Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:3]=1[F:21].S(=O)(O)[O-].[CH:26]([CH:28]=O)=O.[Na+].[OH-].[Na+].Cl>C(O)(=O)C.C(OCC)(=O)C>[F:21][C:3]1[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[C:5]([C:6]([OH:8])=[O:7])[CH:10]=[C:11]2[C:2]=1[N:1]=[CH:28][CH:26]=[N:12]2
Reactant: O=CC=O
Reactant: COC(=O)c1cc(N)c(N)c(F)c1Nc1ccccc1C
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccccc1Nc1c(C(=O)O)cc2nccnc2c1F
Temperature: 65 °C
Reaction time: 1 h

Procedure:
The compound methyl 4,5-diamino-3-fluoro-2-(2-methyl-phenylamino)-benzoate (from Step e, Example 1) is dissolved in 2:1:1.2 v/v/v of 2.0 M acetic acid-4.0 M sodium acetate-methanol. The suspension is warmed to 65° C. (or until homogeneous) and the clear solution is poured into a 0.078 M aqueous sodium glyoxal bisulfite (Aldrich, monohydrate, 1.05 equiv.) solution which is warmed to 70° C. The reaction mixture is stirred gently between 55-75° C. for one hour, and is then cooled to 12° C. with an ice-water bath. Pulverized sodium hydroxide pellets (27 equiv.) are added to the cold solution. The mixture is gently warmed to 30° C. and stirred for 45 minutes. The temperature is raised to 70° C. for 15 minutes. The mixture is allowed to cool and is treated with ethyl acetate. The biphasic mixture is treated with concentrated aqueous hydrochloric acid to achieve pH 0 in the aqueous phase. The organic phase is separated, dried (MgSO4), and concentrated in vacuo to give the desired product. The product may be triturated with an appropriate solvent like dichloromethane or recrystallized from a solvent like ethanol for further purification as necessary.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][C@H:16]([CH2:19][NH2:20])[CH2:15]1)=[N:9][C:8]([O:21][CH3:22])=[CH:7][CH:6]=2.C(N(CC)CC)C.[O:30]=[C:31]1[NH:36][C:35]2[CH:37]=[C:38]([S:41](Cl)(=[O:43])=[O:42])[CH:39]=[CH:40][C:34]=2[S:33][CH2:32]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][C@H:16]([CH2:19][NH:20][S:41]([C:38]3[CH:39]=[CH:40][C:34]4[S:33][CH2:32][C:31](=[O:30])[NH:36][C:35]=4[CH:37]=3)(=[O:43])=[O:42])[CH2:15]1)=[N:9][C:8]([O:21][CH3:22])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(F)c(CCN3CC[C@H](CN)C3)c2n1
Reactant: O=C1CSc2ccc(S(=O)(=O)Cl)cc2N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(CCN3CC[C@H](CNS(=O)(=O)c4ccc5c(c4)NC(=O)CS5)C3)c2n1
Reaction time: 24 h
Yield: 91.2 %

Procedure:
To a stirred solution of [((3R)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine (0.50 g, 1.65 mmole) in dry CH2Cl2 (25 mL) at RT was added triethylamine (0.34 mL, 2.48 mmole) and 3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-sulfonyl chloride (0.47 g, 1.80 mmole). After 24 h, the reaction solution was concentrated under vacuum. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.80 g, 91%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.16 (d, J=9.0 Hz, 1H), 7.34 (m, 3H), 7.03 (d, J=9.0 Hz, 1H), 4.04 (s, 3H), 3.47 (s, 2H), 3.34 (m, 2H), 2.95 (m, 3H), 2.79 (m, 2H), 2.61 (m, 1H), 2.52 (m, 2H), 2.34 (m, 1H), 1.97 (m, 1H), 1.55 (m, 1H). LC-MS (ES) m/e 532 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[N+:7]([O-:9])=[O:8].[NH3:15]>COCCO>[NH2:15][C:2]1[C:3]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: N
Reactant: O=[N+]([O-])c1sc2ccc(F)cc2c1Br
Solvent: COCCO
Product: Nc1c([N+](=O)[O-])sc2ccc(F)cc12
Temperature: 90 °C

