Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH:3]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)ccc1F
Yield: 45.9 %

Procedure:
Mix 4-bromo-1-fluoro-2-nitrobenzene (2 g, 9.17 mmol) and stannous chloride dihydrate (8 g, 35 mmol) in ethanol (20 mL), heat the mixture to reflux for 4 hrs. Cool the reaction to room temperature, dilute with water and adjust pH=12 with sodium hydroxide solution, filter off the solid. Partition the filtrate in water and dichloromethane, collect the organic layer, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give crude product (800 mg, 46.5%). MS: (M+1): 190/192.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[O:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:31][N:32]([C:42]([NH:44][C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][C:34]1[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[O:37][CH:38]=1.CO>ClCCl>[CH3:31][N:32]([C:42]([NH:44][C@H:45]([C:49]([NH:1][C@@H:2]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[O:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][C:34]1[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[O:37][CH:38]=1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cnco1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)co1
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cnco2)C(C)C)co1
Yield: 80 %

Procedure:
Using the procedure of Example 1U but replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-2-(N-((5-oxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane and replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-valine provided, after silica gel chromatography using a gradient of 1%-4% methanol in dichloromethane, 145 mg (80%) of the desired compound. 1 H NMR (CDCl3) δ0.74 (d, J=6.9 Hz, 6H), 1.23 (d, J=6.9 Hz, 6H), 1.39-1.50 (m, 2H), 1.80-1.94 (m, 1H), 2.56-2.74 (m, 4H), 2.83 (s, 3H), 2.94-3.09 (m, 1H), 3.52-3.62 (m, 1H), 3.72-3.84 (m, 1H), 3.88-3.92 (m, 1H), 4.08-4.35 (m, 3H), 4.62 (d, J=6 Hz, 1H), 4.94 (s, 2H), 5.91 (d, J=8.4 Hz, 1H), 6.89 (d, J=9 Hz, 1H), 7.06-7.26 (m, 11H), 7.69 (d, J=9 Hz, 1H), 7.77 (s, 1H), 8.35 (s, 1H). Mass spectrum: (M+NH4)+ =706; (M+H)+ =689. Anal. Calcd for C37H48N6O7.0.5 H2O: C, 63.68; H, 7.08; N, 12.04. Found: C, 63.50; H, 7.13; N, 11.60.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[N:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:18]=[C:19]3[C:28]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=[C:20]3Cl)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:37].[Na+].[Na+]>Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[N:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:18]=[C:19]3[C:28]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH:21][C:20]3=[O:37])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc2ccccc2c2c(CCN3CCN(Cc4ccccc4)CC3)n(-c3ccccc3)nc12
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Product: O=c1[nH]c2ccccc2c2c(CCN3CCN(Cc4ccccc4)CC3)n(-c3ccccc3)nc12
Temperature: 25 °C

Procedure:
1-[2-(4-Benzylpiperazin-1-yl)ethyl]-4-chloro-2-phenyl-2H-pyrazolo[3,4-c]quinoline (0.32 g, 0.66 mmol) was refluxed in 5 mL of 6 N aqueous hydrochloric acid for 1 hour. The mixture was allowed to cool to ambient temperature, and the pH was adjusted to 10 with 10% w/v aqueous sodium carbonate. This mixture was concentrated under reduced pressure, and the residue was purified by automated flash chromatography eluting with a gradient of 0-15% CMA in chloroform. The residue was triturated with acetonitrile, isolated by filtration, and dried to afford 0.050 g of 1-[2-(4-benzylpiperazin-1-yl)ethyl]-2-phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as off-white needles, mp 211-212.5° C. MS (ESI) m/z 464 (M+H)+; Anal. calcd for C29H29N5O: C, 75.14; H, 6.31; N, 15.11. Found: C, 74.84; H, 6.35; N, 15.04.
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][C:34]1[CH:66]=[CH:65][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C:57]5([C:61]([O:63]C)=[O:62])[CH2:60][CH2:59][CH2:58]5)[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:36][CH:35]=1>>[CH3:33][C:34]1[CH:35]=[CH:36][C:37]([C:38]([NH:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C:57]5([C:61]([OH:63])=[O:62])[CH2:58][CH2:59][CH2:60]5)[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:45][CH:46]=2)=[O:39])=[CH:65][CH:66]=1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(C)cc5)cc4)cc3C2=O)CCC1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: Cc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N(C3(C(=O)O)CCC3)C4)cc2)cc1
Yield: 87 %

