Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:8][C:7]1[C:2]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1nccnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2nccnc2Cl)cn1
Temperature: 90 °C
Yield: 53.3 %

Procedure:
To 2,3-dichloropyrazine (1.12 g, 7.52 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.56 g, 7.52 mmol), bis(triphenylphosphine)palladium(II) dichloride (270 mg, 0.38 mmol), and Na2CO3 (2.4 g, 22.56 mmol) in a pressure tube were added 1,2-dimethoxyethane (15 mL) and water (2 mL). The flask was evacuated and flushed with argon (3×) and then sealed and heated at 90° C. overnight. The mixture was concentrated under reduced pressure and purified by silica gel chromatography eluting with 20-100% EtOAc/hexanes to afford 2-chloro-3-(1-methyl-1H-pyrazol-4-yl)pyrazine (780 mg, 53%). LCMS (ESI) m/z 195 (M+H)+.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].C([O:11][C:12]([CH:14]([C:28](=O)[CH3:29])[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27])=O)C>CO>[NH2:7][C:6]1[N:8]=[C:12]([OH:11])[C:14]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:26][CH3:27])=[C:28]([CH3:29])[N:5]=1
Reactant: CCOC(=O)C(Cc1ccc(C(=O)OC)cc1OC)C(C)=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CO
Product: COC(=O)c1ccc(Cc2c(C)nc(N)nc2O)c(OC)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 59.5 %

Procedure:
Guanidine carbonate (8.73 g) was added in one portion to a solution of the product from step (i) (14.7 g) in MeOH (200 mL). The resulting mixture was stirred at 65° C. for 16 h and allowed to cool. The precipitate was collected by filtration and suspended in water (50 mL). The solid was collected by filtration, washed with MeOH (20 mL) and EtOAc (20 mL) to give the subtitle compound as a colourless solid 8.60 g that was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:15])[CH2:13]Br)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C)C=O>[N:16]([CH2:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=1)=[O:15])=[N+:17]=[N-:18]
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of 4′-ethoxycarbonyl-2-bromoacetophenone (2.0 g) in N,N-dimethylformamide (8 ml) was added sodium azide (480 mg) at 0° C., and stirred for 2 hours at room temperature. The reaction mixture was poured into water (100 ml), extracted with diethyl ether (200 ml×2), washed with brine, and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The product was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to give 2-azido-4′-ethoxycarbonylacetophenone (1.46 g).
Reaction SMILES: [F:1][C:2]([F:78])([C:64]1[CH:69]=[CH:68][C:67]([O:70][CH2:71][CH2:72][CH2:73][C:74]([F:77])([F:76])[F:75])=[CH:66][CH:65]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:17]=2[C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][C:26]=2[CH2:34][O:35][C:36](=[O:63])/[CH:37]=[CH:38]/[C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]([F:62])([F:61])[C:47]3[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH2:55][CH2:56][C:57]([F:60])([F:59])[F:58])=[CH:49][CH:48]=3)=[CH:41][CH:40]=2)=[O:13])=[CH:6][CH:5]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:78])([C:64]1[CH:69]=[CH:68][C:67]([O:70][CH2:71][CH2:72][CH2:73][C:74]([F:77])([F:76])[F:75])=[CH:66][CH:65]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=2[C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=2[CH2:34][O:35][C:36](=[O:63])/[CH:37]=[CH:38]/[C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]([F:62])([F:61])[C:47]3[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH2:55][CH2:56][C:57]([F:58])([F:59])[F:60])=[CH:49][CH:48]=3)=[CH:41][CH:40]=2)=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1COC(=O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccc(N)cc2COC(=O)/C=C/c2ccc(OC(F)(F)c3ccc(OCCCC(F)(F)F)cc3)cc2)c(COC(=O)/C=C/c2ccc(OC(F)(F)c3ccc(OCCCC(F)(F)F)cc3)cc2)c1
Yield: 87 %

