Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1C=CC=CC=1>[N:10]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)CCCCI
Reactant: C1CCNCC1
Solvent: c1ccccc1
Product: COC(=O)CCCCN1CCCCC1

Procedure:
30.0 g. (0.124 mole) of methyl δ-iodovalerate and 42.5 g. (0.50 mole) of piperidine were dissolved in 250 ml. of benzene and heated at 60° C. for 3 hours with stirring. A colorless solid began to appear shortly after the materials were combined. The solid was removed by suction filtration, and the benzene evaporated to give methyl δ-piperidinovalerate which distilled as 23.5 g. (95%) of colorless liquid, b.p. 122°-24° C. (12.5 mm.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:18]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:19])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(Cl)C1CCCCC1
Solvent: C1CCOC1
Product: O=C(O)c1cc(NC(=O)C2CCCCC2)ccc1Cl
Reaction time: 16 h
Yield: 98.1 %

Procedure:
A solution of 5-amino-2-chlorobenzoic acid (0.34 g, 2.0 mmol) in THF (10 mL) was charged with cyclohexanecarbonyl chloride (0.27 mL, 1.7 mmol). The reaction was stirred for 16 h and then concentrated in vacuo. The residue was suspended in DCM and filtered to afford the title compounds as a white solid (0.47 g, 97%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([CH3:12])([CH3:11])[C:9]#N)=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl.C(=O)([O-])[OH:25].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:25])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)c1ncccc1Br
Reactant: O=C([O-])O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C=O)c1ncccc1Br
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1.8 g of 2-(3-bromo-pyridin-2-yl)-2-methyl-propionitrile were dissolved in 20 ml of toluene. 5.9 ml of a 25% by weight toluene solution of diisobutylaluminum hydride were added thereto at 0° C. The mixture was stirred for 17 hours at room temperature. Subsequently, dilute hydrochloric acid was added thereto to dissolve the unreacted diisobutylaluminum hydride. Continuing, aqueous saturated sodium hydrogen carbonate solution was added thereto followed by extracting with ethyl acetate. The solvent of the organic phase was distilled off followed by purifying by silica gel column chromatography to obtain 0.44 g of 2-(3-bromo-pyridin-2-yl)-2-methyl-propioaldehyde.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH3:12])[CH3:2].[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH:15]=[CH:14]1>C1C=CC=CC=1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:14]([CH2:15][C:16]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:12])=[O:17])[C:13]([OH:18])=[O:19])=[C:4]1[CH3:12])[CH3:2]
Reactant: O=C1C=CC(=O)O1
Reactant: CCn1c(C)cc2ccccc21
Solvent: c1ccccc1
Product: CCn1c(C)c(C(=O)CC(C(=O)O)c2c(C)n(CC)c3ccccc23)c2ccccc21
Temperature: 25 °C
Yield: 30.8 %

Procedure:
A stirred mixture of 160.0 g (0.97 mole) of 1-ethyl-2-methylindole (95 percent assay), 40.0 g (0.408 mole) of maleic anhydride and 700 ml of benzene was heated at reflux for a period of approximately eighteen hours and then cooled to ambient temperature. The separated solid was collected by filtration and dried in vacuo at 60° C. to obtain 52.4 g of 2,4-bis(1-ethyl-2-methyl-3-indolyl)-4-oxobutanoic acid (Formula VII: R=CH3CH2 ; R1 =CH3 ; Y=H), a white solid melting over the range of 221°-225° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH2:17][C:18](=[C:22]=[O:23])[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2].[C:26]1([NH2:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:23])[NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=1)[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(C1=CC=CC(=C=O)C1)N2
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)Nc3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.3 %

