Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][N:16]3S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([NH:29][C:30]([C:32]3[N:33]=[C:34]([CH2:37][N:38]4[CH2:43][C@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]4)[S:35][CH:36]=3)=[O:31])[CH:11]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[NH:46]1[CH:50]=[C:49]([S:51](Cl)(=[O:53])=[O:52])[CH:48]=[N:47]1.Cl.C(Cl)Cl>N1C=CC=CC=1>[CH3:45][C@H:40]1[O:41][C@@H:42]([CH3:44])[CH2:43][N:38]([CH2:37][C:34]2[S:35][CH:36]=[C:32]([C:30]([NH:29][C:12]3[CH:11]=[C:10]([C:4]4[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][S:51]([C:49]5[CH:50]=[N:46][NH:47][CH:48]=5)(=[O:53])=[O:52])[CH:3]=4)[CH:18]=[C:17]4[C:13]=3[CH:14]=[N:15][NH:16]4)=[O:31])[N:33]=2)[CH2:39]1
Reactant: O=S(=O)(Cl)c1cn[nH]c1
Reactant: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cnn(S(=O)(=O)c4ccc(C)cc4)c3c2)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1cn[nH]c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-{6-[5-Amino-6-(methyloxy)-3-pyridinyl]-1-[(4-methylphenyl)sulfonyl]-1H-indazol-4-yl}-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamide (65 mg) was dissolved in pyridine (2 ml) and 1H-pyrazole-4-sulfonyl chloride (25 mg) was added. The reaction was stirred at RT overnight. 2M HCl (aq) (12 ml) and DCM (12 ml) were added and the reaction was vigorously stirred. The solvent was passed through a hydrophobic frit then removed under nitrogen blow down. IPA (2 ml) and 2M NaOH (aq) (1 ml) were added and the reaction was stirred at RT. The reaction was evaporated to dryness and water (1 ml) and DCM (3 ml) were added, followed by 2M HCl (aq) (1 ml). A precipitate was observed. The mixture was evaporated to dryness. The residue was purified by MDAP using the following method:
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([O:25][CH:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)[CH:24]=1)[C:12]2([CH3:32])[CH3:31].CCN(CC)CC.C(Cl)(=O)C>O>[C:3]([N:28]1[CH2:29][CH2:30][CH:26]([O:25][C:23]2[CH:24]=[C:19]([N:13]3[C:12]([CH3:32])([CH3:31])[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([Cl:8])[CH:10]=4)[C:14]3=[O:18])[CH:20]=[N:21][CH:22]=2)[CH2:27]1)(=[O:4])[CH3:2]
Reactant: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(OC2CCNC2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC(Oc2cncc(N3C(=O)c4ccc(Cl)cc4C3(C)C)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a solution of 5-chloro-3,3-dimethyl-2-[5-(pyrrolidin-3-yloxy)-pyridin-3-yl]-2,3-dihydro-isoindol-1-one trifluoro acetic acid salt (94.2 mg, 0.2 mmol) was added Et3N (1 mmol) and acetyl chloride (23.4 mg, 0.3 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 1 hour before it was poured into H2O (1 mL) and extracted with EtOAc (15 mL×2). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by PrepHPLC to give the title compound (25.5 mg, 35%) as a white solid. MS: 400.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccccc2)CC1
Yield: 87.1 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (2.50 g, 8.40 mmol) and phenylboronic acid (1.23 g, 10.08 mmol) in N,N-dimethylacetamide (25 mL) and water (10 mL). Add tetrakis(triphenylphosphine) palladium(0) (0.49 g, 0.42 mmol) and potassium carbonate (2.80 g, 20.16 mmol). Heat for 4 hr. at 114° C. and allow to cool about 1.5 hr. to room temperature. Partition reaction mixture between MTBE and water. Separate layers. Dry organic layer (sodium sulfate), filter, concentrate and purify (silica gel chromatography eluting with 10:90 to 30:70 ethyl acetate:hexanes), to give 3′-(phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (2.49 g, 87%). MS (ES): m/z=341 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[Cl:8][C:9]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2ccccc2)cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.0 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(2,6-dichlorobenzamido)-4-phenylbenzoate and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and diisopropyl ether was added no the obtained residue and a solid substance was separated by filtration to obtain 0.10 g of 2-(2,6-dichlorobenzamido)-4-phenylbenzoic acid as white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:9][NH2:10])=[O:8].[CH:16]([O-])([O-])OC>>[CH3:15][O:14][CH:3]([O:2][CH3:1])[C:4]1[CH:5]=[C:6]([C:7]2[O:8][CH:16]=[N:10][N:9]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COC([O-])[O-]
Reactant: COC(OC)c1cccc(C(=O)NN)c1
Product: COC(OC)c1cccc(-c2nnco2)c1
Yield: 61.4 %