Procedure:
9.22 g (8.38 mmol) of [4,4′-dinitro-2′-({[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]-methoxy}-phenyl)prop-2-enoyl]oxy}methyl)-1,1′-biphenyl-2-yl]methyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate are dissolved in a mixture of 54 mL of N,N-dimethylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexa-hydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 400 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yields 7.59 g of [4,4′-diamino-2′-({[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoyl]oxy}methyl)-1,1′-biphenyl-2-yl]methyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCO>[CH2:25]([O:24][C:22]([C:21]1[N:18]=[C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[S:17][CH:20]=1)=[O:23])[CH3:26]
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 60 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (131 mg, 0.50 mmol) and ethyl bromopyruvate (74 μl, 0.50 mmol) in EtOH (3 ml) was stirred at 60° C. for 18 hours. The solid was filtered off and washed with cold EtOH, then dried in vacuo to give the title compound as light brown solid (130 mg, 72%). MS ISP (m/e): 359.1 (100) [(M+H)+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[N:4][N:3]=1.[NH2:30][C@H:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]([OH:37])([CH2:35][CH3:36])[CH2:33][CH3:34]>>[CH2:33]([C:32]([OH:37])([CH2:35][CH3:36])[C@H:31]([NH:30][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[N:4][N:3]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:34]
Reactant: O=S(=O)(Oc1ccc2ccccc2c1-c1nnc(Cl)c2ccccc12)C(F)(F)F
Reactant: CCC(O)(CC)[C@H](N)c1ccccc1
Product: CCC(O)(CC)[C@H](Nc1nnc(-c2c(OS(=O)(=O)C(F)(F)F)ccc3ccccc23)c2ccccc12)c1ccccc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 55.3 %

Procedure:
To trifluoromethanesulfonic acid 1-(4-chlorophthalazin-1-yl)-naphthalen-2-yl ester (600 mg, 1.37 mmol) was added 3-((R)-aminophenyl-methyl)pentan-3-ol (1.06 g, 5.49 mmol). The resulting suspension was stirred for 24 hrs at 120° C. The mixture was purified by flash chromatography on silica gel (toluene/EtOAc 10:0→5:1) followed by crystallization from diethyl ether to give 451 mg of the title compound as a white powder as a mixture of diastereomers. (yield: 55%)
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9](=[O:22])[N:8]2CC2C=CC(OC)=CC=2OC)[CH:5]=[N:4][CH:3]=[N:2]1.OP([O-])([O-])=O.[K+].[K+]>C(#N)C.O.C(#N)C>[N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9](=[O:22])[NH:8]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2cncn2)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(N[C@@H]1C(=O)N[C@@H]1Cn1cncn1)OCc1ccccc1
Temperature: 90 °C
Yield: 56.3 %

Procedure:
Prepared in an analogous manner to example 4, step 2 using benzyl ((2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-3-yl)carbamate (101 mg, 0.224 mmol), K2S2O8 (85 mg, 0.313 mmol) and K2HPO4 (50.7 mg, 0.291 mmol) in ACN:water (2:1, 61.5 mL) while heating for 2 h at 90° C. More K2S2O8 (18.1 mg, 0.067 mmol) and K2HPO4 (10.1 mg, 0.058 mmol) were added and heated for another 1.5 h. More K2S2O8 (18.1 mg, 0.067 mmol) and K2HPO4 (10.1 mg, 0.058 mmol) were added and heated for another hour. It was diluted with ACN and concentrated in vacuo, removing most of the ACN. The mixture was diluted with water/DCM then added EtOAc and the layers separated. The aqueous layer was extracted with EtOAc (5×) and the combined organic layers were dried over Na2SO4. The crude residue was purified via silica gel chromatography (MeOH-DCM, 10%) to afford the title compound (38 mg, 56%). LCMS: Rt=0.50 min, m/z=302.2 (M+1) Method 2m_acidic; 1H NMR (500 MHz, ACN-d3) δ 8.17 (s, 1H), 7.92 (s, 1H), 7.49-7.31 (m, 4H), 6.82-6.74 (m, 1H), 6.67 (br s, 1H), 5.18-5.01 (m, 3H), 4.49-4.42 (m, 1H), 4.37-4.30 (m, 1H), 4.21 (q, J=5.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[C:4]([C:22]([F:25])=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:18]2[CH:17]=[N:16][C:15]([C:19]([OH:21])=O)=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.Cl.[CH2:28]([NH:35][OH:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([OH:36])[C:19]([C:15]1[N:16]=[CH:17][C:18]2[N:6]([CH2:5][C:4]3[C:22]([F:25])=[CH:23][CH:24]=[C:2]([Cl:1])[C:3]=3[F:26])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:21])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ONCc1ccccc1
Reactant: O=C(O)c1cc2c3ccccc3n(Cc3c(F)ccc(Cl)c3F)c2cn1
Agent: Cl
Product: O=C(c1cc2c3ccccc3n(Cc3c(F)ccc(Cl)c3F)c2cn1)N(O)Cc1ccccc1

