Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][C:14]=2[NH2:26])=[C:9]2[CH2:28][N:29]([S:33]([C:36]3[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=3)(=[O:35])=[O:34])[C:30]([CH3:32])([CH3:31])[C:8]2=[N:7]1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.[N:53]1([C:59](Cl)=[O:60])[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1.O1CCCC1>O>[CH2:1]([O:3][C:4]([N:6]1[C:10]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][C:14]=2[NH:26][C:59]([N:53]2[CH2:58][CH2:57][O:56][CH2:55][CH2:54]2)=[O:60])=[C:9]2[CH2:28][N:29]([S:33]([C:36]3[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=3)(=[O:35])=[O:34])[C:30]([CH3:32])([CH3:31])[C:8]2=[N:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1N)CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1NC(=O)N1CCOCC1)CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Temperature: 60 °C
Reaction time: 168 h
Yield: 30.7 %

Procedure:
A mixture of 3-[2-Amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (308 mg, 0.5 mmol), N,N-diisopropylethylamine (0.104 mL, 0.6 mmol, 1.2 eq), morpholine-4-carbonyl chloride (1.2 mL, 10 mmol, 20 eq) and tetrahydrofuran (20 mL) was stirred at 60° C. for 7 days. The reaction mixture was then poured into water (100 mL), extracted with dichloromethane (100 mL), dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel (acetone as eluant) affording 112 mg of 5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-{4-(4-methyl-piperazin-1-yl)-2-[(morpholine-4-carbonyl)-amino]-benzoylamino}-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester that was treated with 10 mL of methanol/triethylamine 8:2 and stirred at room temperature overnight. The mixture was evaporated to dryness and the residue purified by flash chromatography on silica gel using dichloromethane-methanol-30% NH4OH 96:4:0.4 as eluant, yielding the title compound as white solid (50 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]([C:15]#[N:16])=[N:8][NH:9][C:10]=1[Si](C)(C)C.[OH-].[Na+].Cl>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]([C:15]#[N:16])=[N:8][NH:9][CH:10]=1
Reactant: C[Si](C)(C)c1[nH]nc(C#N)c1-c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1n[nH]cc1-c1cccs1

Procedure:
After a solution of trimethylsilyldiazomethane in hexane (0.6 mol/L, 5 mL) was added to tetrahydrofuran (20 mL) under an argon atmosphere, to this reaction mixture was added a solution of n-butyl lithium in hexane (2.6 mol/L, 1.08 mL) in a dropwise manner over 5 minutes at −78° C., and this mixture was stirred at same temperature for 20 minutes. And then to this reaction mixture was added a solution of 2-thiophene-2-ylmethylene malononitrile (0.32 g) in tetrahydrofuran (5 mL) in a dropwise manner over 20 minutes. To this reaction mixture was added saturated aqueous ammonium chloride solution, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. This residue was washed with hexane to give 4-thiophene-2-yl-5-trimethylsilanyl-1H-pyrazole-3-carbonitrile (0.496 g). To the 4-thiophene-2-yl-5-trimethylsilanyl-1H-pyrazole-3-carbonitrile were added methanol (20 mL) and 1.0 mol/L aqueous sodium hydroxide solution (20 mL), and this mixture was heated to reflux for 2 hours. This reaction mixture was acidified (pH1) with adding 1.0 mol/L hydrochloric acid, the precipitated solid was collected by filtration. This obtained solid was washed with water, dried under reduced pressure at 50° C. to give the title compound (0.154 g).
Reaction SMILES: [Na:1].CO[CH:4]1[O:9][CH2:8][CH:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])[CH2:6][O:5]1.O1[C:36]2([CH2:41][CH2:40]C[CH2:38][CH2:37]2)OCC(CO)C1>>[Na:1].[O:9]1[C:4]2([CH2:40][CH2:41][CH2:36][CH2:37][CH2:38]2)[O:5][CH2:6][CH:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])[CH2:8]1
Reactant: OCC1COC2(CCCCC2)OC1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Agent: [Na]
Product: Cc1c(OCC2COC3(CCCCC3)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 8.4 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using 1,5-dioxaspiro[5.5]undec-3-ylmethanol obtained in the step (25a) to obtain the title compound (125 mg, total yield: 8.4%) as a light yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[S:16]([C:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][N:27]=1)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:32][C:31]4[C:26]([S:16]([C:19]5[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=5)(=[O:18])=[O:17])=[N:27][CH:28]=[CH:29][CH:30]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Cc1ccc(S(=O)(=O)c2ncccc2N)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)c2ncccc2NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 2-tosylpyridin-3-amine (50 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 436.5, found 437.1 (M+1)+. Retention time 3.16 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1Cl.[CH2:11]([SH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(O)(C)C>[CH2:11]([S:18][C:7]1[CH:6]=[N:5][N:4]([CH3:9])[C:3](=[O:10])[C:2]=1[Cl:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: SCc1ccccc1
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1ncc(SCc2ccccc2)c(Cl)c1=O
Reaction time: 8 h
Yield: 59.4 %