Procedure:
A mixture of 2-(3-carbonyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (720 mg, 2 mmol), phenylamine (224 mg, 2.4 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.14 g, 3 mmol) in dichloromethane (5 mL) and triethyl-amine (0.7 mL, 5 mmol) was stirred at 25° C. for 12 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.8 g, 93%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C27H28N2O3 (M+H)+: 429.54, observed: 429.1.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:20]=3)[CH:18]=2)=[N:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:22]=[C:21]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=2)[N:20]=[C:19]([N:17]2[CH:18]=[C:14]([C:12]3[S:13][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][N:11]=3)[N:15]=[CH:16]2)[N:24]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.7 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-2-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.075 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (THF/hexane) to yielded the title compound as a light brown solid (0.037 g, 18%). MS (ISN) 519.0 [(M−H)−]; mp 264° C.
Reaction SMILES: B.C1COCC1.B(F)(F)F.CCOCC.[F:16][C:17]1[CH:41]=[CH:40][C:20]([CH2:21][C@H:22]2[C:26](=O)[N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:24]([C:35]([O:37]CC)=[O:36])[CH2:23]2)=[CH:19][CH:18]=1.[Cl-].[NH4+].[OH-].[Li+]>C(Cl)Cl.O>[C:31]([O:30][C:28]([N:25]1[CH2:26][C@H:22]([CH2:21][C:20]2[CH:40]=[CH:41][C:17]([F:16])=[CH:18][CH:19]=2)[CH2:23][C@H:24]1[C:35]([OH:37])=[O:36])=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(=O)[C@@H]1C[C@@H](Cc2ccc(F)cc2)C(=O)N1C(=O)OC(C)(C)C
Agent: B
Agent: FB(F)F
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(F)cc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Step (c) 1M borane in THF (10 mL, 10 mmol) followed by boron trifluoride diethyl etherate (1.25 mL, 10 mmol) were added to a solution of (2S,4R)-1-tert-butyl 2-ethyl 4-(4-fluorobenzyl)-5-oxopyrrolidine-1,2-dicarboxylate (1.8 g, 5 mmol) in methylene chloride (20 mL) at 0° C. The reaction was allowed to warm to ambient temperature while stirring for 1 hour. The mixture was cooled to 0° C. and then saturated ammonium chloride (25 mL) was slowly added. Water was added to dissolve precipitated solids and then the mixture was extracted with methylene chloride. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in methanol (15 mL) and then water (5 mL) followed by lithium hydroxide (1.05 g, 25 mmol) were added to the solution. The mixture was stirred at ambient temperature for 1 hour, concentrated under reduced pressure and diluted with water (20 mL). The aqueous solution was partitioned with methyl tert-butyl ether and the aqueous phase was separated, filtered, cooled to 0° C., acidified (pH≦3) with 6N hydrochloric acid and extracted twice with methylene chloride. The combined extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give (2S,4R)-1-(tert-butoxycarbonyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxylic acid (1.31 g, 81%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.22-7.18 (m, 2H), 7.03-6.99 (m, 2H), 4.29-4.22 (m, 2H), 3.57-3.50 (m, 1H), 3.07 (dd, J=8.0, 10.4, 1H), 2.68-2.65 (m, 2H), 2.58-2.50 (m, 1H), 2.04-1.97 (m, 2H), 1.44, 1.41 (2 s, 9H); MS (EI) for C17H22FNO4. found 322.1 (M-H)−.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH2:19][CH2:18][N:17]3[S:24]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])(=[O:26])=[O:25])=[O:13])=[CH:7][CH:6]=1)C.[OH-].[Na+]>O1CCCC1.CO>[Cl:33][C:31]1[CH:30]=[CH:29][C:28]([O:34][CH3:35])=[C:27]([S:24]([N:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:36])=[O:3])=[CH:6][CH:7]=4)=[O:13])[CH:15]=3)[NH:20][CH2:19][CH2:18]2)(=[O:26])=[O:25])[CH:32]=1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCN3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCNc2ccc(C(=O)Nc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-benzoic acid ethyl ester (30 mg, 0.06 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was treated with NaOH 2N (2 mL) and warmed until a clear solution was obtained. The mixture was stirred at room temperature 2 hours, the organic solvents were then partially removed. The aqueous slurry was acidified with HCl 1N (4 mL) and the resulting precipitate filtered, washing with water. 4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-benzoic acid was obtained as a white solid, 26 mg (91%), MS (ISP): m/e=499.9, 501.9 (M−H); δH (300 MHz; d6-DMSO) 12.67 (1H, s), 10.15 (1H, s), 7.91 (4H, s), 7.89 (1H, s), 7.81 (1H, s), 7.73 (1H, d), 7.63 (1H, d), 7.23 (1H, d), 6.88 (1H, bs), 6.66 (1H, d), 3.64 (2H, bs), 3.53 (3H, s), 2.99 (2H, bs).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:16][CH:17]([CH3:19])[CH3:18])/[CH:10]=[CH:11]/[C:12]([O:14]C)=[O:13])=[O:7])([CH3:4])[CH3:3].O.[Li+].[OH-]>C1COCC1.CO>[CH3:4][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:16][CH:17]([CH3:19])[CH3:18])/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[O:7])([CH3:1])[CH3:3]
Reactant: COC(=O)/C=C/[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](/C=C/C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of methyl (2E,4S)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-6-methyl-2-heptenoate (5.00 g, 18.43 mmol) in THF (15 mL), MeOH (15.0 mL), and water (15 mL) was added LiOH (2.206 g, 92.00 mmol). After stirring for 2 h at RT, the reaction mixture was concentrated in vacuo. The reaction mixture was acidified with 6 M aq. HCl to pH=5 and then extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (4.7 g, 99%) as a white semi-solid. LC-MS m/z 158 (M+H-Boc)+, 0.94 min (ret time).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[C:12]3/[C:13](=[O:21])[NH:14][C:15]4[C:20]/3=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:8][CH:9]=2)[NH:4][N:3]=1.N1C2C(=CC=CC=2)CC1=O.N1C2C(=CC=C(C=O)C=2)C=N1>>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7](/[CH:11]=[C:12]3/[C:13](=[O:21])[NH:14][C:15]4[C:20]/3=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:6]=2)[CH:2]=[N:3]1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2c(I)n[nH]c2c1
Agent: O=C1Cc2ccccc2N1
Agent: O=Cc1ccc2cn[nH]c2c1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2cn[nH]c2c1
Yield: 51 %

