Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(O)=O.[Na+].[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[NH:16][S:15](=[O:18])(=[O:17])[CH2:14][C:13]=2[CH:19]=1)([O-:8])=[O:7].I[CH3:21]>O>[CH3:21][N:16]1[C:12]2[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:19][C:13]=2[CH2:14][S:15]1(=[O:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc2c(c1)CS(=O)(=O)N2
Reactant: CI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1c2ccc([N+](=O)[O-])cc2CS1(=O)=O
Temperature: 80 °C
Yield: 62.3 %

Procedure:
NaHCO3 (0.2 g, 2.4 mmol) is dissolved in H2O (3 mL) and 5-Nitro-1,3-dihydro-2H-2,1-benzisothiazole-2,2-dione (1) (0.41 g, 1.9 mmol) is added with stirring. The mixture is heated to 80° C. for 0.5 hrs and a yellow solid formed. The mixture is cooled to 0° C. and filtered. The solid is washed with cold H2O (5 mL) then with cold EtOH (15 mL). The yellow solid thus obtained is dried under high vacuum then dissolved in dry DMF (3.5 mL). Iodomethane (0.15 mL, 2.1 mmol) is added and the solution heated to 100° C. for 2 hrs. The solution is cooled to room temperature then poured into ice water (50 mL). The solid is collected by filtration and gave crystals (0.27 g, 62%) after recrystallization from EtOH. Mp 214-6° C. HRMS (FAB) calcd for C8H8N2O4S +H1 229.0283, found 229.0280.
Reaction SMILES: [CH2:1]([C:7]1[N:8]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=1)[CH2:11][CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:21]1(=[O:28])[O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22]1>C(Cl)Cl>[CH2:1]([C:7]1[N:8]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:14]=1[C:21](=[O:28])[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:11][CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C1CCCC(=O)O1
Reactant: CCCCCCc1cc(-c2ccccc2)c2n1CCC2
Solvent: ClCCl
Product: CCCCCCc1c(C(=O)CCCC(=O)O)c(-c2ccccc2)c2n1CCC2