Procedure:
A solution of 3-bromo-5-fluoro-2-nitrobenzo[b]thiophene (1.51 g, 5.47 mmol) in 10 ml of 2-methoxyethanol was placed in a steel bomb. 2-Methoxyethanol (15 ml) was saturated with ammonia at 0° C. and the obtained solution was added to the steel bomb. The bomb was sealed, heated to 90° C. for 16 hours and cooled in an ice bath. After ammonia gas was sufficiently released, the reaction mixture was poured onto ice water (250 ml). The precipitate was filtered off, washed with water and dried. Yield 1.06 g (91%) of 3-amino-5-fluoro-2-nitrobenzo[b]thiophene.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[N:17][C:18]([NH:21][C:22]3[N:23]=[CH:24][C:25]4[C:31]([CH3:32])=[C:30]([C:33]([O:35]CC)=[CH2:34])[C:29](=[O:38])[N:28]([CH:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)[C:26]=4[N:27]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:44]>C(Cl)(Cl)Cl>[ClH:44].[C:33]([C:30]1[C:29](=[O:38])[N:28]([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:26]2[N:27]=[C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([N:11]4[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]4)=[CH:16][N:17]=3)[N:23]=[CH:24][C:25]=2[C:31]=1[CH3:32])(=[O:35])[CH3:34]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCCNCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
To a solution 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-[1,4]diazepane-1-carboxylic acid tert-butyl ester (116 mg, 0.20 mmol) in chloroform (5 mL) was added hydrogen chloride (2 M ethereal solution, 5.0 mL, 10.0 mmol). The reaction mixture was stirred at RT for 12 h. The solvents were evaporated and the residue was dissolved in ethanol. The ethanol was evaporated to give 6-acetyl-8-cyclopentyl-2-(5-[1,4]diazepan-1-yl-pyridin-2-ylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt (47 mg, 0.10 mmol). MS (APCI+) 432, 462 (M+1, 100); 1H NMR δ(400 MHz, DMSO-d6) 9.19 (br, 2H), 8.99 (s, 1H), 7.91 (s, 1H), 7.78-7.75 (m, 2H), 5.88-5.80 (m, 1H), 3.80-3.77 (m, 3H), 3.25 (br, 3H), 3.16 (br, 2H), 2.44 (s, 3H), 2.34 (s, 3H), 2.49-2.18 (m, 2H), 2.12-2.10 (m, 2H), 1.93 (br, 2H), 1.81-1.78 (m, 2H), 1.61-1.58 (m, 2H); Anal. Calc'd for C25H31N7O2, 2.80HCl, 0.45C3H8O2: C, 53.35; H, 6.25; N, 16.25. Found: C, 52.96; H, 6.62; N, 15.95.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8].[CH:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22](O)[CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([O:12][C:22]1[CH:21]=[CH:20][C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1)=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)NCSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(=O)NCSC[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 81 %

Procedure:
BocCys(Acm)ONp is prepared from BocCys(Acm)OH (Novabiochem, Laufelingen, CH) and p-nitrophenol by reaction with N,N'-dicyclohexylcarbodiimide (DCC) in etyl acetate and used without purification for the preparation of Boc-Cys(Acm)-Pro-OH (XII) by reacting it with H-Pro-OH in DMF/etyl acetate/H2O at 0° C. while keeping pH neutral by addition of Et3N. Yield 81%. Purity>95% (TLC).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:18])[NH:9][C:10](=[O:17])[N:11]3[CH2:16][CH:15]=[CH:14][S:13][C:12]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:9]2[C:8](=[O:18])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:12]3[S:13][CH:14]=[CH:15][CH2:16][N:11]3[C:10]2=[O:17])=[CH:22][CH:21]=1
Reactant: O=c1[nH]c(=O)n2c(c1-c1ccccc1)SC=CC2
Reactant: Cc1ccc(CCl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1ccc(Cn2c(=O)c(-c3ccccc3)c3n(c2=O)CC=CS3)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 32.9 %

