Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC#N>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:13]=[CH:12][CH2:11][NH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C=CCNC1

Procedure:
A solution of 5-2 (19.0 g, 63 mmol), Mg(ClO4)2 (2.8 g, 12.7 mmol), and CH3CN was heated at 50° C. for 2 hr. The cooled solution was diluted with CHCl3 and then washed with 1N HCl, sat. NaHCO3, and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 75% EtOAc/hexanes→EtOAc) gave 5-3 as a brown solid.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)=[CH:19][CH:18]=1>C(O)(C)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH2:15][CH:2]([OH:1])[CH2:3][N:4]4[C:12](=[O:13])[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]4=[O:14])[CH2:31][CH2:30]3)=[N:27][CH:28]=2)=[CH:19][CH:18]=1
Reactant: Clc1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Solvent: CC(C)O
Product: O=C1c2ccccc2C(=O)N1CC(O)CN1CCN(c2ncc(-c3ccc(Cl)cc3)cn2)CC1
Reaction time: 2 h

Procedure:
0.022 mol of 2-(2,3-epoxypropyl)isoindole-1,3(2H)dione, 0.02 mol of 1-(5-(4-chlorophenyl)-2-pyrimidinyl)piperazine and 70 ml of isopropanol are heated to boiling for 2 hours. The mixture is evaporated and the residue is purified by column chromatography on silica gel 60. After elution with methylene chloride/alcohol (96:4), the compound is stirred with alcohol and filtered off with suction.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[K+].[K+].[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=1>CN(C=O)C>[CH2:28]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(C(=O)OC)c1
Temperature: 60 °C
Yield: 93.3 %

Procedure:
A mixture of 1.98 g (9.42 mmol) of dimethyl 5-hydroxyisophthalate 3.0 g (21.7 mmol) of K2CO3 and 1.8 mL (15.1 mmol) of BnBr in 30 mL of DMF was heated at 60° C. for 18 h. After the mixture was filtered through cotton, water and CHCl3 were added. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (15% EtOAc/hexanes) provided the 2.64 g of dimethyl 5-(benzyloxy)isophthalate as a colorless solid in 93% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccc(F)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-fluoro-phenylboronic acid to give [1-(4-fluoro-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 319(MH+). 1H NMR(CDCl3): δ 2.26(s, 3H), δ 5.89(s, 1H), δ 7.25(m, 3H), δ 7.32(br, 1H), δ 7.55(m, 1H), δ 7.65(s,1H), δ 7.70(m, 4H), δ 7.87(d,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:36])[O:11][C:12]2[C:17]([C:18]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=1)=[CH:16][CH:15]=[C:14]([OH:34])[C:13]=2I.C([Sn](CCCC)(CCCC)[C:42]([O:44]CC)=[CH2:43])CCC.Cl.C(Cl)Cl>O1CCOCC1.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:42]([C:13]1[C:14]([OH:34])=[CH:15][CH:16]=[C:17]2[C:12]=1[O:11][C:10](=[O:36])[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[C:18]2[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:22][CH:21]=1)(=[O:44])[CH3:43]
Reactant: O=c1oc2c(I)c(O)ccc2c(Cc2ccc(OCCN3CCCC3)cc2)c1-c1ccc(Cl)cc1Cl
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)c1c(O)ccc2c(Cc3ccc(OCCN4CCCC4)cc3)c(-c3ccc(Cl)cc3Cl)c(=O)oc12
Temperature: 25 °C
Yield: 13.5 %