Procedure:
5 mmoles of 5-(n-hexyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine 69 are reacted in 20 ml of CH2Cl2 with 5 mmoles (0.5 g) of glutaric acid anhydride and 11 mmoles (1.47 g) of AlCL3 similarly to the procedure for preparing the 5-(diphenyl-2,3-dihydro-1H-pyrrolizinyl)-5-oxovaleric-acids. The product is purified by column chromatography (silica gel, 1st n-hexane/ether 1+1, 2nd ether). After the eluates are concentrated, 71 remains as an oil.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:26]([OH:32])[CH2:27][O:28][CH2:29][CH2:30]O>>[C:1]1([CH2:11][C:12]([O:14][CH2:30][CH2:29][O:28][CH2:27][CH2:26][OH:32])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCCOCCO
Reactant: O=C(O)Cc1cccc2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(Cc1cccc2ccccc12)OCCOCCO
Temperature: 120 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
A mixture of 1-naphthylacetic acid (5) (2.0 g, 0.011 mol), PTSA (200 mg, 1.1 mmol), and diethylene glycol (6) (8 ml, 72.8 mmol) was stirred at 120° C. under N2. The reaction mixture became homogeneous after 1 h, and the stirring was continued for 15 h. After the reaction was completed (confirmed by TLC), the reaction mixture was poured into 50 ml of icewater mixture. The aqueous reaction mixture was extracted by EtOAc (3×50 ml) and dried over anhydrous MgSO4. The crude product was purified by column chromatography (SiO2, EtOAc/hexanes: 8/2) to yield 2.25 g (76%) of 7 as a colorless oil. 1H NMR (CDCl3, 500 MHz, 20° C.): d 7.83 (d, 1H, J=7.1 Hz ), 7.72-7.64 (m, 2H), 7.40-7.26 (m, 4H), 4.11 (t, 2H, J=4.7Hz), 3.96 (s, 2H), 3.46 (overlapped m, 4H), 3.26 (t, 2H, J=4.4 Hz), 1.90 (s, 1H). 13C NMR (CDCl3, 90 MHz, 20° C.): d 171.7, 134.0, 132.2, 130.6, 128.9, 128.2, 126.5, 126.0, 125.7, 123.9, 72.4, 65.8, 64.2, 61.2, 39.3.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:55])([CH3:54])[C:48]([NH:50][CH2:51][CH2:52][OH:53])=[O:49].NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:41])[NH:46][C:47]([C:48](=[O:49])[NH:50][CH2:51][CH2:52][OH:53])([CH3:55])[CH3:54])=[CH:33][CH:32]=3)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)C(=O)NCCO
Agent: CC(C)(N)C(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCC(=O)NC(C)(C)C(=O)NCCO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 2-(2-amino-2-methylpropionyl-amino)ethanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-propionamide, respectively.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[C:38]([F:51])[C:37]=1[OH:52]>>[NH2:26][CH:23]1[CH2:24][CH2:25][N:21]([C:18]2[N:19]=[CH:20][C:15]([NH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([C:40]5[CH:39]=[C:38]([F:51])[C:37]([OH:52])=[C:36]([Cl:35])[CH:41]=5)[CH:11]=4)[N:6]=[CH:5][C:4]=3[C:1](=[O:3])[CH3:2])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC(N)C2)nc1
Yield: 13.9 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(3-acetyl-6-bromoquinolin-4-ylamino) pyridin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.19 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (76 mg, 0.28 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (13 mg, 16% over two steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.29 (s, 1H), 8.29-8.20 (m, 2H), 8.05-7.99 (m, 2H), 7.84 (dd, J=9.2, 2.6 Hz, 1H), 7.15 (d, J=11.6 Hz, 1H), 7.07 (s, 1H), 7.00 (d, J=9.2 Hz, 1H), 4.17-4.09 (m, 1H), 4.07-4.00 (m, 1H), 3.90-3.81 (m, 1H), 3.80-3.71 (m, 2H), 2.79 (s, 3H), 2.65-2.52 (m, 1H), 2.36-2.25 (m, 1H); ESI MS m/z 492 [C26H23ClFN5O2+H]+; HPLC 97.6% (AUC), tR=9.73 min.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].C1CCN2C(=NCCC2)CC1.[F:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[C:28](/[N+]([O-])=O)\[CH3:29])=[CH:23][CH:22]=1>C1COCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([CH3:29])=[CH:2][NH:1][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:23][CH:22]=1
Reactant: C/C(=C\c1ccc(F)cc1)[N+](=O)[O-]
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1[nH]cc(C)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
Ethyl isocyanoacetate (4.36 mL, 42.09 mmol) and DBU (6.28 mL, 42.09 mmol) was added to a solution of (E)-1-fluoro-4-(2-nitroprop-1-enyl)benzene (6.0 g, 33.14 mmol) in THF (60 mL) at 0° C. The reaction mixture was stirred for 30 min at room temperature; quenched with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (1×100 mL) and brine (75 mL), dried (Na2SO4) and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel; 60-120 mesh). The pure product was eluted with 10% EtOAc in petroleum ether to yield the desired compound (6.0 g, 73%) as pale yellow solid.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19]Br)(C)(C)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCO>[C:23]1([NH:22][CH2:19][CH2:18][S:17][C:9]2[N:8]([CH2:7][C:6]([OH:5])=[O:21])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)Cn1c(SCCBr)nc2ccccc21
Solvent: CCO
Product: O=C(O)Cn1c(SCCNc2ccccc2)nc2ccccc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To tert-butyl[2-(2-bromo-ethylsulfanyl)-benzoimidazol-1-yl]-acetate (Intermediate 4-I, 25 mg, 0.065 mmol) in EtOH (0.7 ml) is added aniline (31.3 mg, 0.34 mmol). The resulting mixture is heated up to 70° C. for 1 h. After cooling the solvent is evaporated in vacuo and the crude ester is dissolved in TFA/dichloromethane (3:2, 2 ml) and stirred at rt for 2 h. Evaporation of the solvents in vacuo affords a crude product that is purified by chromatography on silica-gel (dichlromethane/MeOH, 100:7.5), yielding the pure title compound: tR=2.11 min (LC-2), ESI-MS (pos.): m/z 328.33 [M+H]+, ESI-MS (neg.): m/z 326.34 [M−H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([NH:16]C(=O)C)=[N:13][C:12]=2[CH3:20])[CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CCO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[CH3:20])[CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2ccnc(C(C)(C)C)c2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1ccnc(C(C)(C)C)c1
Yield: 69.9 %

