Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[C:27]([OH:35])=[N:28][CH:29]=[C:30]([CH:34]=1)[C:31]([OH:33])=O.CCN(C(C)C)C(C)C.Cl.[F:46][C:47]1[C:48]([C@H:53]([C:55]2[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=2)[NH2:54])=[N:49][CH:50]=[CH:51][CH:52]=1.Cl.FC(F)(F)C1C=CC([C@@H](C2C(C(F)(F)F)=CC=CN=2)N)=CC=1>C(Cl)Cl>[Br:25][C:26]1[C:27](=[O:35])[NH:28][CH:29]=[C:30]([C:31]([NH:54][C@H:53]([C:48]2[C:47]([F:46])=[CH:52][CH:51]=[CH:50][N:49]=2)[C:55]2[CH:60]=[CH:59][C:58]([C:61]([F:62])([F:63])[F:64])=[CH:57][CH:56]=2)=[O:33])[CH:34]=1
Reactant: O=C(O)c1cnc(O)c(Br)c1
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F)c1c[nH]c(=O)c(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of HATU (0.332 g, 0.874 mmol) in DCM (2 mL) was added 5-bromo-6-hydroxynicotinic acid (0.191 g, 0.874 mmol) and DIPEA (0.406 mL, 2.331 mmol). The resulting mixture was then stirred at rt for 5 min, then (S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine hydrochloride (Intermediate 2) (0.200 g, 0.583 mmol) was added. The mixture was then stirred at rt overnight. The mixture was purified by silica gel column chromatography using an ISCO instrument (0%-100% EtOAc/hexane) to give the title compound as a brown oil.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[SH:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[OH-].[Na+]>C(O)C.O>[N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[NH:4][C:3]=1[CH2:2][S:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Sc1ncccn1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1cnc(SCc2nc3ccccc3[nH]2)nc1

Procedure:
10.0 g (0.06 mole) of 2-chloromethylbenzimidazole are added to a solution of 6.7 g (0.06 mole) of 2-mercaptopyrimidine and 2.4 g (0.06 mole) of sodium hydroxide in 200 ml of ethanol and 20 ml of water. The mixture is maintained under reflux for 2 hours and the ethanol evaporated off. The residue is taken up with water (50 ml) and extracted with ethyl acetate (3×50 ml), the organic phase is dried with sodium sulfate, filtered and evaporated to a volume of 40 ml of solution, in which there crystallize 10.2 g (70%) of 2-(2-benzimidazolylmethylthio)pyrimidine, melting point 154°-155° C.
Reaction SMILES: [C:1]1([CH:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][NH:9][C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:22]1[S:23][C:24]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:25]=2[N:26]=1.Cl>C1(C)C=CC=CC=1>[Cl:31][C:29]1[CH:28]=[CH:27][C:25]2[N:26]=[C:22]([N:10]3[CH:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8](=[O:18])[NH:9]3)[S:23][C:24]=2[CH:30]=1
Reactant: O=C1NNC(c2ccccc2)C1c1ccccc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1NN(c2nc3ccc(Cl)cc3s2)C(c2ccccc2)C1c1ccccc1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
The reaction was conducted under a dry nitrogen atmosphere. A suspension of 4,5-diphenyl-3-pyrazolidinone (1.19 g, 5.00 mmol) in 35 mL toluene was treated with 0.40 g NaH (60% in mineral oil; hydride content 0.24 g, 10.0 mmol, 2.00 eq.), and the mixture stirred at 45° C. for 2 hours. 2,6-Dichlorobenzothiazole (1.02 g, 5.00 mmol, 1.00 eq.) was added and stirring continued at 80° C. for 20 hours. After cooling, the reaction mixture was poured onto 30 mL ice-cooled 0.5N HCl, extracted with EtOAc, and the separated organic phase washed twice with brine, dried over Na2SO4, and the solvent evaporated in vacuo. The residue was recrystallized from Et2O:hexane to provide 1.46 g (72%) light tan crystals: mp 170.5°-2.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([NH:15][C@H:16]([C:18]([OH:20])=O)[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].[NH:21]1[C@@H:29]2[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:23][C@H:22]1[C:30]([OH:32])=[O:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Na+].[Cl-]>C(#N)C.CN(C=O)C.C(N(CC)CC)C>[CH3:2][CH2:1][O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:21]1[C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][C@@H:24]2[C@@H:29]1[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:20])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5]
Reactant: O=C(O)[C@@H]1C[C@H]2CCCC[C@@H]2N1
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@H]2CCCC[C@@H]21
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To 2.79 g of (S)-1-(N-(1-(ethoxycarbonyl)-3-phenylpropyl)-L-alanine and 1.75 g of (2S,3aR,7aS)-octahydro-1H-indol-2-carboxylic acid in 100 ml of acetonitrile and 5 ml DMF first 2.9 ml of triethylamine and then with stirring 3.8 g O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate were and the stirring of the mixture was continued for 30 minutes at room temperature. Finally, 300 ml of saturated NaCl solution was added and the mixture was extracted twice with 100 ml of ethyl acetate. After isolation of the product, which was done by the same way as in example 1, 3.96 g (92%) of trandolapril was obtained.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[CH3:20][C:21]1[C:28]([CH3:29])=[CH:27][C:24]([CH:25]=[O:26])=[C:23]([N+:30]([O-:32])=[O:31])[CH:22]=1.C(O)(=O)C>O1CCCC1.O>[OH:26][CH:25]([C:24]1[CH:27]=[C:28]([CH3:29])[C:21]([CH3:20])=[CH:22][C:23]=1[N+:30]([O-:32])=[O:31])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: C#CC(=O)OCC
Reactant: Cc1cc(C=O)c([N+](=O)[O-])cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C#CC(O)c1cc(C)c(C)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 108.4 %

