Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O>C(O)C>[C:12]1([C:10]2[N:1]=[C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ncccn1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Product: c1ccc(-c2cn3cccnc3n2)cc1
Yield: 102.4 %

Procedure:
A mixture of 9.5 g of 2-aminopyrimidine (0.1 mole), 20 g of ω-bromoacetophenone (0.1 mole) and 200 ml of 95% ethanol is refluxed for three hours and then heated at 60° for an additional 12 hours with stirring. After cooling, the reaction product is condensed to a thick liquid by evaporating it in a rotary evaporator. The residue is mixed with 500 ml of methylene chloride and 100 ml of 3 N sodiumhydroxide solution. The mixture is stirred for 10 minutes and then separated in two layers in a separatory funnel. The lower layer (solvent) is collected, washed with 100 ml of water and then evaporated to dryness under reduced pressure. The residue is washed with 2-propanol on a glass filter and dried in vacuum to yield about 20 g of 2-phenylimidazo(1,2-a)pyrimidine, m.p. 200° to 202° C.
Reaction SMILES: [Br-].Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:13][N+:14]([CH2:19][CH3:20])([CH2:17][CH3:18])CC)[N:6]=[CH:5][N:4]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([NH2:35])=[CH:32][CH:33]=2)[CH:28]=[N:27]1.N1CC[CH:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])CC1>CC#N>[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([NH:35][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[CH2:13][N:14]4[CH2:17][CH2:18][CH:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:20][CH2:19]4)[N:6]=[CH:5][N:4]=3)=[CH:32][CH:33]=2)[CH:28]=[N:27]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Reactant: CC[N+](CC)(CC)Cc1cccc2ncnc(Cl)c12
Agent: [Br-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(Cc2cccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Temperature: 55 °C
Yield: 26.3 %

Procedure:
A mixture of 14A (120 mg, 0.34 mmol) and 1-(3-fluorobenzyl)-1H-indazole-5-amine (81.0 mg, 0.34 mmol; prepared as described in US 2003/0186983 A1) in CH3CN (1.2 ml) was heated at 55° C. for 45 min. After cooling to rt, tert-butyl piperidin-4-ylcarbamate (672 mg, 3.34 mmol) was added and the mixture was heated at 60° C. for 16 h. After cooling to rt. this mixture was then diluted with CH3CN (2.4 mL), and heated at 70° C. for 4 h and at 80° C. for 4 d. The reaction mixture was concentrated in vacuo and the residue was purified by prep HPLC to give 21A (52 mg, 27%). It has an analytical HPLC retention time=2.86 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4 over 4 minutes, 4 mL/min, monitoring at 220 nm) and a LC/MS M++H=582+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[C:16]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:25]3[O:24][CH:28]=[CH:27][CH:26]=3)=[CH:3][CH:4]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Oc1ccc(C(=C2CCCCCCC2)c2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(C(=C2CCCCCCC2)c2ccc(-c3ccco3)cc2)cc1
Yield: 76 %

Procedure:
The procedure described for 202 was employed. A round-boltomed flask was charged with 4-[(4-bromophenyl)(cyclooctylidene)methyl]phenol (49) (0.150 g, 0.404 mmol), PdCl2(PPh3)2, (0.028 g, 0.40 mmol), 2-furanylboronic acid (0.090 g, 0.80 mmol), Na2CO3 (0.086 g, 0.808 mmol), and THF/H2O (4:1, 5 mL). The reaction mixture was refluxed for 10 h. Standard workup and purification by flash silica gel chromatography provided 110 mg (76%) of the title compound 203 as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.27 (s, 1H), 7.70 (d, J=0.9 Hz, 1H), 7.59 (d, J=6.0 Hz, 2H), 7.15 (d, J=6.3 Hz, 2H), 6.94 (d, J=6.6 Hz, 2H), 6.86 (d, J=2.4 Hz, 1H), 6.67 (d, J=6.3 Hz, 1H), 6.55 and 6.54 (dd, J1=2.4 Hz, J2=1.2 Hz, 1H), 2.48-2.47 (m, 4H), 1.60 (br s, 2H), 1.50-1.45 (m, 8H), 2.37 (br s, 4H), 1.62 (br s, 8H). LCMS (ESI): m/z 357 (M−H)−.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[N+:18]([O-])=O.S.[Na]>C(O)(=O)C.O>[CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[NH2:18]
Reactant: CC(C)CNc1c([N+](=O)[O-])c2nnnn2c2cnccc12
Agent: S
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CNc1c(N)c2nnnn2c2cnccc12
Yield: 90.8 %