Procedure:
The compound of example 582 was prepared analogous to compound of example 98 by hydrolysis of compound of example 581.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:11]([O-:13])=[O:12])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[K+].[Cl:15][C:16]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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]>[Cl:15][C:16]1[CH:23]=[C:22]([C:2]2[CH:3]=[C:4]([C:8]3([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]3)[CH:5]=[N:6][CH:7]=2)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: O=C([O-])C1(c2cncc(Br)c2)CC1
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cncc(C3(C(=O)O)CC3)c2)cc1Cl
Temperature: 100 °C

Procedure:
To a suspension of potassium 1-(5-bromopyridin-3-yl)cyclopropanecarboxylate (28 mg, 0.1 mmol), 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (26 mg, 0.1 mmol), PdCl2(dppf).CH2Cl2 (4.08 mg, 5.0 mmol) in DMF (1 mL) was added 2M Na2CO3 (0.1 mL, 0.2 mmol), and the mixture was heated to 100° C. for 2 h. The mixture was concentrated and purified by silica chromatography eluting with a 0-10% MeOH-DCM gradient to give 1-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)cyclopropanecarboxylic acid. MS: (ESI) m/z 299.0, 301.0 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[CH3:15][C:16]1[CH:17]=[C:18]([CH2:30][NH2:31])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH2:30][C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[C:16]([CH3:15])[CH:17]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(CN)cnc1OCC(F)(F)C(F)F
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)C(F)F
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (360 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (350 mg, 1.3 mmol, Step-1 of Intermediate-1) and (5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine (410 mg, 1.3 mmol, Amine-51) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([N:38]=[N+:39]=[N-:40])(CCCC)CCCC)CCC.N([O-])=O.[Na+].S(=O)(=O)(O)N>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]2[NH:40][N:39]=[N:38][N:22]=2)=[CH:23][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(C=Cc2ccccc2OCc2ccccc2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C(=Cc1ccccc1OCc1ccccc1)c1ccc(-c2nnn[nH]2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 4-[2-(2-benzyloxyphenyl)ethenyl]-benzonitrile as a mixture of isomers (7.88 g) and tri-n-butyltin azide (20.03 ml, 2.53M solution in toluene) in toluene 100 ml was heated at reflux for 66 hours. The mixture was cooled (ice bath) and added dropwise to excess sodium nitrite and stirred for 30 minutes. Sulphamic acid (9 g) was added and the mixture left to stand at 5° C. for 18 hours. The resulting yellow precipitate (9.7 g) was filtered off, dried and mixed with potassium carbonate (7.56 g) in DMF (20 ml) and stirred for 10 minutes. Pivaloyloxymethyl chloride (4.78 ml) was added to the mixture and it was stirred for 18 hours, diluted with ethyl acetate (200 ml), and washed with 1M HCl (100 ml), sodium bicarbonate (100 ml) and brine (100 ml), dried (magnesium sulphate), filtered and evaporated. The residue was purified by subjecting to chromatography on silica gel using methanol : dichloromethane (0:100 to 30:70 gradient) as eluant. There was thus obtained N-2-(pivaloyloxymethyl)-5-{-4-[2-(2-benzyloxyphenyl)ethenyl]-phenyl}tetrazole (7.64 g) and N-1-(pivaloyloxymethyl)-5-{-4-[2-(2-benzyloxyphenyl)ethenyl]-phenyl}tetrazole (1.67 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([CH2:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH2:19])=[O:18])[N:3]=1.[CH3:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1.CS(C)=O>N1C=CC=CC=1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([NH:1][S:29]([C:27]1[S:28][C:24]([CH3:23])=[CH:25][CH:26]=1)(=[O:31])=[O:30])=[N:3][N:4]2[CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH2:19])=[O:18]
Reactant: COc1cccc2c1c(N)nn2Cc1cccc(C(N)=O)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(C)s1)nn2Cc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44 %

Procedure:
3-{[3-Amino-4-(methyloxy)-1H-indazol-1-yl]methyl}benzamide (for a preparation see Intermediate 12) 22 mg, 0.07 mmol) was dissolved in pyridine (1.6 mL) and added to 5-methyl-2-thiophenesulfonyl chloride (20 mg, 0.1 mmol). The reaction mixture was shaken at room temperature for 5 min and then stood overnight at room temperature. DMSO (0.2 mL) was added to the reaction mixture and purified by MDAP on Atlantis column using Acetonitrile Water with a Formic acid modifier. The solvent was evaporated in vacuo using the Genevac to give the title compound (14.2 mg, 44%) LCMS (System A) RT=0.92 min, ES+ve m/z 457 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C@@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:11])[O:8]CC)[C@H:3]1[C:13]([O:15][C@H:16]([C:30]#[N:31])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1)=[O:14].O1CCOCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:1][C:2]1([CH3:32])[C@@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:8])[OH:11])[C@H:3]1[C:13]([O:15][C@H:16]([C:30]#[N:31])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1)=[O:14]
Reactant: CCOC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C(/F)C(=O)O
Temperature: 25 °C
Yield: 41.9 %