Procedure:
A mixture of 3-(2,4-dichlorophenyl)-7-hydroxy-8-iodo-4-(4-(2-pyrrolidin-1-yl-ethoxy)-benzyl)-chromen-2-one (187 mg, 0.294 mmol), tributyl(1-ethoxyvinyl)tin (119 μL, 0.353 mmol) and Pd(Ph3P)4 (34 mg, 0.0294 mmol) in anhydrous dioxane (6 mL) was stirred at reflux temperature for 2 h. After cooling to room temperature, aqueous 1M HCl was added, and the resulting mixture was stirred for 20 min. CH2Cl2 was added and the layers were separated. The aqueous layer was further extracted with CH2Cl2 (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The resultant residue was purified using flash chromatography (silica gel, 19:1→9:1 CH2Cl2:MeOH) to afford a light brown solid (48 mg, 84% pure by HPLC) that was recrystallized from AcOEt/hexane to provide the title compound as a yellow solid (22 mg, 14%).
Reaction SMILES: [N:1]([C:4]1[N:8]([CH2:9][CH2:10][CH2:11][C:12](OCC)=[O:13])[C:7]2[C:17]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:19]=[C:20]([Cl:21])[C:6]=2[N:5]=1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[NH2:1][C:4]1[N:8]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:7]2[C:17]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:19]=[C:20]([Cl:21])[C:6]=2[N:5]=1
Reactant: CCOC(=O)CCCn1c(N=[N+]=[N-])nc2c(Cl)ccc(C(CC)CC)c21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(N)n(CCCCO)c12
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of ethyl 4-[2-azido-4-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (190 mg, 0.500 mmol) in tetrahydrofuran (3.0 mL) was added lithium aluminum hydride (57 mg, 1.5 mmol) portionwise at 0° C. After stirring for 1 hr, sodium sulfate decahydrate (300 mg) was added to the mixture, which was stirred for 1 hr. Insoluble materials were filtered off and the filtrate was concentrated in vacuo to give the title compound (135 mg, 0.435 mmol, 87%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:53]=[CH:52][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:22]([O:30]CC3C=CC(OCC4N=C(C5C=CC=CC=5)OC=4C)=CC=3)=[N:21]2)=[CH:17][CH:16]=1.C(O)C>[C].[Pd].O1CCCC1>[OH:30][C:22]1[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:24][N:20]([CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:6][C:2]=3[CH3:1])=[CH:53][CH:52]=2)[N:21]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
A mixture of ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-carboxylate (2.84 g), 5% palladium-carbon (5.00 g), ethanol (25 ml), and tetrahydrofuran (25 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hours. After removal oh the catalyst by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration, and ethyl 3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-carboxylate (968 mg, yield: 56%) was obtained. This was recrystallized from tetrahydrofuran-hexane. Melting point: 152–153° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:12][S:13]([C:7]1[CH:6]=[C:5]([N+:8]([O-:10])=[O:9])[CH:4]=[C:3]([CH3:11])[C:2]=1[F:1])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Product: Cc1cc([N+](=O)[O-])cc(S(=O)(=O)Cl)c1F
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A dry reaction flask equipped with a magnetic stirring bar, nitrogen inlet and reflux condenser was charged with 2-fluoro-5-nitrotoluene (6.20 g, 40 mmol) followed by chlorosulfonic acid (10.60 mL, 160 mmol) at 0° C., and then the reaction was stirred at 100° C. for 24 hours. After cooling it to the room temperature, the reaction was poured over ice-water (Caution!) and extracted with ethyl acetate (3×200 mL). Removal solvent under a reduced pressure afforded 3-chlorosulfonyl-4-fluoro-5-methylnitrobenzene intermediate, which was stirred in EtOAc (50 mL) and NH4OH (30%, 50 mL) for 2-3 hours. The separated organic phase was then evaporated to afford a crude material, which was purified by column chromatography (silica gel, hexanes then 10-20% EtOAc in hexanes) to afford 3-aminosulfonyl-4-fluoro-5-methylnitrobenzene. LCMS: purity: 96%; MS (m/e): 235 (MH+).
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][C:2]1=O.P(Cl)(Cl)([Cl:15])=O.[OH-].[Na+]>C(#N)C>[Cl:15][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:11])[CH2:7][CH2:8][CH2:9][C:10]=2[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=C1CCCc2nc(Cl)ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a suspension of 7,8-dihydroquinoline-2,5(1H,6H)-dione (1.5 g, 9.19 mmol) in acetonitrile (22 mL) was added dropwise phosphorous oxychloride (1.714 mL, 18.39 mmol). The resulting solution was heated to 100° C. and stirred for 2 h. The reaction was cooled to RT and poured into ice-cold water. After basifying the mixture with 2 M sodium hydroxide solution it was extracted with ethyl acetate (3×). After each extraction the pH of the aqueous phase was checked and if necessary adjusted by adding 1 M sodium hydroxide solution. The combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness. The crude was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate) yielding a colourless solid. Amount 1.23 g. Yield 74%.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=3)[S:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH2:26])[CH3:22]>>[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH:26][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=3)[S:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1)[CH3:22]
Reactant: CCN(CC)CCN
Reactant: O=c1c2cc(O)ccc2sc2c([N+](=O)[O-])ccc(Cl)c12
Product: CCN(CC)CCNc1ccc([N+](=O)[O-])c2sc3ccc(O)cc3c(=O)c12