Procedure:
N5-(2-Methylpropyl)-4-nitrotetrazolo[1,5-a][1,7]naphthyridin-5-amine (1.5 g, 5.22 mmol) was suspended in acetic acid (75 mL). An excess of sodium hydrogen sulfide was dissolved in a minimum of water and added to the suspension. The reaction mixture turned red and all of the material went into solution. The reaction mixture was extracted twice with dichloromethane (150 mL). The extracts were combined, washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum to provide 1.22 g of N5-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine as a light yellow solid, m.p. 203-204.5° C. Analysis: Calculated for: C12H15N7: % C, 56.02; % H, 5.88; % N, 38.11; Found: % C, 55.68; % H, 5.81; % N, 37.74.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[N:19]=[C:18](Cl)[N:17]=[C:16]4[C:12]=3[N:13]=[CH:14][N:15]4[CH2:21][CH3:22])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[N:19]=[C:18]([N:25]4[C:24]([CH3:23])=[CH:28][C:27]([CH3:29])=[N:26]4)[N:17]=[C:16]4[C:12]=3[N:13]=[CH:14][N:15]4[CH2:21][CH3:22])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCn1cnc2c(Nc3ccc4c(c3)OCO4)nc(Cl)nc21
Reactant: Cc1cc(C)[nH]n1
Product: CCn1cnc2c(Nc3ccc4c(c3)OCO4)nc(-n3nc(C)cc3C)nc21

Procedure:
Was prepared according to Example 6 from benzo[1,3]dioxol-5-yl-(2-chloro-9-ethyl-9H-purin-6-yl)-amine and 3,5-dimethylpyrazole.
Reaction SMILES: [N:1]1([C:5](=[O:26])[CH2:6][C:7]2[CH:24]=[CH:23][C:10]([O:11][CH2:12][CH2:13][C@@H:14]3[CH2:16][C@@H:15]3[CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:9][C:8]=2[F:25])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:34](=O)([O:40]N1C(=O)CCC1=O)[O:35][CH2:36][CH:37]1[CH2:39][CH2:38]1>ClCCl.[NH4+].[Cl-]>[CH:37]1([CH2:36][O:35][C:34]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][O:11][C:10]3[CH:23]=[CH:24][C:7]([CH2:6][C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)=[O:26])=[C:8]([F:25])[CH:9]=3)[CH2:22][CH2:21]2)=[O:40])[CH2:39][CH2:38]1
Reactant: O=C(OCC1CC1)ON1C(=O)CCC1=O
Reactant: O=C(Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)cc1F)N1CCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCC3CC3)CC2)cc1F)N1CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-((1R,2S)-2-{2-[4-(2-azetidin-1-yl-2-oxoethyl)-3-fluorophenoxy]ethyl)cyclopropyl)piperidine (Step B, Example 11; 0.30 g, 0.93 mmol) in dichloromethane (4.6 mL) under a nitrogen atmosphere was added triethylamine (0.36 mL, 2.6 mmol) and cyclopropylmethyl 2,5-dioxopyrrolidin-1-yl carbonate (0.35 g, 1.67 mmol). The resulting solution was stirred for 18 h at ambient temperature. The solution was diluted with saturated NH4Cl(aq.) (10 mL). The resulting layers were separated and the aqueous phase extracted with dichloromethane (2×30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the obtained residue by CombiFlash chromatography (12 g silica gel, 0 to 25% EtOAc in heptane) provided the title compound as an off white semi-solid. LC/MS (m/z): 459.3 (M+H)+. GPR119 Human EC50: 2.0 nM.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[C:15]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>CCOCC.C1(C)C=CC=CC=1>[C:15]1([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: c1ccc2occc2c1
Reactant: O=C1CCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C1=C(c2cc3ccccc3o2)CCC1