Procedure:
A mixture of 9-phenyl-4H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione (0.26 g), p-methylbenzylchloride (0.21 g) and potassium carbonate (0.28 g) in DMF (5 ml) was stirred at 100° C. for 15 hours. The reaction solution was concentrated to dryness. The resulting residue was dissolved in dichloroethane and was washed with water and dried. m-Chloroperbenzoic acid (0.2 g) was added to the dichloroethane solution little by little under ice cooling, and it was allowed to stand at room temperature for 15 hours. The reaction solution was washed with saturated aq. sodium bicarbonate, and dried, and then trifluoro acetic acid anhydride (0.5 ml) was added thereto and the mixture was refluxed for 15 hours. Oily product obtained by concentration of the resulting solution was dissolved in toluene (20 ml), and a catalytic amount of p-toluene sulfonic acid was added thereto and the mixture was refluxed for 10 hours. The reaction solution was washed with sodium bicarbonate and water, followed by concentration to dryness. The obtained crude crystals were recrystallized from ethyl ether to give colorless crystals (0.12 g, 33%).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:25])[CH:17]([NH:18][C:19](=[S:24])[CH2:20][CH2:21][CH:22]=[CH2:23])[C@H:4]2[S:3]1.C(O)(=O)C>CN(C)C=O.[Zn]>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:25])[CH:17]([NH:18][C:19](=[S:24])[CH2:20][CH2:21][CH:22]=[CH2:23])[C@H:4]2[S:3]1
Reactant: C=CCCC(=S)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C=CCCC(=S)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12
Reaction time: 1 h
Yield: 94.4 %

Procedure:
Zinc powder (5.55 g) was added to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylate (5.55 g) in anhydrous dimethylformamide (55.5 ml) and then acetic acid (5.5 ml) was dropwise added to the solution, after which the mixture was stirred for 1 hour. After the reaction, zinc powder was filtered off and washed with ethyl acetate. The filtrate and the washings were combined, after which the solution was poured into a mixture of 5% hydrochloric acid (250 ml) and ethyl acetate (100 ml), and then extracted. The aqueous layer was further extracted twice with ethyl acetate. The ethyl acetate layer was combined, and the combined ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, and then dried over magnesium sulfate. After the solution was concentrated under reduced pressure till the volume of the solution becomes about 40 ml. Crystals precipitated were collected by filtration and washed with isopropyl ether and dried to give colorless crystals of 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid (3.69 g), mp 121° to 123° C. Moreover the filtrate was concentrated and the obtained crystals were washed with isopropyl ether and then dried to give 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid (0.75 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:15]1([C@@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C@@H:21]([NH:23][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: C[C@H](N)c1ccccc1
Product: COc1cccc2cc(C(=O)N[C@@H](C)c3ccccc3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and 1-(S)-phenylethylamine to give N-[1-(S)-phenylethyl]-7-methoxybenzofuran-2-carboxamide (Compound 359a). Successively, it was formylated to give N-[1-(S)-phenylethyl]-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 359b), then compound 359b was reacted with methylamine hydrochloride to give compound 359 as a white solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[CH3:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]12[C:44]2[C:35](=[CH:36][C:37]3[O:42][CH2:41][CH2:40][O:39][C:38]=3[CH:43]=2)[O:34][CH2:33]1.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[CH3:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][N:5]=1)[C:27](=[O:32])[C:26]12[C:44]2[C:35](=[CH:36][C:37]3[O:42][CH2:41][CH2:40][O:39][C:38]=3[CH:43]=2)[O:34][CH2:33]1
Reactant: FC(F)(F)c1cccnc1CCl
Reactant: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2
Agent: BrCC1CCCCO1
Agent: Cl
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2Cc1ncccc1C(F)(F)F