Procedure:
2.1 g of 3-dimethoxymethylbenzhydrazide and 12.7 g of methyl orthoformate were reacted at atmospheric pressure for 24 hours while distilling off the methanol formed. Excessive methyl orthoformate was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/ethyl acetate=3/1) to obtain 1.35 g of colorless oily 2-(3-dimethoxymethylphenyl)-1,3,4-oxadiazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:30][CH2:31]OS(C)(=O)=O)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:43][CH2:42][CH2:41][C@@H:38]1[CH2:39][OH:40].CN(C=O)C>CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]([CH2:30][CH2:31][N:37]3[CH2:43][CH2:42][CH2:41][C@@H:38]3[CH2:39][OH:40])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:28])([F:29])[F:27])[CH:20]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCOS(C)(=O)=O)CC1
Reactant: OC[C@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC[C@@H]2CO)CC1
Yield: 100.8 %

Procedure:
Add 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-methanesulfonyloxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg; 1 equiv; 933 μmol); D-prolinol (3.00 equiv; 2.80 mmol; 283 mg); DMF (1 mL) and heat at 50° C. for 18 h in a sealed vessel. Dilute with EA, wash with saturated sodium bicarbonate, brine, dry MgSO4, filter and purify on 40 g silica gel with 1-10% MeOH/DCM to provide the title compound (506.9 mg; 0.94 mmol; 100%). MS (ES+): m/z=541 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH2:26])=[CH:23]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].N1C=CC=CC=1.[C:39]1([CH3:49])[CH:44]=[CH:43][CH:42]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:40]=1>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH:26][S:45]([C:41]3[CH:42]=[CH:43][CH:44]=[C:39]([CH3:49])[CH:40]=3)(=[O:47])=[O:46])=[CH:23]2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc4ccc(N)cc4c3)c2cc1OC
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2nccc(Oc3ccc4ccc(NS(=O)(=O)c5cccc(C)c5)cc4c3)c2cc1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 7-(6,7-dimethoxyquinolin-4-yloxy)naphthalen-2-amine (0.168 g, 0.48 mmol) in 20 mL of CH2Cl2 was added K2CO3 (0.134 g, 0.96 mmol), and pyridine (1 mL). The mixture was cooled to 0° C. and m-toluenesulfonyl chloride (0.110 g, 0.58 mmol) was added and the solution was stirred for 16 h at RT under an atmosphere of nitrogen. The reaction was diluted with water and extracted with CH2Cl2 3×. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a Gilson Prep HPLC system. The fractions were collected, combined, treated with NaHCO3(aq) and extracted with EtOAc 3×. The organic layer was dried (Na2SO4), filtered and concentrated to afford the desired compound. MS (ESI, pos. ion) m/z: 501.0 (M+1). Mass Calc'd for C28H24N2O5S: 500.573.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Li])(C)(C)C.C[O:21][B:22](OC)[O:23]C.Cl>C1COCC1>[C:4]([O:3][C:1]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[B:22]([OH:23])[OH:21])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COB(OC)OC
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Temperature: -20 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a cooled (-78° C.) solution of N-BOC aniline (5 g1 25.87 mmol) in THF (111.1 mL) was added tert-butyl lithium (38.9 mL, 66.7 mmol) and the mixture was stirred under an argon atmosphere for E5 min. It was then allowed to warm up to -20° C. and stirred at that temperature for 2 h. Trimethylborate was added (11.94 mL, 105.6 mmol) and the mixture was stirred until it warmed up to room temperature. Then, it was cooled to 0° C. and aqueous 10% HCl was added to pH=6.5. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried and concentrated to a crude product, which was washed with a mixture of EtOAc-hexane (5:95) to give the title compound as a yellow solid (53%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1.[N:27]([CH2:30][CH3:31])=[C:28]=S>>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:24][CH3:25])=[CH:9][C:10]3[C:11]4[N:18]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:28]([NH:27][CH2:30][CH3:31])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: CCN=C=S
Reactant: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Product: CCNc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1C(C)COC
Yield: 52 %

