Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:70])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:68])[C:57]4[CH:62]=[CH:61][C:60]([O:63][C:64]([F:67])([F:66])[F:65])=[CH:59][CH:58]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:70])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56](=[O:68])[C:57]4[CH:62]=[CH:61][C:60]([O:63][C:64]([F:67])([F:65])[F:66])=[CH:59][CH:58]=4)=[CH:53][CH:54]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)cc3)cc2C1=O
Yield: 84 %

Procedure:
The compound of example 158 was prepared analogous to compound of example 98 by hydrolysis of compound of example 157.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][C:3]=1[CH2:15][O:16][CH3:17].[F:18][C:19]1[CH:20]=[CH:21][C:22]2=[C:23]([CH:39]=1)[O:24][CH2:25][C:26]1[CH:36]=[C:35]([CH:37]=[O:38])[CH:34]=[CH:33][C:27]=1/[C:28]/2=[C:29](/[CH3:32])\[C:30]#[N:31]>>[F:18][C:19]1[CH:20]=[CH:21][C:22]2=[C:23]([CH:39]=1)[O:24][CH2:25][C:26]1[CH:36]=[C:35]([CH:37]([OH:38])[C:2]3[N:6]4[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]4=[N:4][C:3]=3[CH2:15][O:16][CH3:17])[CH:34]=[CH:33][C:27]=1/[C:28]/2=[C:29](/[CH3:32])\[C:30]#[N:31]
Reactant: COCc1nc2c(C(F)(F)F)cccn2c1I
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: COCc1nc2c(C(F)(F)F)cccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 81.9 %

Procedure:
[step 4] Using 3-iodo-2-(methoxymethyl)-8-(trifluoromethyl)imidazo[1,2-a]pyridine (700 mg, 1.97 mmol) obtained in step 3 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (288 mg, 0.98 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-(3-fluoro-8-{hydroxy[2-(methoxymethyl)-8-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (420 mg, 82%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N+:5]([O-:13])[C:6]([CH3:12])=[CH:7][C:8]=1[N+]([O-])=O.[CH3:14][O-:15].[Na+]>CO>[CH3:1][O:2][C:3]1[N:4]=[N+:5]([O-:13])[C:6]([CH3:12])=[CH:7][C:8]=1[O:15][CH3:14]
Reactant: C[O-]
Reactant: COc1n[n+]([O-])c(C)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)[n+]([O-])nc1OC

Procedure:
3-Methoxy-6-methyl-4-nitropyridazine 1-oxide (1 g) was converted and worked up analogously to example 1 g). Chromatography of the crude product was unnecessary. The solvent used was methanol (30 ml), and the base sodium methoxide (as 30% solution in methanol, 1.1 ml). Yield: 900 mg LC-MS Rt: 0.29 min [M+H]+:171.1
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]1(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][O:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](COc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 13.5 %

Procedure:
Dissolve (R)-(+)-2-(tert-butoxycarbonylamino)-1-propanol (1.75 g, 10 mmol) and phenol (0.95 g, 10 mmol) in anhydrous THF (75 mL). Cool to 0° C., add triphenylphosphine (4.0 g, 15 mmol) and diisopropylazodicarboxylate dropwise and stir at ambient temperature for 18 h. Pour the mixture into water (300 mL), basify to pH 10 with 5N aqueous NaOH, and extract with ethyl ether (3×100 mL). Wash the organic phase with brine, dry over MgSO4, filter and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as an off-white solid (340 mg, 14%).
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]2[N:5]([C:9](=[S:21])[NH:10][C:11]=2[C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=[CH:7][N:8]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:22]([S:21][C:9]1[N:5]2[CH:6]=[CH:7][N:8]=[C:3]([NH2:2])[C:4]2=[C:11]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:10]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1nccn2c(=S)[nH]c(-c3cc4ccccc4[nH]3)c12
Reactant: BrCc1ccccc1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccn2c(SCc3ccccc3)nc(-c3cc4ccccc4[nH]3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.8 %