Procedure:
The title compound is prepared by coupling of 9-(3-chloro-2,6-difluorobenzyl)-9H-β-carboline-3-carboxylic acid and N-benzyl hydroxylamine hydrochloride under conditions similar to those provided in step (b) of example 7.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16]([CH3:22])[C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1.C([O-])(O)=O.[Na+]>C1COCC1>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:19]1[CH2:20][CH2:21][C@@H:17]([N:16]([CH3:22])[CH3:15])[CH2:18]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CN(C)[C@@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)[C@@H]1CCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Temperature: 25 °C

Procedure:
To a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.67 mL, 4.78 mmol) in THF (25 mL) was added (R)-N,N-dimethylpyrrolidin-3-amine (0.66 g, 5.74 mmol) and NaHCO3 (1.1 g, 13.15 mmol). The reaction was stirred at RT and monitored by LCMS for disappearance of starting material and formation of product. The mixture was concentrated, diluted with CH2Cl2, washed with H2O and then brine. Drying with MgSO4 was followed by filtration and concentration to afford the product as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[N:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:27]2[CH:28]=[CH:23][N:24]=[C:25]([N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)[N:26]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Clc1ccnc(N2CCCC2)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccnc(N4CCCC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide and 4-chloro-2-pyrrolidin-1-ylpyrimidine as the starting materials.
Reaction SMILES: [I:1][CH:2]1[CH:8]2[CH2:9][C:5]([CH3:18])([C:6](=[O:17])[N:7]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:8]2[CH2:9][C:5]([CH3:18])([C:6](=[O:17])[N:7]2[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(C)CCC(I)C1C2
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(=O)C2(C)CC=C(I)C1C2
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-iodo-1-methyl-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate, 52d, (7.6 g, 20.8 mmol) in 100 mL of toluene was added 1,8-diazabicyclo[5.4.0]undec-7-ene (6.2 mL, 41.6 mmol). The reaction was warmed to reflux and stirred overnight. The reaction was concentrated in vacuo and the resulting residue was purified by silica gel chromatography (4:1 Hexanes:EtOAc), yielding 4.9 g of the desired product, 52e.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][NH:10][C:4]=2[CH:3]=1.[OH-].[Na+].[H][H]>[Pd].C(O)C>[CH:11]1[C:8]2[CH2:9][NH:10][C:4]3[CH:3]=[CH:2][CH:16]=[CH:15][C:5]=3[O:6][C:7]=2[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ccc2c(c1)NCc1ccccc1O2
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2c(c1)CNc1ccccc1O2
Yield: 68.1 %

Procedure:
A solution of 2.0 g of 8-chloro-10,11-dihydrodibenz [b,f][1,4]oxazepine, 0.77 g of sodium hydroxide, and 5% palladium on carbon in 50 mL of ethanol (3A) was shaken at 60 psi hydrogen in a Parr hydrogenator at room temperature for 3.67 hours. The catalyst was filtered from the reaction and the solution was evaporated under vacuum. The residue was taken up in chloroform, washed with water and brine, dried over magnesium sulfate, and evaporated under vacuum to yield 1.16 g (68.1%) of 10,11-dihydrodibenz[b,f][1,4]oxazepine as a tan solid. Mp: 74°-76° C.
Reaction SMILES: [CH2:1]([NH:6][C:7](=[O:28])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[C@H:14]([CH3:26])[NH:15]C(OCC1C=CC=CC=1)=O)[CH2:2][CH2:3][CH2:4][CH3:5].CCOCC>Br.C(O)(=O)C>[CH2:1]([NH:6][C:7](=[O:28])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[C@H:14]([CH3:26])[NH2:15])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 1 h
Yield: 152.5 %