Procedure:
1-[[2-(Diethylamino)ethyl]amino]-7-hydroxy-4-nitro-9H-thioxanthen-9-one was prepared similarly from 10 g of 1-chloro-7-hydroxy-4-nitrothioxanthone and 8.3 g of N,N-diethylethylenediamine to provide 7.3 g as a tan solid which was used without further purification.
Reaction SMILES: COCCOC1C=CN2C(C3C=CC4C(=C(N)C=CC=4)N=3)=CN=C2C=1.[F:26][C@H:27]1[C@@H:32]([NH:33][C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:43]=2[N:42]=[C:41]([C:44]2[N:48]4[CH:49]=[CH:50][C:51]([O:53][CH2:54][CH2:55][O:56][CH3:57])=[CH:52][C:47]4=[N:46][CH:45]=2)[CH:40]=[CH:39]3)[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]1.Cl.O1CCOCC1>CO>[F:26][C@H:27]1[C@@H:32]([NH:33][C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:43]=2[N:42]=[C:41]([C:44]2[N:48]4[CH:49]=[CH:50][C:51]([O:53][CH2:54][CH2:55][O:56][CH3:57])=[CH:52][C:47]4=[N:46][CH:45]=2)[CH:40]=[CH:39]3)[CH2:31][CH2:30][NH:29][CH2:28]1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(N[C@H]5CCN(C(=O)OC(C)(C)C)C[C@H]5F)c4n3)cnc2c1
Agent: COCCOc1ccn2c(-c3ccc4cccc(N)c4n3)cnc2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COCCOc1ccn2c(-c3ccc4cccc(N[C@H]5CCNC[C@H]5F)c4n3)cnc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.5 %

Procedure:
Preparation of N-(cis)-3-fluoropiperidin-4-yl)-2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-amine: (cis)-tert-Butyl 3-fluoro-4-(2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ylamino)piperidine-1-carboxylate (0.050 g, 0.093 mmol) was dissolved in MeOH (1 mL) the solution was treated with 4 M hydrogen chloride in dioxane (0.583 ml, 2.33 mmol). The mixture was stirred at ambient temperature for 4 hours, then concentrated in vacuo. The residue was redissolved and re-concentrated from MeOH three times. This material was purified by silica gel chromatography, eluting with (6% NH4OH in MeOH)/ethyl acetate to provide the desired product (16 mg). 1H NMR (400 MHz, CDCl3) δ 9.89 (d, 1H), 8.14 (s, 1H), 8.05 (d, 1H), 7.77 (d, 1H), 7.38-7.29 (m, 1H), 7.08 (d, 1H), 7.02 (s, 1H), 6.85-6.74 (m, 2H), 6.30 (d, 1H), 4.89 (d, J=49 Hz, 1H), 4.26-4.19 (m, 2H), 3.87-3.78 (m, 2H), 3.79-3.69 (m, 1H), 3.54-3.42 (m, 1H), 3.48 (s, 3H), 3.27-3.18 (m, 1H), 3.04-2.87 (dd, 1H), 2.79 (t, 1H), 2.17-2.09 (m, 1H), 2.00-1.86 (brd, 1H), 1.81-1.67 (m, 1H), 1.30-1.22 (m, 1H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:21]=[CH:20][C:8]([O:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Na].[CH3:23][O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][S:36]([C:38]2[NH:42][C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[N:39]=2)=[O:37])[C:30]=1[CH3:47]>ClCCl.C(N(CC)CC)C>[CH3:23][O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][S:36]([C:38]2[N:39]([S:2]([C:5]3[CH:21]=[CH:20][C:8]([O:9][CH2:10][C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)=[O:12])=[CH:7][CH:6]=3)(=[O:4])=[O:3])[C:40]3[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=3[N:42]=2)=[O:37])[C:30]=1[CH3:47]
Reactant: O=C(COc1ccc(S(=O)(=O)Cl)cc1)Nc1ccccn1
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2ccc(OCC(=O)Nc3ccccn3)cc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
170 mg of 2-[p-(chlorosulfonyl)phenoxy]-N-(2-pyridyl)acetamide was added to 191 mg of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole sodium salt in dichloromethane (15 ml) and triethylamine (0.1 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water. Organic layer was dried over anhydrous magnesium sulfate, and evaporated. Residual material was lyophilized in vacuo to give 244 mg of the titled product.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O)#[N:9].[C:18]([OH:30])(=[O:29])[CH2:19][NH:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.O.C(OCC)C>[O:29]=[C:18]1[O:30][C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:20][C:19]1=[CH:13][C:12]1[CH:11]=[C:10]([CH:17]=[CH:16][CH:15]=1)[C:8]#[N:9]
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: N#Cc1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cccc(C=C2N=C(c3ccccc3)OC2=O)c1
Yield: 73.6 %

