Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].C(N(CC)CC)C.Cl.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29]([C@@H:31]3[CH:36]4[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]4)[CH2:32]3)=[O:30])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:1]([NH:3][C:4]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:29]([C@@H:31]3[CH:36]4[CH2:35][CH2:34][N:33]([CH2:38][CH2:37]4)[CH2:32]3)=[O:30])=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reactant: CCN=C=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reaction time: 18 h

Procedure:
21.6 mg (0.30 mmol) of ethyl isocyanate and 84.8 μl (0.61 mmol) of triethylamine are added to a solution of 60 mg (0.15 mmol) of ((3R)-N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at room temperature, 5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction, washed with water and dried under high vacuum. 57 mg (88.0% of theory) of the title compound are obtained.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].[C:15]([CH2:18][C:19](=O)[CH3:20])(=[O:17])[CH3:16]>>[NH2:10][C:9]1[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=[C:19]([CH3:20])[C:18]=1[C:15](=[O:17])[CH3:16]
Reactant: N#Cc1ccccc1N
Reactant: CC(=O)CC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CC(=O)c1c(C)nc2ccccc2c1N

Procedure:
1-(4-Amino-2-methylquinolin-3-yl)ethanone was prepared analogously to Intermediate 2a, Example 6, by tin tetrachloride-promoted reaction of 2-aminobenzonitrile and acetyl acetone in a manner known from the literature (Tetrahedron 51:12277 (1995)).
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10](=S)[NH:9][C:8](=[S:14])[N:7]([CH2:15][CH3:16])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH2:17]([NH2:19])[CH3:18].C>O>[CH:1]1([C:4]2[NH:12][C:11]3[C:10]([NH:19][CH2:17][CH3:18])=[N:9][C:8](=[S:14])[N:7]([CH2:15][CH3:16])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: CCn1c(=S)[nH]c(=S)c2[nH]c(C3CC3)nc21
Reactant: CCN
Solvent: O
Product: CCNc1nc(=S)n(CC)c2nc(C3CC3)[nH]c12
Temperature: 150 °C

Procedure:
8-cyclopropyl-3-ethyl-2,6-dithioxanthine (20.19 g) prepared according to the method of example 2(i), and 70% ethylamine in water (320 ml 4.0M) were placed in a 450 ml pressure reactor and heated to 150° C. for 6 hours. The reaction solution was cooled to room temperature, treated with 2 portions of charcoal (0.2 g) filtered, and evaporated to dryness. The residue was triturated in menthol (300 ml), concentrated to about 200 ml, and the solid collected (16.48 g), mp 265° with decomposition.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][S:12]([CH2:15][CH2:16][C:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:19])[CH3:18])(=[O:14])=[O:13].[CH2:31](I)[CH3:32]>CN(C=O)C.CCOC(C)=O>[CH2:31]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][S:12]([CH2:15][CH2:16][C:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH3:18])[CH3:19])(=[O:13])=[O:14])[CH3:32]
Reactant: CC(C)(CCS(=O)(=O)CCOCCOCCO)NC(=O)OCc1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCCOCCOCCS(=O)(=O)CCC(C)(C)NC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 26.8 %