Procedure:
35.8 g (200 millimoles) of 4,5-dichloro-2-methylpyridazin-3(2H)-one are suspended in 300 ml of isopropanol and the suspension is colled to -20° C. A solution of 24.8 g (200 millimoles) of benzyl mercaptan and 20.2 g (200 millimoles) of triethylamine in 200 ml of isopropanol is added dropwise at this temperature, after which stirring is continued for 1 hour at -10° C. and overnight at room temperature. The resulting precipitate is filtered off under suction, washed with isopropanol and water and dried under reduced pressure to give 31.7 g (60%) of a product of melting point 102°-104° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[N:4][C:3]=1[C:8]([O:10]CC)=[O:9].[OH-].[Na+].Cl>O.C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[N:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1nnccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnnc1C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 169.6 %

Procedure:
To a solution of ethyl 4-methylpyridazine-3-carboxylate (240 mg, 1.4 mmol) in H2O/THF was added 7.5 N aq. NaOH (1.25 eq, 0.25 mL) and the mixture was stirred for 1 hour at 60° C. Concentrated HCl was added to pH 2 and subsequently the volatiles were removed in vacuo. The residue was first stirred with EtOAc and the solids were collected by filtration then stirred with THF and the solids were again collected by filtration. The solids were extracted with MeOH and removal of the volatiles afforded 4-methylpyridazine-3-carboxylic acid (328 mg) as a brown solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:6]2[CH:5]=[C:4]1[C:14]([O:16]CC)=[O:15])[CH3:2].[OH-].[Li+]>C1COCC1.CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:6]2[CH:5]=[C:4]1[C:14]([OH:16])=[O:15])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OC)cnc2n1CC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(C(=O)O)cc2cc(OC)cnc21
Reaction time: 0.01 h
Yield: 60.5 %

Procedure:
To a solution of ethyl 1-ethyl-5-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (60 mg, 0.24 mmol) in THF (2 ml) and MeOH (0.5 ml) was added lithium hydroxide (35 mg, 1.45 mmol) in water (2 mL). A cloudy solution formed which became clear after 30 s. The reaction mixture was allowed to stand at room temperature for 18 hr then concentrated under a stream of nitrogen. 2M HCl (2 ml, aqueous) was added to the crude product and the resulting solid filtered then dried under reduced pressure to give the title compound as an off-white solid (32 mg, 60%).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][CH2:29][C@H:28]([C:32]([O:34]CC)=[O:33])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:5])[CH3:4].CO>O>[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][CH2:29][C@H:28]([C:32]([OH:34])=[O:33])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)[C@H]1CCCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCC[C@H](C(=O)O)C3)ccc2n1CC1CCOCC1
Reaction time: 8 h

