Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11](OCC)=[O:12].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[N:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[N:5]=[CH:4][C:3]=1[CH2:11][OH:12]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(CO)c1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
A solution of ethyl 5-bromo-1-tert-butyl-1H-pyrazole-4-carboxylate (685 mg, 2.49 mmol) in THF (20 mL) was cooled to −78° C. and treated with diisobutylaluminum hydride (7.47 mL, 7.47 mmol, 1 M THF), dropwise. The mixture was stirred at −78° C. for 30 minutes and then warmed to room temperature for 18 hours. The mixture was quenched with ethyl acetate 10 mL) and stirred 15 minutes. The mixture was then treated with saturated aqueous Rochelle's salt (25 mL) and stirred 1 hour at room temperature. The mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (10-80% ethyl acetate/heptane gradient, 25 g silica gel) to yield 460 mg of (5-bromo-1-tert-butyl-1H-pyrazol-4-yl)methanol as a clear oil. +APCI (M+H) 233.1, (M+2+H) 235.1; 1H NMR (400 MHz, CDCl3, δ): 7.51 (s, 1H), 4.53 (d, 2H), 1.74 (s, 9H), 1.55 (t, J=5.8 Hz, 1H).
Reaction SMILES: OC[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([C:18]3[CH:19]=[C:20]4[C:25](=[C:26]([CH3:28])[CH:27]=3)[N:24]=[CH:23][C:22]([C:29]([NH2:31])=[O:30])=[C:21]4[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)(=[O:17])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.[OH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]C1C=CC(B(O)O)=CC=1>>[OH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([C:18]3[CH:19]=[C:20]4[C:25](=[C:26]([CH3:28])[CH:27]=3)[N:24]=[CH:23][C:22]([C:29]([NH2:31])=[O:30])=[C:21]4[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)(=[O:17])=[O:16])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: OCCCCCc1ccc(B(O)O)cc1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CO)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CCCCCO)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 64, using 4-(5-hydroxypentyl)phenylboronic acid in place of 4-(hydroxymethyl)phenylboronic acid. ES/MS calcd. for C35H36N3O5S+ 610.2. Found m/z=610.3 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]3[CH:19]3[CH2:20][CH2:21]3)=[CH:13][C:12]=1[F:17])[CH2:27]2
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: Clc1cccc2c1CNC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2nc(N3Cc4cccc(Cl)c4C3)c(F)cc2c1=O
Yield: 18.8 %

Procedure:
310 mg of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4- oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 660 mg of 4-chloroisoindoline, 0.42 ml of triethylamine, and 5 ml of anhydrous chloroform were processed in the same manner as in Example 107 to produce 75 mg of 7-(4-chloro-2- isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid.
Reaction SMILES: C([NH:9][C:10](=[S:23])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[NH:11]([CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[C:10]([NH2:9])=[S:23]
Reactant: CC(C)(C)OC(=O)NCCCNC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCNC(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of material from Example 58 (6.89 g, 20.43 mmol) in MeOH (40 mL) is slowly added aqueous 5M NaOH (4.49 mL, 22.47 mmol) and the reaction is allowed to stir for 1 h at room temp. The solvent is removed in vacuo, the residue is neutralized with acetic acid and partitioned between water and EtOAc. The water layer is extracted with EtOAC, the organic layers are combined, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give 3.43 g (50.2%) of the title compound. LC/MS (Condition A): ret. T=2.54 min, (M+Na) 256.13.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([OH:15])[CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C@@H:11]1[CH2:26][OH:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(=N)O[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl.C1CCCCC1.C(OCC)(=O)C>[C:1]([O:9][C@H:10]1[C@H:14]([OH:15])[CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C@@H:11]1[CH2:26][O:27][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: O=C(O[C@H]1[C@H](O)CN(C(=O)OCc2ccccc2)[C@@H]1CO)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O[C@H]1[C@H](O)CN(C(=O)OCc2ccccc2)[C@@H]1COCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.5 %

Procedure:
The compound (3.37 g, 9.07 mmol) synthesized in Example 1 (1h) was dissolved in methylene chloride:cyclohexane (1:2, 180 mL) and benzyl trichloroacetoimidate (2.0 mL, 10.88 mmol) and trifluoromethanesulfonic acid (2.57 mL, 15.3 mmol) were added thereto, followed by stirring of the mixture at room temperature for 1 hour. After saturated aqueous sodium hydrogencarbonate solution (20 mL) was added to the reaction mixture at 0° C. and the mixture was diluted with ethyl acetate (200 mL), it was washed with water (300 mL) and saturated aqueous sodium hydrogencarbonate solution (300 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 5:1-2:1, V/V) to obtain 4.71 g of pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][CH:14]1[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:18]3[CH2:17][CH2:16][NH:15][CH:14]([CH3:13])[CH2:19]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CC1CNCCN1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: CC1CN(c2ccnc3cc(Cl)ccc23)CCN1