Procedure:
A solution of 60% sodium hydride (50 mg, 1.3 mmol) in DMF (4 ml) was cooled to 0° C. under N2 and benzyl 4-(2-(2-(2-hydroxyethoxy)ethoxy)ethylsulfonyl)-2-methylbutan-2-ylcarbamate (419.6 mg, 1.005 mmol) in DMF (1 ml) was added dropwise. Ethyl iodide (100 ul, 1.25 mmol) was added dropwise. The solution was stirred for 3 h, diluted with EtOAc (300 ml), washed with 2×100 ml sat. NaCl, dried on MgSO4, and concentrated in vacuo. The resulting residue was purified by flash chromatography (30% to 80% EtOAc in hexanes) to afford the title compound as a clear oil (119.8 mg, 0.2691 mmol, 27%). 1H NMR (CDCl3, 400 MHz) δ 1.18 (t, J=4.4 Hz, 3H), 1.32 (s, 6H), 2.17-2.21 (m, 2H), 3.12-3.17 (m, 2H), 3.48-3.58 (m, 10H), 3.87 (dd, J=5.6, 5.6 Hz, 2H), 5.03-5.06 (m, 3H), 7.3-7.4 (m, 5H). LRMS (ESI/APCI): 446 [M+H]+, 468 [M+Na]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[C:13]1(/[CH:19]=[CH:20]/B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C(Cl)(Cl)Cl.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>[CH:20](/[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1)=[CH:19]\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: O=C1COc2ccc(Br)nc2N1
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: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=C1COc2ccc(/C=C/c3ccccc3)nc2N1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (10.0 g, 44 mmole) and trans-2-phenylvinylboronic acid (9.0 g, 61 mmole), were dissolved in 1,4-dioxane (200 mL) and the solution was degassed with argon. (Ph3P)4Pd (2.5 g, 2.2 mmole) was added, followed by a solution of K2CO3 (15 g, 109 mmole) in H2O (100 mL). The reaction was heated at reflux under argon overnight, then was cooled to room temperature and diluted with chloroform (400 mL). The solution was washed sequentially with H2O and brine, dried (Na2SO4), and concentrated in vacuo. The solid residue was recrystallized from hot EtOAc to afford the title compound (6.4 g, 57.5%): LC-MS (ES) m/e 253 (M+H)+.
Reaction SMILES: C[S:2]([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[C:8]([C:34]#[N:35])=[CH:7][N:6]=1)(=O)=O.[C:36]1(S)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CCN(C(C)C)C(C)C.O[Li].O>C1COCC1.O>[C:36]1([S:2][C:5]2[N:10]=[C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=4)[NH:13][CH:12]=3)[C:8]([C:34]#[N:35])=[CH:7][N:6]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Sc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Agent: [Li]O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1cnc(Sc2ccccc2)nc1-c1c[nH]c2ncc(C(F)(F)F)cc12
Reaction time: 1.5 h
Yield: 47 %

Procedure:
2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (75 mg, 0.15 mmol) was heated with benzenethiol (31 uL, 0.30 mmol, 2.0 Eq.) and DIPEA (78 uL, 0.45 mmol, 3.0 Eq.) in THF (2 mL) under microwave conditions at 100° C. for 10 minutes. A solution of LiOH.H2O (32 mg, 0.75 mmol, 5.0 Eq.) in water (1 mL) was added to the mixture and the reaction left to stir for 90 minutes. The reaction was partitioned between EtOAc and water and the aqueous phase extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resultant solid was purified by column chromatography (ISCO Companion™, 12 g column, 0-30% EtOAc/Petroleum Ether) and lyophilized to give the title compound as a pale yellow solid (28 mg, 47% over 2 steps).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[C:12](=[O:14])=[O:13].CCOCC>O1CCCC1.O.C(OCC)C>[F:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[C:4]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=O
Reactant: Fc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: O=C(O)c1c(F)cccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 5 h