Procedure:
According to the method described for (E)-3-((3-iodo-1H-indazol-6-yl)methylene)-indolin-2-one, oxindole (67 mg, 0.216 mmol) and 1H-indazole-6-carbaldehyde (73 mg, 0.238 mmol) gave (E)-3-((1H-indazol-6-yl)methylene)indolin-2-one (32 mg, 51%). 1H NMR (400 MHz, CD3OD) δ 8.14 (s, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.89 (s, 2H), 7.65 (d, J=7.6 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.25 (t, J=7.7 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 6.87 (t, J=7.6 Hz, 1H); MS ESI 262.0 [M+H]+, calcd for [C16H11N3O+H]+ 262.10.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>>[CH2:33]([N:35]([CH2:36][CH3:37])[C:9]1[C:8]2[C:13](=[CH:14][C:15]([Cl:16])=[C:6]([NH:5][CH2:4][C:3]3[C:2]([CH3:1])=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:32])[CH:7]=2)[N:12]=[C:11]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:10]=1)[CH3:34]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: CCNCC
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(NCc3c(C)cccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI): predicted mass calcd. for C25H27ClN6O2, 479.0
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[CH:7]=1>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:5]([NH2:16])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1ccccc1F
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(5-Fluoro-2-nitrophenyl)-(2-fluorophenyl)amine (3.04 g, 12.16 mmol) was dissolved in EtOAc (120 mL) and the flask evacuated and flushed with nitrogen gas. 10% Pd/C (0.3 g) was added and the reaction mixture stirred under an atmosphere of hydrogen gas, at RT overnight. A further amount of 10% Pd/C (0.3 g) was added and the reaction mixture stirred under an atmosphere of hydrogen gas for an extra 2 h. The resultant mixture was filtered through Celite® and the filtrate concentrated in vacuo to afford the title compound as a dark yellow oil, which solidified on standing (2.89 g, 95%). 1H NMR (CDCl3, 400 MHz): δ 7.05-6.87 (2H, m), 6.83-6.68 (3H, m), 6.68-6.59 (2H, m), 5.36 (1H, s), 3.49 (2H, s)
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.[H-].[Na+].CI.[C:20](=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.CN(C)C=O>[CH3:20][N:13]1[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=3)[C:9]=2[CH:11]=[CH:12]1
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CI
Product: Cn1ccc2c3c(N)nc(N)nc3ccc21
Reaction time: 1 h