Procedure:
2.5 g of N-benzyloxycarbonyl-L-alanyl-L-proline n-pentylamide were dissolved in 15 ml of 4-N hydrogen bromide in acetic acid and the solution was stirred for 1 hour at room temperature. 150 ml of dry ether were added. An oil precipitated out and was allowed to settle. The ether was decanted off and the procedure repeated using 150 ml of fresh ether. On evaporation there were obtained 2.5 g of L-alanyl-L-proline n-pentylamide in the form of a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7](O[Si](C)(C)C)=[C:6](O[Si](C)(C)C)[CH2:5][CH2:4]1)[CH3:2].[ClH:20].Cl.[C:22]([CH:25]([NH2:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[NH:24])[NH2:23]>>[ClH:20].[ClH:20].[NH2:24][C:22]1[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:31][C:7]2[CH2:8][CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]=2[N:23]=1
Reactant: CCOC(=O)C(N)C(=N)N
Reactant: CCN1CCC(O[Si](C)(C)C)=C(O[Si](C)(C)C)CC1
Agent: Cl
Product: CCOC(=O)c1nc2c(nc1N)CCN(CC)CC2

Procedure:
This compound was prepared analogous to Example 22 from 1-ethyl-2,3,6,7-tetrahydro-4,5-bis(trimethylsilyloxy)-azepine and ethyl 2-amidino-2-aminoacetate dihydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:29][S:30]([C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31].CC(C)([O-])C.[K+].Cl>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([CH2:29][S:30]([C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=[CH:35][CH:34]=3)(=[O:31])=[O:32])[CH:20]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(COc2ccc([N+](=O)[O-])cc2)CC1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(COc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)CC1
Temperature: -40 °C
Reaction time: 5 h
Yield: 74.1 %

Procedure:
A mixture of 4-(4-nitrophenoxymethyl)piperidine-1-carboxylic acid benzyl ester (0.8 g, 2.16 mmoles) and 1-chloromethanesulfonylnaphthalene (1.03 g, 4.3 mmoles) in THF (50 ml) at −78° C., under nitrogen, was treated dropwise with a solution of 1M potassium t-butoxide (6.5 ml, 6.5 mmoles) over a 30 minute period, allowed to warm to −40° C., stirred at −40° C. for 5 hours, poured into cold 2N HCl and extracted with EtOAc. The extracts were combined, dried over Na2SO4, and concentrated under vacuum. The resultant was purified by normal phase HPLC on a silica column, using as eluent 40% EtOAc/hexane, to afford the title compound as an off-white solid (0.9 g, 1.6 mmoles).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:9]1[CH:14]=[C:13]([S:15][CH3:16])[N:12]=[CH:11][N:10]=1)C(OC)=O.C[O-].[Na+].Cl>CO>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:9]1[CH:14]=[C:13]([S:15][CH3:16])[N:12]=[CH:11][N:10]=1
Reactant: COC(=O)C(C(=O)OC)c1cc(SC)ncn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1cc(SC)ncn1
Temperature: 60 °C

Procedure:
A mixture of 2-(6-methylsulfanyl-pyrimidin-4-yl)-malonic acid dimethyl ester 3 (3.35 g, 13 mmol) and sodium methoxide (0.300 ml of 25% w/v solution, 1.30 mmol, 0.1 eq.) in MeOH (100 ml) is heated at 60° C. for 3 hours. The reaction mixture is cooled to room temperature, neutralized with 1N HCl solution (1.30 mL) and concentrated. The residue, is extracted with ethyl acetate. The organic layer is washed with brine and dried over Na2SO4, filtered and concentrated. The crude product is purified by silica gel flash chromatography eluting with ethyl acetate in hexanes from 0% to 50% to afford (6-methylsulfanyl-pyrimidin-4-yl)-acetic acid methyl ester as a yellow oil. 1H NMR 400 MHz (CDCl3) δ 8.86 (s, 1H), 7.18 (s, 1H), 3.73 (s, 3H), 3.70 (s, 2H), 2.55 (s, 3H).
Reaction SMILES: [C:1]([S:7][CH2:8]/[C:9](=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:10]([OH:12])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[O:12]=[C:10]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])/[C:9](/[CH2:8][S:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[CH:13]\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)C(=O)SC/C(=C/c1ccccc1)C(=O)O
Reactant: NCCC(=O)OCc1ccccc1
Product: CC(C)(C)C(=O)SC/C(=C/c1ccccc1)C(=O)NCCC(=O)OCc1ccccc1