Procedure:
A solution of 2.5 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylate, 10 ml of dioxane, 2.5 ml of water and 1 g of p-toluene sulfonic acid manohydrate was refluxed for 24 hours and then allowed to cool to room temperature. Methylene chloride was added to the mixture and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 60-40-1 cyclohexane-ethyl acetate-acetic acid mixture to obtain 980 mg of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-hydroxy-propenyl]-cyclopropane-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].Cl.[NH2:24][CH2:25][CH2:26][OH:27].CC(O)C.CCN(C(C)C)C(C)C>O>[Br:1][C:2]1[C:3]([NH:24][CH2:25][CH2:26][OH:27])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: NCCO
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCO)c(Br)c1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 0.5 g, 1.264 mmol), 2-aminoethanol hydrochloride (0.123 g, 1.896 mmol), iPrOH (4 mL) and DIPEA (0.442 mL, 0.327 g, 2.53 mmol) were subjected to MW irradiation at 140° C. for 2 h. The vial was cooled to RT and the RM was poured into water (100 mL) and the resulting precipitate was collected by filtration. The obtained solid was washed with water (50 mL) and dried to afford the title compound without further purification. LC-MS (Condition 6) tR=1.14 min, m/z=419.8 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[C:16]([F:30])=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)[C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[CH:10][N:9]2[CH:31]=1)=O)C.[NH3:32].CO>>[Cl:29][C:25]1[CH:24]=[C:23]([C:17]2[C:18]([O:21][CH3:22])=[CH:19][CH:20]=[C:15]([CH2:14][C:11]3[CH:12]=[CH:13][C:8]4[N:9]([CH:31]=[C:6]([C:4]([NH2:32])=[O:3])[N:7]=4)[CH:10]=3)[C:16]=2[F:30])[CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cn2cc(Cc3ccc(OC)c(-c4cccc(Cl)c4)c3F)ccc2n1
Reactant: N
Solvent: CO
Product: COc1ccc(Cc2ccc3nc(C(N)=O)cn3c2)c(F)c1-c1cccc(Cl)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 71 %

Procedure:
Into an 8 mL vial was added 6-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (I-37) synthesized above (37 mg, 0.084 mmol) and 2 mL of 7N NH3/MeOH. After stirring for 20 hours at 60° C., the reaction was concentrated. Trituration with ether provided 6-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,2-a]pyridine-2-carboxylic acid amide (P-429) (24.5 mg, 71%) as a white solid. 1H-NMR (400 MHz, DMSO-d6): 8.42 (s, 1H), 8.30 (s, 1H), 7.64 (br s, 1H), 7.53 (d, J=4.6 Hz, 1H), 7.42 (m, 5H), 7.30 (m, 1H), 7.23 (dd, 1H, J=9.6, 1.6 Hz), 6.97 (d, 1H), 8.4 Hz), 3.95 (s, 2H), 3.74 (s, 3H) ppm. LC/MS=83.4%, 410.0 (APCI+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23]>C(O)C>[S:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:3]([C:5]2[CH:6]=[C:7]([OH:15])[C:8]([OH:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)[CH2:2]1
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1S
Solvent: CCO
Product: O=[N+]([O-])c1cc(C2=Nc3ccccc3SC2)cc(O)c1O
Temperature: 25 °C

Procedure:
A mixture of 2.78 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone, 1.51 g of 2-aminothiophenol and 50 ml of ethanol is heated to boiling under reflux for 1 hour. The reaction mixture is then cooled to room temperature, whereupon the crystals are removed by filtration under suction. There is obtained 5-(2H-1,4-benzothiazin-3-yl)-3-nitropyrocatechol of m.p. 302°-304° (from N,N-dimethylformamide/methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][C@H:45]3[CH3:54])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][C@H:45]3[CH3:54])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@H]4C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(CN3CCN(S(C)(=O)=O)C[C@H]3C)cc2-c2nc(C)nc(N)n2)cc1F

Procedure:
The title compound was prepared from (R)-4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine via a similar deprotection step as previously described in Example 178, Step 4, using trifluoroacetic acid and trifluoromethanesulfonic acid, and isolated as a yellow solid. m/z (ESI, +ve ion) 518 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.95 (s, 1H) 8.71 (d, J=2.35 Hz, 1H) 8.41 (d, J=2.15 Hz, 1H) 8.33-8.40 (m, 1H) 8.27 (d, J=2.15 Hz, 1H) 7.90 (br. s., 1H) 7.76 (br. s., 1H) 3.93 (s, 3H) 3.91 (s, 1H) 3.13-3.30 (m, 3H) 2.87-2.95 (m, 1H) 2.85 (s, 3H) 2.53-2.79 (m, 3H) 2.44 (s, 3H) 2.14-2.28 (m, 1H) 1.16 (d, J=6.26 Hz, 3H).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.[Si:10]([O:17][C@H:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C@H:20]([CH:36]=[O:37])[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][C@H:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C@H:20]([CH:36]([OH:37])[C:2]2[N:3]=[CH:4][N:5]3[CH:9]=[CH:8][S:7][C:6]=23)[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: Ic1ncn2ccsc12
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C(O)c2ncn3ccsc23)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 69.5 %