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 5′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, (5′-methyl-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (62%) as a colorless solid: mp 137-139° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J=4.6 Hz, 1H), 8.22 (d, J=7.5 Hz, 1H), 7.57-7.50 (m, 1H), 7.02-6.94 (m, 2H), 6.72 (d, J=7.9 Hz, 1H), 6.47 (s, 1H), 6.40 (s, 1H), 5.29-5.03 (ABq, 2H), 4.76-4.64 (ABq, 2H), 4.18-4.06 (m, 4H), 2.18 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.4, 155.0, 153.0, 152.9, 144.5, 140.9, 138.2, 135.5 (q, 4J=5.31 Hz), 132.5, 132.5, 129.3, 124.5, 124.4 (q, 1J=273.6 Hz), 123.5 (q, 2J=32.3 Hz), 123.5, 122.2, 112.3, 109.3, 99.1, 79.7, 64.7, 64.1, 57.8, 42.4 (q, J=3.1 Hz), 21.0; MS (ES+) m/z 469.0 (M+1).
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]3[C:31]4[C:26](=[C:27](Br)[CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][O:23]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C[Si]([N:37]=[C:38]=[O:39])(C)C>C1COCC1.O1CCOCC1>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]3[C:31]4[C:26](=[C:27]([C:38]([NH2:37])=[O:39])[CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][O:23]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: COc1ccc(N2CCN(CCC3OCCc4c(Br)cccc43)CC2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(CCC3OCCc4c(C(N)=O)cccc43)CC2)cc1
Reaction time: 0.25 h

Procedure:
A mixture of t-butyl lithium (2 eqs, 1.7M in hexane) in THF (2 ml/mmol bromide) is cooled to -78° for 10 minutes before adding the 1-(4-methoxyphenyl)-4-[2-(5-bromoisochroman-1-yl)ethyl]piperazine (LXXIV, EXAMPLE 100) in THF (4 ml/mmol) dropwise over 10 minutes. A freshly distilled solution of trimethylsilylisocyanate (1.5 eqs) is added via syringe as a solution in dioxane (4 volume equivalents) at once. After 15 minutes, the cooling bath is removed and the mixture allowed to warm to 20°-25°. The reaction mixture is quenched with ammonium chloride, the organics are removed under reduced pressure, and the aqueous residue is extracted two times with methylene chloride, dried over sodium sulfate, filtered and concentrated. The crude material is purified by flash chromatography on silica gel. In this manner, 1-(4-methoxyphenyl)-4-[2-(5-bromoisochroman-1-yl)ethyl]piperazine (LXXIV, EXAMPLE 100, 345 mg) is converted to the corresponding amide, the title compound, mp 185°-186°.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:32][N:33]([CH3:37])[CH2:34][C:35]#[CH:36].CN(C=O)C>N(CC)CC.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:36]#[C:35][CH2:34][N:33]([CH3:37])[CH3:32])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCN(C)C
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CN(C)CC#Cc1cc(CN2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2 (PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 1-dimethylamino-2-propyne (0.065 mL). Anhydrous DMF (10 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 1% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), 3% MeOH in CH2Cl2 (1L), 5% MeOH in CH2Cl2 (1L), and 6% MeOH in CH2Cl2 (1L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 153.5 mg (55%) of the desired product as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CS([O:11][CH2:12][C:13]([CH3:18])([N+:15]([O-:17])=[O:16])[CH3:14])(=O)=O.O[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[C:30]1[N:31]([CH3:35])[N:32]=[CH:33][CH:34]=1>CC(N(C)C)=O>[CH3:35][N:31]1[C:30]([C:21]2[CH:22]=[C:23]([NH:26][C:27](=[O:29])[CH3:28])[CH:24]=[CH:25][C:20]=2[O:11][CH2:12][C:13]([CH3:18])([N+:15]([O-:17])=[O:16])[CH3:14])=[CH:34][CH:33]=[N:32]1
Reactant: CC(C)(COS(C)(=O)=O)[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(O)c(-c2ccnn2C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1ccc(OCC(C)(C)[N+](=O)[O-])c(-c2ccnn2C)c1
Temperature: 160 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
Cesium carbonate (7.04 g, 21.6 mmol) was added to a solution of 2-methyl-2-nitropropyl methanesulfonate (2.39 g, 12.1 mmol) and N-(4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)phenyl)acetamide (2.00 g, 8.65 mmol) in dimethylacetamide (15 mL) and the mixture was stirred at 160° C. After 2 h, the solvent was evaporated, and the residue was triturated with water. The precipitate was isolated by filtration, washed with water and dried in vacuo to afford the product (2.38 g, 83%) as a tan solid. LCMS m/z (%)=333.4 (M+H 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 6 H), 2.02 (s, 3 H), 3.53 (s, 3 H), 4.32 (s, 2 H), 6.15 (d, J=2.02 Hz, 1 H), 7.14 (d, J=8.84 Hz, 1 H), 7.44 (d, J=1.77 Hz, 1 H), 7.49 (d, J=2.78 Hz, 1 H), 7.62 (dd, J=8.97, 2.65 Hz, 1 H), 9.94 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[C:19](/[C:21]([OH:23])=[O:22])\[CH3:20])[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:9]([CH3:29])[NH:8][C:7]=1[CH3:30])=[O:5])[CH3:2].[CH2:31](Br)[CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[C:19](\[CH3:20])/[C:21]([O:23][CH2:31][CH3:32])=[O:22])[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:9]([CH3:29])[NH:8][C:7]=1[CH3:30])=[O:5])[CH3:2]
Reactant: CCBr
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1/C=C(\C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1/C=C(\C)C(=O)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
A suspension of Compound A (4 g), ethyl bromide (1 g) and potassium carbonate (30 g) in dimethylformamide (60 ml) was stirred at room temperature for 6 h. The mixture was poured into water and extracted with ethyl acetate, then washed thoroughly with water and dried over Na2SO4. Evaporation of the solvent gave an oil which was triturated with petrol and recrystallized from petrol ether to give the title compound as a white solid (3.2 g). M.p. 105°-106°.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[NH:27][N:26]=[C:25]3[C:28]4[C:33]([C:34](=[O:35])[C:24]=23)=[C:32]([NH:36][C:37](=[O:45])[NH:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:31]=[CH:30][CH:29]=4)[CH2:19][CH2:18]1)=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[C@H:12]12[CH2:14][C@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[C:15]([N:17]1[CH2:18][CH2:19][CH:20]([C:23]2[NH:27][N:26]=[C:25]3[C:28]4[C:33]([C:34](=[O:35])[C:24]=23)=[C:32]([NH:36][C:37](=[O:45])[NH:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:31]=[CH:30][CH:29]=4)[CH2:21][CH2:22]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)N1CCC(c2[nH]nc3c2C(=O)c2c(NC(=O)NN4CCOCC4)cccc2-3)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc2c1C(=O)c1c-2n[nH]c1C1CCN(C(=O)N2C[C@@H]3C[C@H]2CN3)CC1)NN1CCOCC1

