Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24]2[CH:25]=[C:26]([N:43]([CH:53]3[CH2:55][CH2:54]3)CC3C=CC(OC)=CC=3)[C:27]3[N:28]([C:30]([C:33]([NH:35][C:36]4[CH:41]=[CH:40][N:39]=[CH:38][C:37]=4[F:42])=[O:34])=[CH:31][N:32]=3)[N:29]=2)[CH2:19][CH2:18]1.[N:56]1([C:62](OC(C)(C)C)=[O:63])[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.C(O)(C(F)(F)F)=O>ClCCl.CN(C1C=CN=CC=1)C>[CH:53]1([NH:43][C:26]2[C:27]3[N:28]([C:30]([C:33]([NH:35][C:36]4[CH:41]=[CH:40][N:39]=[CH:38][C:37]=4[F:42])=[O:34])=[CH:31][N:32]=3)[N:29]=[C:24]([NH:23][C@H:20]3[CH2:21][CH2:22][C@H:17]([NH:16][C:62]([N:56]4[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]4)=[O:63])[CH2:18][CH2:19]3)[CH:25]=2)[CH2:54][CH2:55]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)C2CC2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccncc1F)c1cnc2c(NC3CC3)cc(N[C@H]3CC[C@H](NC(=O)N4CCNCC4)CC3)nn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To di-tert-butyl dicarbonate (10.66 μL, 0.046 mmol) in dichloromethane (1 mL) was added DMAP (2.80 mg, 0.023 mmol) followed by 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (25 mg, 0.046 mmol, 83A). The clear yellow solution was stirred at room temperature for 10 minutes then tert-butyl piperazine-1-carboxylate (8.55 mg, 0.046 mmol) was added, and stirred at room temperature for 1 hr. TFA (0.5 mL) was added, and after 10 minutes, the reaction mixture was concentrated to dryness, taken up in DMSO and methanol and purified using reverse phase HPLC to isolate 8-(cyclopropylamino)-N-(3-fluoropyridin-4-yl)-6-((trans)-4-(piperazine-1-carboxamido)cyclohexylamino)imidazo[1,2-b]pyridazine-3-carboxamide (22 mg, 0.027 mmol, 59.5% yield) as a white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.39 minutes [M+H]=537.37. 1H NMR (500 MHz, METHANOL-d3) δ ppm 8.90 (1H, t, J=6.64 Hz), 8.76 (1H, d, J=3.67 Hz), 8.50 (1H, d, J=5.96 Hz), 8.05-8.22 (1H, m), 6.11 (1H, s), 3.84-4.03 (1H, m), 3.61-3.72 (4H, m), 3.58 (1H, t, J=10.77 Hz), 3.14-3.27 (4H, m), 2.51-2.62 (1H, m, J=6.76, 6.76, 3.67, 3.44 Hz), 2.19 (2H, d, J=12.37 Hz), 1.98 (2H, d, J=13.29 Hz), 1.21-1.69 (4H, m), 0.84-1.05 (2H, m), 0.51-0.71 (2H, m)
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](=O)[NH:9][N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]1=[O:18].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:8]1[C:7]2[N:2]([CH3:1])[C:3](=[O:18])[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][C:6]=2[CH:11]=[N:10][N:9]=1
Reactant: CCOC(=O)c1cc2cn[nH]c(=O)c2n(C)c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2cnnc(Cl)c2n(C)c1=O
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
In a RBF equipped with reflux condenser, ethyl 1-methyl-2,8-dioxo-1,2,7,8-tetrahydropyrido[2,3-d]pyridazine-3-carboxylate (1.65 g, 6.63 mmol) was treated with phosphorus oxychloride (8.00 mL, 85.8 mmol). The reaction mixture was stirred in an oil bath at 110° C. for 90 min, and then cooled to RT. The volatiles were removed in vacuo and the residue was treated with CH2Cl2 then concentrated in vacuo. The residue was treated with CH2Cl2/Et2O and the resulting suspended solid was collected by suction filtration and dried in vacuo to give ethyl 8-chloro-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylate as a green solid. MS (ESI, pos. ion) m/z: 268 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (t, J=7.0 Hz, 3H), 4.09 (s, 3H), 4.45 (q, J=7.0 Hz, 2H), 8.29 (s, 1H), 9.11 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]2[S:13][C:12]([C:14]([F:17])([F:16])[F:15])=[N:11][CH:10]=2)[C:6](=[O:18])[N:5]=[C:4](SC)[N:3]=1.Cl.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=2)=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:34][CH2:33][N:32]([C:4]3[N:3]=[C:2]([CH3:1])[N:7]([CH2:8][C:9]4[S:13][C:12]([C:14]([F:17])([F:16])[F:15])=[N:11][CH:10]=4)[C:6](=[O:18])[N:5]=3)[CH2:31][CH:30]=2)=[CH:25][CH:24]=1
Reactant: CSc1nc(C)n(Cc2cnc(C(F)(F)F)s2)c(=O)n1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nc(N2CC=C(c3ccc(F)cc3)CC2)nc(=O)n1Cc1cnc(C(F)(F)F)s1
Yield: 61.5 %