Procedure:
From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine (for a preparation see Intermediate 17) (70 mg) and isothiocyanatoethane (50 mg) to give the title compound as beige solid (42 mg, 52%). LCMS (formate) Rt 0.78 min, MH+ 410
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:18][CH3:19])[CH2:5][CH:6]=[CH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)[CH3:3]>C(O)(=O)C.O.[Fe]>[CH2:18]([N:4]([CH2:2][CH3:3])[CH2:5][CH:6]=[CH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[CH3:19]
Reactant: CCN(CC)CC=CCc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)CC=CCc1ccc(N)cc1
Reaction time: 2 h

Procedure:
To a solution of 25 g (0.45 mole) of iron filings in 200 ml acetic acid, add a solution of 8.5 g (0.03 mole) N,N-diethyl-4-(4-nitrophenyl)-2-buten-1-amine hydrochloride in 50 ml water. Temperature rises to about 40° C., stir for 2 hr then filter off the excess iron. Adjust the pH of the filtrate to about 12 with sodium hydroxide, and extract with 3×100 ml methylene chloride. Take the combined extracts, dry over Na2SO4, then treat with charcoal. Evaporate the solvent to provide the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([NH2:35])=[CH:32][CH:33]=2)[CH:28]=[N:27]1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([NH:35][C:9]3[C:8]4[C:13](=[CH:14][CH:15]=[CH:16][C:7]=4[O:6][C@H:4]([CH3:5])[C:3]([N:2]([CH3:19])[CH3:1])=[O:18])[N:12]=[CH:11][N:10]=3)=[CH:32][CH:33]=2)[CH:28]=[N:27]1
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Reactant: COc1cccc(Cn2ncc3cc(N)ccc32)c1
Product: COc1cccc(Cn2ncc3cc(Nc4ncnc5cccc(O[C@H](C)C(=O)N(C)C)c45)ccc32)c1
Yield: 58 %

Procedure:
Using the same procedure as in Example 18, (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (220 mg, 0.84 mmol) and 1-(3-methoxybenzyl)-1H-indazol-5-amine (1.1 equivalents) were reacted to give the title compound as a beige foam (242 mg, 58%); NMR spectrum (CDCl3) 1.72 (d, 3H), 3.05 (s, 3H), 3.14 (s, 3H), 3.73 (s, 3H), 5.42 (q, 1H), 5.57 (s, 2H), 6.74 (s, 1H), 6.78-6.81 (m, 3H), 7.20 (t, 1H), 7.36 (d, 1H), 7.46 (d, 1H), 7.59 (t, 1H), 7.80 (d, 1H), 8.06 (s, 1H), 8.40 (s, 1H), 8.61 (s, 1H), 10.85 (br s, 1H); Mass spectrum MH+ 497.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH2:3][OH:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:9]=1)[CH:3]=[O:4]
Reactant: CC(C)(CO)COCc1ccc(F)c(Oc2ccccc2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C=O)COCc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
A solution of 2,2-dimethyl-3-(4-fluoro-3-phenoxybenzyloxy)propan-1-ol (5.0 g) in dichloromethane (30 cm3) was added dropwise to a stirred suspension of pyridinium chlorochromate (6.77 g) in dichloromethane (20 cm3) whilst the reaction temperature was maintained within the range 0°-5° C. When the addition was complete the mixture was allowed to warm to the ambient temperature over a period of 2 hours. The solvent was removed and the residual oil (3.0 g) purified by column chromatography using a silica gel column and eluting with a 10:1 (by volume) mixture mixture of petroleum ether (boiling range 40°-60° ) and diethyl ether to yield 2,2-dimethyl-3-(4-fluoro-3-phenoxybenzyloxy)propan-1-al (1.5 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:11].[Br:13]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5]([Cl:11])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][Br:13]
Reactant: NC(=O)CCC(=O)NBr
Reactant: COC(=O)c1c(C)cccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(Cl)cccc1CBr