Procedure:
4,7-Dichloroquinoline (0.5 g, 2.5 mmol) and 2-methylpiperazine (1.25 g, 12.5 mmol) are reacted according to method A yielding the product as a brown oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[C:11]2([CH2:21][CH2:20][C:14]3([CH2:18][CH2:17][NH:16][C:15]3=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1>C1COCC1>[O:7]1[C:11]2([CH2:21][CH2:20][C:14]3([CH2:18][CH2:17][NH:16][CH2:15]3)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1CC2(CCC3(CC2)OCCO3)CN1
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a suspension of LiAlH4 (21 g, 558.56 mmol) in anhydrous THF (500 mL) was added a solution of 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (59 g, 279.28 mmol) in anhydrous THF (400 mL) dropwise at 0° C. in 1 h. The reaction mixture was heated to reflux and stirred for 2 h, then quenched with water at 0° C. until no bubble escaped and filtered. The filtere cake was washed with a mixture of DCM and MeOH (1/1 (v/v), 500 mL). The filterate was concentrated in vacuo and the residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the product as a yellow solid (52 g, 94%).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[C:18]([Br:19])=[CH:17][C:16]2[C:11](=[C:12]([Cl:21])[CH:13]=[C:14](Br)[CH:15]=2)[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1>C1COCC1.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>[C:1]([Si:5]([O:8][C:9]1[C:18]([Br:19])=[CH:17][C:16]2[C:11](=[C:12]([Cl:21])[CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2c(Cl)cc(Br)cc2cc1Br
Reactant: COc1ccc([Mg]Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2c(O[Si](C)(C)C(C)(C)C)c(Br)cc3cccc(Cl)c23)cc1
Yield: 68.8 %

Procedure:
A solution of tert-butyl[(3,6-dibromo-8-chloro-2-naphthyl)oxy]dimethylsilane (1.95 g, 4.32 mmol), 4-methoxyphenylmagnesium bromide (13.8 mL of 0.5 N solution, 6.9 mmol), and tetrakis(triphenylphosphine)palladium (0.25 g, 0.21 mmol) in THF (10 mL) were stirred at reflux for 8 hr. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with water, dried with sodium sulfate, filtered, evaporation of the solvent, and purified on a silica column (5% ethyl acetate—hexanes) to yield 1.42 g (69%) of the title compound as a white solid: 1H NMR (CDCl3): δ 0.36 (6H, s), 1.10 (9H, s), 3.87 (3H, s), 7.01 (2H, d, J=8.78 Hz), 7.33(1H,d, J=1.36 Hz), 7.58 (2H, d, J=8.75 Hz), 7.73 (1H, s), 7.78 (1H, d, J=1.62 Hz), 8.10 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:24]=[C:23]([C:25](=O)[C:26]#[CH:27])[CH:22]=[CH:21][C:20]=2[CH3:29])[C:5]([CH3:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].Cl.[OH:32][C:33]([CH3:38])([CH3:37])[C:34]([NH2:36])=[NH:35].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][N:36]=[C:34]([C:33]([OH:32])([CH3:38])[CH3:37])[N:35]=3)[CH:22]=[CH:21][C:20]=2[CH3:29])[C:5]([CH3:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Reactant: CC(C)(O)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Temperature: 85 °C
Yield: 48.7 %

Procedure:
To a solution of the 5-chloro-6-(2,4-difluoro-benzyloxy)-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-3H-pyrimidin-4-one of Step D (20 mg, 0.05 mmol) in acetonitrile (1 mL) as added 2-hydroxy-2-methylpropionamidine HCl (9 mg, 0.07 mmol) and potassium carbonate (20 mg, 0.15 mmol) and the slurry was heated at 85° C. for eighteen hours. The reaction was returned to ambient temperature and filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a white solid (12.5 mg, 50% yield). MS (M+H): 513; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.65 (s, 6H), 2.18 (s, 3H), 2.21 (s, 3H), 5.51-5.60 (m, 2H), 6.88-6.97 (m, 2H), 7.55-7.60 (m, 3H), 7.93 (s, 1H), 8.14 (d, J=8.61 Hz, 1H), 8.78 (d, J=5.09, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]([OH:20])=[O:19])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[CH2:22](O)[CH3:23]>S(=O)(=O)(O)O>[C:1]1([C:7]2[CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]([O:20][CH2:22][CH3:23])=[O:19])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Temperature: 80 °C
Reaction time: 72 h

