Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:7][CH2:6][C:5]([C:9]([CH3:20])([CH3:19])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([CH3:8])[O:4]1.[CH3:21][C@H:22]1[CH2:27][C@@H:26]([CH3:28])[CH2:25][NH:24][CH2:23]1>CCOCC>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:9]([C:5]2([CH3:8])[O:4][CH:3]([CH2:2][N:24]3[CH2:25][C@H:26]([CH3:28])[CH2:27][C@H:22]([CH3:21])[CH2:23]3)[CH2:7][CH2:6]2)([CH3:20])[CH3:19])=[CH:13][CH:14]=1
Reactant: CC(C)(COc1ccc(Cl)cc1)C1(C)CCC(CBr)O1
Reactant: C[C@@H]1CNC[C@H](C)C1
Solvent: CCOCC
Product: C[C@@H]1C[C@H](C)CN(CC2CCC(C)(C(C)(C)COc3ccc(Cl)cc3)O2)C1
Yield: 45 %

Procedure:
16 g (0.044 mole) of 2-bromomethyl-5-[1-(4-chlorophenoxy)-2-methylprop-2-yl]-5-methyl-tetrahydrofuran are stirred together with 11 g (0.097 mole) of cis-3,5-dimethylpiperidine at a bath temperature of 140° C. for about 14 hours. The resulting reaction mixture is taken up in ether and the mixture is washed several times with water, dried over sodium sulphate and concentrated in vacuo. The oily residue is purified by column chromatography (silica gel 60, ether-petroleum ether 1:1). 7.8 g (45% of theory) of 5-[1-(4-chlorophenoxy)-2-methylprop-2-yl]-2-(cis)-(3,5-dimethylpiperidin-1-ylmethyl)-5-methyl-tetrahydrofuran of refractive index nD20 1.5049 are obtained.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:38]=[CH:37][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:20]2)=[CH:16][CH:15]=1.[O:39]1[CH:43]=[CH:42][C:41]([CH2:44]O)=[CH:40]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C1(C)C=CC=CC=1>[O:39]1[CH:43]=[CH:42][C:41]([CH2:44][O:13][C:14]2[CH:38]=[CH:37][C:17]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:21]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:20]3)=[CH:16][CH:15]=2)=[CH:40]1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: OCc1ccoc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccoc3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A toluene solution (1.04 g) of 40% diethyl azodicarboxylate was added dropwise slowly to a mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (699 mg), 3-furanmethanol (0.172 ml), triphenylphosphine (577 mg) and tetrahydrofuran (20 ml) at room temperature. After the solution was stirred at room temperature overnight, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(3-furylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (385 mg, yield: 45%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:36]2[CH:37]=[CH:38][CH:39]=C[C:35]=2[N:34]=N1.CC1CCCN1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:34]3[CH2:35][CH2:36][CH2:37][CH:38]3[CH3:39])=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CC1CCCN1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CCCN1C(=O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2-methyl-pyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH2:3]1.[NH2:12][C:13]1[CH:14]=[C:15](O)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[ClH:19].[ClH:19].[NH2:12][C:13]1[CH:14]=[C:15]([O:8][CH:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4]3[O:11][CH:10]=[CH:9][C:5]2=3)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: Nc1cc(O)ccc1Cl
Reactant: CN1Cc2occc2C(O)C1
Product: CN1Cc2occc2C(Oc2ccc(Cl)c(N)c2)C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-amino-4-chlorophenol instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)[N:14]=[CH:13]1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)[N:14]=[CH:13]1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(CN4CCOCC4)cc3c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
To a solution of methyl 4-methyl-3-[6-(morpholin-4-ylmethyl)-4-oxoquinazolin-3(4H)-yl]benzoate (0.62 g) in methanol (10 ml) and water (4 ml) was added 2N NaOH (2.35 ml) and stirred at room temperature for 4 hours. 1N HCl was added and the reaction was allowed to stand for 16 hours and then concentrated. The residue was dissolved in methanol (40 ml), inorganics removed by filtration. The filtrate concentrated to give 4-methyl-3-[6-(morpholin-4-ylmethyl)-4-oxoquinazolin-3(4H)-yl]benzoic acid as a solid (0.60 g). Mass Spectrum: M+H+ 380.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.Br[CH2:21][C:22]([NH2:24])=[O:23]>>[C:17]([C:9]1[C:10]([C:13]([F:16])([F:14])[F:15])=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:21][C:22]([NH2:24])=[O:23])[C:4]([CH2:3][CH:2]([CH3:19])[CH3:1])=[CH:12]2)#[N:18]
Reactant: NC(=O)CBr
Reactant: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(N)=O

