Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[OH:17][CH2:16][C:15]1[C:9]2[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][C:10]=2[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)c1cccc2cc(-c3ccccc3)oc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc2cc(-c3ccccc3)oc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
2-Phenylbenzofuran-7-carboxylic acid (40 g) is dissolved in tetrahydrofuran (300 ml) and the solution is added dropwise to a suspension of lithium aluminum hydride (19.12 g) in tetrahydrofuran (130 ml) under ice-cooling. After the mixture is stirred at 70° C. for 2 hours, water is added to the mixture to decompose excess lithium aluminum hydride and its complex. Insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to remove solvent. The residue is dissolved in ethyl acetate, and the solution is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is recrystallized from a mixture of ethyl acetate and n-hexane, whereby 7-hydroxymethyl-2-phenylbenzofuran (34.4 g) is obtained. Yield: 91%.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[CH2:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=O)[C:3]=12.O.[NH2:24][NH2:25]>C(O)C>[CH2:11]([N:10]1[N:9]=[CH:8][C:7]2[C:2]3[NH:25][N:24]=[C:17]4[C:16]5[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=5[CH2:14][CH2:13][C:4]([C:3]=34)=[N:5][C:6]1=2)[CH3:12]
Reactant: NN
Reactant: CCn1ncc2c(Cl)c3c(nc21)CCc1ccccc1C3=O
Solvent: CCO
Solvent: O
Product: CCn1ncc2c3[nH]nc4c3c(nc21)CCc1ccccc1-4
Yield: 97 %

Procedure:
A mixture of 11.0 g. of 4-chloro-1-ethyl-10,11-dihydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin5(1H)one (0.035 mol.), 4.5 g. of hydrazine hydrate 98% (0.09 mol.) and 125 ml. of abs. ethanol is refluxed for 3 hours with stirring. Then the reaction solution is filtered while hot and allowed to crystallize in a refrigerator. The crystallized 2,5,7,8-tetrahydro-5-ethyl-1,2,4,5,6-pentaazabenzo[6,7]cyclohepta[1,2,3-cd]-as-indacene which is filtered off, washed with alcohol and ether, melts at 229°-231°. Evaporation of the mother liquor to dryness and treatment with water yields a further crop of 1.9 g. of the product. Total yield 97%. Recrystallization from ethanol elevates the melting point to 230°-232°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]([N:16]2[CH2:20][CH2:19][CH2:18][CH:17]2[CH3:21])[N:3]=1.[CH3:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:25][CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[CH:28]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:24]4[C:23]([CH3:22])=[CH:28][C:27]([N+:29]([O-:31])=[O:30])=[CH:26][N:25]=4)[CH2:33][CH2:34]3)[N:3]=[C:4]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[CH3:21])[N:5]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: CC1CCCN1c1nc(Cl)cc(-c2ccc(F)c(Cl)c2)n1
Reactant: Cc1cc([N+](=O)[O-])cnc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc([N+](=O)[O-])cnc1N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(N3CCCC3C)n2)CC1