Procedure:
1.5N butyllithium (15.8 ml, 24.88 mmole) was added under the argon atmosphere to a solution of diisopropylamine (3.66 ml, 26.1 mmole) in tetrahydrofuran (50 ml) at -78° C., and the mixture was stirred for 30 minutes. To the reaction mixture were next added a solution of ethyl propiolate (2.20 ml, 21.71 mmole) in tetrahydrofuran (10 ml) and a solution of 4, 5-dimethyl-2-nitrobenzaldehyde (2.60 g, 14.51 mmole) in tetrahydrofuran (20 ml) in this sequence, and the reaction mixture was stirred at -78° C. for further 1.5 hours. After a solution of acetic acid (3.2 ml, 53.3 mmole) in tetrahydrofuran (10 ml) followed by water were added, the reaction mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with dilute hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous saline in this sequence. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(4,5-dimethyl-2-nitrophenyl)-2-butynoate as an oil (4.363 g).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:14]([N:21]1[CH2:11][C:5]2[C:4](=[CH:9][C:8]([F:10])=[CH:7][CH:6]=2)[C:3]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1cc(F)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1c2cc(F)ccc2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A mixture of 2-bromomethyl-5-fluoro-benzoic acid methyl ester (0.094 g, 0.5 mmol), benzylamine (0.076 mL, 0.7 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-6-fluoro-2,3-dihydro-isoindol-1-one (0.085 g, 70.7%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.24 (s, 2H), 4.79 (s, 2H), 7.18-7.39 (m, 7H), 7.55 (m, 1H). GC-MS: m/z 241 (M)+, 164 (M−77)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([O:28][CH3:29])[CH:27]=3)=[CH:18][CH:17]=2)([CH3:15])[CH:12]([CH3:14])[CH3:13])=[CH:9][CH:10]=1)[NH2:4].[C:30]([O:33][CH2:34][C:35](O)=[O:36])(=[O:32])[CH3:31].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:30]([O:33][CH2:34][C:35]([O:1]/[N:2]=[C:3](/[NH2:4])\[C:5]1[CH:6]=[N:7][C:8]([C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([O:28][CH3:29])[CH:27]=3)=[CH:18][CH:17]=2)([CH3:15])[CH:12]([CH3:13])[CH3:14])=[CH:9][CH:10]=1)=[O:36])(=[O:32])[CH3:31]
Reactant: COc1cncc(-c2ccc(C(C)(c3ccc(C(N)=NO)cn3)C(C)C)cc2)c1
Reactant: CC(=O)OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1cncc(-c2ccc(C(C)(c3ccc(/C(N)=N\OC(=O)COC(C)=O)cn3)C(C)C)cc2)c1
Reaction time: 1 h