Procedure:
The (E)-2-pivaloylthiomethyl -3-phenylpropenoic acid above is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2>N1C=CC=CC=1.[O-2].[Cr+6].[O-2].[O-2]>[O:12]=[C:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH:2]=[O:1])[CH:4]=2)[NH:8]1
Reactant: O=C1Cc2cc(CO)ccc2N1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Product: O=Cc1ccc2c(c1)CC(=O)N2
Yield: 46.5 %

Procedure:
Chromium(VI) oxide (240 mg, 2.4 mmol) was added to ice-cooled pyridine (3 mL). To the formed yellow suspension was added additional pyridine (2 mL) and 5-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (130 mg, 0.8 mmol) dissolved in pyridine (3 mL). The reaction was quenched after 15 min by the addition of water (50 mL) and extracted with ethyl acetate. The organic phases were dried (Na2SO4) and evaporated in vacuo. The crude product was purified on a silica gel column using methylene chloride/methanol, (10:1), as the eluent to give 60 mg (46% yield) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]=[N+:10]([O-:21])[C:11]2[CH:17]=[C:16]3[O:18][CH2:19][CH2:20][C:15]3=[CH:14][C:12]=2[N:13]=1>COCCOC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[N:9]=[N+:10]([O-:21])[C:11]2[CH:17]=[C:16]3[O:18][CH2:19][CH2:20][C:15]3=[CH:14][C:12]=2[N:13]=1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)OCC3
Reactant: CN(C)CCN
Solvent: COCCOC
Product: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)OCC3
Yield: 65.4 %

Procedure:
N,N-Dimethyl-1,2-ethanediamine (0.40 mL, 3.6 mmol) was added to a stirred solution of chloride 196 (270 mg, 1.2 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 4 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 197 (216 mg, 65%) as a yellow solid: mp (MeOH/EtOAc) 153-157° C.; 1H NMR δ 7.50 (s, 1H, H-9), 7.40 (t, J=1.4 Hz, 1H, H-5), 5.73 (br s, 1H, NH), 4.67 (t, J=8.3 Hz, 2H, H-7), 3.48-3.53 (m, 2H, CH2N), 3.53 (dt, J=8.3, 1.4 Hz, 2H, H-6), 2.55 (dd, J=6.1, 5.9 Hz, 2H, CH2N), 2.28 [s, 6H, N(CH3)2]; 13C NMR δ 158.3, 158.2, 146.1, 140.6, 130.6, 121.8, 96.6, 71.9, 57.7, 45.1 (2), 38.8, 29.7. Anal. calcd for C13H17N5O2.¼CH3OH: C, 56.2; H, 6.4; N, 24.7. Found: C, 56.1; H, 6.2; N, 25.0%.
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[CH:16]C=CN=3)=[N:11][C:7]=2[CH:6]=1.[CH3:37][N:38]1C=CC(C(O)=O)=[N:39]1>>[F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[CH:16][N:38]([CH3:37])[N:39]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccc(F)cc2F)cn1
Reactant: Cn1ccc(C(=O)O)n1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccn(C)n4)nc3cc2Oc2ccc(F)cc2F)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 203 or in accordance with the method or by combining it with an ordinary method but using 4-(2,4-difluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 229 and 1-methyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([F:18])=[CH:20][CH:21]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2ccc(F)cc2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using 4-Fluoroaniline instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a yellow solid, MS (ISP): m/e=326.1 (M+H+).