Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>[F:9][CH:10]([F:19])[O:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([I:1])[CH:17]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(OC(F)F)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(OC(F)F)cc1I
Reaction time: 16 h
Yield: 42 %

Procedure:
To a suspension of N-iodosuccinimide (1.12 g, 0.005 mol) in acetic acid (15.0 mL) was added 4-(difluoromethoxy)phenol (0.8 g, 0.005 mol) under nitrogen. Sulfuric acid (0.147 g, 0.0015 mol) was added and the resulting dark brown suspension was stirred at room temperature for 4 hours before the addition of N-iodosuccinimide (0.6 g, 0.0025 mol). The mixture was stirred for 16 hours before diluting with citric acid (1.0 M aqueous solution, 20.0 mL) and water (20.0 mL). The aqueous layer was extracted with dichloromethane (2×30.0 mL). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to afford a dark purple oil. This was concentrated in vacuo from toluene (3×20.0 mL) to afford a brown oil. The aqueous layer was concentrated in vacuo. Both organic and aqueous crude residues were purified by flash column chromatography on the ISCO™ (40 g SiO2) eluting with ethyl acetate:heptane (gradient 0:1 to 1:1, by volume) to afford the title compound as a yellow oil, 0.604 g, 42% yield.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH:14][CH2:15][C:16]2([CH3:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=1)(=O)=O.[Cl:25][C:26]1[C:27](B(O)O)=[CH:28][C:29]([F:32])=[N:30][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:25][C:26]1[C:27]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH:14][CH2:15][C:16]3([CH3:22])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:8]=2)=[CH:28][C:29]([F:32])=[N:30][CH:31]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: CC1(CNc2nc(OS(=O)(=O)C(F)(F)F)ccc2F)CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC1(CNc2nc(-c3cc(F)ncc3Cl)ccc2F)CCOCC1
Temperature: 102 °C
Reaction time: 0.28 h

Procedure:
A mixture of 5-fluoro-6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)aminopyridin-2-yl trifluoromethanesulfonate (600 mg, 1.611 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (565 mg, 3.22 mmol), PdCl2(dppf)-CH2Cl2 adduct (132 mg, 0.161 mmol) in DME (8 mL) and 2M aqueous Na2CO3 (3 mL, 6.00 mmol) in a sealed tube was heated at 102° C. for 10 hr. The mixture was cooled to ambient temperature and was diluted with EtOAc (˜100 mL) and saturated aqueous NaHCO3 solution. The separated organic layer was washed with saturated aqueous NaHCO3 solution (2×), dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/heptane=0/100 for 3 min, EtOAc/heptane=0/100 to 30/70 over 17 min, then EtOAc/heptane=30/70] providing 5′-chloro-2′,5-difluoro-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine as a colorless oil. Yield: 490 mg. LCMS (m/z): 354.2 [M+H]+; Retention time=1.05 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[CH3:11].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[CH2:11][Br:31]
Reactant: COC(=O)c1cccc(Br)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(Br)c1CBr
Temperature: 90 °C

Procedure:
3-Bromo-2-methyl-benzoic acid methyl ester (2.0 g, 8.73 mmol) is dissolved in carbon tetrachloride (35 mL). The solution is kept under an inert atmosphere by bubbling nitrogen through the mixture while benzoyl peroxide (106 mg, 0.44 mmol) and N-bromosuccinimide (1.55 g, 8.73 mmol) are added. The mixture is purged with vacuum and nitrogen, and is then refluxed at 90° C. for 2 hours. The reaction mixture is cooled to 0° C. and filtered. The filtrate is evaporated to yield the title compound, which is used as such for the next step.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C@H:14]([N:18]1[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:19]1)[CH2:13][CH2:12]2.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=[O:37])=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.C(OCC)C>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:24]2[CH2:23][CH2:22][C:20]3([CH2:19][N:18]([C@H:14]4[C:15]5[C:11](=[CH:10][C:9]([C:4]6[N:5]=[CH:6][CH:7]=[CH:8][N:3]=6)=[CH:17][CH:16]=5)[CH2:12][CH2:13]4)[CH2:21]3)[CH2:26][CH2:25]2)=[O:37])=[CH:31][CH:30]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: c1cnc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)N2CCC3(CC2)CN([C@@H]2CCc4cc(-c5ncccn5)ccc42)C3)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.3 %