Procedure:
Heat a mixture of 4-chloro-6-(3-chloro-4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl) -pyrimidine (210 mg), 1-(3-Methyl-5-nitro-pyridin-2-yl)-piperazine, and DIEA (185 mg, 1.44 mmol) in DMA at 120°C. for 16 h. Concentrate under reduced pressure and partition between EtOAc and brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:4) to afford the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10]([OH:12])=[O:11].FC1C(F)=C(F)C=CC=1S(Cl)(=O)=O.C(N(CC)CC)C.[Cl:33][CH2:34][CH2:35][CH2:36]I>CN(C=O)C>[Cl:33][CH2:34][CH2:35][CH2:36][S:10]([C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=1[F:1])(=[O:12])=[O:11]
Reactant: O=S(O)c1ccc(F)c(F)c1F
Reactant: ClCCCI
Agent: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(CCCCl)c1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 30.6 mmol 2,3,4-trifluoro-benzenesulfinic acid (acid (prepared in analogy to example 2.20(a) from 2,3,4-trifluoro-benzenesulfonyl chloride) and 91.8 mmol triethylamine in 20 ml DMF was added 61.2 mmol 1-chloro-3-iodopropane, and the mixture stirred at room temperature for 1 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed twice with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:4) to afford the title compound. MS (m/e): 275.2 ({37Cl}M+H+, 33%), 273.1 ({35Cl}M+H+, 100%),
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].N1C=CC=CC=1C1C=CC=CN=1.[CH3:22][O:23][C:24]([C:26]1[C:35]2[C:30](=[CH:31][C:32]([CH2:36]C(Cl)=O)=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)=[O:25].Cl>C1COCC1.CCOCC>[CH3:22][O:23][C:24]([C:26]1[C:35]2[C:30](=[CH:31][C:32]([CH2:36][C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: COC(=O)c1cccc2cc(CC(=O)Cl)ccc12
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)Cc1ccc2c(C(=O)OC)cccc2c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 8.56 g (64.8 mMol) of malonic acid monoethyl ester and 112 mg (0.72 mMol) 2,2′-bipyridine in 200 ml THF is cooled to −78° C. Then 60 ml of a 1.6 M solution of nbutyllithium in THF are added dropwise (color changes from yellow to red!). Warming the mixture up to −10° C., renders the mixture turn to yellow again. Addition of another 10 ml of a 1.6 M solution of nbutyllithium in THF results in a persistent red color of the mixture. After cooling to −78° C., a suspension of 36 mMol 6-chlorocarbonylmethyl-naphthalene-1-carboxylic acid methyl ester in 250 ml THF is added during 40 min and then stirring is continued for 1 h. The dark mixture is poured into 200 ml of 1 N HCl and 400 ml ether, the aq. phase separated off and extracted with 2 portions of EtOAc. The organic layers are washed with brine, dried (Na2SO4) and concentrated to the title compound which can be used in the Step 3.6 as such. Pure product can be obtained by chromatography (Combi Flash; hexane/EtOAc 85:15): MS: [M−1]=313; HPLC: tRet=15.5.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[N:3]=1.N1C(C)=CC=CC=1C.[CH:20]1([CH2:25][C@H:26]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[C:27](Cl)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[CH:20]1([CH2:25][C@H:26]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[C:27]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])([CH3:11])[CH3:9])[N:3]=2)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
In a round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 56 mg, 0.36 mmol), 2,6-lutidine (57 μL, 0.49 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride in methylene chloride (˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes to 45% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (102 mg, 74%) as a white foam: [α]30589=−13.3° (c=0.12, methylene chloride); ES-HRMS m/e calcd for C21H27N3O2Cl2 (M+H)+ 424.1553, observed 454.1553; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 6H, 2×CH3), 1.09 (m, 2H, CH2), 1.34-1.79 (m, 8H, 4×CH2), 2.03 (m, 1H, CH), 3.80 (m, 1H, ArCHCO), 3.86 (s, 2H, NCH2), 4.65 (s, 1H, OH), 6.45 (s, 1H, Ar), 7.35 (brd, 1H, Ar), 7.51 (s, 1H, Ar), 7.58 (m, 2H, Ar), 10.73 (s, 1H, NH).
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[N:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:22][CH:21]=1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 100 °C

Procedure:
To a 150 mL pressure vessel was added ethyl 2-chloronicotinate (3.1 g, 17 mmol), 4-(pyridin-2-ylamino)phenol (3.14 g, 17 mmol), and cesium carbonate (5.8 g, 18 mmol) followed by DMSO. The solution was sealed and heated to 100° C. for 20 h. It was cooled and diluted with water and extracted five times with ethyl acetate. The combined organic were washed with brine, dried over sodium sulfate, filtered, and concentrated to a dark brown residue. The residue was taken up in dichlormethane and adsorbed onto silica gel before being purified with flash chromatography (0 to 50% ethyl acetate:hexanes), affording the product as a pale orange solid. MS (ESI, pos. ion) m/z: 336.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19]([C:21]3[NH:22][C:23]([CH3:27])=[C:24]([Cl:26])[CH:25]=3)=[O:20])[C@H:14]([O:28][CH3:29])[CH2:13]2)[N:3]=1.[CH3:30][OH:31].Cl>C[O-].[Na+]>[Cl:26][C:24]1[CH:25]=[C:21]([C:19]([NH:18][C@H:15]2[CH2:16][CH2:17][N:12]([C:4]3[N:3]=[C:2]([O:31][CH3:30])[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=3)[CH2:13][C@H:14]2[O:28][CH3:29])=[O:20])[NH:22][C:23]=1[CH3:27]
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)c3cc(Cl)c(C)[nH]3)[C@H](OC)C2)nc(Cl)n1
Reactant: CO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COc1nc(C(=O)O)cc(N2CC[C@H](NC(=O)c3cc(Cl)c(C)[nH]3)[C@H](OC)C2)n1
Temperature: 85 °C