Procedure:
Synthesized as described in Example 4 using 2-(2-methylpropyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 2-bromoacetamide: 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J=8.5 Hz, 1H), 7.71 (bs, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.34 (bs, 1H), 6.51 (d, J=2.2 Hz, 1H), 4.91 (s, 2H), 2.61 (d, J=7.0 Hz, 2H), 1.95 (m, 1H), 0.92 (d, J=6.6 Hz, 6H); MS (ES) m/z 324 (M+1).
Reaction SMILES: N[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][C@H:8]([NH:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C@H:7]([CH2:35][CH3:36])[CH2:6]1)=[O:4].[C:37]([BH3-])#[N:38].[Na+].[CH3:41]O>>[CH2:35]([C@H:7]1[C@@H:8]([NH:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[CH:17][CH:16]=2)(=[O:13])=[O:14])[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][NH:38][CH2:37][CH3:41])[CH2:6]1)[CH3:36]
Reactant: CC[C@@H]1CN(C(=O)CN)CC[C@@H]1NS(=O)(=O)c1ccc(NC(=O)c2ccccc2C)c2ccccc12
Reactant: CO
Reactant: [BH3-]C#N
Agent: [Na+]
Product: CCNCC(=O)N1CC[C@H](NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3ccccc23)[C@H](CC)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 25° C. solution of (±)-(cis)-N-{4-[1-(2-amino-acetyl)-3-ethyl-piperidin-4-ylsulfamoyl]-naphthalen-1-yl}-2-methyl-benzamide (C-131) (65 mg, 0.128 mmol) in MeOH (4 mL) was added acetyl aldehyde (5.62 mg, 0.128 mmol) and sodium cyanoborohydride (40 mg, 0.64 mmol). After stirring for 2 h at 25° C., the solution was concentrated in vacuo to give a solid. The resultant solid was purified by reverse phase HPLC to provide the title compound. 1H NMR (300 MHz, MeOD) δ 8.85 (d, 1H), 8.33 (d, 1H), 8.25 (d, 1H), 7.94 (d, 1H), 7.71 (m, 3H), 7.43 (m, 1H), 7.35 (m, 2H), 3.55 (m, 5H), 3.20 (m, 2H), 2.85 (m, 2H), 2.56 (s, 3H), 1.25 (m, 7H), 0.50 (m, 3H); LC/MS m/z 537 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:13][CH:14](Cl)[CH3:15])[C:10](=[O:12])[CH3:11].[CH3:17][NH:18][CH3:19].C1C=CC=CC=1>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:13][CH:14]([N:18]([CH3:19])[CH3:17])[CH3:15])[C:10](=[O:12])[CH3:11]
Reactant: CNC
Reactant: CC(=O)N(CC(C)Cl)c1c(C)cccc1C
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)N(CC(C)N(C)C)c1c(C)cccc1C
Temperature: 60 °C
Yield: 90.3 %

Procedure:
A mixture of 3.0 g (12.5 mmoles) of 1-[N-(2,6-dimethylphenyl)-acetamido]-2-chloro-propane and 9.4 ml of a 18 w/v % ethanolic dimethylamine solution is heated at 60° C. for 3 hours in a bomb. The mixture is cooled, admixed with 50 ml of benzene and 10 ml of water, and the organic phase is separated. The aqueous phase is extracted twice with 10 ml of benzene, each. The benzene solutions are combined, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. 2.8 g (90.3%) of 1-[N-(2,6-dimethylphenyl)-acetamido]-2dimethylamino-propane are obtained as a thick, light yellow oil; b.p.: 140°-141° C./120 Pa. The hydrochloride monohydrate of the base melts at 170°-172° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[CH2:11]Br>>[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[CH2:11][N:4]1[CH:5]=[CH:6][C:2]([NH2:1])=[N:3]1
Reactant: Nc1cc[nH]n1
Reactant: Fc1cc(CBr)cc(F)c1F
Product: Nc1ccn(Cc2cc(F)c(F)c(F)c2)n1

Procedure:
Prepared in analogy to example 10a) starting with 3-amino-1H-pyrazole and 3,4,5-trifluorobenzyl bromide. The title compound was obtained as a brown oil (Yield=31%). MS ISP (m/e): 228.2 (100) [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:23])[C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:10][C:9]=2[CH3:24])[CH:5]=[CH:4][N:3]=1.[H][H]>C(O)C.[Pd]>[BrH:1].[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[C:14]([NH:13][C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[CH:2][CH:7]=2)=[C:9]([CH3:24])[N:10]=1)=[O:23]
Reactant: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1ccnc(Br)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Br
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1ccncc1