Procedure:
An acetic anhydride suspension (10 mL) of 3-cyanobenzaldehyde (1.32 g, 10.1 mmol), hippuric acid (1.81 g, 10.1 mmol) and sodium acetate (826 mg, 10.1 mmol) was stirred at 100° C. for 30 minutes. After the reaction mixture was allowed to cool and diethyl ether was added thereto, the solid was taken out by filtration and the filtrate was concentrated under reduced pressure. The solid obtained and the residue were combined and the mixture was suspended in a mixture of ethyl acetate-water. After filtering, the solid was dissolved in dichloromethane, followed by washing with water. The mixture was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (2.04 g, 74%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[CH3:21][N:22]([CH:24](OC)OC)[CH3:23]>>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:10]1[C:9]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[N:8][C:6]2[N:7]=[C:2]([N:1]=[CH:21][N:22]([CH3:24])[CH3:23])[N:3]=[CH:4][C:5]=2[CH:11]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Product: CN(C)C=Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N=CN(C)C)nc2n1

Procedure:
2,7-Diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]-pyrimidine from Example 1 was reacted with DMF dimethyl acetal for 23 hours as described in Example 78. Workup as described above followed by purification on flash silica gel chromatography eluting sequentially with 100:0, 9:1, 4:1, and 7:3 ethyl acetate:methanol gave an oil that was crystallized from ethyl acetate to afford N'-[6-(2,6-dichlorophenyl)-7-[(dimethylamino)-methyleneamino]-pyrido[2,3-d]pyrimidin-2-yl]-N,N-dimethylformamidine, mp 269-272° C. CIMS (1% ammonia in methane): m/z (relative intensity) 418 (MH+ +2, 60), 416 (MH+, 100).
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].O1CCOCC1.C(O)(=O)C>CCCCCC>[OH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:10]1[CH:3]=[CH:7][CH:6]=[CH:5]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccccc1O
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: Oc1ccccc1-n1cccc1