Procedure:
A solution of 5.98 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 200 ml. dry dimethylformamide is stirred under nitrogen and 1.58 g. ca. 50% sodium hydride-mineral oil dispersion is added carefully. After stirring for one hour, a solution of 4.47 g. (2.0 ml.) methyl iodide in 10 ml. dry dimethylformamide is added and stirring is continued. Two hours later, 15 ml. gl. acetic acid are added and the reaction mixture is freed of solvent (in vacuo). The residue is stirred with excess aqueous potassium carbonate solution for several hours and the solids are collected, washed with water and dried. A solution of this crude product in 200 ml. water-10 ml. gl. acetic acid is washed with ether. Basification of the acidic solution gives a precipitate that is washed with water and then is crystallized from methanol-acetone to yield 3.44 g. title compound as a hydrate bearing one-third molecule of water per molecule of diamine, m.p. 250°; NMR (dDMSO): δ 3.88 (singlet, 7-CH3), 7.02 (doublet, J=3Hz, 9H), 7.15 (doublet, J=9Hz, 5 or 6H), 7.41 (doublet, J=3Hz, 8H), 7.72 (doublet, J=9Hz, 5 or 6H) p.p.m.; λmax95%EtOH 234 (ε 25,280), 258 (ε 24,540), 317 (ε 9,090), 345 sh (ε 7,810) nm; λmin95%EtOH 243 (ε 23,570), 280 (ε 2,040)nm.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[C:19]([OH:21])=O)=O)(C)(C)C.[N:22]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:33])[CH:26]=[CH:25][CH:24]=[CH:23]1>>[C:15]([O:14][N:13]=[C:11]1[CH2:12][NH:8][C@H:9]([C:19]([NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)=[O:21])[CH2:10]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: Nc1ccccc1-n1cccc1
Reactant: CC(C)(C)ON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CC(C)(C)ON=C1CN[C@H](C(=O)Nc2ccccc2-n2cccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylic acid, and 2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in 83% purity by LC/MS. MS(ESI+): m/z=341.2.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([Br:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](OC(=O)C)(=[O:18])[CH3:17].S(=O)(=O)(O)O>>[C:16]([O:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([Br:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:18])[CH3:17]
Reactant: C=CCc1c(Br)ccc(C(=O)OC)c1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: C=CCc1c(Br)ccc(C(=O)OC)c1OC(C)=O

Procedure:
254 g of methyl 2-hydroxy-3-allyl-4-bromobenzoate and 191 g of acetic anhydride were introduced into a 1-liter round-bottomed flask and 2 ml of sulphuric acid were then added.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](Cl)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:29][O:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[CH3:29][O:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[C:34]([C:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:9][CH2:10][N:5]([C:3]([N:2]([CH3:28])[CH3:1])=[O:4])[CH2:6][CH2:7]4)=[CH:13][C:14]=3[N:15]=2)=[CH:33][N:32]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Reactant: CN(C)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)N(C)C)CC4)cc3n2)c(OC)n1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid dimethylamide was reacted with 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine in General Procedure A. Purification on silica yielded 109. NMR (CDCl3): 2.48-2.51 (m, 4H, 2×CH2), 2.76 (s, 6H, 2×CH3), 3.21-3.24 (m, 4H, 2×CH2), 3.77-3.80 (m, 4H, 2×CH2), 3.93-3.96 (m, 4H, 2×CH2), 3.99 (s, 3H, CH3), 4.01 (s, 3H, CH3), 7.25 (s, H, ArH), 8.83 (s, H, ArH). MS: (ESI+): MH+=529.35
Reaction SMILES: NC(N)=N.[N+]([O-])(O)=O.NC(N)=N.C([O:16][CH:17]1[C:18]([O:72][CH:73]([O:75][CH2:76][CH3:77])[CH3:74])([CH3:71])[CH2:19][CH2:20][CH:21]([O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH2:22][C:23]([O:25][CH:26](/[C:31](/[CH3:62])=[CH:32]/[CH:33]=[CH:34]/[C:35]([CH3:61])([O:53][Si:54]([CH2:59][CH3:60])([CH2:57][CH3:58])[CH2:55][CH3:56])[CH2:36][CH:37]2[O:52][CH:38]2[CH:39]([CH3:51])[CH:40]([O:43][Si:44]([CH2:49][CH3:50])([CH2:47][CH3:48])[CH2:45][CH3:46])[CH2:41][CH3:42])[CH:27]([CH3:30])[CH:28]=[CH:29]1)=[O:24])(=O)C.COC(C)(C)C.[Cl-].[NH4+]>CO>[CH2:76]([O:75][CH:73]([O:72][C:18]1([CH3:71])[CH:17]([OH:16])[CH:29]=[CH:28][CH:27]([CH3:30])[CH:26](/[C:31](/[CH3:62])=[CH:32]/[CH:33]=[CH:34]/[C:35]([CH3:61])([O:53][Si:54]([CH2:59][CH3:60])([CH2:57][CH3:58])[CH2:55][CH3:56])[CH2:36][CH:37]2[O:52][CH:38]2[CH:39]([CH3:51])[CH:40]([O:43][Si:44]([CH2:45][CH3:46])([CH2:49][CH3:50])[CH2:47][CH3:48])[CH2:41][CH3:42])[O:25][C:23](=[O:24])[CH2:22][CH:21]([O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH2:20][CH2:19]1)[CH3:74])[CH3:77]
Reactant: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)CC(=O)OC(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)O[Si](CC)(CC)CC)O[Si](CC)(CC)CC)C(C)C=CC1OC(C)=O
Agent: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)CC(=O)OC(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)O[Si](CC)(CC)CC)O[Si](CC)(CC)CC)C(C)/C=C/C1O
Agent: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)CC(=O)OC(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)O[Si](CC)(CC)CC)O[Si](CC)(CC)CC)C(C)/C=C/C1OC(C)=O
Agent: N=C(N)N
Solvent: O=[N+]([O-])O
Solvent: CO
Solvent: COC(C)(C)C
Product: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)CC(=O)OC(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)O[Si](CC)(CC)CC)O[Si](CC)(CC)CC)C(C)C=CC1O
Temperature: 24.700000762939453 °C
Reaction time: 6 h