Procedure:
2-Phenyl-4-quinolone-6-carboxylic acid (1.3 grams) obtained in Example 2 is dissolved in 80 ml of ethanol and 0.5 ml of concentrated sulfuric acid. The solution is stirred for three days at 80° C., water is added thereto, crystals which separate out therefrom are collected by filtration. These are washed with water and dried to give 1.4 grams of ethyl 2-phenyl-4-quinolone-6-carboxylate, colorless powder, melting at above 300° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[O:13])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>O1CCCC1>[C:27]([NH:1][C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:17][CH:16]=3)=[O:13])=[CH:25][CH:26]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:29])[CH3:28]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccnc1-c1ccc(C(=O)Nc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
The product from Example 3 (150 mg, 0.435 mmol) in acetic anhydride (0.24 mL, 2.54 mmol) was heated in tetrahydrofuran (2 mL) at 40° C. overnight. The mixture was allowed to cool to room temperature and concentrated under reduced pressure to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.68 (s, 1H), 8.53 (dd, J=4.6 Hz, 1.5 Hz, 1H), 8.06 (m, 2H), 7.91 (dd, J=8.1 Hz, 1.3 Hz, 1H), 7.7–7.78 (m, 4H), 7.36–7.45 (m, 3H), 1.97 (s, 3H), 1.29 (s, 9H); MS (ESI30 ) m/z 388 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:32])[CH:12]([NH:13][C:14](=[O:31])[CH:15]([CH:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]3=C=O)[NH:16]OC(C3CC3)C)[C@H:4]2[S:3]1.CCOCC>C(O)=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:32])[CH:12]([NH:13][C:14](=[O:31])[CH:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH2:16])[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(NOC(C)C3CC3)C3C=CC=CC3=C=O)[C@H]2S1
Solvent: O=CO
Solvent: CCOCC
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccccc3)[C@H]2S1
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
A solution of 2-methyl-7-[N-(1-cyclopropylethoxy)-carbonyl-2-phenylglycyl]amino-3-cephem-4-caboxylic acid (2.0 g) in formic acid (10 ml) was stirred for 2.5 hours at room temperature. After the reaction was completed, ether (30 ml) was added to the reaction mixture, and the supernatent was removed three times by decantation. Colorless powder was collected by filtration and washed with ether. Thus obtained powder was suspended in a mixture of acetonitrile (15 ml) and water (1 ml), and the suspension was stirred for 1.5 hours under ice-cooling. The precipitate was collected by filtration and dried to give 2-methyl-7-(2-phenylglycyl)amino-3-cephem-4-carboxylic acid (1.13 g), mp 168.5° to 171° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:33])[C@@H:22]([NH:25]C(OC(C)(C)C)=O)[CH2:23][CH3:24])=[CH:9]1)=O)(C)(C)C.ClCCl.Cl>C(OCC)C>[NH2:25][C@@H:22]([CH2:23][CH3:24])[C:21]([NH:20][CH2:19][CH2:18][CH2:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][CH:9]=1)=[O:33]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCc1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC[C@H](N)C(=O)NCCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 20 mL cintillation vial was charged with 3-[3-(2-(S)-tert-butoxycarbonylamino-butyrylamino)-propyl]-indole-1-carboxylic acid tert-butyl ester (280 mg, 0.61 mmol), dichloromethane (3.6 mL), and 1M hydrogen chloride in diethyl ether (3.0 mL). The resulting mixture was stirred at room temperature for 4 h, then concentrated in-vacuo and the residue placed under high vacuum overnight to yield 2-(S)-amino-N-[3-(1H-indol-3-yl)-propyl]-butyramide. 1H NMR (300 MHz, CD3OD) δ 7.51 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.95-7.09 (m, 3H), 3.11-3.39 (m, 3H), 2.77-2.82 (m, 2H), 1.78-2.01 (m, 4H), and 0.94 (t, J=7.4 Hz, 3H); MS (ES+) 260 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:15]1([N:14]=[C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(=O)c1cccn1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Nc1ccccc1)c1cccn1C
Yield: 43 %