Procedure:
A mixture of 2-[(1R)-5-pyrimidin-2-yl-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane dihydrochloride (3-1e, 600 mg, 1.40 mmol), p-methoxyphenylacetic acid (232 mg, 1.40 mmol), HBTU (529 mg, 1.40 mmol) and triethylamine (1.2 mL, 8.6 mmol) in 5 mL of DMF was stirred at room temperature for 20 hours. The solvent was removed in vacuo, the residue was azeotroped with toluene and partitioned between 1N NaOH (50 mL) and ethyl acetate (50 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified on an Analogix (Analogix Inc., Burlington, Wis.) 24 g silica column (1-15% MeOH in DCM in 30 minutes) to give the product as a light foam. This solid was stirred with diethyl ether (80 mL) for 18 h and filtered to give the title compound as a light grey solid (540 mg, 82%). MS (ES+) 469.5 (M+H)+ 1H NMR (CDCl3) δ 1.52-1.58 (m, 2H), 1.65-1.72 (m, 2H), 1.87-1.95 (m, 1H), 2.12-2.21 (m, 1H), 2.82-2.90 (m, 1H), 3.02-3.15 (m, 5H), 3.33 (t, 2H), 3.52 (t, 2H), 3.65 (s, 2H), 3.78 (s, 3H), 3.94-3.97 (m, 1H), 6.82-6.87 (m, 2H), 7.12-7.17 (m, 3H), 7.35 (d, 1H), 8.24 (d, 1H), 8.28 (s, 1H), 8.78 (d, 2H). [α]D20=+43.2 deg (c=8 mg/mL, MeOH).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][CH:25]([CH2:34][OH:35])[CH2:26][NH:27][C:28]1[CH2:32][S:31][C:30](=[O:33])[N:29]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:32]2/[C:28]([NH:27][CH2:26][CH:25]([OH:24])[CH2:34][OH:35])=[N:29][C:30](=[O:33])[S:31]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(NCC(O)CO)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NCC(O)CO)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.86 g) in 2-propanol (20 mL) were added 4-[(2,3-dihydroxypropyl)amino]-1,3-thiazol-2(5H)-one (1.56 g) and piperidinium acetate (0.794 g). The reaction mixture was stirred at 80° C. for 1 hr, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and recrystallized from ethyl acetate/heptane to give the title compound (1.22 g).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:27])[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[N:14][N:15]2[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)(C)(C)C.[ClH:29]>ClCCl>[NH2:7][CH2:8][C:9]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[N:14][N:15]2[CH2:20][CH2:21][N:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1)=[O:27].[ClH:29]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cccc2c1cnn2CCN1CCCC1
Agent: Cl
Solvent: ClCCl
Product: NCC(=O)Nc1cccc2c1cnn2CCN1CCCC1
Reaction time: 3 h

Procedure:
{[1-(2-Pyrrolidin-1-yl-ethyl)-1H-indazol-4-ylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (1.00 g, 2.58 mmol) and a solution of HCl (5 mL, 4M in dioxane) was in dichloromethane (30 mL) was stirred for 3 hours. The mixture was filtered and rinsed with dichloromethane to provide the title compound as the bis-HCl salt. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.78–2.00 (m, 4H), 2.88–3.00 (m, 2H), 3.45 (m, 2H), 3.67 (m, 2H), 4.09 (m, 2H), 4.85 (t, 2H, J=6.45), 7.40–7.77 (m, 3H), 8.30 (s, 3H), 8.59 (s, 1H), 10.9 (s, 1H), 11.11 (s, 1H); MS (DCI/NH3) m/z 288 [M+H]+.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)#[N:5].CCN(C(C)C)C(C)C>C(O)C>[OH:3][NH:2][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[NH:5]
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(C#N)CC2)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(C(=N)NO)CC2)cc1
Reaction time: 2 h