Procedure:
A mixture of N-[5-(2-tert-butyl-pyridin-4-yl)-4-methyl-thiazol-2-yl]-acetamide (Step 1.3) (2 g, 7 mmol), a 6N aqueous solution of HCl (10 mL) and EtOH (50 mL) is stirred for 2 h at 85° C., allowed to cool, quenched by addition of a saturated solution of NaHCO3 and extracted with DCM/MeOH (9:1, v/v). The organic phase is washed with a saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH, 1:0→96:4) to afford 1.21 g of the title compound as a yellow solid: ESI-MS: 248.1 [M+H]+; TLC: Rf=0.36 (DCM/MeOH, 9:1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[CH:17]=[CH:16][N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH:14]=1)=[O:12].O1CCOCC1.[OH-].[Na+].CCOCC>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[CH:17]=[CH:16][NH:15][CH:14]=1)=[O:12]
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)c3ccc4ccccc4c3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(c1cc[nH]c1)c1ccc2ccccc2c1
Yield: 50.8 %

Procedure:
Into a flask was placed 46 g (0.12 mole) of 3-(2-naphthalenoyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole, 250 mL of 1,4-dioxane and 59.8 mL (0.18 mole) of 3 N NaOH. The reaction mixture was stirred overnight after which Et2O and water were added. The organics were separated off, washed with water, brine and dried (Na2SO4). Evaporation of the solvent in vacuo and crystallization from toluene gave 13.5 g of (51%) 3-(2-naphthalenoyl)-1H-pyrrole. mp134-136° C. CIMS m/z 223 (MH+). 1H NMR (300 MHz, CDCl3) δ 8.35 (Ar, 1H); 7.9 (Ar, 4H); 7.7 (Ar, 1H); 7.5 (Ar, 2H); 7.4 (Ar, 1H); 6.85 (Ar, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.[Na].BrC1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[C:15]2[CH:22]=[O:23].ClCCl>CN1CCCC1=O.O.[Cu]I>[CH3:21][O:20][C:19]1[C:3]([C:2]([F:7])([F:6])[F:1])=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([CH:22]=[O:23])=[C:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:13]=[CH:12]2
Reactant: COc1ccc2c(C=O)c(OCc3ccccc3)ccc2c1Br
Reactant: O=C(O)C(F)(F)F
Agent: [Cu]I
Agent: [Na]
Solvent: ClCCl
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc2c(C=O)c(OCc3ccccc3)ccc2c1C(F)(F)F
Temperature: 180 °C
Yield: 58 %

Procedure:
A suspension of copper (I) iodide (35.5 g, 0.186 mol), trifluoroacetic acid, sodium salt (50 g, 0.37 mol), and 5-bromo-6-methoxy-2-(phenylmethoxy)-1-naphthalenecarboxaldehyde (17.3 g, 0.047 mol, described in Example 6) in anhydrous 1-methyl-2-pyrrolidinone (150 mL) was stirred vigorously and heated at 180° C. under argon for 1.5 hours, then cooled. The mixture was then suspended in 1 L of water and 1 L of ether and filtered through Solka-Floc*. The filtrate was separated into two phases and the ether layer was washed with water (3X) and then washed with saturated NaCl and dried over Na2SO4. The Solka-Floc filter cake was then washed thoroughly with dichloromethane and the filtrate was washed with water (3X), and then with brine and dried over Na2SO4. After filtration and concentration, the residues from the ether and dichloromethane solutions were combined, dissolved in dichloromethane (250 mL) and filtered through silica gel with additional dichloromethane. The filtrate was concentrated and chromatographed on silica gel with 1:1 hexane:dichloromethane to give 9.8 g (58% yield) of the title compound of suitable purity for subsequent reaction, m.p. 143°-145° C. (from ethanol).
Reaction SMILES: C(OC1C=C(C(C)C)C=CC=1C(Cl)=O)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH3:49])[C:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)([CH3:28])[NH:26][C:25]([C:36]3[CH:41]=[CH:40][C:39]([C:42](C)([CH3:44])[CH3:43])=[CH:38][C:37]=3[O:46][CH2:47][CH3:48])=[N:24]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2([CH3:49])[C:27]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)([CH3:28])[NH:26][C:25]([C:36]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:38][C:37]=3[O:46][CH2:47][CH3:48])=[N:24]2)=[CH:21][CH:22]=1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Agent: CCOc1cc(C(C)C)ccc1C(=O)Cl
Product: CCOc1cc(C(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1