Procedure:
A mixture of 3-fluorobenzotrifluoride (25.0 g, 0.15 mol) in tetrahydrofuran (200 ml) was cooled to -78° C. in a dry ice/acetone bath under nitrogen atmosphere. To this solution was added dropwise with rapid stirring N-butyl lithium (1.6M, 95.2 ml) at such rate that the temperature did not exceed -60° C. When the addition was complete, the mixture was allowed to stir at -78° C. for an additional five hours. The mixture was then poured over a slurry of dry ice/ether and allowed to come to room temperature. The solvent was removed by evaporation under reduced pressure to obtain a white solid residue. This solid was dissolved in a minimum amount of water, the solution was extracted with diethyl ether (2×100 ml) and the aqueous phase was acidified to pH 2 with dilute hydrochloric acid. An oil formed and this was dissolved in diethyl ether; the solution was washed several times with water and dried over magnesium sulfate. The solvent was removed by evaporation under reduced pressure to give a white solid. NMR analysis indicated this product was a mixture of the title compound and an isomer. A yield of 15.6 g (50 percent of theory) was obtained.
Reaction SMILES: [I-].[Li+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[C:11](C(OC)=O)([CH2:15][CH:16]=[CH2:17])[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:9][C:8]=2[CH:30]=1.C(OCC)(=O)C>N1C=CC=CC=1.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH:11]([CH2:15][CH:16]=[CH2:17])[CH:10]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH2:9][C:8]=2[CH:30]=1
Reactant: C=CCC1(C(=O)OC)C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: C=CCC1C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Lithium iodide (0.90 g; 6.7 mmole) was added to 7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-3-(2-propenyl)-2H-1-benzazepin-2-one (670 mg; 1.68 mmole) in pyridine (5 ml), three drops of water were added, and the mixture was refluxed with stirring overnight. The solution was dissolved into ethyl acetate and washed with 1N hydrochloric acid (three times). The organic layer was dried (magnesium sulfate) and concentrated. The crude, brownish solid was dissolved into ethyl acetate and suction-filtered through a pad of silica gel (to remove some of the brown color). The silica gel was rinsed several times with ethyl acetate, and the organic solution was concentrated and vacuum dried, leaving 0.52 g of the title compound as an off-white solid.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C@@H:12]([C@@H:20]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:21]([NH:23][NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[N:34]1([CH2:39][C:40](O)=[O:41])[CH:38]=[CH:37][N:36]=[CH:35]1.C(N1CCOCC1)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:9][CH2:10][CH2:11][C@@H:12]([C@@H:20]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:21]([NH:23][N:24]([C:40](=[O:41])[CH2:39][N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1)[CH2:25][CH:26]([CH3:27])[CH3:28])=[O:22])[C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](CCNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(O)Cn1ccnc1
Agent: Br
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)Cn1ccnc1)[C@H](CCNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A solution of 0.763 g of 2(R)-[3-benzamido-1(S)-(tert-butoxycarbonyl)propyl]-2′-isobutyl-4-methylvalerohydrazide and 0.780 g of 2-(1H-imidazol-1-yl)acetic acid hydrogen bromide in 8 ml of dimethylformamide was cooled to 0° C. under nitrogen and treated with 0.45 ml of N-ethylmorpholine and 0.720 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. Evaporation of the solvent gave a residue which was dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride. Drying over anhydrous magnesium sulfate, filtration, and evaporation gave 0.914 g of 2(R)-[3-benzamido-1(S)-(tert-butoxycarbonyl)propyl]-2′-[2-(1H-imidazol-1-yl)acetyl]-2′-isobutyl-4-methylvalerohydrazide in the form of an off-white foam.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:9])[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(Cl)Cl.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN(C)C=O.[C:49]1([S:55]([N:58]2[C:62]3=[N:63][CH:64]=[C:65]([NH2:73])[C:66]([NH:67][CH:68]4[CH2:72][CH2:71][O:70][CH2:69]4)=[C:61]3[CH:60]=[CH:59]2)(=[O:57])=[O:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:49]1([S:55]([N:58]2[C:62]3=[N:63][CH:64]=[C:65]([NH:73][C:6]([C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:9])=[O:8])[C:66]([NH:67][CH:68]4[CH2:72][CH2:71][O:70][CH2:69]4)=[C:61]3[CH:60]=[CH:59]2)(=[O:56])=[O:57])[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCOC1
Reactant: CC(=O)O[C@H](C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](C)C(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCOC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
(R)-2-acetoxypropanoic acid (0.306 g, 2.32 mmol) was dissolved in methylene chloride (20 mL, 200 mmol;). Triethylamine (0.42 mL, 3.0 mmol;) was added, followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.972 g, 2.56 mmol;) dissolved in N,N-dimethylformamide (2 mL, 20 mmol;). After 15 minutes, 1-benzenesulfonyl-N-(tetrahydro-furan-3-yl)-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (0.728 g, 2.03 mmol) was added and the reaction was stirred 64 h at room temperature. The volatiles were removed under reduced pressure and the residue was dissolved in 100 ml EtOAc. This was shaken with 50 ml saturated aqueous NaHCO3. The layers were separated and the aqueous phase was extracted with EtOAc (2×50 ml). The combined organics were dried with MgSO4, filtered and concentrated. This material was then dissolved in a minimum volume of CH2Cl2 and injected onto a 40 g silica gel column which had been equilibrated with heptane. It was then eluted with a gradient of 0% to 100% ethyl acetate in heptane. The product containing fractions were combined and evaporated under reduced pressure to give the title compound as a clear oil (0.596 g, 62%). 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=7.6 Hz, 2H), 7.88 (s, 1H), 7.60-7.43 (m, 4H), 7.21 (d, J=7.2 Hz, 1H), 6.62 (d, J=4.1 Hz, 1H), 5.11-4.95 (m, 2H), 4.59-4.48 (m, 1H), 4.01-3.74 (m, 4H), 2.33-2.21 (m, 1H), 2.19 (d, J=3.3 Hz, 3H), 2.03-1.95 (m, 1H), 1.59 (d, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH3:15])[CH:9]=[C:8]2Cl)(=[O:3])[CH3:2].C(NC1C=C2C(=CC=1)NC(C)CC2)(=O)C.N1C2C(=CC=CC=2)CCC1.C([O:44][CH:45]=[C:46]([C:52](OCC)=O)[C:47]([O:49]CC)=[O:48])C.NC1C=C2C3N(C=C(C(O)=O)C2=O)C(C)CCC=3C=1.C(OC(=O)C)(=O)C>>[C:1]([NH:4][C:5]1[CH:14]=[C:13]2[C:12]3[N:11]([CH:52]=[C:46]([C:47]([OH:49])=[O:48])[C:45]2=[O:44])[CH:10]([CH3:15])[CH2:9][CH2:8][C:7]=3[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(=O)Nc1ccc2nc(C)cc(Cl)c2c1
Agent: CC(=O)Nc1ccc2c(c1)CCC(C)N2
Agent: CC1CCc2cc(N)cc3c(=O)c(C(=O)O)cn1c23
Agent: c1ccc2c(c1)CCCN2
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc2c3c(c1)c(=O)c(C(=O)O)cn3C(C)CC2
Temperature: 140 °C

