Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5]C)=O.[Na].[C:11]1([N:17]2[C:21]([NH2:22])=[C:20]([CH:23]=O)[N:19]=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO.O>[C:11]1([N:17]2[C:21]3[NH:22][C:3](=[O:5])[C:2]([C:1]([O:8][CH3:9])=[O:7])=[CH:23][C:20]=3[N:19]=[N:18]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Nc1c(C=O)nnn1-c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2nnn(-c3ccccc3)c2[nH]c1=O
Reaction time: 18 h
Yield: 49.1 %

Procedure:
Dimethyl malonate (0.31 ml, 2.7 mmol) was added at room temperature to a stirred solution of sodium (0.065 g, 2.7 mmol) dissolved in dry methanol (8 ml) under nitrogen. A solution of 1-phenyl-4-formyl-5-amino-1,2,3-triazole (Bull. Soc. Chim. Belg., 1988, 97, 85-86) (0.50 g, 2.66 mmol) in dry methanol (4 ml) was added and the mixture was stirred for 18 h. The white suspension was diluted with water (50 ml) and the solids were collected and dissolved in dichloromethane-methanol (2:1, 100 ml). The solution was washed with aqueous citric acid (1 M, 50 ml), dried (Na2SO4), filtered and concentrated to give 3-phenyl-5-oxo-6-methoxycarbonyl-4H-1,2,3-triazolo[4,5-b]pyridine (0.353 g, 49%) as a white powder. δH (360 MHz; DMSO) 3.89 (3H, s), 7.56 (1H, t, J=7.5), 7.68 (2H, dd, J=7.5 and 7.5), 8.09 (2H, d, J=7.5), 8.92 (1H, s) and 12.67 (1H, br s); m/z (ES+) 271 (M+H+).
Reaction SMILES: [C:1]1([C@@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]1([CH3:19])[O:18][CH2:17][CH:16]2[CH:14]([O:15]2)[CH2:13][O:12]1>CC(O)C>[CH3:10][C:11]1([CH3:19])[O:18][CH2:17][C@@H:16]([OH:15])[C@H:14]([NH:9][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH2:13][O:12]1
Reactant: CC1(C)OCC2OC2CO1
Reactant: C[C@H](N)c1ccccc1
Solvent: CC(C)O
Product: C[C@H](N[C@@H]1COC(C)(C)OC[C@H]1O)c1ccccc1
Yield: 35 %

Procedure:
The known method by T. Inaba, A. G. Birchler, Y. Yamada, S. Sagawa, K. Yokata, K. Ando and I. Uchida, J. Org. Chem., 1998, 63, 7582 for the preparation of the enantiomer of the title compound was followed. (S)-1-Phenylethanamine (30.4 ml, 236 mmol) and 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (34 g, 236 mmol) were dissolved in iPrOH (16 ml) and heated under reflux for 16 h. The mixture was stirred and cooled in an ice bath. Hexanes (90 ml) was added. After 1 h the colourless crystalline solid was filtered off, washed with hexanes and dried to give (5S,6R)-2,2-dimethyl-6-((S)-1-phenylethylamino)-1,3-dioxepan-5-ol (21.9 g, 35%). The 1H NMR was in agreement with that described for the enantiomer of the title compound by T. Inaba, A. G. Birchler, Y. Yamada, S. Sagawa, K. Yokata, K. Ando and I. Uchida, J. Org. Chem., 1998, 63, 7582. [α]D 20 −96.6 (c, 1.01, MeOH). Lit. (T. Inaba, A. G. Birchler, Y. Yamada, S. Sagawa, K. Yokata, K. Ando and I. Uchida, J. Org. Chem., 1998, 63, 7582) [α]D 25 +96.2 (c 1.00, MeOH) for the enantiomer.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:41][C:42]1[C:43]([CH3:59])=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47](O)=[O:48]>CN(C)C=O>[Br:41][C:42]1[C:43]([CH3:59])=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47]([NH:7][C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)=[O:48]
Reactant: Nc1ccnnc1
Reactant: Cc1cc(OCc2ccccc2)c(C(=O)O)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)c(C(=O)Nc2ccnnc2)cc1Br
Reaction time: 0.17 h