Procedure:
A solution of 8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazine-3(2H)-thione hydrobromide (10 mg, 0.04 mmol) and benzyl bromide (5.1 uL, 0.043 mmol) in DMF (1.0 mL) was charged with N,N-diisopropylethylamine (18 uL, 0.11 mmol) and stirred at rt for 2 h. The solvent was then removed in vacuo and the crude product was dissolved in purified by preparative TLC eluting with 3% NH3/MeOH in DCM to afford 2.5 mg 3-(benzylthio)-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine. 1H NMR (400 MHz, MeOD) δ ppm 4.25 (s, 2H), 6.76 (s, 1H), 6.92 (d, J=5.05 Hz, 1H), 7.06-7.14 (m, 3H), 7.14-7.23 (m, 4H), 7.28 (d, J=5.05 Hz, 1H), 7.48(d, J=8.08 Hz, 1H), 7.63 (d, J=8.08 Hz, 1H); MS (ES+): m/z 373.35 [MH+].
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].Cl[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][C:12]#[N:13].O>COCCOC>[NH2:13][C:12]1[CH:11]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[O:5][C:4]=1[C:3]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CO
Reactant: CC(C)(C)C(Cl)=CC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1oc(C(C)(C)C)cc1N
Temperature: 85 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
To a slurry of NaH (5.98 g, 0.24 mol, 2.6 equiv) in anh. DME (800 mL) at 0° C. was added methyl glycolate (23.0 g, 0.26 mol, 2.8 equiv) over 20 min. The mixture was stirred for 1 h at room temp. and a solution of 3-chloro-4,4-dimethyl-2-pentenenitrile (13.1 g, 0.091 mol) in DME (100 mL) was added. The resulting solution was heated to 85° C. for 42 h, cooled to room temp., and treated with H2O (100 mL). The resulting mixture was separated between H2O (200 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layers were washed with a saturated NaCl solution, dried (Na2SO4), and concentrated under reduced pressure. The residual oil was purified by flash chromatography (300 g SiO2, gradient from 50% CH2Cl2/hexane to 20% EtOAc/CH2Cl2) to give methyl 3-amino-5-tert-butylfuran-2-carboxylate as a yellow solid (2.98 g, 17%): mp 91-2° C.; TLC (20% EtOAc/hexane) Rf0.36; 1H NMR (CDCl3) δ1.26 (s, 9H), 3.84 (s, 3H), 4.54 (br s, 2H), 5.75 (s, 1H); 13C NMR (CDCl3) δ28.5 (3C), 33.0, 50.7, 98.5, 128.8, 131.0, 160.7, 168.3.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:30][S:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:36]([C:35]2[CH:38]=[CH:39][C:32]([S:31][CH3:30])=[CH:33][CH:34]=2)[OH:37])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(C(O)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 107.9 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (6.0 g, 23.3 mmol) in dry tetrahydrofuran (300 mL) at −78° C. was added n-butyllithium in n-hexane (1.6 M, 10 mL, 16 mmol). The mixture was stirred at −78° C. for 5 min and then treated with 4-methylsulfanylbenzaldehyde (2.4 g, 15.8 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×500 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with dichloromethane (2×5 mL) and dried in vacuo to afford (1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-phenyl)-methanol (7.0 g, 73%) as a white solid: LC/MS m/e calcd for C21H18N2O3S2 [M+H]+ 411.52, observed 411.3.
Reaction SMILES: [Cl:1][C:2]1([Cl:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[O:11]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[CH:21]([OH:24])[C:22]#[N:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1([Cl:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([O:24][CH:21]([C:22]#[N:23])[C:20]1[CH:25]=[CH:26][CH:27]=[C:18]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1)=[O:8]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C(=O)Cl)C1(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)C(C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)C1(Cl)Cl
Temperature: 10 °C
Reaction time: 16 h