Procedure:
To a 1,4-dioxane solution (500 μL) of 6-methyl-4-(methylthio)-1-{[2-(trifluoromethyl)thiazol-5-yl]methyl}-1,3,5-triazin-2(1H)-one (38.7 mg, 0.120 mmol) synthesized in Reference Synthesis Example 374, 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (30.8 mg, 0.144 mmol) and N,N-diisopropylethylamine (41.1 μL, 0.240 mmol) were added and the resultant mixture was stirred under reflux by heating for 1 day. After the completion of the reaction, the reaction solution was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→0/1) to obtain the title compound (33.3 mg, yield: 61%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[CH2:9][O:8][C:7]=2[CH:23]=1.S(Cl)([Cl:26])=O.N1C=CC=CC=1>ClCCl>[Cl:26][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[CH2:9][O:8][C:7]=2[CH:23]=1
Reactant: CCOC(=O)C=C1c2ccccc2COc2cc(CO)ccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C=C1c2ccccc2COc2cc(CCl)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 1-b (6.58 g) was dissolved in 200 ml of dichloromethane, and 6.2 ml of thionyl chloride and 6.9 ml of pyridine were added to the solution. The mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The obtained product was unstable and immediately subjected to the subsequent reaction without purification.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]12([OH:16])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]([O:16][C:6]12[CH2:13][CH:12]3[CH2:11][CH:10]([CH2:9][CH:8]([CH2:14]3)[CH2:7]1)[CH2:15]2)=[O:4]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Product: O=C(CCl)OC12CC3CC(CC(C3)C1)C2

Procedure:
There was added slowly at 10° C. and under nitrogen 24 ml of chloracetyl chloride to 30.5 g (0.2 mole) of 1-adamantanol and 12 g of magnesia in suspension in 400 ml of chloroform; it was then brought under reflux for some hours. It was cooled, the inorganic material was filtered off and the solvent evaporated. The crude product was crystallized in hexane. 90% of the product melting 79° C. (capillary) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[Na].C(O)C.[Cl:16][CH:17]=[CH:18][CH2:19]Cl>O>[Cl:16][CH:17]=[CH:18][CH2:19][N:4]1[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([CH3:1])=[N:3]1
Reactant: CCOC(=O)c1c[nH]nc1C
Reactant: ClC=CCCl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn(CC=CCl)nc1C

Procedure:
Ethyl 3-methylpyrazole-4-carboxylate (5.0 g) was added to sodium alcoholate prepared from 0.75 g of metallic sodium and 30 ml of ethanol. To the homogeneous mixture was added 3.6 g of 1,3-dichloropropene, and the mixture was refluxed for 2 hours. After the reaction, the reaction mixture was discharged into water and extracted with ethyl acetate. The extract was chromatographed on a silica gel column, and the column was eluted with hexane/ethyl acetate to give 2.5 g (34%) of a Z isomer of ethyl 1-(gamma-chloroallyl)-3-methylpyrazole-4-carboxylate and 1.5 g (20 %) of its E isomer. The Z isomer (2.5 g) was stirred under heat for 4 hours together with a mixture of 25 ml of ethanol, 2.5 g of sodium hydroxide and 25 ml of water. After the reaction, the reaction mixture was cooled to room temperature, and with cooling, concentrated hydrochloric acid was added to adjust its pH to 4 to 5. The precipitated crystals were collected by filtration and dried. Recrystallization from water gave 0.3 g (yield 14%) of the Z isomer of 1-(gamma-chloroallyl)-3-methylpyrazole-4-carboxylic acid. m.p. 96°-100° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[N:25]=[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:27][C:28]=3[C:29]([F:32])([F:31])[F:30])=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.[ClH:45]>CO>[ClH:45].[N:11]1([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[N:25]=[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:27][C:28]=3[C:29]([F:32])([F:30])[F:31])=[O:23])=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1ccc(N2CCCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
A mixture of 4-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.64 g, 3.1 mmol) in methanol (50 mL) and hydrogen chloride in dioxane (4M, 10 mL, 40 mmol) was stirred at room temperature for 24 hr. The solvents were removed under vacuum to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-[1,4]diazepan-1-yl-phenyl)-amide hydrochloride salt (1.57 g, 99% yield) as a white solid. ES-MS for the neutral form C22H21F3N4O2 calcd. (m/e) 430, observed 431 (M+H).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][CH:22]([CH2:36][CH3:37])[C@@H:23]([C:25]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][N:26]=1)[OH:24]>>[CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([NH:21][C@H:22]([C:23]([C:25]2[N:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:27][N:26]=2)=[O:24])[CH2:36][CH3:37])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(N)[C@H](O)c1noc(-c2ccccc2)n1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1
Product: CC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1)C(=O)c1noc(-c2ccccc2)n1