Procedure:
4-Pyridazinamine (207 mg, 2.18 mmol), diisopropylethylamine (0.52 ml, 2.97 mmol) and HATU (904 mg, 2.38 mmol) were added to a solution of 5-bromo-4-methyl-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 9; 636 mg, 1.98 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred for 2 hours, after 10 minutes a solid had crashed out of solution. The solid was filtered and washed with ethyl acetate (10 ml) to yield the title compound. 475 mg.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[CH3:21][C:22]([CH3:24])=[O:23]>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[C:22]([OH:23])([CH3:24])[CH3:21]
Reactant: CC(C)=O
Reactant: Fc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(O)c1c(F)cncc1Br
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 48.2 %

Procedure:
n-BuLi 1.6M in hexanes (11.25 ml, 18.00 mmol) was added dropwise to a solution of diisopropylamine (2.78 ml, 19.50 mmol) in THF (50.0 ml) at −78° C. under N2. The resulting mixture was warmed up to −40° C. and stirred for 10 min and recooled to −78° C. 3-bromo-5-fluoropyridine (2.64 g, 15 mmol) in 5 mL THF was added dropwise at this temperature. After 30 min, acetone (3.30 ml, 45.0 mmol) was added dropwise and the resulting mixture was stirred for 30 min at −78° C., and then for another 30 min at 0° C. The mixture was quenched with saturated NH4Cl and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The residue was purified via Biotage (0-30% AcOEt/heptane, SNAP50) giving 10a (1.691 g, 48%) as a yellow oil. LC-MS (M+1) 235.9, t=1.18 min.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][N:6]1[C:10]([C:11](=[O:34])[NH:12][C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:16]3[CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:27]=[C:15]3[CH:14]=2)=[C:9]([C:35](O)=[O:36])[CH:8]=[N:7]1>>[N:19]1([C:17]2[N:16]3[CH:25]=[C:26]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:27]=[C:15]3[CH:14]=[C:13]([NH:12][C:11]([C:10]3[N:6]([CH3:5])[N:7]=[CH:8][C:9]=3[C:35]([N:1]3[CH2:4][CH2:3][CH2:2]3)=[O:36])=[O:34])[N:18]=2)[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1
Reactant: C1CNC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1

Procedure:
The title compound was prepared in analogy to Example 13, Step 2, using azetidine and 1-methyl-5-(5-morpholin-4-yl-2-phenyl-imidazo[1,2-c]pyrimidin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (Example 73, Step 1). MS (m/e)=487.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4](I)[N:3]=1.[C:11](B(O)O)([CH3:13])=[CH2:12].COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([C:11]([CH3:13])=[CH2:12])[N:3]=1
Reactant: C=C(C)B(O)O
Reactant: COc1ccc(I)nc1Br
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: CCO
Solvent: COCCOC
Product: C=C(C)c1ccc(OC)c(Br)n1
Temperature: 80 °C

Procedure:
In a tube were placed 2-bromo-6-iodo-3-methoxypyridine (700 mg, 2.236 mmol), isopropenylboronic acid (212 mg, 2.460 mmol), DME (7.5 mL), EtOH (2.8 mL), and 1M aq. Na2CO3 (5.6 mL). The mixture was degassed with N2. Next, Pd(PPh3)4 (206 mg, 0.179 mmol) was added and the mixture was degassed again with N2. The tube was sealed and heated at 80° C. for 16 hours. The reaction was then cooled to room temperature, diluted with EtOAc (100 mL), and washed with saturated NaHCO3 and brine (50 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 15% EtOAc/hexanes) afforded 2-bromo-6-isopropenyl-3-methoxypyridine. Rf=0.38 (25% EtOAc/hexanes). LCMS=230.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.36 (d, J=8.5 Hz, 1H), 7.07 (d, J=9.4 Hz, 1H), 5.81 (s, 1H), 5.21 (s, 1H), 3.92 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([C:22](=[O:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[BH4-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1C(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reaction time: 1 h
Yield: 42.3 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(2-methoxybenzoyl)pyridin-2-yl)cyclopropanecarboxamide (0.50 g, 1.2 mmol) was suspended in 25 mL of methanol. Sodium borohydride (0.454 g, 12.0 mmol) was added in small portions. After stirring for one hour the reaction mixture was evaporated to dryness and purified on 40 g of silica gel utilizing a gradient of 15-70% ethyl acetate in hexanes to yield the pure product as a white solid (0.2125 g, 0.5078 mmol, 42%). ESI-MS m/z calc. 418.6, found 419.3 (M+1)+. Retention time 2.59 minutes.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][N:4]([C:14]2[C:15]([CH3:20])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:3]1=[O:21].[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23].C(Cl)Cl>>[OH:28][C:22]([C:24]([F:27])([F:26])[F:25])=[O:23].[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([C:14]2[C:15]([CH3:20])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:3]1=[O:21]
Reactant: Cc1ncccc1N1CC(C(=O)OC(C)(C)C)N(C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncccc1N1CC(C(=O)O)N(C)C1=O