Procedure:
2,2-Dichloro-3,3-dimethylcyclopropanoyl chloride (2.69g) was dissolved in dry toluene (50ml) and this solution was added dropwise to a stirred solution of 3-phenoxymandelonitrile (3.0g) and triethylamine (2.69g) in dry toluene (50ml) maintained at 10°C. The mixture was then stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was washed in turn with 5 % sulphuric acid, saturated sodium bicarbonate and water, and then dried (Na2SO4). The solvent was removed under reduced pressure and the residue purified by chromatography on silica gel eluting in turn with toluene, 1 : 1 toluene/hexane and toluene. The required product was obtained as an oil nD20 1.5630.
Reaction SMILES: C(O[C:4]1(OCC)[CH2:8][CH2:7][CH2:6]O1)C.[CH3:12][O:13][C:14](=[O:26])[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH2:23])=[C:17]([O:24][CH3:25])[CH:16]=1>C(O)(=O)C>[CH3:12][O:13][C:14](=[O:26])[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([N:23]2[CH:4]=[CH:8][CH:7]=[CH:6]2)=[C:17]([O:24][CH3:25])[CH:16]=1
Reactant: COC(=O)c1cc(OC)c(N)c(OC)c1
Reactant: CCOC1(OCC)CCCO1
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c(-n2cccc2)c(OC)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9 g. of diethoxy-tetrahydrofuran and 5 ml. of glacial acetic acid was added dropwise at room temperature to a solution of 10.5 g. of 4-amino-3,5-dimethoxy-benzoic acid methyl ester in 50 ml. of glacial acetic acid with stirring. The mixture was stirred at 100° C. for an additional 30 minutes, cooled with ice, filtered under vacuum, dried and recrystallized from cyclohexane, whereby there was obtained 3,5-dimethoxy-4-(pyrrol-1-yl)-benzoic acid methyl ester having a melting point of 145°-146° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH2:18]1[O:28][C:27]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=2[O:19]1.[Cl-].[NH4+]>O1CCCC1>[OH:24][CH:23]([C:22]1[CH:25]=[CH:26][C:27]2[O:28][CH2:18][O:19][C:20]=2[CH:21]=1)[C:3]#[C:2][C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])=[O:4]
Reactant: C#CC(=O)OCCOCCOC
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCOCCOC(=O)C#CC(O)c1ccc2c(c1)OCO2
Reaction time: 0.17 h

Procedure:
A solution of 6.9 g (40 mmol) of 2-(2-methoxyethoxy)-ethyl propiolate in 60 ml of tetrahydrofuran was treated at -78° under argon with 25 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 6 g (40 mmol) of 3,4-methylenedioxy-benzaldehyde in 60 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 30 minutes then brought to room temperature and treated with 100 ml of saturated ammonium chloride solution The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 600 g of silica gel (elution agent methylene chloride/ether 4:1). There was obtained 2-(2-methoxyethoxy)ethyl 4-hydroxy-4-[3,4(methylenedioxy)phenyl]-2 -butynoate as a yellow oil.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C@@H:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[C@H:6]([CH:14]=O)[CH2:5]1)[CH:2]=[CH2:3].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N1C[C@@H](C2C=CSC=2)[C@H](C=O)C1)C1C=CC=CC=1>>[CH2:1]([N:4]1[CH2:8][C@@H:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[C@H:6]([CH2:14][N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@@H](C=O)[C@H](c2ccsc2)C1
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: O=C[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccsc1
Product: C=CCN1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](c2ccsc2)C1

Procedure:
The title compound was prepared from 1-allyl-3-(S)-formyl-4-(R)-(3-thienyl)pyrrolidine and 4-(4-fluorophenyl)piperidine by according to procedures described in Example 241, Step 5 with the change that 1-Allyl-3-(S)-formyl-4-(R)-(3-thienyl)pyrrolidine replaced 1-benzyl-3-(S)-formyl-4-(R)-(3-thienyl)pyrrolidine. 1H NMR (CDCl3) is consistent with structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Br:11][C:12]1[CH:13]=[C:14]([CH:20]=O)[C:15]([O:18][CH3:19])=[N:16][CH:17]=1.N1CCCCC1>C(O)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:20]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[C:15]([O:18][CH3:19])=[N:16][CH:17]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1ncc(Br)cc1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ncc(Br)cc1C=C1C(=O)Nc2ccccc21
Temperature: 80 °C
Yield: 55.5 %

Procedure:
To a solution of indolinone (130 mg, 0.98 mmol) in ethanol (5 mL) was added 5-bromo-2-methoxypyridine-3-carbaldehyde (J. Het. Chem, 1985, (22), 1583-1592) (200 mg, 0.98 mmol, 1 eq), followed by piperidine (0.194 mL, 1.9 mmol, 2 eq). The reaction mixture was heated at 80° C. for 2 hours and then allowed to cool to room temperature. The precipitate that formed was collected by filtration and washed with ethanol to give the title compound (180 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:11][OH:12])=[C:4]([F:20])[C:3]=1[NH:21][C:22]1[CH:26]=[C:25]([CH:27]2[CH2:29][CH2:28]2)[NH:24][N:23]=1.[C:30](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[CH:27]1([C:25]2[NH:24][N:23]=[C:22]([N:21]3[C:3]4[C:4]([F:20])=[C:5]([NH:9][C@H:10]([C:13]5[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=5)[CH2:11][OH:12])[C:6]([F:8])=[CH:7][C:2]=4[N:1]=[CH:30]3)[CH:26]=2)[CH2:29][CH2:28]1
Reactant: CC(=O)O
Reactant: Nc1cc(F)c(N[C@@H](CO)c2ccc(F)cc2)c(F)c1Nc1cc(C2CC2)[nH]n1
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OC[C@H](Nc1c(F)cc2ncn(-c3cc(C4CC4)[nH]n3)c2c1F)c1ccc(F)cc1