Procedure:
Similarly prepared according to the general procedure given for Example 43 but using (R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid, prepared as described in reference 21, and (S)-2-amino-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)-butan-1-ol, prepared as in reference 26; MS: 519 (M+Na), LC-MS retention time 4.5 min; 1H NMR (CDCl3) 8.19 (d, J=7 Hz, 2H), 7.65–7.51 (m. 3H), 6.64 (d, J=7 Hz, 1H), 5.44–5.38 (m, 1H), 3.69–3.38 (m, 8H), 3.05–2.98 (m, 1H), 2.76 (dd, J=16 Hz & 10 Hz, 1H), 2.26 (dd, J=16 Hz & 3 Hz, 1H), 2.10 (m, 1H), 1.80 (m, 1H), 1.75–1.59 (m, 6H), 1.28–1.13 (m, 5H), 1.03–0.98 (t, J=7 Hz, 3H), 0.92–0.81 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[Sn](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:3]1[C:2]([C:25]2[N:24]([CH3:23])[CH:28]=[CH:27][N:26]=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1-c1nccn1C
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 2-(3-chloro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 425; 34.1 mg, 0.109 mmol), 1-methyl-2-(tributylstannyl)-1H-imidazole (Indofine Chemical Company, Inc.; 0.042 mL, 0.131 mmol) and Pd(PPh3)4 (Strem Chemicals, Inc.; 12.60 mg, 10.90 μmol) in toluene (2.0 mL) was stirred under argon at 110° C. for 1 h. The reaction mixture was then cooled to RT and diluted with hexanes (10 mL). The precipitated solid was collected by vacuum filtration (fine glass frit), sequentially washed with hexanes (10 mL) and Et2O (10 mL), and dried in vacuo to provide 2-(2-methyl-3-(1-methyl-1H-imidazol-2-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (34.7 mg, 0.097 mmol, 89% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.70 (1H, br. s.), 7.97 (1H, dd, J=7.1, 1.3 Hz), 7.91 (1H, s), 7.85 (1H, dd, J=8.2, 1.2 Hz), 7.75-7.82 (1H, m), 7.66 (1H, d, J=0.6 Hz), 7.07 (1H, d, J=2.0 Hz), 6.98 (1H, br. s.), 3.79 (3H, s), 3.42 (2H, td, J=6.8, 2.2 Hz), 2.88 (2H, br. s.), 2.83-2.86 (3H, m). m/z (ESI, +ve) 359.0 (M+H)+.
Reaction SMILES: C(O)C.[C-:4]#[N:5].[Na+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1>O>[F:17][C:16]([F:19])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:4]#[N:5])=[CH:10][CH:11]=1
Reactant: [C-]#N
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(OC(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
150 g of ethanol, 28 ml of water, and 31.5 g of sodium cyanide were initially charged, and 127.5 g of 4-bromomethyl-1-trifluoromethoxybenzene were added. The reaction mixture was stirred at 90° C. for 3.5 hours and then poured into 250 ml of water and extracted twice with 50 ml portions of dichloromethane. The combined organic phases were concentrated and the residue was distilled at 18 hPa. This gave 81.5 g of (4-trifluoromethoxyphenyl)acetonitrile as a colorless liquid (76.3% of theory) of b.p. 110-112° C.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:22]([O:29][C:30]([NH:32][CH2:33][C:34](Cl)=[O:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]([NH:32][CH2:33][C:34]([N:19]1[CH2:18][CH2:17][C:16](=[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1)=[O:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)CNC(=O)OCc1ccccc1
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Product: O=C(NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)OCc1ccccc1
Yield: 61 %

Procedure:
The title compound, a white crystalline, was prepared by acylation of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine with N-benzyloxycarbonylglycine chloride in a similar way as described under Example 19. Yield: 61%
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:24])=[C:13]([C:19]([O:21]CC)=O)[C:14](=[O:18])[NH:15]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:24])=[C:13]([C:19]([NH:29][CH2:28][CH:25]3[CH2:27][CH2:26]3)=[O:21])[C:14](=[O:18])[NH:15]2)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Product: O=C(NCC1CC1)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
Ethyl 7-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate was treated with cyclopropylmethyl amine in a manner similar to that described in Example 2. The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.85 (1H, br), 10.85 (1H, br), 10.11 (1H, br),8.20 (1H, br m), 7.39-7.25 (6H, br m), 4.01 (2H, br s), 3.33-3.13 (2H, br m), 1.20-0.90 (1H, m), 0.44 (2H, m), 0.19 (2H, m); HRMS calcd for C20H19N3O3+H+: 350.1505. Found: 350.1517.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15](Br)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:36]1[O:37][CH:38]=[CH:39][CH:40]=1)CCC.O>O1CCCC1.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:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:36]1[O:37][CH:38]=[CH:39][CH:40]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3ccco3)cc12
Yield: 74.7 %