Procedure:
Benzofuran was treated with butyllithium in ether followed by cyclopentanone. The resulting alcohol was dehydrated with toluenesulfonic acid in toluene to afford 2-cyclopenten-1-ylbenzofuran. Treatment with maleimide gave a cycloadduct which was aromatized by treatment with tetrachloroquinone. 1H NMR (DMSO-d6) δ 11.29 (s, 1H), 8.60 (d, 1H), 7.82 (d, 1H), 7.66 (t, 1H), 7.52 (t, 1H), 3.23 (m, 4H), 2.30 (quintet, 2H). MS m/e 276 (M−H)−.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:14]([N:21]1[CH2:11][C:5]2[C:4](=[CH:9][C:8]([F:10])=[CH:7][CH:6]=2)[C:3]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(F)ccc1CBr
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2cc(F)ccc2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A mixture of 2-bromomethyl-5-fluoro-benzoic acid methyl ester (0.094 g, 0.5 mmol), benzylamine (0.076 mL, 0.7 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-6-fluoro-2,3-dihydro-isoindol-1-one (0.085 g, 70.7%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.24 (s, 2H), 4.79 (s, 2H), 7.18-7.39 (m, 7H), 7.55 (m, 1H). GC-MS: m/z 241 (M)+, 164 (M−77)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:6][CH:5]=1.O=[CH:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>C(O)CCC.C(OCC)(=O)C>[C:25]([O:24][C:23](=[O:29])[NH:22][CH2:21][CH:20]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH2:11][CH2:10][N:9]1[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:18][CH:17]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: COc1ccc(CNCCc2ccsc2)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CCc3ccsc3C2CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 44.4 %

Procedure:
A solution of 4.11-A (5.6 g, 19.7 mmol) and t-butyl (2-oxoethyl)carbamate (12.6 g, 78.9 mmol) in butanol (118 mL) was heated to 140° C. for 16 h in a reaction vessel equiped with a Dean-Stark trap. The reaction mixture was cooled to 25° C. and diluted with ethyl acetate. The starting material 4.11-A precipitates as a white solid which was collected. The ethyl acetate filtrate was washed with saturated sodium bicarbonate (2×100 mL) and brine (100 mL), dried with Na2SO4, filtered, and concentrated to give a crude oil which was purified using flash column chromatography (100% hexane →30% EtOAc/hexane) to yield 4.11-B as an amber oil (3.4 g, 44%). 1H NMR (500 MHz, CDCl3): δ 7.26–7.25 (m, 2H), 7.18 (d, J=4.9 Hz, 1H), 6.88–6.85 (m, 2H), 6.81 (d, J=4.9 Hz, 1H), 5.05–5.00 (M, 1H), 3.81 (s, 3H), 3.80–3.78 (m, 1H), 3.72–3.64 (m, 2H), 3.57–3.53 (m, 1H), 3.20–3.15 (m, 1H), 3.15–3.08 (m, 1H), 2.90–2.78 (m, 2H), 2.48–2.45 (m, 1H), 1.42 (s, 9H); LCMS found for C21H29N2O3S (M+H)+: m/z=389.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C@H:11]([S:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][C@H:9]2[CH2:33][O:34][CH2:35][C:36]2[CH:41]=[C:40]([F:42])[C:39](F)=[CH:38][C:37]=2[F:44])[CH:5]=[CH:4][N:3]=1.[CH3:45][OH:46].[H-].[Na+].CN([CH:52]=[O:53])C>>[F:44][C:37]1[CH:38]=[C:39]([O:53][CH3:52])[C:40]([F:42])=[CH:41][C:36]=1[CH2:35][O:34][CH2:33][C@@H:9]1[CH2:10][C@@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][N:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:46][CH3:45])[N:7]=1
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2c2ccnc(Cl)n2)cc1F
Reactant: CO
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1nccc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COCc2cc(F)c(OC)cc2F)n1
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of 0.24 (0.4 mmol) (2S,4R)-2-Chloro-4-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine in 8 ml DMF was treated at 0° C. with 0.05 ml (1.2 mmol) MeOH and 0.054 g (1.24 mmol) 55% NaH. The reaction was kept at this temperature (6 h) and warmed up over night to RT. After extraction with aqueous saturated NH4Cl/Et2O (3×), the organic phases were washed with aq. 10% NaCl, dried (Na2SO4) and evaporated. Flash chromatography (CH2Cl2 EtOAc 95:5) gave 0.14 g (54%) (2S,4R)-4-[2-(2,5-Difluoro-4-methoxy-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-2-methoxy-pyrimidine, MS: 640 (MH+). TFA/triisopropylsilane deprotection, (see General method for S-deprotection, Method D) gave (3R,5S)-5-(2,5-Difluoro-4-methoxy-benzyloxymethyl)-1-(2-methoxy-pyrimidin-4-yl)-pyrrolidine-3-thiol, MS: 398 (MH+).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[CH2:31][C@H:32](O)[CH2:33][C@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:37]([N:40](C(C)C)[CH2:41][CH3:42])(C)[CH3:38].CS(Cl)(=O)=[O:48]>C(OCC)(=O)C>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[CH2:31][C@@H:32]([N:40]4[CH2:41][CH2:42][O:48][CH2:38][CH2:37]4)[CH2:33][C@H:17]3[CH2:16]2)=[O:14])[CH:4]=[C:3]([C:2]([F:35])([F:1])[F:36])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@@H]2C[C@@H](O)CN2C[C@H]1Cc1c[nH]c2ccccc12
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@@H]2C[C@H](N3CCOCC3)CN2C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,5-bis(trifluoromethyl)phenyl-[(3R,7R,8aS)-7-hydroxy-3-(1H-indol-3-ylmethyl)hexahydropyrrolo[1,2-a]pyrazin-2-yl]-methanone (0.54 g) in ethyl acetate (20 mL) was added diisopropylethylamine (2 mL) and methanesulfonyl chloride (0.2 mL). The resulting mixture was stirred overnight at room temperature and concentrated in vacuo. To the residue was added morpholine (4 mL) and the mixture was heated at 95° C. for 4 hours. The excess morpholine was removed in vacuo and the residue purified by preparative HPLC to afford 3,5-bis(trifluoromethyl)phenyl-[(3R,7S,8aS)-3-(1H-indol-3-ylmethyl)-7-(morpholin-4-yl)-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl]-methanone (81 mg). MH+ 581 (compound 6).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C([Li])CCC.[CH3:17][C:18]1([CH3:28])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]([CH:26]=[O:27])=[CH:19]1>O1CCCC1>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:26]([C:20]3[C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23][C:18]([CH3:28])([CH3:17])[CH:19]=3)[OH:27])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC1(C)C=C(C=O)C(C)(C)CC1
Reactant: Brc1ccc2cnccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)C=C(C(O)c2ccc3cnccc3c2)C(C)(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
A solution of 6-bromoisoquinoline (416 mg, 2 mmol) in tetrahydrofuran (8 mL) was added dropwise into n-butyl lithium (1.6 M in hexane, 1.25 mL, 2 mmol) at −78° C. and the reaction was stirred for 30 minutes. A solution of the product of Example 10g (150 mg, 1 mmol) in tetrahydrofuran (2 mL) was added and the reaction was stirred at −78° C. for 1 hour and then slowly warmed to room temperature. The mixture was quenched with the addition of saturated aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (167.3 mg, Yield: 63%). 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.52 (d, J=6.0 Hz, 2H), 7.96 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.4 Hz, 1H), 5.49 (s, 1H), 5.32 (d, J=15.2 Hz, 1H), 1.63-1.44 (m, 4H), 1.21 (s, 3H), 1.01 (s, 3H), 0.97 (s, 3H), 0.91 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26](F)[CH:25]=2)=[CH:4][CH:3]=1.[CH3:31][NH:32][CH3:33]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)=[N:12][N:11]3[C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:32]([CH3:33])[CH3:31])[CH:25]=2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnc(F)c4)n3n2)CC1
Solvent: O
Product: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnc(N(C)C)c4)n3n2)CC1
Temperature: 150 °C