Procedure:
NaOH (0.15 mL, 2M, 0.3 mmol) was added to a solution of ethyl (3S)-1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}piperidine-3-carboxylate (265 mg, 0.54 mmol) in a 1:1 mixture of MeOH:H2O (10 mL) at ambient temperature. The reaction mixture was stirred overnight and diluted with water (50 mL). The solvent was concentrated to 50 mL. The resulting solution was neutralized with HCl solution, the product was extracted with EtOAc and dried over anhydrous Na2SO4. The solvent was concentrated to provide the title compound as white solid. Yield: 220 mg (88%); MS (ESI) (M+H)+=464.1.
Reaction SMILES: [OH-].[Li+].OC(CCCCNC(=O)C(F)(F)F)C(N1CCC[C@H]1C(OCC)=O)=O.FC(F)(F)C(NCCC[CH2:36][C@H:37]([O:50][P:51]([CH:55]([NH:60][C:61](=[O:85])[C@@H:62]([NH:78][C:79]([CH:81]1C[CH2:83][CH2:82]1)=[O:80])[CH2:63][CH2:64][CH2:65][CH2:66][NH:67][C:68]([O:70][CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)=[O:69])[CH2:56][CH2:57][CH2:58][CH3:59])([O:53]C)=[O:52])[C:38]([N:40]1[CH2:49][CH2:48][CH2:47][C@H:41]1[C:42]([O:44]CC)=[O:43])=[O:39])=O.N>O1CCOCC1.O.C(O)(C)C>[C:72]1([CH2:71][O:70][C:68]([NH:67][CH2:66][CH2:65][CH2:64][CH2:63][C@H:62]([NH:78][C:79]([CH:81]2[CH2:82][CH2:83]2)=[O:80])[C:61]([NH:60][CH:55]([P:51]([OH:53])([O:50][C@@H:37]([CH3:36])[C:38]([N:40]2[CH2:49][CH2:48][CH2:47][C@H:41]2[C:42]([OH:44])=[O:43])=[O:39])=[O:52])[CH2:56][CH2:57][CH2:58][CH3:59])=[O:85])=[O:69])[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1
Reactant: CCCCC(NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)C1CCC1)P(=O)(OC)O[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)N1CCC[C@H]1C(=O)OCC
Agent: CCOC(=O)[C@@H]1CCCN1C(=O)C(O)CCCCNC(=O)C(F)(F)F
Agent: N
Agent: [Li+]
Solvent: O
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCCCC(NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)C1CC1)P(=O)(O)O[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
1N Lithium hydroxide (10 ml.) is added to a solution of the ethyl ester product from part (c) (800 mg., 1.15 mmole) in p-dioxane (10 ml.) and the reaction mixture is worked up according to the procedure of Example 4 part (g) to yield 670 mg. of 1-[(S)-2-[[[1-[[(S)-6-[[(phenylmethoxy)carbonyl]amino]-2-[(cyclopropylcarbonyl)amino]-1-oxohexyl]amino]pentyl]hydroxyhosphinyl]oxy]-1-oxopropyl]-L-proline (isomer B). TLC (silica gel; isopropanol: ammonia:water, 7:2:1) Rf =0.43.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:18]3[N:19]=[C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)=[CH:26][C:25]=4[O:37][CH3:38])[N:21]=[CH:22][C:17]=3[CH:16]=[CH:15][C:14]2=[O:39])[CH:8]=1)=[O:5].[CH3:40][NH:41][CH3:42]>>[CH3:40][N:41]([CH3:42])[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:18]3[N:19]=[C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)=[CH:26][C:25]=4[O:37][CH3:38])[N:21]=[CH:22][C:17]=3[CH:16]=[CH:15][C:14]2=[O:39])[CH:8]=1)=[O:5]
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)CCCl)c3)c2n1
Reactant: CNC
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)CCN(C)C)c3)c2n1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
3-Chloro-N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)propanamide (57 mg, 0.086 mmol) was treated with dimethylamine (2.0 M in THF, 2.00 mL, 4.00 mmol) and stirred at 50° C. for 90 min then stirred at RT for 72 h. The reaction mixture was then purified by chromatography on silica gel on an ISCO Combiflash RF (24 g Redisep HP (Gold), using a gradient of 0-20% 2M NH3/MeOH in DCM) affording 3-(dimethylamino)-N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)propanamide (44.6 mg, 0.066 mmol, 76% yield) as a yellow-orange amorphous foam. m/z (ESI, +ve ion) 557.0 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.71 (1H, s), 7.92 (1H, d, J=9.4 Hz), 7.57-7.61 (1H, m), 7.56 (1H, s), 7.44 (1H, d, J=7.8 Hz), 7.06 (1H, d, J=8.0 Hz), 6.58 (1H, d, J=2.5 Hz), 6.53 (1H, d, J=9.4 Hz): 6.12 (1H, br. s.), 3.88 (3H, s), 3.10-3.19 (4H, m), 2.77 (2H, q, J=6.7 Hz), 2.63-2.68 (4H, m), 2.57-2.62 (2H, m), 2.39 (3H, s), 2.33 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:16][C:17]([O:19]C(C)(C)C)=O)=[C:4]([NH:8][C:9](OC(C)(C)C)=[O:10])[S:5][C:6]=1[CH3:7].C(OCC)(=O)C(OCC)=O.O>C(O)(=O)C>[CH3:7][C:6]1[S:5][C:4]2[NH:8][C:9](=[O:10])[C:17](=[O:19])[NH:16][C:3]=2[C:2]=1[CH3:1]
Reactant: Cc1sc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)c1C
Solvent: O
Solvent: CCOC(=O)C(=O)OCC
Solvent: CC(=O)O
Product: Cc1sc2[nH]c(=O)c(=O)[nH]c2c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
Crude di-t-butyl 4,5-dimethylthiophene-2,3-dicarbamate (9.7 g) was dissolved in 70 ml of acetic acid and 70 ml of diethyl oxalate and heated at reflux for three hours. 70 ml of water was added to the hot solution to precipitate the product. After 24 hours of stirring at room temperature the title compound was isolated by filtration, recrystallised from ethanol/acetic acid (65:35) to yield 1.5 g (41%) of crystals. M.p.>300° C. MS: 196. 1H-NMR (DMSO-D6, δ): 2.0 (s, 3H), 2.2 (s, 3H), 11.8 (s, 1H), 12.1 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH:9]=[CH:8]2.Br.[OH-].[Na+]>O>[OH:2][C:3]1[CH:4]=[C:5]([C:14]2[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH:9]=[CH:8]2
Reactant: COc1cc(-c2ccc(C)nc2C)cc2ccc(=O)[nH]c12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-c2cc(O)c3[nH]c(=O)ccc3c2)c(C)n1