Procedure:
A solution of tert-butyl(6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.48 g, 1 mmol), tri-n-butyl(2-furyl)tin (0.31 ml, 1 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) in tetrahydrofuran (20 ml) was refluxed at 80° C. for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-6-(2-furyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.35 g, 76.1%) as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][F:27]>>[F:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Reactant: FCCCCCBr
Product: O=C(c1ccc(OCCCCCF)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure E except the reaction mixture is stirred at room temperature overnight starting from (4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 1-bromo-5-fluoropentane. MS (ES+) 363.3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].[S:24]1[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[S:26]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[C:30]2[S:24][C:25](=[S:26])[NH:27][C:28]2=[O:29])=[CH:13][CH:12]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc(OCc2c(F)cccc2Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2c(F)cccc2Cl)cc1

Procedure:
Under a nitrogen atmosphere in a round bottom flask 4-[(2-chloro-6-fluorophenyl)methoxy]benzaldehyde (1.00 g, 3.78 mmol) was dissolved in acetic acid (19 ml). To this solution was added sodium acetate (1.08 g, 13.2 mmol) and then rhodanine (0.50 g, 3.75 mmol). The reaction mixture was then heated to reflux and maintained at this temeprature. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[N:25][C:26]([C:29]#[CH:30])=[CH:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:24]=[N:25][C:26]([C:29]#[C:30][C:2]3[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[CH:4][CH:3]=3)=[CH:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: Ic1ccc(OCCN2CCCC2)cc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)nn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)cc3)nn2)cc1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-phenoxy)-ethyl]-pyrrolidine (200 mg, 0.63 mmol) and 3-(4-chloro-phenyl)-6-ethynyl-pyridazine (135 mg, 0.63 mmol).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:12]=[N:11][NH:10][C:9]=1[NH2:13])=[O:7].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[C:22]([N:26]([CH2:31][C:32]#[CH:33])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[CH2:31]([N:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:10]3[N:11]=[CH:12][C:8]([C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[O:7])=[C:9]3[N:13]=[CH:16][CH:17]=2)[CH:21]=1)[S:27]([CH3:30])(=[O:29])=[O:28])[C:32]#[CH:33]
Reactant: C#CCN(c1cccc(C(=O)C=CN(C)C)c1)S(C)(=O)=O
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C#CCN(c1cccc(-c2ccnc3c(C(=O)c4cccs4)cnn23)c1)S(C)(=O)=O
Yield: 77.1 %

Procedure:
0.1 g (0.33 mmol) of 4-thiophene-2-carbonyl-2H-pyrazol-3-ylamine and 0.063 g (0.33 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-2-propynyl-methanesulfonamide were dissolved in 10 ml of glacial acetic acid. After refluxing for 8 hours, the solvent was removed by reduced pressure distillation. To the resultant residue 10 ml of dichloromethane and 10 ml of a saturated solution of sodium bicarbonate were added. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporate to dryness to yield an oil which, in the presence of ethyl acetate gave a yellow solid, 111 mg (yield=78%) N-2-propynyl-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-methanesulfonamide.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:11]=[CH:10][O:9][C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[CH3:14]I>CN(C=O)C>[Br:1][C:2]1[C:3]2[CH:11]=[CH:10][O:9][C:4]=2[C:5](=[O:8])[N:6]([CH3:14])[CH:7]=1
Reactant: CI
Reactant: O=c1[nH]cc(Br)c2ccoc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2ccoc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
To a solution of the title compound of step 1 (500 mg, 2.3 mmol) stirred at 0° C. in DMF (5 mL) was added NaH (68 mg, 2.81 mmol, 60% in mineral oil). After stirring at 0° C. for 30 min, methyl iodide (400 mg, 2.8 mmol) was added dropwise. The ice bath was removed, and mixture was stirred at rt for 4 h. The reaction mixture was treated with saturated NH4Cl (aq. 30 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE/EtOAc=10:1) to give the title compound (500 mg, 94%). 1H NMR (CDCl3, 400 MHz) δ 7.78 (d, J=2.0 Hz, 1H), 7.30 (s, 1H), 6.70 (d, J=2.0 Hz, 1H), 3.66 (s, 3H). LCMS (M+H)+=229.