Procedure:
Cis(±)methyl 2-chloro-6-(4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)pyrimidine-4-carboxylate (Example 23; 0.12 g, 0.27 mmol) was dissolved in 0.5 M sodium methoxide in MeOH (5.4 ml, 2.7 mmol) and heated in the microwave for 1.5 h at 85° C. The reaction mixture was acidified with 1N HCl and the product was extracted with EtOAc, dried with MgSO4 and concentrated to a solid which was purified by reverse phase chromatography (gradient elution from 20-50% CH3CN in water with 0.5% TFA). Freeze drying yielded product as a white solid. MS (ES) MH+: 424 for C18H22ClN5O5; NMR: 1.62 (s, 1H), 1.75 (s, 1H), 2.14 (s, 3H), 3.26 (s, 3H), 3.53 (m, 3H), 3.87 (s, 3H), 4.22 (s, 2H), 6.88 (d, J=2.64 Hz, 1H), 7.07 (s, 1H), 7.66 (d, J=7.91 Hz, 1H), 11.63 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:3][CH2:4][CH:5]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])=[CH:12][CH:11]=2)[CH:6]1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.[CH:38]1[CH:43]=[C:42]2[CH:44]([CH2:51][O:52][C:53]([NH:55][C@H:56]([C:67](O)=[O:68])[CH2:57][C:58]3[CH:63]=[CH:62][C:61]([N:64]=[N+:65]=[N-:66])=[CH:60][CH:59]=3)=[O:54])[C:45]3[C:50]([C:41]2=[CH:40][CH:39]=1)=[CH:49][CH:48]=[CH:47][CH:46]=3.C1C2C(COC(=O)N(CCCCC(=O)NC3C=CC(N4C(=O)C(CCC(O)C5C=CC=CC=5)C4C4C=CC(OC)=CC=4)=CC=3)C3C=CC=CC=3)C3C(=CC=CC=3)C=2C=CC=1>CN(C)C=O>[CH:43]1[C:42]2[CH:44]([CH2:51][O:52][C:53](=[O:54])[NH:55][CH:56]([C:67](=[O:68])[NH:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17](=[O:23])[NH:16][C:13]3[CH:12]=[CH:11][C:10]([N:7]4[C:8](=[O:9])[CH:5]([CH2:4][CH2:3][CH:2]([OH:1])[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:6]4[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[CH:15][CH:14]=3)[CH2:57][C:58]3[CH:59]=[CH:60][C:61]([N:64]=[N+:65]=[N-:66])=[CH:62][CH:63]=3)[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:41]=2[CH:40]=[CH:39][CH:38]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCN)cc2)cc1
Reactant: [N-]=[N+]=Nc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCN(C(=O)OCC3c4ccccc4-c4ccccc43)c3ccccc3)cc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCNC(=O)C(Cc3ccc(N=[N+]=[N-])cc3)NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)cc1
Yield: 82.2 %

Procedure:
200 mg (0.40 mmol) of product 9 and 340 mg (0.79 mmol) of Fmoc-p-azido-Phe-OH 10 (Bachem) are solved in 4 ml DMF (dimethylformamide) and reacted according to production of product 8. 300 mg (82%) of product 11 is obtained in form of an amorphic solid compound: C54H53N7O7 (912.07) MS (ESI+) 912.5 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]3[CH2:14][C:11]3([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.O1CCCC1.[Pd]>[CH3:14][C:11]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[NH:10][C:9]2=[C:4]([NH2:1])[CH:5]=[CH:6][CH:7]=[C:8]2[O:13][CH2:12]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2c1N1CC1(c1ccccn1)CO2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(c2ccccn2)COc2cccc(N)c2N1
Reaction time: 6 h
Yield: 31.1 %

Procedure:
A mixture of 7-nitro-1a-pyridin-2-yl-1a,2-dihydro-1H-azireno[2,1-c][1,4]benzoxazine (100 mg, 0.4 mmol) in methanol (6 mL) and tetrahydrofuran (2 mL) was degassed with nitrogen in a Parr bottle followed by addition of palladium (10% on carbon) (30 mg, 0.28 mmol). The reaction was charged with hydrogen to 40 psi and shaken for 6 hrs. The reaction was filtered and concentrated to give crude 3-methyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine (0.030 g. 30%). LCMS calculated for C14H16N3O (M+H)+: m/z=242.1. found: 242.1.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]=2[CH:3]=1.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:2]1[N:7]=[N:6][C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]=2[CH:3]=1)[NH2:18]
Reactant: NN
Reactant: Clc1cc2c(nn1)-c1ccccc1CCC2
Solvent: CCO
Product: NNc1cc2c(nn1)-c1ccccc1CCC2