Procedure:
A mixture of 8-methoxy-6-[2,6-dimethylpyrid-3-yl]-2-(1H)-quinolone (0.15 g) and 48% aqueous HBr (5 cm3) was heated under reflux for 19 hours. The mixture was diluted with water (20 cm3), basified to pH7 with 5M sodium hydroxide solution, and extracted with CHCl3 (3×50 cm3). The combined and dried (MgSO4) chloroform extracts were evaporated in vacuo to afford a solid which was recrystallised from ethyl acetate to give 8-hydroxy-6-[2,6-dimethylpyrid-3-yl]-2-(1H)-quinolone, m.p. 276°-277°, (0.132 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:18][CH2:17][C:14]3([CH2:16][O:15]3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.Cl([O-])(=O)(=O)=O.[Li+].C(#N)C>[Cl-].[Na+].O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:18][CH2:17][C:14]([CH2:16][NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=3)([OH:15])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: N#Cc1ccc(CCN2CCC3(CC2)CO3)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(NCC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Yield: 36.6 %

Procedure:
A mixture of the compound (242 mg) obtained in Step 3 of Example 1, methyl 4-aminobenzoate (756 mg), anhydrous lithium perchlorate (106 mg) and anhydrous acetonitrile (1 mL) was heated under reflux for two hours under nitrogen atmosphere. To the mixture was added brine (5 mL) and the residue was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solid residue obtained by removal of the solvent was washed two times by suspending in tert-butyl methyl ether to obtain the titled compound (144 mg) as powder.
Reaction SMILES: [NH3:1].[NH2:2][CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([O:12]CC)=O)[N:5]=1>C(O)C>[NH2:2][CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([NH2:1])=[O:12])[N:5]=1
Reactant: CCOC(=O)c1nc(CN)n(C)n1
Reactant: N
Solvent: CCO
Product: Cn1nc(C(N)=O)nc1CN
Reaction time: 8 h

Procedure:
Ammonia gas was passed for 20 minutes at −10° C. into a solution of 6.8 g (not more than 23.2 mmol) of ethyl 5-aminomethyl-1-methyl-1H-[1,2,4]-triazole-3-carboxylate in 200 ml of ethanol. Stirring was continued for one hour at 0° C. and overnight at room temperature. Since the reaction was incomplete, the procedure of passing in gas was repeated twice more (as described above) and the mixture was stirred overnight at 0° C. The mixture was concentrated on a rotary evaporator and the residue was purified by column chromatography (dichloromethane +5-10% methanol, Rf=0.3 in dichloromethane/methanol 9:1). This gave 4.71 g as colorless oil. 1H NMR (270 MHz, DMSO-d6): δ=1.4 (s, 9H), 3.85 (s, 3H), 4.3 (d, J=5 Hz, 3H), 7.4 (bs, 1H), 7.6 (bs, 1H), 7.65 (bs, J=5 Hz, 1H).
Reaction SMILES: C(S(O[CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C@@H:10]1[CH2:23]OS(CCC)(=O)=O)(=O)=O)CC.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)C.CO.[OH-].[Na+]>[CH2:31]([N:38]1[CH2:23][C@@H:10]2[C@H:9]([CH2:14][CH2:13][C@H:12]([OH:15])[C@H:11]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:8]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCS(=O)(=O)OC[C@H]1CC[C@H](O)[C@@H](c2ccccc2C)[C@@H]1COS(=O)(=O)CCC
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: Cc1ccccc1[C@H]1[C@@H]2CN(Cc3ccccc3)C[C@H]2CC[C@@H]1O
Temperature: 140 °C