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (600 mg, 3.00 mmol) (prepared as described in step (iii) of Example 13) and 3-bromo-2-methylpyridine (515 mg, 3.00 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1464 mg, 4.49 mmol), Xantphos™ (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.6 mg, 0.075 mmol) and the mixture was heated under reflux under argon for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give 1,1-dimethylethyl 3-methyl-1-(2-methyl-3-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (738 mg, 85%). LC/MS [M+H]+=292. (ii) A solution of 1,1-dimethylethyl 3-methyl-1-(2-methyl-3-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (738 mg, 2.53 mmol) in TFA/DCM (1:2, 12 ml) was stirred at room temperature for 6 hours. The solution was evaporated and the residue was co-evaporated with toluene and dried to give crude 3-methyl-1-(2-methyl-3-pyridinyl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜2.5 mmol) which was used in the next step.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=O.[C:13]([NH:16][CH2:17][CH2:18][NH2:19])(=[O:15])[CH3:14]>O1CCCC1>[C:13]([NH:16][CH2:17][CH2:18][NH:19][CH2:2][C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4])(=[O:15])[CH3:14]
Reactant: CC(=O)NCCN
Reactant: O=CC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)NCCNCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
Benzyl glyoxylate (3.28 g, 20.0 mmol) in dry tetrahydrofuran (15 ml) was added dropwise in monoacetylethylenediamine (1.53 g, 15 mmol) in dry tetrahydrofuran (60 ml) at room temperature. After 2 hours, the tetrahydrofuran was removed under vacuum, and the residue was dissolved in dry methanol (100 ml). Upon cooling to 0° C., 1.55 g of sodium cyanoborohydride was added, immediately followed by dropwise addition of 1.54 ml of acetic acid. The reaction was allowed to warm to room temperature and stirred for 40 minutes. The volatiles were removed under vacuum, and the residue was extracted from aqueous sodium bicarbonate with ethyl acetate. The combined organic layers were dried with sodium sulfate, and the volatiles were removed. The residue was purified by column chromatography on silica (LPS-1) (loading with 2% methanol/dichloromethane and eluting with 5% methanol/dichloromethane to yield 1.46 g of the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C@H:27]([NH:30][C:31]([C@@H:33]4[CH2:38][CH2:37][CH2:36][CH2:35][N:34]4C(OC(C)(C)C)=O)=[O:32])[C:28]#[N:29])=[CH:22][CH:21]=3)=[CH:19][C:14]=2[S:13][C:12]1=[O:46])(C(C)(C)C)(C)C.C(OCC)C>C(O)=O>[C:28]([C@@H:27]([NH:30][C:31]([C@@H:33]1[CH2:38][CH2:37][CH2:36][CH2:35][NH:34]1)=[O:32])[CH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[CH:17]=[CH:16][C:15]3[N:11]([CH2:10][CH2:9][OH:8])[C:12](=[O:46])[S:13][C:14]=3[CH:19]=2)=[CH:25][CH:24]=1)#[N:29]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@H](C#N)Cc1ccc(-c2ccc3c(c2)sc(=O)n3CCO[Si](C)(C)C(C)(C)C)cc1
Solvent: CCOCC
Solvent: O=CO
Product: N#C[C@H](Cc1ccc(-c2ccc3c(c2)sc(=O)n3CCO)cc1)NC(=O)[C@@H]1CCCCN1
Yield: 86 %

