Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[N:10]=[C:11](SC)SC.Cl.Cl.[NH2:18][CH2:19][C@@:20]1([OH:27])[C@@H:25]2[CH2:26][N:22]([CH2:23][CH2:24]2)[CH2:21]1>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[NH:10][C:11]1[O:27][C@@:20]2([C@@H:25]3[CH2:26][N:22]([CH2:23][CH2:24]3)[CH2:21]2)[CH2:19][N:18]=1
Reactant: NC[C@]1(O)CN2CC[C@H]1C2
Reactant: CSC(=Nc1nc2cccnc2s1)SC
Agent: Cl
Product: c1cnc2sc(NC3=NC[C@@]4(CN5CC[C@H]4C5)O3)nc2c1
Yield: 67 %

Procedure:
Dimethyl thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate and (3S*,4S*)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloride were reacted according to the method of EXAMPLE 4, STEP D to afford (3R*,4S*)—N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine (87.6 mg, 0.290 mmol, 67% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (br. s., 1H) 8.31 (dd, J=4.77, 1.51 Hz, 1H) 7.90 (dd, J=8.03, 1.51 Hz, 1H) 7.38 (dd, J=8.03, 4.77 Hz, 1H) 4.03 (d, J=10.54 Hz, 1H) 3.81 (d, J=10.54 Hz, 1H) 2.96 (dd, J=13.55, 1.76 Hz, 1H) 2.73-2.88 (m, 3H) 2.61-2.73 (m, 1H) 2.40-2.49 (m, 2H) 1.52-1.70 (m, 1H) 1.25-1.44 (m, 1H). MS(LC/MS) R.T.=0.32; (M+H=302.22).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[S:33][C:34]([CH3:37])=[CH:35][N:36]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>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.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[S:33][C:34]([CH3:37])=[CH:35][N:36]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: Cc1cnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1cnc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3c(c2)ncn3C2CC2)s1
Temperature: 140 °C
Yield: 37.8 %

Procedure:
To a microwave tube equipped with a stifling bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (120 mg, 0.292 mmol), 2-bromo-5-methylthiazole (103.9 mg, 0.584 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.96 mL, 0.96 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (33.7 mg, 0.029 mmol) was added. The tube was sealed and heated in microwave at 140° C. for 15 minutes. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give off-white solids, 42.2 mg (yield 37.8%). 1H NMR (300 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.62 (d, J=1.3 Hz, 1H), 7.60 (broad s, 1H), 7.55 (m, 1H), 7.37 (d, J=1.3 Hz, 1H), 4.79 (p, J=6.0 Hz, 1H), 3.78-3.64 (m, 1H), 3.45-3.35 (m, 1H), 3.24-3.15 (m, 1H), 2.92-2.72 (m, 1H), 2.48 (d, J=1.2 Hz, 3H), 2.42-2.21 (m, 2H), 1.33 (d, J=6.0 Hz, 3H), 1.16-1.07 (m, 2H), 1.06-0.99 (m, 2H) ppm; MS (ESI+) m/z 383.90 (M+H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([N+:15]([O-])=O)[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3]>C(O)(=O)C.C(O)C.[Fe]>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][CH:6]=[C:5]2[O:4][CH2:1][CH:2]=[CH2:3]
Reactant: C=CCOc1ccnc2c([N+](=O)[O-])cccc12
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: C=CCOc1ccnc2c(N)cccc12
Yield: 90.9 %

Procedure:
A mixture of 4-allyloxy-8-nitroquinoline (110 mg) and iron (268 mg) in acetic acid (0.4 ml) and ethanol (1.6 ml) was refluxed for 1 hour. Insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane, and the solution was washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (ethyl acetate-n-hexane) to give 8-amino-4-allyloxyquinoline (87 mg).
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5](Cl)[N:4]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH2:17].C(N(CC)CC)C.C(O)(=O)C>COC(O)C>[NH2:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([NH:17][CH2:16][C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)[N:4]=1
Reactant: NCc1cccs1
Reactant: Nc1nc(O)cc(Cl)n1
Agent: COC(C)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Nc1nc(O)cc(NCc2cccs2)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
2-Amino-6-chloro-4-pyrimidinol, monohydrate (85%, 100 g, 0.5197 mol) was suspended in methoxyethanol (700 ml) and 2-thienylmethylamine (96%, 61.3 g, 0.5197 mol) was added to the suspension. The mixture was heated under reflux for two hours and then 73 ml (d=0.726; 0.52 mol) of triethylamine was added and the refluxing continued for an additional 18 hours. The reaction mixture was poured into ice water (1000 ml), acidified with acetic acid (ph 4.0) and the precipitated solid was filtered, washed, and dried. Yield: 110 g (72.6%). This was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])=[C:4]([F:17])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]([O:25][CH2:26][CH3:27])=[CH2:24])CCC.C(Cl)Cl.C(O)(C(F)(F)F)=O.C(OC=C)=C>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].CCOC(C)=O.CCCCCCC.C1(C)C=CC=CC=1>[CH2:26]([O:25][C:23]([C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])=[C:4]([F:17])[CH:3]=1)=[CH2:24])[CH3:27]
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(Br)cc1F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C=COC=C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C(OCC)c1ccc([C@H](C)N[S@](=O)C(C)(C)C)c(F)c1
Temperature: 100 °C
Yield: 61.6 %

Procedure:
To a microwave vial with stir bar was added (R)—N—((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1 g, 3.10 mmol) followed by the addition of tributyl(1-ethoxyvinyl)stannane (2.24 g, 6.21 mmol), TEA (1.3 mL, 9.31 mmol) and PdCl2(dppf).CH2Cl2 adduct (0.127 g, 0.155 mmol). To the solids was then added toluene (10 mL). Vial capped and heated by microwave irradiation at 100° C. for 30 min. To this reaction mixture was added 1 ml of TFA to try to convert vinyl ether to the ketone which was unsuccessful. Resulting reaction mixture allowed to stir 5 min at room temperature. Reaction mixture was then quenched with a saturated solution of NaHCO3 to pH 8. Aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 40 to 100%) provided (R)—N—((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (0.60 g, 1.91 mmol, 62% yield) as a yellow viscous residue. 1H NMR (400 MHz, CDCl3) δ 1.20 (s, 9H) 1.43 (t, J=6.94 Hz, 3H) 1.56-1.63 (m, 5H) 3.36 (d, J=3.13 Hz, 1H) 3.92 (q, J=6.96 Hz, 2H) 4.23 (br. s., 1H) 4.65 (s, 1H) 4.79-4.91 (m, 1H) 7.30 (s, 2H) 7.40 (d, J=8.02 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>ClCCl>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH2:10][CH2:9]2)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: Cc1nccc(N2CCN(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nccc(N2CCN(C(=O)N3CCN(S(=O)(=O)c4ccc(Cl)cc4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(tert-butoxycarbonyl)-4-(1-(2-methylpyrimidin-4-yl)piperazin-4-ylcarbonyl)piperazine (700 mg) was stirred in dichloromethane (20 ml) and triethylarnine (1.34 ml) and cooled in an ice-bath. 4-chlorobenzenesulphonylchloride (0.56 g) was added and reaction allowed to warm to room temperature and then stirred overnight. The mixture was evaporated and the residue was purified by chromatography on silica gel using in gradient of dichloromethane to 8% methanol in dichloromethane as eluent to give a foam. This was triturated with diethylether to give 1-(4-chlorophenylsulphonyl)-4-[1-(2-methylpyrimidin-4-yl)piperazin-4-ylcarbonyl]piperazine a colourless solid 1.05 g ;m.p. 183-184° C.; NMR (CDCl3): 8.15 (m, 1H), 7.7 (m, 2H), 7.55 (m, 2H), 6.3 (m, 1H), 3.65 (m, 4H), 3.45 (m, 4H), 3.35 (m, 4H), 3.05 (m, 4H), 2.5 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(OC)cc1

Procedure:
A suspension of 300 g of 4-methoxycinnamic acid (J. Chem. Soc., Chem. Comm., 355, (1978)) and 25 ml of concentrated sulfuric acid in 1.7 liters of methanol is heated to reflux for 96 hours. The solution is concentrated, cooled, and filtered to give as a white solid, 4-methoxycinnamic acid methyl ester, mp 85°-86° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][CH:5]([OH:28])[CH2:4]1)[CH3:2].[H-].[Na+].Cl[C:32]1[CH:37]=[N:36][C:35]([C:38]#[N:39])=[CH:34][N:33]=1>CN(C=O)C>[CH2:1]([CH:3]1[CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][CH:5]([O:28][C:32]2[N:33]=[CH:34][C:35]([C:38]#[N:39])=[N:36][CH:37]=2)[CH2:4]1)[CH3:2]
Reactant: CCC1CC(O)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Reactant: N#Cc1cnc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1CC(Oc2cnc(C#N)cn2)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 70.2 %

Procedure:
To 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.098 g, 0.24 mmol, prepared using FF from Preparation #KK.1) in DMF (1 mL) was added NaH (0.012 g, 0.29 mmol, 60% dispersion in mineral oil) portionwise. After about 5 min, 2-chloro-5-cyanopyrazine (0.039 g, 0.28 mmol, ArkPharm) was added. The reaction mixture was heated at about 70° C. for about 2 h. After cooling to ambient temperature, ice water (2 mL) was added and the mixture was extracted with DCM (3×5 mL). The organic layers were combined and the solvents were removed under reduced pressure. The residue was purified using silica gel chromatography (12 g) eluting with a gradient of 20-80% EtOAc in DCM to give 5-(3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile (0.085 g, 69%): LC/MS (Table 1, Method b) Rt=2.84 min; MS m/z: 505 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:12]([CH3:25])=[N:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[C:15]=3[CH3:16])=[CH:9][N:8]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.[CH2:36]([O:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50](B2OC(C)(C)C(C)(C)O2)=[CH:49][C:48]=1[NH:62][S:63]([CH3:66])(=[O:65])=[O:64])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH2:36]([O:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[C:12]([CH3:25])=[N:13][N:14]([CH2:17][C:18]5[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=5)[C:15]=4[CH3:16])=[CH:9][N:8]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=4)(=[O:27])=[O:28])[C:5]3=[N:6][CH:7]=2)=[CH:49][C:48]=1[NH:62][S:63]([CH3:66])(=[O:64])=[O:65])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2ccc(OCCOCc3ccccc3)c(NS(C)(=O)=O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCOCc5ccccc5)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 55.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of step-i of example-14) (150 mg, 0.271 mmol) was coupled with N-(2-(2-(benzyloxy)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (intermediate 28) (242 mg, 0.542 mmol) in sodium carbonate (86 mg, 0.813 mmol) Pd(PPh3)2Cl2 (10 mg, 0.0135 mmol), Toluene/ethanol/water (5/2.5/1 ml) to afford 120 mg (55.8% yield) of the titled compound after purification by column (SiO2-eluted by 30% EA in hexanes). MS: m/z=794.1 (M+1).
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([CH2:17][NH:18][C:19]([CH:21]2[CH:26]3[CH:22]2[CH2:23][NH:24][CH2:25]3)=[O:20])[CH:7]=1)[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[CH3:34][C:35]([CH3:40])([CH3:39])[CH2:36][CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(OCC)(=O)C.CCCCCC>[CH3:34][C:35]([CH3:40])([CH3:39])[CH2:36][CH2:37][N:24]1[CH2:25][CH:26]2[CH:22]([CH:21]2[C:19]([NH:18][CH2:17][C:8]2[CH:7]=[C:6]([CH2:2][CH:3]([CH3:5])[CH3:4])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=2)=[O:20])[CH2:23]1
Reactant: CC(C)(C)CC=O
Reactant: CC(C)Cc1cc(CNC(=O)C2C3CNCC32)nn1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)Cc1cc(CNC(=O)C2C3CN(CCC(C)(C)C)CC32)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
The 6-((5-isobutyl-1-phenyl-1H-pyrazole-3-yl)methylcarbamoyl)-3-azabicyclo[3.1.0]hexane hydrochloride (93.5 mg, 0.249 mmol) prepared in Example 11 and a molecular sieve were dried in vacuum and dissolved in 2 mL of methylene chloride. Then, triethylamine (35 μL, 0.249 mmol) was added dropwise at 0° C. After adding 3,3-dimethylbutyraldehyde (31 μL, 0.249 mmol) dropwise, the mixture was stirred at room temperature for 1 hour. After adding sodium triacetoxyborohydride (159 mg, 0.748 mmol), the mixture was stirred for 2 hours and 30 minutes. The completion of the reaction was confirmed by TLC (hexane:ethyl acetate=1:2). After the reaction was completed, the reaction mixture was diluted with methylene chloride and extracted several times with saturated sodium bicarbonate. The organic layer was dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (CH2Cl2:MeOH=15:1) to obtain 67.3 mg (63.9%) of the target compound.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].[CH3:11][CH:12]([C:17](=O)[CH2:18][CH3:19])[C:13](OC)=[O:14].O>CO.C(O)(=O)C>[CH2:18]([C:17]1[N:10]=[CH:8][N:9]=[C:13]([OH:14])[C:12]=1[CH3:11])[CH3:19]
Reactant: CCC(=O)C(C)C(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCc1ncnc(O)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.5 %

Procedure:
A mixture of 25% sodium methoxide in methanol (24.16 ml, 100 mmol) in methanol was stirred during the addition of formamidine acetate (5.73 g, 55.0 mmol) and methyl 2-methyl-3-oxopentanoate (Intermediate 39, 7.21 g, 50 mmol) and the reaction mixture was stirred at room temperature for 3 hours. Water (20 ml) and acetic acid (20 ml) were then added and the solution was concentrated under reduced pressure removing most of the organic solvent from the reaction mixture which was then washed with brine and extracted with ethyl acetate (×3). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The resulting yellow residue was purified by trituration with ether, the resulting colourless solid was collected, washed with ether and dried to give the title compound as a clear solid (2.8 g);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][N:12]=1)[C:5](O)=[O:6].S(Cl)([Cl:27])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][N:12]=1)[C:5]([Cl:27])=[O:6]
Reactant: CCCCCCCCc1cnc(-c2ccc(C(=O)O)cc2F)nc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCc1cnc(-c2ccc(C(=O)Cl)cc2F)nc1

Procedure:
3-Fluoro-4-(5-n-octylpyrimidine-2-yl)benzoic acid (1.66 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 3-fluoro-4-(5-n-octylpyrimidine-2-yl)benzoic acid chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10](=O)[CH:11]([CH3:23])[C:12](=[O:22])[CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CS(O)(=O)=O>C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][C:12](=[O:22])[C:11]=2[CH3:23])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(C(=O)C(C)C(=O)CC(=O)c2ccccc2)c1
Reactant: Nc1ccccc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Product: CCOc1cccc(-c2c(C)c(=O)cc(-c3ccccc3)n2-c2ccccc2)c1

Procedure:
In 500 ml of xylene were dissolved 15.0 g (0.046 mole) of 1-(3-ethoxyphenyl)-2-methyl-5-phenyl-1,3,5-pentanetrione, 43.0 g (0.47 mole) of aniline and 8.8 g (0.092 mole) of methanesulfonic acid. The reaction mixture was heated under reflux for 30 minutes in a reactor fitted with a Dean-Stark apparatus. After cooling, the reaction mixture was filtered to remove solid matter, followed by removal of the solvent by distillation. The residue was extracted with chloroform and the resultant solution in chloroform (the extract) was washed first with 100 ml of 10% hydrochloric acid and then with 100 ml of a 10% aqueous solution of sodium hydroxide. The chloroform solution was washed further with water and was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was subjected to chromatography on a silica gel column (eluent: ethyl acetate). Upon recrystallization of the resultant crystals from acetone, 5.3 g of 2-(3-ethoxyphenyl)-3-methyl-1,6-diphenyl-4-(1H)-pyridinone having a melting point of 146°-149° C. was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([BH3-])#N>C(O)(=O)C.ClC(Cl)C>[CH2:11]([NH:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1sc(N)c(C#N)c1C
Agent: [BH3-]C#N
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1sc(NCc2ccccc2)c(C#N)c1C
Reaction time: 0.08 h

Procedure:
To a solution of 2-amino-4,5-dimethylthiophene-3-carbonitrile (151 mg, 1.0 mmol) and benzaldehyde (106 mg, 1 mmol) in 15 mL of 4% acetic acid in dichloroethane was added silica supported cyanoborohydride (2.0 g. 2.0 mmol). The reaction was placed in a microwave reactor for 5 minutes at 135° C. Silica supported cyanoborohydride was removed by filtration, and the product was purified by prep HPLC using acetonitrile/water as solvent. MS 243 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:22](Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26].O>C1COCC1>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]([C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NCc1ccc(Br)cc1)C(=O)O
Reactant: CCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)N(Cc1ccc(Br)cc1)[C@H](C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A mixture made up of 5 g (17.47 mmol) of N-(4-bromobenzyl)-L-valine and 5.9 g (70.24 mmol) of sodium bicarbonate in 50 mL of dry THF is left under stirring and under nitrogen atmosphere for one hour. The preceding suspension is cooled to 0° C. and to it is added over a period of 15 min. 4.2 mL (35.41 mmol) of valeroyl chloride. The mixture is then left to react at 20-25° C. for 3 h, 50 mL of water is added and the THF is distilled at low pressure. The resulting solution is taken to pH 2 with HCl 35% and the remains of THF distilled off completely. The solid obtained is filtered, washed with 50 mL of water and dried in a vacuum over to provide 5.9 g (91.2%) of N-(4-bromobenzyl)-N-valeryl-L-valine. The solid is recrystallised from a mixture of EtOH/H2O 2:1. M.p.=123° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[F:29][C:30]([F:37])([F:36])[CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:33]2[CH2:34][CH2:35][CH:31]([C:30]([F:37])([F:36])[F:29])[CH2:32]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: FC(F)(F)C1CCNC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(F)(F)F)C3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 3-(trifluoromethyl)pyrrolidine via General Procedure E to give 19.9 mg of 289 following reverse phase purification. MS (Q1) 501.2 (M)+
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)CCC.Br[C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=1[NH2:22]>>[CH3:27][C:25]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[CH:26]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Cc1ccc(N)c(Br)c1
Product: Cc1ccc(N)c(-c2nccs2)c1
Yield: 7.4 %

Procedure:
2-Tributylstannanyl-thiazole (600 mg, 1.6 mmol) was reacted with 2-bromo-4-methylaniline (220 mg, 1.2 mmol) according to general procedure [B] for the preparation of substituted anilines described above, which gave the title compound (17 mg, 8%). [M+1] 191.