Procedure:
Prepared in a similar fashion as described for example CXXVI, step 7, using the 3-(1-((5-t-butoxycarbonyl-(1S,4S)-(+)- 2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl)piperidin-4-yl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one as the starting material. mp 196-198° C. (TFA salt); ESI-MS (M+H) calc'd for C26H33N8O4: 521.2613, found: 521.2613.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][C:8]([F:16])=[C:7]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[N:6]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.O>[CH:1]1([NH:4][C:5]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]([F:16])=[C:7]([N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[N:6]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(F)c(N2CCN(C)CC2)nc1NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2nc(NC3CC3)c(C(=O)O)cc2F)CC1
Yield: 63.6 %

Procedure:
Following the procedure of Example G-2, the reaction of ethyl 2-cyclopropylamino-5-fluoro-6-(4-methylpiperazinyl)-3-pyridinecarboxylate (Example F-2, 0.86 g, 2.67 mmol) with NaOH (1.40 g, 35 mmol) in THF (5 mL) and water (2 mL) provided 0.50 g of the title compound as a foam.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][C:10]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.Cl>CO.[Pd]>[NH2:1][C:4]1[C:12]2[O:11][C:10]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc2nc(-c3nnn[nH]3)oc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1cccc2nc(-c3nnn[nH]3)oc12
Reaction time: 18 h

Procedure:
1.59 g of the nitro compound obtained in Example 40, Step 3, above, is suspended in 46 ml of methanol to which 1 ml of concentrated hydrochloric acid, and 0.17 g of 5% palladium on carbon are added. The mixture is stirred under hydrogen at atmospheric pressure for 18 hours, filtered, and the filtrate concentrated in vacuo to obtain 5-(7-aminobenzoxazol-2-yl)tetrazole.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:27][NH2:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:28][CH3:27])=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CNC)cc2C)ncn1
Reaction time: 24 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with methylamine (0.25 ml, 2M in THF; 0.5 mmol) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 15 hours a further portion of methylamine (1 ml, 2M in THF; 2 mmol) was added. After stirring for a further 24 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid.