1.C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[C:18]3[N:19]=[C:20]([NH:24][C@@H:33]4[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:32]4[NH2:34])[N:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[O:13])[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1cccc2cccnc12)c1csc2cnc(On3nnc4ccccc43)nc12
Reactant: O=C(Nc1cccc2cccnc12)c1csc2cnc(Cl)nc12
Agent: N[C@@H]1CCCC[C@@H]1N
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H]1CCCC[C@H]1Nc1ncc2scc(C(=O)Nc3cccc4cccnc34)c2n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of the mixture of 80 mg of 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid quinolin-8-ylamide and 2-(benzotriazol-1-yloxy)-thieno[3,2-d]pyrimidine-7-carboxylic acid quinolin-8-ylamide and 0.17 g (1.41 mmole) of cis-1,2-diaminocyclohexane (from step a) in Dioxane (3 mL) was stirred at 60° C. for overnight. The reaction were cooled down and diluted with CH2Cl2, washed with aqueous Na2CO3, brine, dried over anhydrous Na2SO4, concentrated and purified by flash chromatography (silica gel, 40 g, 0% to 30% MeOH (0.7 N) in CH2Cl2) to 40 mg of 2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid quinolin-8-ylamide as light yellow solid. MH+/Z=419.