Procedure:
Alternatively, 3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (1.6 g) was heated with anhydrous hydrazine (4 mL) in ethanol (50 mL) at 100° C. for 4.75 h. The solvent was removed under vacuum. The residue was partitioned between chloroform and 1M saturated aqueous potassium carbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine as a brown solid; 1H NMR (CDCl3, 300 MHz) 7.74 (m, 1H), 7.30 (m, 2H), 7.17 (m, 1H), 6.92 (s, 1H), 2.49 (m, 2H), 2.39 (m, 2H), 2.12 (m, 2H) ppm; MS (ES) 227 (M+H).
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]5[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:21][CH2:20]5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:37][C:38]([OH:55])([CH3:54])[CH2:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1>>[C:31]([Si:28]([CH3:29])([CH3:30])[O:27][CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][CH:19]([N:15]2[C:14]([C:8]3[S:9][C:10]4[CH2:11][CH2:12][O:13][C:4]5[CH:3]=[C:2]([C:43]6[CH:42]=[N:41][N:40]([CH2:39][C:38]([CH3:54])([OH:55])[CH3:37])[CH:44]=6)[CH:36]=[CH:35][C:5]=5[C:6]=4[N:7]=3)=[N:18][CH:17]=[N:16]2)[CH2:24][CH2:23]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCC(n2ncnc2-c2nc3c(s2)CCOc2cc(Br)ccc2-3)CC1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4C4CCN(CCO[Si](C)(C)C(C)(C)C)CC4)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-(2-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperidin-4-yl}-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 1-{4-[2-(2-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-piperidin-4-yl}-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propan-2-ol. MS(ESI+) 650.3
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:14]=2[F:23])[N:3]=1.[C:24](Cl)(=O)C(Cl)=O>ClCCl.CN(C=O)C>[CH3:24][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([F:11])[C:2]([Cl:1])=[N:3][C:4]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Si:19]([CH3:20])([CH3:22])[CH3:21])=[CH:15][C:14]=1[F:23]
Reactant: C[Si](C)(C)c1ccc(Nc2nc(Cl)c(F)cc2C(=O)O)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(Cl)nc1Nc1ccc([Si](C)(C)C)cc1F
Temperature: 25 °C
Yield: 92.4 %

Procedure:
To a suspension of 6-chloro-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acid (7.6 g, 21.3 mmol) in dichloromethane (100 mL) and DMF (1 mL) was added oxalyl chloride (9.1 mL, 106.4 mmol) dropwise over 20 minutes. The reaction mixture was stirred at reflux for 18 hours and then concentrated in vacuo and the residue azeotroped with toluene. The resultant residue was taken up in cold (0° C.) methanol (100 mL). The resultant solution was heated at reflux for 1 hour, then cooled to room temperature and filtered. The precipitate was washed with cold methanol and dried under vacuum at 45° C. to give the title compound as a yellow solid (7.3 g, 92%). LCMS (method B): RT=5.38 min, [M+H]+=371.
Reaction SMILES: C(C=C([NH:9][C@@H:10]1[C:35](=[O:36])[N:12]2[C@@H:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C@@:14]([Cl:18])([CH3:17])[CH2:15][S:16][C@H:11]12)C)(OCC)=O.Cl>C(Cl)(Cl)Cl.CC(C)=O>[NH2:9][C@@H:10]1[C:35](=[O:36])[N:12]2[C@@H:13]([C:19]([O:21][CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:20])[C@@:14]([Cl:18])([CH3:17])[CH2:15][S:16][C@H:11]12
Reactant: CCOC(=O)C=C(C)N[C@@H]1C(=O)N2[C@@H]1SC[C@@](C)(Cl)[C@@H]2C(=O)OC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: C[C@@]1(Cl)CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
A solution of benzhydryl 7β-(1-carbethoxy-1-propen-2-ylamino)-3β-chloro-3α-methylcepham-4α-carboxylate (107 mg) and 1N hydrochloric acid (0.1 ml) in a mixture of chloroform and acetone (1:1; 2 ml) is stirred at room temperature for 1 hour. The reaction mixture is washed with water, dried, and evaporated to remove the solvent. The residue is treated with a mixture of ether and petroleum ether to give solid benzhydryl 7β-amino-3β-chloro-3α-methylcepham-4α-carboxylate (60 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[C:11]([C:13]1[CH:31]=[CH:30][C:16]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:29])=[C:24]([CH:28]=2)[C:25](Cl)=[O:26])=[O:18])=[CH:15][CH:14]=1)#[N:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:25](=[O:26])[C:24]2[CH:28]=[C:20]([NH:19][C:17](=[O:18])[C:16]3[CH:30]=[CH:31][C:13]([C:11]#[N:12])=[CH:14][CH:15]=3)[CH:21]=[CH:22][C:23]=2[CH3:29])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1C(=O)Cl
Reactant: CCCc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1ccc(NC(=O)c2cc(NC(=O)c3ccc(C#N)cc3)ccc2C)cc1
Yield: 16.4 %