Procedure:
Compound 1a (350 mg, 0.896 mmol) was added to a stirred solution of acetoxyacetic acid (126 mg, 1.07 mmol), 1[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (205 mg, 1.07 mmol) and 1-hydroxybenzotriazole (157 mg, 1.16 mmol) in DCM (8.00 mL) at rt. After approximately 1 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound 1b, which was used without further purification in the subsequent reaction. m/z (ES) 491 (MH)+ 1HNMR (500 MHz, CDCl3): δ 8.90 (s, 1H), 8.51 (s, 1H), 8.29 (s, 1H), 7.92 (d, 1H, J=8.5 Hz), 7.83 (s, 1H), 7.54 (d, 2H, J=8.0 Hz), 7.50 (d, 2H, J=8.0 Hz), 7.35 (d, 1H, J=8.3 Hz), 5.21 (br, 2H), 4.90 (s, 2H), 4.03 (s, 3H), 3.17 (m, 1H), 2.22 (s, 3H), 1.76 (s, 3H), 0.88 (d, 3H, J=6.4 Hz), 0.84 (d, 3H, J=6.6 Hz).
Reaction SMILES: CC1OCCC1.[F:7][C:8]1[CH:9]=[C:10]2[C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][N:14]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:11]2=[N:12][CH:13]=1.Cl[C:37]1[N:42]=[C:41]([NH:43][C@@H:44]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:45][C:46]([O:48][CH3:49])=[O:47])[C:40]([F:54])=[CH:39][N:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:54][C:40]1[C:41]([NH:43][C@@H:44]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:45][C:46]([O:48][CH3:49])=[O:47])=[N:42][C:37]([C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([F:7])[CH:9]=3)[N:14]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)(=[O:28])=[O:27])[CH:15]=2)=[N:38][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: COC(=O)C[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC1CCCO1
Solvent: O
Product: COC(=O)C[C@@H](Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Temperature: 115 °C
Reaction time: 2 h

Procedure:
A 2-MeTHF (253 mL)/water (56 mL) solution of 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (24.3 g, 58.3 mmol), methyl (R)-methyl 3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-4,4-dimethylpentanoate, 6a, (14.1 g, 48.6 mmol) and K3PO4 (30.9 g, 146 mmol) was purged with nitrogen for 0.75 h. XPhos (2.8 g, 5.8 mmol) and Pd2(dba)3 (1.1 g, 1.2 mmol) were added and the reaction mixture was stirred at 115° C. in a sealed tube for 2 h. The reaction mixture was cooled and the aqueous phase was removed. The organic phase was filtered through a pad of Celite and the mixture was concentrated to dryness. The residue was purified on silica gel (EA/Hex) to provide the desired product, 8a, (23.2 g): LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT=2.18 minutes (M+H) 245.28.
Reaction SMILES: COC1C=C(C=CC=1OC)C[NH:7][C:8]1[NH:9][C:10]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[C:11]2[C:15]([N:16]=1)=[N:14][CH:13]=[N:12]2.O>C(O)(C(F)(F)F)=O>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:10]1[NH:9][C:8]([NH2:7])=[N:16][C:15]2[C:11]=1[N:12]=[CH:13][N:14]=2
Reactant: COc1ccc(CNc2nc3ncnc-3c(-c3ccco3)[nH]2)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Yield: 67.8 %

Procedure:
A solution of N-(3,4-dimethoxybenzyl)-6-(2-furyl)-1H-purine-2-amine (194 mg, 0.55 mmol) in TFA (1 mL) was heated at 60° C. for 30 min, poured into water, extracted with EtOAc and the combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2; 5% MeOH in EtOAc). The resulting yellow solid was dissolved in MeOH, treated with HCl (1-M in Et2O) and filtered to give the title compound (75 mg, 57%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: Brc1cccnc1
Product: Brc1ccc2c(ccn2-c2cccnc2)c1

Procedure:
5-Bromo-N-(3-pyridyl)indole is prepared from 5-bromoindole and 3-bromopyridine using methodology described in the previous examples.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].C(N(CC)CC)C.[Cl:13][C:14]1[N:15]=[C:16]([C:20](Cl)(Cl)Cl)[NH:17][C:18]=1[Cl:19]>C(O)C>[Cl:13][C:14]1[N:15]=[C:16]([C:20]2[S:4][C:3]([NH2:5])=[N:2][N:1]=2)[NH:17][C:18]=1[Cl:19]
Reactant: Clc1nc(C(Cl)(Cl)Cl)[nH]c1Cl
Reactant: NNC(N)=S
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nnc(-c2nc(Cl)c(Cl)[nH]2)s1
Temperature: 50 °C
Yield: 76.2 %