Procedure:
A mixture of 2-chloro-6-methyl-benzoic acid methyl ester (1.84 g, 10 mmol), N-bromosuccinamide (1.95 g, 11 mmol), and benzoyl peroxide (0.056 g, 0.21 mmol) in carbon tetrachloride (20 mL) was heated at reflux until the starting materials were mostly consumed. Workup afforded 2-bromomethyl-6-chloro-benzoic acid methyl ester. The material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15]#[N:16])=[N:6]1.C[O-].[Na+].CO.[Cl-].[NH4+:27].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15](=[NH:27])[NH2:16])=[N:6]1
Reactant: N#Cc1nc(-c2nccs2)n(Cc2ccccc2F)n1
Reactant: [NH4+]
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CO
Product: N=C(N)c1nc(-c2nccs2)n(Cc2ccccc2F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To 1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carbonitrile (Intermediate-5, 0.74 mmol) was added sodium methoxide/MeOH (0.5M, 4 equiv, 5.9 mL). After stirring at ambient temperature for 3 h, additional portion of sodium methoxide/MeOH (1 equiv) was added. After 2 h, ammonium chloride (10 equiv) was added and the resultant mixture was stirred at ambient for 17 h. The reaction mixture was conc. Half-saturated NaHCO3/1N NaOH solution (10:1) was added and the aqueous mixture was extracted with EtOAc. The organic phases were dried over Na2SO4, filtered and conc. to afford 1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboximidamide as a white solid (>99% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:34])([O:4][C:5]([C@H:7]([NH:25][C@H:26]([C:31](O)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])=[O:6])[CH3:3].OC1C2N=N[NH:41][C:40]=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.CN>C(N(CC)CC)C.ClCCl.O>[CH3:34][C:2]([O:4][C:5](=[O:6])[C@H:7]([NH:25][C@H:26]([C:31]([NH:41][CH3:40])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])([CH3:3])[CH3:1]
Reactant: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)O
Reactant: Oc1cccc2[nH]nnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CNC(=O)[C@H](CC(C)C)N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
300 mg of N-[(R)-1-[(1,1-dimethylethoxy)carbonyl]-3-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)propyl]-L-leucine, prepared as in Example L, was added to 120 mg of hydroxybenzotriazol.H2O, 150 mg of dicyclohexylcarbodiimide, 600 mg methylamine-hydrochoride, and 30 mL dichloromethane. 0.5 ; mL triethylamine was added and the mixture was stirred for 18 h. The mixture was filtered through celite and the solvent was removed by evaporation. The resulting residue was purified by silica chromatography using hexane:ethyl acetate:dichloromethane (2:1:1) as eluent to give the title compound as a white solid; 320 mg.
Reaction SMILES: Cl.[CH2:2]([NH:6][CH2:7][CH2:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=[O:10])[CH:3]([CH3:5])[CH3:4].C(O)C.[OH-].[Na+].[Na]>CC(C)=O>[CH2:2]([NH:6][CH2:7][CH2:8][CH:9]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[OH:10])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CNCCC(=O)c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)=O
Solvent: CCO
Product: CC(C)CNCCC(O)c1cccs1
Reaction time: 4 h
Yield: 74.9 %