Procedure:
7-[[(2S,4R)-4-t-Butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]hydroxymethyl]-imidazo[5,1-b]thiazole (4.18 g) was prepared in the same manner as in step a) of Synthesis Example 1, except that 3.39 g of 7-iodoimidazo[5,1-b]thiazole and 4.61 g of (2S,4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine-2-aldehyde were used as the starting compounds.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>CCOCC>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1cc(Cl)cnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of 2,5-dichloronicotinic acid A54 (20.2 g, 0.105 mol) in methanol (500 mL) was cooled to 0° C. and neat thionyl chloride (38 mL, 63 g, 0.525 mol) was added over ˜30 min. The reaction mixture was stirred at 0° C. for 1 hour. The cooling bath was removed, the reaction temperature was allowed to warm to rt, and the reaction was allowed to stir for an additional 2 days at room temperature and the solvent was removed under reduced pressure to give an off-white residue. The residue was dissolved in Et2O (˜500 mL) and the resulting solution was washed successively with saturated aqueous NaHCO3 solution (˜300 mL), water (˜300 mL), and brine (˜300 mL). The organic layer was separated, dried over anhydrous MgSO4, and filtered. Removal of the solvent under reduced pressure yielded methyl 2,5-dichloronicotinate (21.0 g, 97%) as a white solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:42])[C@@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:42])[C@@H:33]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: N[C@H](Cc1ccccc1)C(=O)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
92 mg (0.160 mmol) of diastereomer B of (2R*,4S*)-2-benzyl-1-((R)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 25 mg (0.640 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR56## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (350:50:1) Rf =0.49, FD-MS: M+ =478.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[C:4]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])=[N:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:12])[CH:3]=1.[CH:34]([OH:37])([CH3:36])[CH3:35]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:37][CH:34]([CH3:36])[CH3:35])[N:5]=[C:4]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])=[N:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:12])[CH:3]=1
Reactant: CC(C)O
Reactant: N#Cc1c(N)cc(C(=O)NCC2CCN(Cc3cnc(-c4ccccc4F)s3)CC2)nc1Cl
Product: CC(C)Oc1nc(C(=O)NCC2CCN(Cc3cnc(-c4ccccc4F)s3)CC2)cc(N)c1C#N

Procedure:
According to the same procedure described in Example 204, using the compound prepared in Example 393 instead of the compound prepared in Example 215 and isopropanol instead of 1-cyclopropylethanol, the title compound having the following physical data was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][O:23][CH2:22]3)[C:17]([OH:19])=O)[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][O:23][CH2:22]3)[C:17]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[O:19])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCCOC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: COc1cn(C(CC2CCCOC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
440 mg (purity 82%, 0.87 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-3-yl)propanoic acid (mixture of racemic diastereomers) and 184 mg (0.95 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 742 mg (purity 85%, quant.)
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][N:5]([CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:6](=[O:17])[CH2:7][N:8]1[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]1=[O:10].[OH-].[Na+]>CO>[C:22]([NH:21][CH2:20][CH2:19][CH2:18][N:5]([C:6](=[O:17])[CH2:7][N:8]1[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]1=[O:10])[CH2:4][C:3]([OH:29])=[O:2])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: COC(=O)CN(CCCNC(=O)OC(C)(C)C)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cn(CC(=O)N(CCCNC(=O)OC(C)(C)C)CC(=O)O)c(=O)[nH]c1=O

Procedure:
N-(N′-BOC-3′-aminopropyl)-N-[(1-thyminyl)acetyl]glycine methyl ester (3.02 g, 0.00732 mol) was dissolved in methanol (25 mL) and stirred for 1.5 h with 2 M sodium hydroxide (25 mL). Methanol was removed by evaporation in vacuo, and the pH adjusted to 2 with 4 M hydrochloric acid at 0° C. The product was isolated as white crystals by filtration, washed with water (3×10 mL), and dried over sicapent, in vacuo. Yield: 2.19 g (75%). Anal. for C17H26N4O7, H2O, found (calc.) C: 49.95 (49.03) H: 6.47 (6.29) N: 13.43 (13.45). The compound showed satisfactory 1H and 13C-NMR spectra.