Procedure:
6-Acetamido-4-chloro-2-methylquinoline is reduced catalytically to the novel compoound 6-acetamido-2-methyl-1,2,3,4-tetrahydroquinoline. The tetrahydroquinoline is condensed with diethyl ethoxymethylenemalonate by heating without a solvent for 1 hour at 140° C. Polyphosphoric acid is added, and the solution is heated at 100° C. for one-half hour. The product, 9-amino-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid is reacted with acetic anhydride as described in Example 49 to provide 9-acetamido-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. >310° C. The product is characterized by spectral analysis and elemental analysis, which are found to be consistent with the indicated structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH3:31][S:32]([NH:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:31][S:32]([NH:35][C:36]1[CH:37]=[C:38]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][N:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)[CH:39]=[CH:40][CH:41]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
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
Product: CS(=O)(=O)Nc1cccc(-c2cc(C(N)=O)c3[nH]nc(C4CCN(S(=O)(=O)CCCN5CCCC5)CC4)c3c2)c1
Yield: 17.7 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 27) (24 mg, 0.048 mmols), {3-[(methylsulfonyl)amino]phenyl}boronic acid (31 mg, 0.144 mmols), potassium carbonate (40 mg), and Pd(PPh3)4 (3 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (5 mg, 18%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[CH:46][CH:47]=[C:26]([F:25])[CH:27]=4)=[CH:35][CH:34]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: CC1(C)OB(c2ccc(Oc3cccc(F)c3)cc2)OC1(C)C
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4)cc3)c3c(N)ncnc32)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
Into a 100 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv), 2-[4-(3-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (255 mg, 0.81 mmol, 1.20 equiv), sodium carbonate (143 g, 1.35 mol, 1998.01 equiv), ethylene glycol dimethyl ether (50 mL), water (15 mL), and Pd(PPh3)4 (40 mg, 0.03 mmol, 0.05 equiv). The resulting solution was stirred overnight at 80° C. and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 260 mg (76%) of tert-butyl (3R)-3-[4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:50]1[CH2:55][CH2:54][CH:53]([O:56][C:57]2[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=2)[C:60]#[N:61])[CH2:52][CH2:51]1>CN(C=O)C.O>[C:60]([C:59]1[CH:58]=[C:57]([CH:64]=[CH:63][CH:62]=1)[O:56][CH:53]1[CH2:54][CH2:55][N:50]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[N:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:51][CH2:52]1)#[N:61]
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)nn1
Reactant: N#Cc1cccc(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(OC2CCN(C(=O)CNC(=O)c3cn(-c4ccccc4)nn3)CC2)c1
Reaction time: 0.03 h
Yield: 32.6 %