Procedure:
Into a solution of Compound 27 (21.0 mg, 0.05 mmol) in ethanol (2.0 mL) was added 10% Pd/C (10.0 mg). The mixture was stirred under 1 atmosphere of hydrogen for overnight. The mixture was filtered through a short plug of silica to give Compound 54, 19.4 mg, 92%) as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH3:26][O:27][C:28]1[N:29]=[CH:30][C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)=[N:32][CH:33]=1.NC1C=NC(OC)=CN=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[CH3:26][O:27][C:28]1[N:29]=[CH:30][C:31]([NH:34][C:35]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:36])=[N:32][CH:33]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: COc1cnc(NC(=O)Oc2ccccc2)cn1
Agent: COc1cnc(N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cnc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)cn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A solution of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.371 g, 1.00 mmol) (from Example 1, Step 5) and phenyl 5-methoxypyrazin-2-ylcarbamate (0.254 g, 1.2 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 2-amino-5-methoxypyrazine) in DMSO (2.5 mL) was treated with diisopropylethylamine (0.155 g, 1.2 mmol) and was heated to 60° C. After 4 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated to a white solid. Trituration with diethyl ether provided the title compound as a white solid (365 mg, 75%). MS (APCI 10V) AP+ 486.25; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (t, J=5.46 Hz, 2H) 2.44 (t, J=5.46 Hz, 2H) 3.47 (t, J=5.46 Hz, 2H) 3.54 (t, J=5.46 Hz, 2H) 3.83 (s, 3H) 6.37 (s, 1H) 7.02-7.05 (m, 2H) 7.11 (d, J=7.8 Hz, 1H) 7.21 (d, J=8.57 Hz, 1H) 7.39 (dt, J=7.6 Hz, 2 Hz, 1H) 7.99 (d, J=1.6 Hz, 1H) 8.21 (dd, J=9.2 Hz, 2.7 Hz, 1H) 8.53 (m, 2H) 9.18 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]COC)=[C:14]([O:22][CH3:23])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:8][C:9](=[O:24])[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:22][CH3:23])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1ccc(CNC(=O)OCc2ccccc2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(CNC(=O)OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.6 %

Procedure:
A solution of 13 (0.795 g, 2.4 mmol) in CH2Cl2 (5 mL) was treated with trifluoroacetic acid (2.5 mL) slowly and stirred for 5 min at room temperature. After cooling to 0° C., the reaction mixture was neutralized with saturated NaHCO3 solution, diluted with H2O and extracted with CH2Cl2 several times. The combined organic layer was washed with H2O and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel using EtOAc:Hex (2:1) as eluant to give 14 as white solid (680 mg, 99%).
Reaction SMILES: [CH:1]([NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=2[N+:24]([O-])=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C([O-])=O.[NH4+].C(Cl)Cl>CO.[Pd]>[NH2:24][C:15]1[CH:16]=[CH:17][C:18]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:19][C:14]=1[NH:13][C@@H:10]1[CH2:9][CH2:8][C@H:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:12][CH2:11]1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(S(C)(=O)=O)ccc2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(S(C)(=O)=O)ccc2N)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of cis-N-Isopropyl-4-(5-(methylsulfonyl)-2-nitrophenylamino)cyclohexanecarboxamide (0.120 g, 0.313 mmol) in MeOH (1.2 mL) was added 5% Pd/C (0.067 g, 0.031 mmol) and ammonium formate (0.154 mL, 3.13 mmol) (exotherm). The reaction mixture was stirred at 20° C. for 1 hour and then the mixture was filtered through a pad of Celite® brand filter aid, washing with MeOH. The filtrate was concentrated under vacuum, and the remaining residue was dissolved in DCM then washed with water. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography, eluting with 0-80% 90:10:1 DCM/MeOH/NH4OH:DCM to afford cis-4-(2-amino-5-(methylsulfonyl) phenylamino)-N-isopropylcyclohexanecarboxamide as a pale yellow oil (0.107 g, 97% yield). MS (ESI pos. ion) m/z: 354.2 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[Cl:31][C:32]1[S:33][C:34]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][C:36]=1[Cl:37]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:37][C:36]1[CH:35]=[C:34]([S:38]([NH:1][C:2]2[CH:30]=[CH:29][C:5]3[NH:6][C:7]([C:12]4[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]5[C:20]([C:21]=4[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=5)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=3[CH:3]=2)(=[O:40])=[O:39])[S:33][C:32]=1[Cl:31]
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)s1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4cc(Cl)c(Cl)s4)ccc3N2)c(O)c2cccnc21
Temperature: 100 °C
Yield: 49 %