Procedure:
In a pressure tube was placed a solution of crude [(1S,2R,3R,4S)-4-hydroxy-3-(2-methylphenyl)cyclohexane-1,2-diyl]di(methylene) dipropanesulfonate (Step 1.85 g, 184 mmol) in ˜120 mL ethanol and benzylamine (70.2 mL, 643 mmol). The pressure tube was sealed and heated at 140° C. in an oil bath for 3 hr. The tube was cooled to RT and opened. LC-MS showed that the reaction was completed. The resulting mixture was diluted with 180 mL methanol and 100 mL 5 N aq. NaOH. The ethanol, some of water and benzylamine were removed under vacuum. The residue was dissolved in ethyl acetate and diluted with water. The organic layer was separated and the aqueous was extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and the solvent was evaporated under vacuum. The combined organics were concentrated, and the residue oil was purified by column chromatography (1:9 methanol:ethyl acetate. 1H-NMR (CDCl3): δ: 7.35-7.10 (9H, m), 3.81-3.62 (3H, m), 2.94 (1H, t, J=8.1 Hz), 2.83 (1H, t, J=10.0 Hz), 2.52 (2H, m), 2.40 (1H, t, J=10.0 Hz), 2.36 (3H, s), 2.20 (1H, m), 2.02-1.85 (3H, m), 1.60 (1H, m), 1.36 (1H, m). M++1: 322.19.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[CH3:16][P:17]([C:20]1[N:25]=[C:24]([O:26][CH3:27])[C:23]([NH2:28])=[CH:22][CH:21]=1)([CH3:19])=[O:18]>>[Cl:15][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][C:2]([NH:28][C:23]2[C:24]([O:26][CH3:27])=[N:25][C:20]([P:17]([CH3:16])([CH3:19])=[O:18])=[CH:21][CH:22]=2)=[N:3][CH:4]=1
Reactant: COc1nc(P(C)(C)=O)ccc1N
Reactant: Clc1ncc(Cl)c(Nc2ccccc2)n1
Product: COc1nc(P(C)(C)=O)ccc1Nc1ncc(Cl)c(Nc2ccccc2)n1

Procedure:
This compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-phenylpyrimidin-4-amine with 6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in Example 32)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:15]([C:25]([OH:27])=[O:26])[CH2:14]2)=[CH:4][C:3]=1[O:28][CH3:29].[Si](C=[N+]=[N-])(C)(C)[CH3:31]>CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C@H:15]([C:25]([O:27][CH3:31])=[O:26])[CH2:14]2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc2ccnc(O[C@@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)c2cc1Br
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](Oc2nccc3cc(OC)c(Br)cc23)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a solution of compound 122 in MeOH (0.1 M) was added TMS-diazomethane (4.2 eq.) and the mixture was stirred at RT for 20 min. Volatiles were evaporated and the crude purified by chromatography to obtain 1-tert-butyl 2-methyl (2S,4R)-4-[(7-bromo-6-methoxyisoquinolin-1-yl)oxy]pyrrolidine-1,2-dicarboxylate as a pale orange foam (79%). To the previous compound dissolved in toluene (0.1 M) tetrakis-(triphenylphospin)-palladium(0) (0.1 eq.) and vinyltri-N-butyltin (1 eq) were added and the mixture was heated at 100° C. for 20 h. Volatiles were evaporated and the residue purified by chromatography to obtain 1-tert-butyl 2-methyl (2S,4R)-4-[(6-methoxy-7-vinylisoquinolin-1-yl)oxy]pyrrolidine-1,2-dicarboxylate as a pale yellow foam (45%) that was treated with HCl 4N in dioxane (26 eq) at RT. After 30 min volatiles were evaporated to obtain the title compound 123 in quantitative yield. MS (ES+) m/z 329 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9]O[C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+:21]>CN(C)C=O>[O:1]=[C:2]1[C:11]2[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][NH:21][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: [NH4+]
Reactant: CCOC(=O)c1coc2c1C(=O)CCCC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2c1C(=O)CCCC2
Temperature: 115 °C
Yield: 50.7 %

Procedure:
A mixture of ethyl 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-3-carboxylate (3.48 g,15.7 mmol ) and ammonium acetate (2.41 g, 31.3 mmol) in N,N-dimethylformamide (25 mL) was heated at 115° C. for 6 hours. The mixture was concentrated in vacuo, ice water was added, and extracted 2× with dichloromethane. The combined organic layers were washed with saturated aqueous sodium bicarbonate then brine, dried over sodium sulfate, filtered through a small pad of Silica gel (5% methyl alcohol / dichloromethane), and the filtrate concentrated in vacuo to give ethyl 4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylate (1.76 g). A solution of this ester in aqueous 5N sodium hydroxide (30 mL) and ethyl alcohol(6 mL) was heated at reflux for 1 hour, then cooled in an ice bath. The mixture was acidified with hydrochloric acid; the resulting precipitate was collected, rinsed with water followed by diethyl ether and allowed to dry to give 4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid (1.17 g). m.p. 225-227° C.