Procedure:
rac-(4S*,5R*)-4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-isopropyl-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was prepared from 2-ethoxy-4-isopropyl-benzoyl chloride (prepared from 2-hydroxy-4-isopropyl-benzoic acid in 3 steps) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) in an analogous manner as described in example 2 (method 1).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](F)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[F:14].[OH-:16].[K+].[CH3:18]O>>[F:14][C:5]1[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]([O:16][CH3:18])=[CH:9][C:4]=1[C:3]([OH:2])=[O:15]
Reactant: COC(=O)c1cc(F)c([N+](=O)[O-])cc1F
Reactant: CO
Reactant: [OH-]
Agent: [K+]
Product: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of methyl-2,5-difluoro-4-nitrobenzoate (10 g, 46 mmol) in methanol (100 mL) was added potassium hydroxide (7.73 g, 184 mmol) in two batches. The reaction mixture was stirred in an oil bath at 80° C. for 1 h. It was then concentrated, acidified with HCl. Solid was filtered, washed with water and dried to give the product as light yellow powder (10 g, quantitative yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.95 (s, 3H) 7.66 (d, J=4 Hz, 1H) 8.01 (d, J=8 Hz, 1H). [M+H] calc'd for C8H6FNO5, 216. found 216.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:41])[C@H:24]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:41])=[O:22])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to Nε-Cbz-L-lysine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O.C1(C(OOC(=O)C2C=CC=CC=2)=O)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:10][C:3]1[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(Cl)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(Cl)c1CBr
Reaction time: 8 h

Procedure:
In a 250 mL round bottom flask, 1-chloro-3-methoxy-2-methylbenzene (5.0 g, 31.9 mmol) was dissolved in CCl4 (50 mL). To the solution, 1-bromopyrrolidine-2,5-dione (5.8 g, 32.6 mmol) and benzoyl benzenecarboperoxoate (70 mg) were added in sequence. The resulting mixture was refluxed for 4 hours and left at room temperature overnight. The mixture was filtered. The filtrate was evaporated to provide crude product of 2-(bromomethyl)-1-chloro-3-methoxybenzene as a colorless liquid, which was used for next step without further purification.
Reaction SMILES: [C:1]([O:6]CC)(=O)[C:2]([CH3:4])=O.[NH2:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=1>CO.CO.CO>[CH3:4][C:2]1[C:1](=[O:6])[NH:9][C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:15]=2[N:16]=1
Reactant: Nc1cccnc1N
Reactant: CCOC(=O)C(C)=O
Solvent: CO
Product: Cc1nc2cccnc2[nH]c1=O
Temperature: 25 °C

Procedure:
Ethyl pyruvate (1.22 mL) was dissolved in methanol (10 mL) and added to a cold solution of 2,3-diaminopyridine (1.09 g) in methanol MeOH (20 mL) and the mixture was stirred at ambient temperature. The solid was filtered off and washed with cold methanol to afford 2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (1.1 g) as a grey solid. 1.0 g of this material was suspended in acetonitrile (10 mL) and phosphoryl chloride (1.16 mL) was added. The mixture was heated at 120° C. for 0.5 h under MW conditions. The crude mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford IIId (460 mg) as a red solid sufficiently pure for the next step.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:32]=[C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([NH:22][C:19](=[O:21])[CH3:20])=[CH:24][CH:25]=3)[N:31]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: CC(=O)Nc1ccc(NC(=N)N)cc1
Solvent: O=[N+]([O-])O
Product: CC(=O)Nc1ccc(Nc2nccc(-c3sc(C)nc3C)n2)cc1