Procedure:
Under a nitrogen atmosphere and warming to hold the outside temperature at 25° C., 104 mL (20.8 mmol) of a 0.2 M solution of guanidine/guanidine nitrate in methanol was added to a methanol (79 mL) solution containing 18.4 g of (8E,12E,14E)-7-acetoxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide, following which stirring was carried out for 6 hours with maintaining the internal temperature at from 24.9 to 24.5° C. The reaction mixture was then ice-cooled and 276 mL of t-butyl methyl ether was added, following which 184 mL of a 10% aqueous solution of ammonium chloride was added. The organic phase was then separated, washed successively with water (184 mL) and a 4% saline solution (184 mL), and subsequently dried over magnesium sulfate (18.4 g). After drying, the magnesium sulfate was removed by filtration, following which the filtrate was washed with t-butyl methyl ether (55 mL) then evaporated at 40° C., yielding 19.7 g of a crude form (yellow oily substance) of the title compound (content: 73.4%; by weight, 14.5 g).
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[N:18]1([CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[C:30](OCC)=O)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(O)(=O)C>C(O)C.O.CCOCC>[CH:2]1([N:7]2[C:11]3=[N:12][C:30]([C:29]4[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=4[O:27][CH2:26][CH2:25][CH2:24][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1ccccc1OCCCN1CCOCC1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccccc3OCCCN3CCOCC3)nc(=O)c1-2
Temperature: 25 °C
Yield: 65.9 %

Procedure:
Sodium spheres (0.42 g) were dissolved in ethanol (20 ml) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.02 g, 9.10 mmol) was added, followed by ethyl 2-[3-(4-morpholinyl)propoxy]benzoate (5.33 g). The reaction mixture was refluxed for 3 days, then stirred at room temperature, and then the solvent was stripped. The residue was dissolved in water (250 ml), acidified to a pH of about 7 with acetic acid and extracted with CHCl3. The organic layers were washed with brine, dried over MgSO4 and stripped to afford an oil. The oil was taken up in ether, filtered and the filtrate was stripped and purified by column chromatography on silica eluting with EtOAc (100%) followed by EtOAc/MeOH (80/20) to afford 2.71 g of 1-cyclopentyl-3-ethyl-6-[2-[3-(4-morpholinyl)propoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one, as a liquid [labelled as Example 26(b)]. The free base was treated with EtOH.HCl and 1.14 g of the hydrochloride salt (labelled as Example 26(c) was obtained, m.p. 220°-221° C.