Procedure:
9.1 g (0.1 mol) of thiosemicarbazide and 40.4 g (0.4 mol) of triethylamine were stirred in 200 ml of ethanol until a clear solution had formed. 25.4 g (0.1 mol) of 4,5-dichloro-2-trichloromethyl-imidazole were added to this solution incrementally at 0°-5° C., while stirring. The mixture was stirred for a further 1 hour with cooling, for 1 hour at room temperature and for 1 hour at 50° C. After cooling, the amine-hydrochloride was filtered off and the filtrate was evaporated in vacuo. The residue was treated with water, the mixture was acidified with hydrochloric acid and the product was filtered off, washed with water and dried. 18 g (76.5% of theory) of 2-(4,5-dichloro-imidazol-2-yl)-5-amino-1,3,4-thiadiazole were obtained. Melting point: 147° C. (with decomposition) (from ethyl acetate/ligroin).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:32]([CH3:33])=[CH:31][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C>CO.C1COCC1.C(O)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:32]([CH3:33])=[CH:31][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCOCC4)c3)sc2c1-c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2nc(-c3ccnc(N4CCOCC4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-morpholinopyridin-4-yl)benzo[d]thiazol-6-yl)acetate (4.2 mg, 0.00724 mmol) 5M NaOH (29 μL) in methanol (0.2 mL) and THF (1.0 mL) was stirred at 40° C. overnight. Acetic acid (1 drop) and DMF (0.3 mL) were added and mixture concentrated to ˜0.5 mL, diluted with DMF/H2O, filtered and purified by Gilson HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give product after lyophilization. LCMS-ESI+: calc'd for C29H31ClN3O4S: 552.2 (M+H+); Found: 552.3 (M+H+); 1H NMR (400 MHz, CD3OD) δ 8.12 (d, J=6.2 Hz, 1H), 7.94 (s, 1H), 7.69 (s, 1H), 7.67 (d, J=2.1 Hz, 1H), 7.61 (d, J=2.1 Hz, 1H), 7.59 (dd, J=4.2, 2.1 Hz, 2H), 7.47 (dd, J=6.2, 1.5 Hz, 1H), 5.26 (s, 1H), 3.91-3.79 (m, 4H), 3.74-3.62 (m, 4H), 2.63 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1)([CH3:3])[CH3:2].C1CN([P+](ON2N=[N:49][C:44]3[CH:45]=[CH:46][CH:47]=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1(CN)CC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:45]1([CH2:44][NH:49][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([S:13]([N:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5]3)(=[O:14])=[O:15])=[CH:17][CH:18]=2)[CH2:47][CH2:46]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)c1cn(S(=O)(=O)c2ccc(C(=O)O)cc2)c2ccccc12
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cn(S(=O)(=O)c2ccc(C(=O)NCC3CC3)cc2)c2ccccc12
Yield: 87.1 %

Procedure:
Stir mixture of 4-(3-isopropyl-indole-1-sulfonyl)-benzoic acid (0.181 g, 0.53 mmol), PyBOP (0.243 g, 0.55 mmol) and cyclopropylmethyl amine (0.064 g, 0.59 mmol) in CH2Cl2 (20 mL) add Hunigs base (0.28 mL, 1.62 mmol) under N2. Stir the resulting mixture overnight at ambient temperature. Extract the reaction with H2O, wash with brine dry (MgSO4), filter, evaporate and chromatograph using hexane-EtOAc (0-100%) to give 0.183 g of the title compound as an off white solid: Mass spectrum (m/e) (M+H) 397.1593; found 397.1586.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:26]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:13])([F:15])[F:14]
Reactant: O=C=Nc1ccccc1
Reactant: C[C@@](O)(C(=O)Nc1ccc(N)cc1Cl)C(F)(F)F
Solvent: CCOCC
Product: C[C@@](O)(C(=O)Nc1ccc(NC(=O)Nc2ccccc2)cc1Cl)C(F)(F)F
Reaction time: 22 h