Procedure:
256.4 mg (3.69 mmol) Hydroxylamine hydrochloride are added to a mixture of 1.0 g (3.69 mmol) (S)-N-{1-[4-(1-cyano-piperidin-4-yl)-phenyl]ethyl}-acetamide (XXVII.1) and 0.63 mL (3.69 mmol) DIPEA in 20 mL ethanol. The mixture is refluxed for 4 h, an additional amount of 50 mg hydroxylamine hydrochloride is added and refluxing is continued for 2 h. The solvent is removed in vacuo and water is added. The mixture is then purified by HPLC (RP C18 Xbridge, water (+0.1% ammonia)/MeOH) to yield the desired product.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)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>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1
Reactant: OB(O)c1cccs1
Reactant: COC(=O)c1ccc(Br)o1
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: [Na+]
Product: COC(=O)c1ccc(-c2cccs2)o1
Reaction time: 26 h
Yield: 90.8 %

Procedure:
Methyl 5-bromofuran-2-carboxylate (150 mg, 0.73 mmol), Pd(PPh3)4 (42 mg, 0.04 mmol), 2M Na2CO3 (0.73 ml, 1.46 mmol) and thiophen-2-ylboronic acid (121 mg, 0.95 mmol) in 1,4-dioxanes (7 ml) and was warmed to 90° C. The solution was then held at this temperature for 26 hours then cooled and washed with 1M HCl (2×20 mL), brine (2×20 mL) then dried (MgSO4) followed by filtration and evaporation to dryness. The resulting residue was then purified by flash column chromatography (5% EtOAc/hexanes) to obtain methyl 5-(thiophen-2-yl)furan-2-carboxylate (138 mg, 91%) as a yellow oil. 1H NMR (500 MHz, DMSO-d6) δ 7.69 (dt, J=5.0, 0.9 Hz, 1H), 7.59 (dt, J=3.6, 0.8 Hz, 1H), 7.40 (dd, J=3.7, 0.6 Hz, 1H), 7.23-7.15 (m, 1H), 6.99 (d, J=3.7 Hz, 1H), 3.83 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 158.1, 152.5, 142.3, 131.2, 128.5, 127.7, 125.8, 120.7, 107.5, 51.8; HRMS (ESI) calcd for [C10H8O3S+H]+ 209.0267. found 209.0272. Method D with methyl 5-(thiophen-2-yl)furan-2-carboxylate (100 mg, 0.48 mmol) afforded 5-(thiophen-2-yl)furan-2-carboxylic acid (92 mg, 99%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.16 (bs, 1H), 7.68 (dd, J=5.0, 1.1 Hz, 1H), 7.56 (dd, J=3.6, 1.1 Hz, 1H), 7.30 (d, J=3.6 Hz, 1H), 7.18 (dd, J=5.0, 3.7 Hz, 1H), 6.95 (d, J=3.6 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 159.1, 152.0, 143.5, 131.5, 128.5, 127.4, 125.5, 120.0, 107.4; HRMS (ESI) calcd for [C9H6O3S+H]+ 195.0110. found 195.0112. Method B with 5-(thiophen-2-yl)furan-2-carboxylic acid (75 mg, 0.39 mmol) afforded the title compound VPC16b1145 (46 mg, 37%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.69 (bs, 1H), 8.72 (s, 1H), 7.81 (d, J=3.8 Hz, 1H), 7.73 (t, J=4.4 Hz, 2H), 7.22 (dd, J=4.9, 3.7 Hz, 1H), 7.07 (d, J=3.8 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 162.2, 156.0, 153.2, 143.2, 142.5, 141.9, 131.1, 128.4, 128.1, 126.5, 120.7, 107.8; HRMS (ESI) calcd for [C12H7N3O4S2+H]+ 321.9951. found 321.9963.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:30])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:38]1([CH2:41][NH:42][CH2:43][CH2:44][CH3:45])[CH2:40][CH2:39]1>C(O)C>[CH:38]1([CH2:41][N:42]([CH2:43][CH2:44][CH3:45])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:19])=[O:18])=[CH:13][C:12]=3[CH3:30])=[O:9])[CH:3]=2)[CH2:40][CH2:39]1
Reactant: CCCNCC1CC1
Reactant: Cc1cc(S(=O)(=O)NCCC(=O)OC(C)(C)C)ccc1NC(=O)c1cc(Cl)ncn1
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NCCC(=O)OC(C)(C)C)cc2C)ncn1
Temperature: 160 °C