Procedure:
To a mixture of 3-(isobutylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (4.2 g, 19.4 mmol) and ethanol (10 mL) at 4° C. sodium hydroxide (1.6 g of a 50% aqueous solution) was added in about 20 minutes. Afterwards, neat sodium borhydride (0.37 g, 9.7 mmol, 1.0 eq) was added in several portions in about 30 minutes. At the end of the addition, the suspension was stirred for 4 h at the same temperature, then acetone (10.0 mL) was added dropwise in 20 minutes and the mixture was stirred for 10 additional minutes. Afterwards the precipitate was removed by filtration and the mixture was concentrated under vacuum affording an orange oil. The crude product was purified by column chromatography using a 40:10:1 (v:v:v) mixture of methylene chloride/methanol/ammonium hydroxide (25% aqueous solution) affording 3.1 g (76% yield) of product.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][OH:14])[CH2:8]1.[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([O:22][C:23]([N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][OH:14])[CH2:8]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 84.6 %

Procedure:
An aqueous solution (20 mL) of sodium carbonate (6.90 g, 65.1 mmol) was added to 3-piperidinylmethanol (5.00 g, 43.4 mmol) in tetrahydrofuran (20 mL). While the mixture was chilled in an ice bath, benzyloxycarbonyl chloride (9.36 g, 52.1 mmol) was added and the mixture was stirred for 1 hour and subsequently 7 hours at room temperature. The solvent was then evaporated and ethyl acetate was added to the residue. The mixture was then washed sequentially with water, 0.1 mol/L hydrochloric acid and brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=5:1->1:1) gave 9.15 g (85%) of the desired compound as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:24]=[CH:23][C:16]([O:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:31].[Na+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:31])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])=[CH:23][CH:24]=1
Reactant: [O-][Cl+][O-]
Reactant: CNC(=O)COc1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Agent: CC=C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC#N
Product: CNC(=O)COc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a mixture of 2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenoxy]-N-methylacetamide (120 mg, 0.35 mmol) in acetonitrile/t-butanol (4 mL/4 mL) was added 2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C. followed by the addition of an aqueous solution of sodium chlorite (630 mg, 7.00 mmol) and sodium phosphate (monobasic and monohydrate, 930 mg, 7.00 mmol) in water (5 mL) dropwise via additional funnel. The ice bath was removed and the reaction was stirred at room temperature overnight. The reaction was quenched with sodium sulfite. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by pre-HPLC to give the title compound (60 mg, 47% yield) as a white solid. MS (ES+) 359.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 11.94-11.93 (m, 1H), 8.07 (d, 2H), 7.92 (s, 1H), 7.62 (s, 1H), 7.37 (d, 2H), 7.04 (d, 2H), 4.52 (s, 2H), 2.68 (d, 3H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C([O:17][C:18](=O)[NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)C.CO>O=P(Cl)(Cl)Cl.C(Cl)Cl>[Cl:28][C:25]1[CH:26]=[C:27]2[C:22]([CH2:21][CH2:20][NH:19][C:18]2=[O:17])=[CH:23][CH:24]=1
Reactant: CCOC(=O)NCCc1ccc(Cl)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C1NCCc2ccc(Cl)cc21
Temperature: 25 °C
Yield: 25095.9 %

Procedure:
P2O5 (3.1 g, 0.0495 mmol) was added to a stirred solution of [2-(4-chloro-phenyl)-ethyl]-carbamic acid ethyl ester (2.5 g, 0.01097 mmol) in POCl3 (10 mL) The resulting mixture was heated to reflux for 3 hours. The reaction was monitored by TLC (10% methanol in DCM). The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The concentrate was quenched with chilled water, basified with NaHCO3 solution and extracted with ethylacetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography on silica gel (10% methanol in CHCl3) afforded 500 mg of the product (26.3% yield).