Procedure:
A mixture of (R)-N-[2-chloro-4-aminophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 208) (0.198 g) and phenyl isocyanate (0.09 ml) in diethyl ether (10 ml) was stirred for 22 hours then evaporated to dryness. The residue was partitioned between water (25 ml) and ethyl acetate (50 ml). The organic phase was washed with brine (25 ml), dried and concentrated by evaporation to give the title compound (170 mg) as a foam. NMR: 1.66 (s, 3H), 7.04 (t, 1H), 7.35 (m, 3H), 7.52 (d, 1H), 7.1 (s, 1H), 7.86 (m, 2H), 8.77 (s, 1H), 8.92 (s, 1H), 9.63 (s, 1H); MS (ESP−): 400.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([N:14]1[CH2:42][CH2:41][CH2:40][C@H:15]1[C:16]([NH:18][C@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.CCOC(C)=O.CN1CCOCC1.[N:64]1([C:79]([O:81][CH2:82][C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)=[O:80])[CH2:78][CH2:77][CH2:76][C@H:65]1[C:66]([O:68]N1C(=O)CCC1=O)=O>CCOCC>[N:64]1([C:79]([O:81][CH2:82][C:83]2[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=2)=[O:80])[CH2:78][CH2:77][CH2:76][C@H:65]1[C:66]([NH:1][C@H:2]([C:12]([N:14]1[CH2:42][CH2:41][CH2:40][C@H:15]1[C:16]([NH:18][C@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:68]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: O=C(ON1C(=O)CCC1=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)N[N+](=O)[O-]

Procedure:
The desired compound was prepared from 4.0 g of Boc-Ser(Bzl)-Pro-Arg(NO2)-OBzl, 20 ml of 4N HCl-AcOEt, 1 ml of NMM and 2.2 g of Z-Pro-OSu in the same manner as in Example 26-(4). The ether treatment was performed to obtain the desired compound as a crystalline product.
Reaction SMILES: B(F)(F)F.[C:5]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:12]([OH:19])=[C:11]([CH:20](O)[CH:21]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:10]=1[C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:7])[CH3:6].C(=O)([O-])O.[Na+]>ClCCl>[C:5]([O:8][C:9]1[C:14]([C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:13][C:12]2[O:19][C:21]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:20][C:11]=2[C:10]=1[C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C(O)C(CCC(C)C)CCC(C)C)c1C(C)(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(CCC(C)C)(CCC(C)C)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
BF3 etherate (4.7 ml) was added dropwise to a solution of 4-acetoxy-3,5-di-tert-butyl-2-(2,2-diisoamyl-1-hydroxyethyl)-phenol (17.0 g) in dichloromethane (200 ml) under cooling with ice under a nitrogen atmosphere. After stirring the mixture overnight at room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added. After separating the organic layer, the aqueous layer was subjected to extraction with dichloromethane. The extract was combined with the organic layer, washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off to afford 5-acetoxy-2,2-diisoamyl-4,6-di-tert-butyl-2,3-dihydrobenzofuran [15.5 g (yield, 95%)] as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8](CC=C)[C:7]([C:15]#[N:16])=[N:6][C:5]=2[N:4]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]1=[O:22].N1CCOCC1.CS(C)=O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][C:7]([C:15]#[N:16])=[N:6][C:5]=2[N:4]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]1=[O:22]
Reactant: C=CCn1c(C#N)nc2c1c(=O)n(C)c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n(C)c(=O)c2[nH]c(C#N)nc21
Reaction time: 2.5 h
Yield: 17.8 %

Procedure:
1-Methyl-2,6-dioxo-3-pentyl-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carbonitrile (0.17 g, 0.56 mmol) and morpholine (0.6 ml, 6.7 mmol) were dissolved in THF (5 ml) containing DMSO (0.5 ml). The flask containing the solution was placed under vacuum and the air replaced with nitrogen (x3). Tetrakis(triphenylphosphine)palladium (0) (0.13 g, 0.11 mmol) was added and the solution stirred for 2.5 h. The solution was separated between ethyl acetate (20 ml) and 2N hydrochloric acid (10 ml) and the organics isolated and washed with brine (3×10 ml). The organics were then washed with 2N sodium hydroxide solution (2×10 ml) and the aqueous acidified with 2N hydrochloric acid and extracted with ethyl acetate (2×10 ml). The organics were isolated, dried (MgSO4) and concentrated to yield the title compound (0.026 g, 18%). NMR; δH (400 MHz, CDCl3) 0.92 (t, 3H, J=7 Hz), 1.32-1.43 (m, 4H), 1.79 (m, 2H), 3.54 (s, 3H), 4.15 (t, 2H, J=7.5 Hz,), 14.35 (br. s, 1H); m/z 262[MH+]