Procedure:
A mixture of 2,5-dimethoxytetrahydrofuran (39.6 g), o-aminophenol (36 g), dioxane (300 ml), and glacial acetic acid (180 ml) are heated under reflux for 4 hr. The solvents are removed and the residue distributed between ethyl acetate and 5% NaHCO3. The organic phase is washed with water, dried (MgSO4), filtered, and evaporated. The dark oily residue is subjected to chromatography on 2 kg of silica and eluted with chloroform to afford an oil. After being covered with hexane and stored for several days, the oil solidifies giving the title compound, m.p. 52° - 54° C. (Reported m.p. by Artico, et al., cited above, 45° - 47° C).
Reaction SMILES: [C:1](=[O:5])([O:3][CH3:4])[NH2:2].O=[C:7]([CH2:11][CH2:12][PH:13]([CH2:15][OH:16])=[O:14])[C:8]([OH:10])=[O:9].C(O)(=O)C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.ClC1C=CC=CC=1>[CH3:4][O:3][C:1]([NH:2]/[C:7](=[CH:11]\[CH2:12][PH:13]([CH2:15][OH:16])=[O:14])/[C:8]([OH:10])=[O:9])=[O:5]
Reactant: O=C(O)C(=O)CC[PH](=O)CO
Reactant: COC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)N/C(=C\C[PH](=O)CO)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
5.835 g of methyl carbamate, 0.275 g of p-toluenesulfonic acid monohydrate and 10.000 g of 2-oxo-4-(hydroxymethylphosphinyl)-butanoic acid were added to 16 mL of acetic acid to be suspended. After being dissolved by heating, 80 mL of chlorobenzene was added thereto and then the solution was refluxed with vigorous stirring. A remaining solution was removed appropriately while the internal temperature of the reaction solution was maintained from 106 to 110 deg. C. under a slightly reduced pressure, followed by adding chlorobenzene, the volume of which was equal to the volume of the removed solution. Two hours later, dissipation of almost all the raw materials was confirmed by HPLC measurement. At this point, the area ratio of Z form to E form was 93:7. After removing about 50 mL of the solvent under a reduced pressure, followed by adding 20 mL of acetic acid, and then the resultant was stirred for 1 hour at 80 deg. C. The precipitate which was obtained by cooling the solution gradually to room temperature and stirring over-night, was filtered and then the filtrate was washed with acetic acid. After being washed with acetone, dried for 6 hours from 40 to 50 deg. C. under a reduced pressure, 9.505 g of the objective compound was obtained (72.2% yield, Z:E=99.5:0.5).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:26]=[CH:25][C:11]3/[C:12](=[CH:21]/[C:22](O)=[O:23])/[C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=4[CH2:15][CH2:16][C:10]=3[CH:9]=2)[C:5]2[CH:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:29]=[C:30]([CH3:31])[C:4]=2[N:3]=1.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:39]1([NH:38][C:22](=[O:23])/[CH:21]=[C:12]2\[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH2:15][CH2:16][C:10]3[CH:9]=[C:8]([CH2:7][N:6]4[C:5]5[CH:27]=[C:28]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[CH:29]=[C:30]([CH3:31])[C:4]=5[N:3]=[C:2]4[CH3:1])[CH:26]=[CH:25][C:11]\2=3)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Nc1ccccc1
Reactant: Cc1cc(-c2ccccc2)cc2c1nc(C)n2Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccccc2)cc2c1nc(C)n2Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.3 %

Procedure:
(E)-[2-(2,4-Dimethyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetic acid (0.050 g, 0.103 mmol) obtained in Example 55 was dissolved in DMF (1 mL), aniline (0.018 mL, 0.200 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.047 g, 0.240 mmol) and 1-hydroxybenzotriazole (0.032 g, 0.240 mmol) were added, and the mixture was stirred at room temperature for 15 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the precipitated solid was collected by suction filtration to give the title compound (compound 90) (0.048 g, 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[C:12]2[C:13](=[O:24])[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](Br)[N:18]=3)[CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]1(B(O)O)[CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CN(C=O)C.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>[CH2:1]([O:8][C:9]1[CH:25]=[C:12]2[C:13](=[O:24])[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:26]4[CH2:28][CH2:27]4)[N:18]=3)[CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cc(OCc3ccccc3)nn2CCN1c1cccc(Br)n1
Reactant: OB(O)C1CC1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C1c2cc(OCc3ccccc3)nn2CCN1c1cccc(C2CC2)n1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 45.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (14.5 mg, 0.013 mmol) was added to a stirred suspension of 2-(benzyloxy)-5-(6-bromopyridin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.1 g, 0.25 mmol), cyclopropylboronic acid (0.043 g, 0.5 mmol) and K2CO3 (0.104 g, 0.013 mmol) in a mixture of 1,4-dioxane (1 mL) and DMF (1 mL). The mixture was stirred at 150° C. for 15 minutes under microwave irradiation. The mixture was diluted with water and extracted with AcOEt. The organic layer was separated, washed with a saturated solution of NaCl, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected, the solvents evaporated in vacuo and the residue triturated with DIPE to yield 2-(benzyloxy)-5-(6-cyclopropylpyridin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (41 mg, 45% yield) as a pale yellow solid. C21H20N4O2. 1H NMR (500 MHz, CDCl3) δ ppm 0.92-1.03 (m, 4H), 1.97-2.05 (m, 1H), 4.31 (dd, J=6.6, 5.2 Hz, 2H), 4.50 (dd, J=6.9, 5.2 Hz, 2H), 5.23 (s, 2H), 6.37 (s, 1H), 6.99 (d, J=6.9 Hz, 1H), 7.31-7.36 (m, 1H), 7.36-7.42 (m, 2H), 7.46 (d, J=7.2 Hz, 2H), 7.57 (t, J=7.9 Hz, 1H), 7.76 (dd, J=8.4, 0.6 Hz, 1H).