Procedure:
A solution of (S)-tert-butyl 2-((S)-2-(4-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)phenyl)-1-cyanoethylcarbamoyl)piperidine-1-carboxylate (103 mg) in formic acid (1 ml) was stirred at 50° C. for 10 min. The solvent was removed in vacuo and the residue was purified by flash silica chromatography eluting with 1:14 2M ammonia in methanol/DCM to give, after trituration with diethyl ether, the title compound (60 mg) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:13]([NH2:16])(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](=[S:19])=[S:18].[OH-].[K+:21].C(OCC)(=O)C>CN(C)C=O>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:17]([S-:19])[S-:18])(=[O:14])=[O:15].[K+:21].[K+:21]
Reactant: S=C=S
Reactant: NS(=O)(=O)c1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(N=C([S-])[S-])c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 166.3 %

Procedure:
115.5 g of 2-phenylbenzenesulfonamide were dissolved in 500 ml of dimethylformamide, and 38 g of carbon disulfide and 28 g of potassium hydroxide were added to the resulting solution. The mixture was stirred at room temperature for 7 hours. Potassium hydroxide (28 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Then, 400 ml of ethyl acetate were added dropwise to precipitate pale yellow crystals. The crystals were filtered, and washed with ethyl acetate to give 160 g of potassium N-(2-biphenylylsulfonyl)carbonimidodithioate represented by the following formula: ##STR25##
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:17]3[CH2:23][CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].C(N(CC)C(C)C)(C)C.CN1CCCC1=O.Br[CH2:47][CH2:48][O:49][CH3:50]>>[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:17]3[CH2:23][CH2:22][N:21]([CH2:47][CH2:48][O:49][CH3:50])[CH2:20][C:18]=3[N:19]=2)=[CH:12][CH:13]=1)=[O:6])[CH3:3]
Reactant: COCCBr
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(CCOC)C3)cc1
Yield: 53.4 %

Procedure:
To a solution of 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea, hydrochloride salt (bf) (51 mg, 0.13 mmol) in N,N-Diisopropylethylamine (7.0E1 uL, 0.40 mmol) and N-Methylpyrrolidinone (0.80 mL, 8.3 mmol) was added 1-Bromo-2-methoxyethane (3.01 uL, 0.32 mmol) at room temperature. The reaction was microwaved at 80° C. for 30 minutes. After purification, 30.6 mg white powder pc (52% yield) was obtained: 1H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 8.16 (d, J=8.7 Hz, 2H), 7.46 (d, J=8.7 Hz, 2H), 6.15 (t, J=5.5 Hz, 1H), 3.72 (m, 4H), 3.62 (s, 2H), 3.54 (t, J=5.6 Hz, 2H), 3.47 (m, 4H), 3.28 (s, 3H), 3.18-3.05 (m, 2H), 2.73-2.62 (m, 6H), 1.06 (t, J=7.2 Hz, 3H); LC-MS m/z=441 (M+H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[N:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O-:25])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:8]=[C:7]([O:26][C@@H:27]([C@@H:29]3[CH2:33][C:32](=[O:34])[N:31]([C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=4)[CH3:36])[CH2:30]3)[CH3:28])[C:6]=12.[Br-].[CH:46]1([Zn+])[CH2:48][CH2:47]1>[Cl-].[NH4+]>[CH:46]1([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[C:9]([C:11]4[N:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:9]([CH3:11])([CH3:10])[CH3:8])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:8]=[C:7]([O:26][C@@H:27]([C@@H:29]4[CH2:33][C:32](=[O:34])[N:31]([C@@H:35]([C:37]5[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=5)[CH3:36])[CH2:30]4)[CH3:28])[C:6]=23)[CH2:48][CH2:47]1
Reactant: [Zn+]C1CC1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)[O-])CC5)cn4)cn4ncc(I)c34)CC2=O)cc1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)cn4ncc(C5CC5)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an appropriate sized microwave vial, 4-(6-(3-iodo-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)pyridin-3-yl)piperazine-1-carboxylate 6.48 (35 mg, 0.046 mmol) and [(2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (3.7 mg, 0.0046 mmol) were added. After evacuating and backfilling with nitrogen, THF (1.0 mL) was added followed by cyclopropylzinc bromide (0.55 mL, 0.27 mmol, 0.5M solution in THF). The mixture was stirred at room temperature for 15 min. The reaction was diluted with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl 4-(6-(3-cyclopropyl-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)pyridin-3-yl)piperazine-1-carboxylate 6.49.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][O:18][C:19](=O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:29])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:29])=[CH:13][C:12]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1c[nH]c2ccc(COC(=O)c3ccccc3)cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCC(=O)c1cnc2ccc(COCc3ccccc3)cc2c1Cl
Yield: 67 %