Procedure:
0.10 g (0.25 mmol) of 2-(4-fluorophenyl)-3-(2-fluoropyrid-4-yl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine and 10 mL of dimethylamine are introduced into an autoclave. The mixture is heated at 150° C. overnight and then cooled and poured into water. The product is extracted with chloroform, and the organic phase is dried over sodium sulfate and then concentrated under reduced pressure to give a solid. This solid is crystallized and recrystallized from acetonitrile to give 0.028 g of a white powder after cooling, filtering off and drying.
Reaction SMILES: [O-]Cl=O.[Na+].[CH:5]([C:7]1[N:8]=[C:9]([CH3:12])[NH:10][CH:11]=1)=[O:6].CC(=CC)C.CC([OH:22])(C)C>O.C1COCC1.CCOC(C)=O>[CH3:12][C:9]1[NH:10][CH:11]=[C:7]([C:5]([OH:22])=[O:6])[N:8]=1
Reactant: CC(C)(C)O
Reactant: Cc1nc(C=O)c[nH]1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(C(=O)O)c[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A solution of NaClO2 (2.5 g, 27.5 mmol) and NaH2PO4.H2O (2.3 g, 16.3 mmol) in water (6.1 mL) was added to a solution of 4-formyl-2-methylimidazole (0.30 g, 2.72 mmol), 2-methyl-2-butene (17.0 mL of a 2M solution in THF, 34.0 mmol), tBuOH (2.0 mL), and THF (8.5 mL). The solution was stirred at RT for 3 h. EtOAc (10 mL) was added and the resulting solid was filtered and dried to provide 2-methyl-1H-imidazole-4-carboxylic acid (0.33 g, 97%) as a white solid which was used without further purification. A solution of the above acid (0.035 g, 0.28 mmol) in oxalyl chloride (0.15 mL, 1.67 mmol) was heated under reflux for 1 h and then evaporated to dryness. The residue was stirred with 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.061 g, 0.28 mmol) in CH3CN (3. mL), DMF (1 mL), and DIEA (0.4 mL, 2.3 mmol) at RT overnight. Aqueous Na2CO3 was added, and the solution was extracted with 9:1 CH2Cl2:MeOH. The organic phase was dried (Na2SO4), filtered, and purified by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) to provide the title compound (0.010 g, 7%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (br. s., 1H), 7.93 (s, 1H), 7.83 (t, J=1.47 Hz, 1H), 7.49-7.55 (m, 2H), 7.48 (t, J=2.11 Hz, 1H), 7.39 (t, J=7.97 Hz, 1H), 4.55 (d, J=5.59 Hz, 2H), 2.54 (s, 3H). ES-LCMS: m/z 419.3, 421.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].Br[CH2:11][CH2:12][CH2:13][Cl:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:14][CH2:13][CH2:12][CH2:11][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(CCCCl)C1=O

Procedure:
A mixture of 5,5-dimethylhydantoin (5.25 g), 1-bromo-3-chloropropane (8.5 mL), and Cs2CO3 (20.78 g) in 40 mL DMF was allowed to react overnight. The reaction was poured into 125 mL H2O, extracted with ether, and the combined extracts dried over MgSO4. The crude extract was filtered, then reduced in vacuo to yield a clear oil. The residue was chromatographed (50% EtOAc in hexanes) to yield 3-(3-chloropropyl)-5,5-dimethylimidazolidinedione as a white solid.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:2]=1.[CH3:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH2:8][CH2:9][C:10]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]2[CH3:19])=[O:12])[CH:2]=1
Reactant: O=C(O)CCNc1cccc(-c2ccccc2)c1
Reactant: CC1CCCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCCCN1C(=O)CCNc1cccc(-c2ccccc2)c1
Reaction time: 8 h
Yield: 94 %

Procedure:
To a mixture of the 3-(biphenyl-3-ylamino)-propionic acid 1.6 g (6.6 mmol), 2-methylpiperidine 0.78 g (7.9 mmol), was added the solid O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate 4.7 g (1.3 mmol), and triethylamine 3.86 mL (27 mmol) in 25 mL of dichloromethane and left overnight at room temperature. The reaction mixture was washed with water, the organic layer, dried over magnesium sulfate, filtered, and concentrated under vacuum. The compound was purified using silica gel chromatography and was eluted with ethyl acetate, yield to 2 g material.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[OH-].[Li+].Cl>CO.O>[NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ncc(Br)nc1C(=O)O
Temperature: 90 °C
Yield: 99 %

Procedure:
A mixture of methyl 3-amino-6-bromo-pyrazine-2-carboxylate (5.11 g, 22.02 mmol) and lithium hydroxide (2.637 g, 110.1 mmol) in MeOH (20 mL) and H2O (20 mL) was heated to 90° C. for 2 hours. The reaction mixture was allowed to cool and neutralized with HCl and the resultant precipitate collected by filtration. The sub-title product was taken on to the next step without further purification (4.80 g, 99% Yield).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10]>>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[N:6][C:5]([C:14]3[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=3)=[CH:4][N:3]=2)=[CH:13][CH:12]=1)#[N:10]
Reactant: Brc1cnc(Br)cn1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cnc(-c3ccc(C#N)cc3)cn2)cc1
Yield: 52 %

Procedure:
The same procedure described for 1,4-Bis-(2′-cyanopyridin-5′-yl)phenylene was used by employing 2,5-dibromopyrazine and 4-cyanophenylboronic acid to furnish 74 in 52% yield; mp>300° C. (DMF). 1H NMR (DMSO-d6): δ 7.99 (d, J=8.4 Hz, 4H), 8.39 (d, J=8.4 Hz, 4H), 9.42 (s, 2H).