Procedure:
To a solution of 4.0 ethyl 1-methylpyrrole-2-glyoxylate and 2.23 g aniline in 20 ml toluene is added 30 mg p-toluenesulfonic acid. Heating at reflux for 2 days with water being removed with a Dean-Stark trap is followed by dilution with ether. The precipitate is removed by filtration and the filtrate washed successively with aqueous hydrochloric acid, aqueous sodium bicarbonate and brine. After drying, the solvent is evaporated to afford a residue which is recrystallized twice from isopropanol to give a 43% yield of ethyl α-phenylimino-1-methylpyrrole-2-acetate, m.p. 69°-71° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[N:24])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]([O:21][CH2:22][C:23]#[N:24])=[CH:19][N:20]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(OCC#N)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCOc1cnc(NC2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.6 %

Procedure:
To a stirred solution of 4-(5-cyanomethoxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.67 g, 2.0 mmol, 1.0 equiv) in dichloromethane (15 mL) was added drop by drop 90% trifluoroacetic acid (1.82 mL, 2.55 g, 20 mmol, 10 equiv) and the reaction was stirred at rt for 16 h. The reaction mixture was evaporated and the residue partitioned between water and dichloromethane. The pH of the water phase was adjusted to 9-10 by addition of a sat. solution of potassium carbonate and the mixture extracted three times with dichloromethane. The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol (+25% ammonia in water) to give 0.32 g (69%) of the title compound as colorless oil. MS (ISP): 234.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]([CH3:20])=[C:12]3[C:21]#[N:22])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][S:38](Cl)(=[O:40])=[O:39])=[CH:33][CH:32]=1>>[C:17]([C:16]1[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][S:38]([CH2:37][C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)(=[O:39])=[O:40])[C:12]([C:21]#[N:22])=[C:13]([CH3:20])[NH:14][C:15]=1[CH3:19])#[N:18]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Product: CC1=C(C#N)C(c2ccc3[nH]nc(NS(=O)(=O)Cc4ccc(Cl)cc4)c3c2)C(C#N)=C(C)N1

Procedure:
The title compound was prepared following the procedure described for Example 6 starting from 100 mg (0.256 mmol) tert-butyl 3-amino-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-1H-indazole-1-carboxylate (Example 3A) and 346 mg (1.54 mmol) (4-chlorophenyl)methane-sulfonyl chloride. Yield: 4 mg (3% of th.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[O:8][C:9]3[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=3[C:11]=2[CH2:12][CH2:13][NH:14][CH:15]=1)=[O:5])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[F:30])[C:24](Cl)=[O:25]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[O:8][C:9]3[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=3[C:11]=2[CH2:12][CH2:13][N:14]([C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([F:30])=[C:21]([F:20])[CH:22]=2)[CH:15]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCOC(=O)C1=CNCCc2c1oc1ccccc21
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)c(F)c2)CCc2c1oc1ccccc21

Procedure:
In a manner similar to Step F of Example 32, but using the intermediate 6,7-dihydro-5H-10-oxa-7-azabenzo[a]azulene-9-carboxylic acid ethyl ester and 3,4-difluorobenzoyl chloride, the title compound was prepared; 1NMR (CDCl3): δ 7.46-7.53 (4H, m), 7.34 (2H, m), 7.25 (2H, m), 4.33 (2H, q), 4.21 (2H, t), 3.17 (2H, t), 1.32 (3H, t). MS (ES): 398 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25](Cl)(=[O:27])=[O:26].[CH2:29]([N:31](CC)CC)C.Cl.CN>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([NH:31][CH3:29])(=[O:27])=[O:26]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(S(=O)(=O)NC)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)1H-indole-2-carboxylate (101 mg, 0.219 mmol) in 2 mL of dichloromethane was added triethylamine (0.157 mL, 1.09 mmol), followed by methylamine hydrochloride(44 mg, 0.66 mmol). After one hour, the mixture was partitioned between 100 mL of EtOAc and 100 mL of saturated aqueous NH4Cl solution. The organic phase was washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo to give the titled product. ESI+MS: 457.0 [M+H]−.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:15](O)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[C:19]([F:22])[C:20]=1[F:21]
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Agent: N
Product: Fc1cc(-c2nc(-c3cccnc3)no2)cc(F)c1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3,4,5-trifluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.64 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 8.01-8.13 (m, 2H), 8.56 (ddd, J=8.1, 1.8, 1.6 Hz, 1H), 8.75 (dd, J=4.8, 1.6 Hz, 1H), 9.29 (dd, J=2.0, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 278 (M+H)+.