Procedure:
To the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added 2,3-dichlorothiophene-5-sulfonyl chloride (0.015 g, 0.056 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 15 minutes. The reaction was diluted with ethyl acetate (40 mL), washed with 1 N hydrochloric acid, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 99:1 dichloromethane:methanol to give the title compound (14.8 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.25 Hz, 6 H) 1.56 (m, 2 H) 1.69 (m, 1 H) 4.47 (m, 2 H) 7.50 (m, 2 H) 7.56 (s, 1 H) 7.71 (d, J=8.82 Hz, 1 H) 7.76 (s, 1 H) 8.55 (dd, J=7.91, 2.02 Hz, 1 H) 8.88 (dd, J=4.60, 1.65 Hz, 1 H) 11.28 (s, 1 H) 14.19 (br s, 1 H). MS (ESI−) m/z 640 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9].[CH2:21]([NH2:25])[CH:22]([CH3:24])[CH3:23]>CCOC(C)=O>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:25][CH2:21][CH:22]([CH3:24])[CH3:23])[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=1
Reactant: CC(C)CN
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1Cl
Solvent: CCOC(C)=O
Product: CC(C)CNc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2ccnc12
Temperature: 150 °C
Yield: 85.5 %

Procedure:
In a sealed tube, a mixture of 8-chloro-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (20 mg, 0.062 mmol) and isobutylamine (0.037 mL, 0.37 mmol) was heated at 150° C. for 14 h. The reaction mixture was cooled to RT, poured into AcOEt (5 mL) and washed with a 2.0 M Na2CO3 solution in water (2×2 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→8:2) to yield the title compound (19.1 mg, 0.053 mmol, 85%) as a reddish solid. MS: 359 [M+1]+; HPLC: AtRet=2.61; TLC: RF 0.64 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:15][C:16]1([CH3:19])[O:18][CH2:17]1>CN(C)C=O.O>[CH3:15][C:16]([OH:18])([CH3:19])[CH2:17][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: CC1(C)CO1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc([N+](=O)[O-])n1
Temperature: 100 °C
Yield: 53.4 %

Procedure:
A solution of 3-nitro-1H-pyrazole (Intermediate 2, 200 mg, 1.77 mmol) in N,N-dimethylformamide (5 mL) was treated with potassium carbonate (352 mg, 2.55 mmol) and 1,1-dimethyloxirane (314 mL, 3.54 mmol) and placed in a sealed tube and heated to 100° C. for 1 h. After this time, the reaction was cooled to 25° C., diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were then combined and dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 12 g column, 50-60% ethyl acetate/hexanes) afforded 2-methyl-1-(3-nitro-pyrazol-1-yl)-propan-2-ol (175 mg, 54%) as a clear colorless oil; ES-HRMS m/e calcd for C7H11N3O3 (M+H)+ 186.0873, observed 186.0873. 1H-NMR (300 MHz, CDCl3) δ ppm 1.25 (s, 6H), 2.11 (br s, 1H), 4.18 (s, 2H), 6.92 (d, J=2.4 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[S:14][CH2:13][CH2:12][CH2:11]2.[NH2:16][CH:17]1[CH2:22][O:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:19]=2[CH2:18]1.C(N(CC)CC)C>CN(C)C=O>[CH3:28][O:27][C:26]1[C:19]2[CH2:18][CH:17]([NH:16][CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:15]=3[S:14][CH2:13][CH2:12][CH2:11]4)[CH2:22][O:21][C:20]=2[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cccc2c1CC(N)CO2
Reactant: BrCCCOc1cccc2c1SCCC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc2c1CC(NCCCOc1cccc3c1SCCC3)CO2
Reaction time: 24 h

Procedure:
Under argon, 1.6 g (5.58 mmol) of 8-[(3-bromopropyl)oxy]thiochroman, 1 g (5.58 mmol) of 3-amino-5-methoxy-dihydro-[2H]-benzo[b]pyran and 1.69 g (16.74 mmol) of triethylamine are dissolved in 20 cm3 of dimethylformamide. The mixture is kept at room temperature for 24 hours. The solvent is evaporated off. The residue is taken up in H2O and extracted with methylene chloride. The product is dried over MgSO4. After evaporation, the product is purified over a flash silica column. Eluant: methanol/CH2Cl2 5: 95. The title compound is obtained (yellow oil).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[N:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:38]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:39])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: O=C(Cl)N1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)N5CCCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 68.7 %

Procedure:
Following General Procedure G, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and pyrrolidine-1-carbonyl chloride (25 mL, 0.690 mmol) gave 7-cyclopentyl-2-{5-[4-(pyrrolidine-1-carbonyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (84 mg, 70%). MS (ESI) m/z 532.3 (M+H)+