Procedure:
By condensation between 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-(4-acetamidophenyl)-guanidine nitrate. Pale solid. Mp. 219-220° C. 1H-NMR (DMSO-D6) δ: 2.00 (s, 3H, CH3), 2.61 (s, 3H, CH3), 2.64 (s, 3H, CH3), 7.04 (d, 1H, J=4.9 Hz, pyrimidinyl-H), 7.48 (d, 2H, J=8.8 Hz, Ph-H), 7.64 (d, 2H, J=8.8 Hz, Ph-H), 8.47 (d, 1H, J=5.4 Hz, pyrmidinyl-H), 9.58 (s, 1H, NH), 9.82 (s, 1H, NH). MS (ESI+) m/z 340.02 [M+H]+ (C17H17N5OS requires 339.42).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.Cl[C:26]1[O:27][C:28]2[C:29](=[C:31]([C:35]#[N:36])[CH:32]=[CH:33][CH:34]=2)[N:30]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:26]2[O:27][C:28]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[C:29]=3[N:30]=2)=[CH:11][C:12]=1[F:17]
Reactant: N#Cc1cccc2oc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNc2nc3c(C#N)cccc3o2)C1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 2-chloro-1,3-benzoxazole-4-carbonitrile, and in the same manner as in Example 391, step A, the title compound was obtained.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][N:12]3[Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[Cl:27][CH2:28][C:29]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[Si:17]([CH:21]([CH3:23])[CH3:22])([CH:24]([CH3:26])[CH3:25])[CH:18]([CH3:19])[CH3:20])=[O:30]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Nc3ccccc3)cccc21
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(N(C(=O)CCl)c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.6 %

Procedure:
To a 0° C. solution of phenyl-(1-triisopropylsilanyl-1H-indol-4-yl)-amine XXI (1.09 g, 3 mmol) and TEA (1.35 ml, 9.7 mmol) in DCM (20 ml) was added 2-chloroacetyl chloride (773 μl, 9.7 mmol). The mixture was stirred for 5 minutes and then refluxed for 3 hours. The reaction was cooled to room temperature and partitioned between H2O and DCM. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 2-chloro-N-phenyl-N-(1-triisopropylsilanyl-1H-indol-4-yl)-acetamide XXII as an off-white solid (775 mg, 59% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[NH:7][CH2:8][CH:9]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]=1[CH3:45])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[Cl:29])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:48]1[N:55]=[CH:54][CH:53]=[CH:52][C:49]=1[CH:50]=[O:51]>>[Cl:29][C:22]1[CH:23]=[C:24]([CH3:28])[CH:25]=[C:26]([Cl:27])[C:21]=1[O:20][CH2:19][CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:9]([C:30]2[CH:35]=[CH:34][C:33]([C:48]3[C:49]([CH:50]=[O:51])=[CH:52][CH:53]=[CH:54][N:55]=3)=[CH:32][C:31]=2[CH3:45])[CH2:8][NH:7][C:6](=[O:46])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:12][CH:13]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Reactant: O=Cc1cccnc1Br
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(-c4ncccc4C=O)cc3C)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl{3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and commercially available 2-bromonicotinaldehyde as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 75% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11](Cl)[N:10]=1>>[Cl:8][C:9]1[N:10]=[C:11]([NH:7][CH2:1][C:2]2[O:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=[N:13][CH:14]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NCc1ccco1
Product: Clc1cncc(NCc2ccco2)n1
Yield: 98 %

Procedure:
In a procedure analogous to Example 21, reaction of furfurylamine and 2,6-dichloropyrazine furnished the product (98%).
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C:10](=[CH:11][C:12]3[C:17]2=[N:16][C:15]([Cl:22])=[C:14]([O:23][CH2:24][CH3:25])[CH:13]=3)[CH2:9]1)=O)(C)(C)C.ClCCl>>[Cl:22][C:15]1[N:16]=[C:17]2[C:12](=[CH:13][C:14]=1[O:23][CH2:24][CH3:25])[CH:11]=[C:10]1[N:18]2[CH:19]([CH3:21])[CH2:20][NH:8][CH2:9]1
Reactant: CCOc1cc2cc3n(c2nc1Cl)[C@H](C)CN(C(=O)OC(C)(C)C)C3
Solvent: ClCCl
Product: CCOc1cc2cc3n(c2nc1Cl)C(C)CNC3
Yield: 89.5 %

Procedure:
To a solution of 0.12 g (0.33 mmol) (R)-6-chloro-7-ethoxy-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 3 mL dichloromethane 1.5 mL (2.23 g, 19.6 mmol) trifluoroacetic acid was added. After 1 h the volatile components were evaporated and the residue was purified by column chromatography on silica gel (0.030–0.063 mm) with dichloromethane:methanol:ammonia (19:1:0.1) as eluant to give the desired compound as a light yellow solid (89.5%)