Procedure:
4-n-Propylaniline (0.11 g) was added to a stirred suspension of 5-(4-cyanobenzamido)-2-methylbenzoyl chloride (0.224 g), triethylamine (0.21 ml) and methylene chloride (5 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.049 g); NMR Spectrum: (DMSOd6) 0.87 (t, 3H), 1.56 (m, 2H), 2.33 (s, 3H), 2.48 (m, 2H), 7.13 (d, 2H), 7.28 (d, 1H), 7.63 (m, 2H), 7.83 (m, 3H), 8.01 (d, 1H), 8.1 (m, 2H); Mass Spectrum: M+H+ 398.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:9]3[C:14]([C:15]=2[C:16](=[NH:18])[O-])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[O:4][N:3]=1.[NH2:27][NH2:28]>CCO.CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[C:9]3[C:14]([C:15]=2[C:16](=[N:27][NH2:28])[NH2:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1c(C(=N)[O-])c2ccccc2n1-c1ccc(O)cc1
Reactant: NN
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1c(C(N)=NN)c2ccccc2n1-c1ccc(O)cc1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carbimidate (Example 184) was dissolved in EtOH and 10 eq hydrazine was added. The resulting mixture was stirred at 90° C. for 10 hours. The reaction mixture was diluted with EtOAc and washed with brine. The organic phase was evaporated to dryness in vacuo and then purified using reversed phase preparative HPLC. Fractions were combined, concentrated and the final product was identified by 1H-NMR and LC/MS. Purity was determined by analytical HPLC. ES/MS m/z: 362.21 (M+H), 360.28 (M−H); 1H NMR (methanol-d3, 500 MHz): 7.81 (m, 1H), 7.36-7.32 (m, 3H), 7.08 (m, 2H), 6.90 (m, 2H), 2.16 (s, 3H) and 1.96 (s, 3H).
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:38]([NH2:40])[CH3:39].C1COCC1>>[CH2:38]([NH:40][CH2:26][CH2:25][CH2:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2[S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12])[CH3:39]
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Solvent: C1CCOC1
Product: CCNCCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol -5-yloxy]-propyl ester (0.080 mg, 0.15 mmol) in 10 mL of 2.0 M ethylamine/THF (20 mmoles) was stirred at 90° C. for about 2 hours in a sealed tube. After cooling to ambient temperature the reaction mixture was solvent evaporated. It was dissolved in ethyl acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0.75% ammonium hydroxide/7.5% methanol in chloroform. Drying at 66° C. in vacuo for 20 minutes yielded ethyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine as a light yellow foam (43.0 mg, 70.0%). This was dissolved in methanol and ethereal hydrochloride was added. Concentrating and drying in vacuo at 83° C. for 16 hours gave the hydrochloride as a pale yellow semi-solid (41.7 mg, 62.3%). Mass Spectrum (+EI, [M+H]+) m/z 410; 1HNMR (500 MHz, DMSO-d6): δ14.14-14.18 (br, 1H), 8.74-8.76 (m, 1H), 8.56-8.72 (br, 2H), 8.52 (dd, 1 h, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.54-7.65 (m, 3H), 7.29 (d, 1H, J=2.08 Hz), 7.07-7.10 (m, 1H), 4.09-4.12 (m, 2H), 3.03-3.07 (m, 2H), 2.90-2.97 (m, 2H), 2.05-2.12 (m, 2H), 1.15-1.19 ppm (m, 3H). Elemental Analysis for C22H23N3O3S.1.00 mol HCl.1.20 mol H2O: Calcd: C, 56.51; H, 5.69; N, 8.99; Found: C, 56.20; H, 5.36; N, 8.81.