Procedure:
DIPEA (167.9 mg, 1.3 mmol) was added to a stirred solution of [(1-phenyl-1H-[1,2,3]triazole-4-carbonyl)-amino]-acetic acid (80 mg, 0.32 mmol) in DMF (3 mL) followed by HOBt (48.2 mg, 0.35 mmol) and EDCI (124.5 mg, 0.65 mmol). After 2 minutes of stirring, 3-(piperidin-4-yloxy)-benzonitrile hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (77.5 mg, 0.32 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was added and precipitate was collected. The solid was purified by column chromatography (using 70% ethyl acetate in hexane as eluent) to afford 45 mg (32.6% Yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(3-cyano-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 431.18, 85.06%. 1H NMR (300 MHz, DMSO-d6): δ 9.35 (s, 1H), 8.5 (t, 1H), 8.0 (d, 2H), 7.7-7.6 (m, 2H), 7.58-7.45 (m, 3H), 7.45-7.32 (m, 2H), 4.75 (m, 1H), 4.2 (d, 2H), 4.0-3.9 (m, 1H), 3.8-3.7 (m, 1H), 2.1-1.9 (m, 2H), 1.75-1.5 (m, 2H).
Reaction SMILES: [CH:1]1[C:6]([C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])=[CH:5][CH:4]=[C:3]([NH:19][CH2:20][CH2:21][C:22]2[N:27]=[C:26]3[C:28]([N:30]=[C:31]([NH2:33])[NH:32][C:25]3=[N:24][CH:23]=2)=[O:29])[CH:2]=1.[H][H]>[Pt]=O>[CH:5]1[C:6]([C:7]([NH:9][CH:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])=[CH:1][CH:2]=[C:3]([NH:19][CH2:20][CH2:21][C@@H:22]2[NH:27][C:26]3[C:28]([OH:29])=[N:30][C:31]([NH2:33])=[N:32][C:25]=3[NH:24][CH2:23]2)[CH:4]=1
Reactant: Nc1nc(=O)c2nc(CCNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2[nH]1
Reactant: [H][H]
Agent: O=[Pt]
Product: Nc1nc(O)c2c(n1)NC[C@H](CCNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1)N2

Procedure:
The preparation of N5 -methyltetrahydrohomofolic acid and alkali metal salts thereof is from homofolic acid starting material (HFA) by catalytic reduction with platinum oxide in the dark under hydrogen at a slight overpressure to produce tetrahydrohomofolate (THHF), them immediately reacting this product with formaldehyde to produce 5,11-methylenetetrahydrohomofolate and reducing this methylene intermediate without isolation with sodium borohydride to give the desired 5-methyltetrahydrohomofolate in the disodium salt form. The 5-methyl product is recovered by precipitating side products at a pH of about 3.8 with acetic acid and refrigerating the product filtrate overnight at about 3°-10°C. The filtrate containing the product 5-methyltetrahydrohomofolate (5-MeTHHF) is treated with charcoal, concentrated to an oil and the 5-methyl product is precipitated with absolute ethanol. The 5,11-methylenetetrahydrofolate may be separately recovered and in a second reaction an additional product known as the 5,11-methenyl is formed by reaction with formic acid. These products show increased stability over folate analogues and show biological promise in the treatment of cancer and leukemia as antifolates and specifically against L1210-FR8 tumor in mice.