Procedure:
(R)-2-(4-Amino-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2,6-difluorophenylamino)-2-(4-fluorophenyl)ethanol (Method 104, 0.230 g, 0.57 mmol) and formamidine acetate (0.119 g, 1.14 mmol) in EtOH (10 ml) was heated at reflux for 1 hour. Saturated sodium bicarbonate solution (5 ml) and EtOAc (15 ml) were added. The organic layer was separated, washed with brine (3 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by chromatography (Hex-EtOAc=1:1) to give the title compound as off white solid (0.070 g, 30%). 1H NMR (400 MHz) 12.83 (s, 1H), 8.20 (s, 1H), 7.34 (m, 3H), 7.07 (t, J=8.8 Hz, 2H), 6.14 (s, 1H), 5.14 (d, J=9.6 Hz, 1H), 4.97 (t, J=5.6 Hz, 1H), 4.62 (m, 1H), 3.64-3.74 (m, 2H), 1.97 (m, 1H), 1.00 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 413; Found: [M+H]+ 414.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]2[C:15]([CH3:18])=[N:16][NH:17][C:4]=2[CH:3]=1.[CH:19]1(B(O)O)[CH2:21][CH2:20]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:9]1([O:8][C:6]2[C:5]3[C:15]([CH3:18])=[N:16][NH:17][C:4]=3[CH:3]=[C:2]([CH:19]3[CH2:21][CH2:20]3)[N:7]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1n[nH]c2cc(Cl)nc(OC3CCCCC3)c12
Reactant: OB(O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: Cc1n[nH]c2cc(C3CC3)nc(OC3CCCCC3)c12
Yield: 17.8 %