Procedure:
3-Butyryl-6-(benzoyloxymethyl)-4(1H)-quinolone (30 g) was heated under reflux in phosphorus oxychloride (200 ml) for 30 minutes. The solvent was evaporated and the residue partitioned between dichloromethane and ammonia solution. The organic layer was washed successively .with sodium hydrogen carbonate solution and 50% brine. Dried (anhyd. MgSO4), filtered and evaporated to an oily solid which crystallized on trituration with petroleum ether to give 3-butyryl-4-chloro-6-(benzyloxymethyl)quinoline (21.2 g, 67%), m.p. 85°-6° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:34])[C:16]([C:18]2[S:22][C:21]3=[C:23]([C:26]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:27])[N:24]=[CH:25][N:20]3[CH:19]=2)=O)[N:13]([C:35]([C:55]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][C:62]([N+:65]([O-:67])=[O:66])=[CH:61][CH:60]=2)=[O:56])=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:12]1=[O:68])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:12](=[O:68])[N:13]2[C:35]([C:55]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][C:62]([N+:65]([O-:67])=[O:66])=[CH:61][CH:60]=3)=[O:56])=[C:16]([C:18]3[S:22][C:21]4=[C:23]([C:26]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)=[O:27])[N:24]=[CH:25][N:20]4[CH:19]=3)[C@H:15]([CH3:34])[C@H:14]12)[CH3:10])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Solvent: Cc1ccccc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Yield: 72.8 %

Procedure:
A solution of 54.6 mg of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)methyl]azetidin-2-one in 2 ml of toluene was heated under reflux for 2.5 hr. The solvent was removed by evaporation, and the residue was purified by thin layer chromatography (developed with 5% methanol/ethyl acetate) to give 28.3 mg of (4-nitrobenzyl) (1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:12](=[O:14])[C:3]3=[CH:4][NH:5][C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[C:2]3=[N:26]2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CCCC2
Reactant: COc1ccc(NN)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nc3c4c([nH]cc-3c2=O)CCCC4)cc1

Procedure:
A mixture of 5.44 g of ethyl 4-chloro-5,6,7,8-tetrahydroquinoline-3-carboxylate and 3.45 g of 4-methoxyphenylhydrazine is refluxed 18 hrs in 100 ml toluene. The resulting mixture is stirred with 50 ml 1N NaOH, the layers separated, and the aqueous phase extracted twice with ether. The aqueous layer is then neutralized with aqueous ammonium chloride and filtered. The product is washed with water, and dried to give 2-(4-methoxyphenyl)-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one m.p. 279°-282°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][CH2:15]1)[CH:5]=O.[Cl:22][C:23]1[CH:24]=[C:25]([NH2:31])[C:26]([NH2:30])=[CH:27][C:28]=1[CH3:29]>>[Cl:22][C:23]1[C:28]([CH3:29])=[CH:27][C:26]2[NH:30][C:5]([C:4]3[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]4[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][CH2:15]4)=[C:2]([Cl:1])[CH:3]=3)=[N:31][C:25]=2[CH:24]=1
Reactant: Cc1cc(N)c(N)cc1Cl
Reactant: CN1CCCN(CCCOc2ccc(C=O)cc2Cl)CC1
Product: Cc1cc2[nH]c(-c3ccc(OCCCN4CCCN(C)CC4)c(Cl)c3)nc2cc1Cl
Yield: 7.9 %

Procedure:
This compound was prepared by the method described in Example 1, using 3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-benzaldehyde (61 mg, 0.20 mmol, 1.0 equiv), 4-chloro-5-methyl-benzene-1,2-diamine (31 mg, 0.20 mmol, 1.0 equiv), and Na2S2O5 (48 mg, 0.25 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 7.1 mg (8%) of the title compound. MS (electrospray): mass calculated for C23H28Cl2N4O, 446.16. m/z found, 447.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.96 (d, J=2.2 Hz, 1H), 7.83 (dd, J=8.6, 2.2 Hz, 1H), 7.45 (s, 1H), 7.34 (s, 1H), 7.10 (d, J=8.7 Hz, 1H), 4.08 (t, J=6.0 Hz, 2H), 2.76-2.64 (m, 10H), 2.36 (s, 3H), 2.30 (s, 3H), 1.96-1.88 (m, 2H), 1.80-1.73 (m, 2H).