Procedure:
A solution of tert-butyl 3-(4-(6-chloropyrimidine-4-carboxamido)-3-methylphenylsulfonamido)propanoate (Intermediate 34, 140 mg; 0.31 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in ethanol (4 ml) was treated with N-(cyclopropylmethyl)propan-1-amine (45.3 mg; 0.4 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and then filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give tert-butyl 3-(4-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)propanoate which was used directly without any further purification. The residue was redissolved in DCM (4.5 ml) and treated with TFA (0.5 ml). After stirring at RT for 2 hours the solvent was removed in vacuo to give the title compound as an off-white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:12]3[S:17][C:16]([CH2:18][N:19]4[CH2:24][CH2:23][N:22](S(C)(=O)=O)[CH2:21][CH2:20]4)=[CH:15][C:13]=3[N:14]=2)=[CH:5][N:4]=1.[C:35](Cl)(=[O:37])[CH3:36].CCN(CC)CC.O.C(Cl)Cl>C(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:12]3[S:17][C:16]([CH2:18][N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:15][C:13]=3[N:14]=2)=[CH:5][N:4]=1)[C:35](=[O:37])[CH3:36]
Reactant: CNc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N(C)c1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1
Yield: 28 %

Procedure:
N-methyl-5-(4-morpholino-6-((4-N-methylsulfonylpiperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyridin-2-amine 195 (1 eq.) was stirred with acetyl chloride (1 eq.) and NEt3 (1 eq.) in dry CH2Cl2 (10 mL) at R.T. overnight. Water/CH2Cl2 work up then purification on silica yielded 196 (28%). NMR (CDCl3): 2.17 (s, 3H, CH3), 2.69-2.70 (m, 4H, 2×CH2), 2.81 (s, 3H, CH3), 3.31 (m, 4H, 2×CH2), 3.44 (s, 3H, CH3), 3.88-3.90 (m, 6H, 3×CH2), 4.04-4.07 (m, 4H, 2×CH2), 7.33 (s, H, ArH), 7.39 (m, H, ArH), 8.70 (dd, H, ArH, J=6.08 Hz, 2.3 Hz), 9.47 (d, H, ArH, J=2.12 Hz). MS: (ESI+): MH+ 546.34
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][N:4]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:17].[Na+]>>[NH2:17][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: COc1ncccc1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Product: COc1ncccc1CN
Reaction time: 48 h
Yield: 69.9 %

Procedure:
A round bottom flask was charged with 0.44 g (3.23 mM) of 2-methoxy-3-pyridine carboxaldehyde (24), 1.24 g (16.15 mM) of ammonium acetate, and 0.61 g (19.69 mM) of sodium cyanoborohydride. The flask was then flushed with argon, and then 50 mL of dry MeOH was added by syringe. The reaction was stirred for 2 days, at which point the MeOH was evaporated off 25 mL of water was added, and the mixture was brought to pH 2 with conc. HCl. This was extracted twice with EtOAc to remove the alcohol side product. The mixture was brought to pH 10 using sodium hydroxide pellets, saturated with NaCl, and extracted twice with DCM and once with EtOAc. The combined organics were dried and evaporated to give 0.31 g (69%) of 3-aminomethyl-2-methoxypyridine (25).
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>ClCCl>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([NH:4][CH2:3][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])([CH3:18])[CH3:17])=[CH:6][C:7]=1[C:13]([F:14])([F:15])[F:16])#[N:10]
Reactant: CC(C)(N)CNc1ccc(C#N)c(C(F)(F)F)c1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: CC(C)(CNc1ccc(C#N)c(C(F)(F)F)c1)NC(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(2-Amino-2-methylpropylamino)-2-trifluoromethylbenzonitrile was dissolved in 60 ml of dichloromethane, 0.49 ml of 4-fluorophenyl isocyanate was added dropwise to the solution and then the mixture was stirred at room temperature for 1 hour. The thus precipitated crystals were collected by filtration, washed with dichloromethane and then dried to obtain 1.30 g of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH3:21][C:22]1[C:31]2[C:26](=[C:27]([OH:32])[CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O1CCCC1>[CH2:21]([C:22]1[C:31]2[C:26](=[C:27]([OH:32])[CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: Cc1ccnc2c(O)cccc12
Reactant: CCCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCCc1ccnc2c(O)cccc12
Temperature: 0 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
To a solution of 1.10 ml (7.88 mmol) of diisopropylamine in 20 ml of tetrahydrofuran at 0° C. under argon was added 4.1 ml (6.23 mmol) of 1.52M n-butyl lithium in hexanes dropwise. To the lithium diisopropylamide solution was added 502.0 mg (3.15 mmol) of 4-methyl-8-quinolinol (see example 1A) in 10 ml of tetrahydrofuran over 15 minutes at 0° C. The dark solution, which contained some insoluble material, was allowed to stir for five hours at 0° C., cooled to -78° C. and 0.46 ml (3.31 mmol) of 1-bromohexane was added. After 30 minutes at -78° C., the reaction was allowed to warm gradually from -30° C. to room temperature over 1.5 hours. The solution was allowed to stir for 45 minutes at room temperature, quenched with pH 6.5 phosphate buffer and extracted with ether. The ether extract was washed with water and brine, dried (magnesium sulfate) and evaporated to afford 757 mg of a yellow-brown solid. This material was dissolved in hot hexane, filtered to remove an insoluble residue and the filtrate was evaporated. Recrystallization from heptane provided 511.7 mg of the title compound as yellow plates: melting point 92°-93.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:23][O:24][CH2:25][CH2:26][N:27]([CH3:28])[C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)=[CH:4][N:3]=1
Reactant: CC(=O)NC(C)Cc1ccc(C#Cc2cnc(Cl)nc2)cc1
Reactant: CNCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COCCN(C)c1ncc(C#Cc2ccc(CC(C)NC(C)=O)cc2)cn1
Temperature: 25 °C

Procedure:
28.2 mg (0.09 mmol) N-(1-(4-((2-chloropyrimidin-5-yl)ethynyl)phenyl)propan-2-yl)-acetamide (I69.1) in 1.5 mL DMSO are added to 12.0 mg (0.14 mmol) N-(2-methoxyethyl)-methylamine followed by 21.8 μl (0.14 mmol) DIPEA. The reaction mixture is stirred at r.t. over night and is directly purified by HPLC (MeOH/H2O/TFA).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].CC[O:36][C:37]([CH3:39])=[O:38]>>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:6]2[CH:7]=[CH:11][CH:10]=[CH:9][C:39]=2[C:37]([OH:36])=[O:38])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CCOC(C)=O
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)[C@H](Cc1ccc(Oc2ccccc2C(=O)O)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.08 h

Procedure:
N-(Toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester (2.14 g, 5.16 mmol) was added to a suspension of sodium hydride (60% in oil, 1.1 eq, 228 mg) in xylenes (50 mL) at 0° C. The reaction mixture was stirred for 5 minutes and cuprous bromideodimethyl sulfide complex (1.4 eq, 1.48 g) was added. The reaction mixture was stirred at 23° C. for 0.5 hours. 2-Iodo sodium benzoate (1.5 eq, 8.06 mmol) was added and the reaction mixture was refluxed for 12 hours. EtOAc (100 mL) was added, and the organic layer washed with NH4Cl, 10% HCl, and brine, dried over MgSO4. The crude material was eluted on column chromatography (silica gel), with CHCl3:MeOH 9:1, and the title compound was isolated as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[C:20]1C=CC=C[CH:21]=1.[Na]>C(O)C>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][CH2:20][CH3:21])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)c1ccccc1
Reactant: O=c1[nH]cnc2cc(O)ccc12
Agent: [Na]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CCOc1ncnc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-hydroxyquinazolin-4-one (105 mg, 648 μmol), phosphorous oxychloride (2 ml), and dimethylaniline (85 μl, 671 μmol) was heated at reflux for 15 minutes in an argon atmosphere. The cooled mixture was concentrated under vacuum, and kept in an argon atmosphere to avoid hydrolysis. This residue was dissolved in ethanol (anhydrous, 3 mL), and a solution of sodium (283 mg, 12.34 mmol) in ethanol (3 ml) was added dropwise. The resulting yellow mixture was stirred at room temperature under argon for 2 hours, acidified to pH 6 using NaH2PO4 and extracted with ethyl acetate (3×50 mL). The combined extracts were dried (MgSO4), filtered and concentrated. The white solid (156 mg) was used without further purification.