Procedure:
To a microwave tube was added 6-chloro-4-(cyclohexyloxy)-3-methyl-1H-pyrazolo[4,3-c]pyridine (49 mg, 0.18 mmol), cyclopropylboronic acid (80 mg, 0.9 mmol), Pd(dppf)Cl2 (15 mg, 0.018 mmol). The tube was flushed with nitrogen for 2 minutes before adding a 2 M solution of sodium carbonate in water (0.28 mL) and 1,4-dioxane (2 mL). The tube was sealed and irradiated in a microwave at 160° C. for 25 minutes. The reaction mixture was then filtered and concentrated. The crude product was purified by reverse-phase HPLC to give the title compound (8.7 mg, 17%). LC-MS (Method G): m/z=272.1 [M+H]+; 5.44 min. 1H-NMR (400 MHz, DMSO): δ 12.57 (s, 1H), 6.83 (s, 1H), 5.15 (m, 1H), 2.02 (m, 1H), 1.87 (m, 2H), 1.71 (m, 2H), 1.62 (m, 2H), 1.46 (m, 4H), 0.87 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]([N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[Br:8])=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CN(C=O)C>[Br:8][C:7]1[C:6](=[O:9])[N:5]([CH3:10])[C:3](=[O:4])[C:2]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: CN1C(=O)C(Br)=C(Br)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(Br)=C(N2CCOCC2)C1=O
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a room temperature, stirred solution of 2,3-dibromo-N-methylmaleimide (1 g, 0.004 mol) in DMF (10 mL) was added Cs2CO3 (1.34 g, 0.004 mol) followed by morpholine (360 mg, 0.004 mol) under N2 atmosphere. The reaction mixture was then stirred for 30 minutes, quenched with ice water, and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 3-bromo-1-methyl-4-morpholino-1H-pyrrole-2,5-dione (0.87 g, 85%) as a solid.
Reaction SMILES: [F:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:23]=[CH:24][C:25]5[N:29]=[C:28]([NH:30]C(=O)OC)[NH:27][C:26]=5[CH:35]=4)[CH:20]=[CH:21][C:15]=3[O:14][CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1.[OH-].[K+].Cl.C(OCC)(=O)C>CO>[F:1][CH2:2][CH:3]1[CH2:4][CH2:5][N:6]([C:9]([N:11]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:23]=[CH:24][C:25]5[N:29]=[C:28]([NH2:30])[NH:27][C:26]=5[CH:35]=4)[CH:20]=[CH:21][C:15]=3[O:14][CH2:13][CH2:12]2)=[O:10])[CH2:7][CH2:8]1
Reactant: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCC(CF)CC3)CCO4)cc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCC(CF)CC3)CCO4)cc2[nH]1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of methyl [6-(4-{[4-(fluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-yl]carbamate (example 8) (181 mg, 0.38 mmol, in methanol (6 mL) was added a 2 M aqueous solution of potassium hydroxide (6 mL), and the resulting mixture was stirred at 65° C. overnight. The pH was adjusted to 9 with 1 N aqueous hydrochloric acid, ethyl acetate was added (50 mL), and the organic layer was washed with brine (2×25 mL), dried over sodium sulfate, filtered and concentrated. Purification by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile) provided the title compound as the acetate salt (56 mg, 31% yield) as a colorless solid. 1H NMR (400 MHz, methanol-d4): 7.47 (m, 1H), 7.43 (m, 2H), 7.30 (m, 2H), 7.02 (d, 1H), 4.48 (s, 2H), 4.29 (dd, 2H), 4.19 (m, 2H), 3.71 (m, 4H), 2.85 (m, 2H), 1.95 (s, 3H), 1.87 (m, 1H), 1.72 (m, 2H), 1.36 (m, 2H); MS (EI) for C23H26FN5O2: 424 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[OH:30])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O-:26])=[S:25])=[C:15]([CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:32]([O:38][CH2:39]I)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[OH:30])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:39][O:38][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[S:25])=[C:15]([CH:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C([O-])=S)=C(C4CCOCC4)CS[C@H]23)cs1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Product: CC(C)(C)C(=O)OCOC(=S)C1=C(C2CCOCC2)CS[C@@H]2C(NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12
Yield: 55.5 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(tetrahydropyran-4-yl)thio-3-cephem-4-carboxylate (85 mg) was reacted with iodomethyl pivalate (61 mg), followed by purifying the reaction product in accordance with the procedure of Example 4, yielding the titled compound (56 mg, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)OC(C2C=CC=CC=2)CC3)=[C:7]([NH2:9])[CH:8]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:42]C3C(=CC=C(O)C=3)[CH2:35]2)[CH:31]=[CH:32][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:42][CH:34]([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([F:27])[CH:29]=2)[CH2:35]3)=[C:7]([NH2:9])[CH:8]=1
Reactant: Oc1ccc2c(c1)CC(c1cccc(F)c1)C2
Reactant: COc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)c(N)c1
Product: COc1ccc(Oc2ccc3c(c2)CC(c2cccc(F)c2)C3)c(N)c1

Procedure:
5-Methoxy-2-[2-(3-fluorophenyl)indan-5-yloxy]phenylamine was prepared as described for 5-methoxy-2-(2-phenylchroman-6-yloxy)phenylamine in Example 3(a-b) using 500 mg of 2-(3-fluorophenyl)indan-5-ol. 1H-NMR (400 MHz, CDCl3): 7.26-7.21 (m, 1H), 7.16 (d, 1H, J 2.9 Hz), 7.09 (d, 1H, J 8.2 Hz), 7.02 (d, 1H, J 7.7 Hz), 6.96-6.88 (m, 4H), 6.83 (d, 1H, J 9.1 Hz), 6.72 (dd, 1H, J 2.9, 9.1 Hz), 3.69 (s, 3H), 3.65 (k, 1H, J 8.8 Hz), 3.26-3.19 (m, 2H), 2.94 (dd, 2H, J 8.8, 15.1 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[C:10](=[O:23])[N:9]1[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([C@H:8]1[CH2:12][NH:11][C:10](=[O:23])[N:9]1[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1C(=O)N(C(=O)OCc2ccccc2)C[C@@H]1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)NC[C@@H]1C(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 94 %

Procedure:
To a solution of (R)-3-methyl-2-oxoimidazolidine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (167 mg) in methanol (1.7 ml) was added 10 wt % palladium on carbon at room temperature, and the mixture was stirred for 15 hours under one atom. of hydrogen. Under nitrogen atmosphere, this reaction solution was filtered through Celite, and eluted with methanol. The filtrate was concentrated under reduced pressure to give the titled compound (94 mg).