Azzindani/Open_Reaction_Data huggingface dataset:
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[S:11]([N:14]1[CH2:18][CH:17]([CH2:19][S:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]([CH2:40][OH:41])[CH2:15]1)(=[O:13])=[O:12].[H-].[Na+].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.O>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][CH:17]([CH2:19][S:20][C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:16]([CH2:40][O:41][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:15]1)(=[O:13])=[O:12]
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CC(CO)C(CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc2ccccc2c1)N1CC(COCc2ccccc2)C(CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 0.17 h
Yield: 60.6 %

Procedure:
To a solution of (3RS,4RS)-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanylmethyl-pyrrolidin-3-yl]-methanol (200 mg, 0.345 mmol) in DMF (2 ml) was added 60% NaH (15.2 mg, 0.379 mmol) at 0° C. and stirred for 10 min. Benzyl bromide (45 μl, 0.379 mmol) was added and stirred for 30 min at 0° C. and for 1 h at room temperature. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried, filtered and evaporated. Flash chromatography (hexane/EtOAc 4:1=>1:1) gave 140 mg (61%) of (3RS,4RS)-1-(naphthalene-2-sulfonyl)-3-benzyloxymethyl-4-tritylsulfanylmethyl-pyrrolidine as a colorless foam, MS: 692 (M+Na)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([Br:17])=[C:10]([CH3:18])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[Br:17][C:11]1[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]([NH2:7])=[CH:9][C:10]=1[CH3:18]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc([N+](=O)[O-])c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)cc([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.8 %

Procedure:
(4-Bromo-3-methyl-5-nitro-phenyl)-carbamic acid tert-butyl ester (1000 mg, 2.9 mmol) was dissolved into DCM (10 mL). To this was added TFA (10 mL) and the reaction was stirred at RT for 1 hour. The pH was adjusted to 8 with 1 N NaOH and the solvents were removed in vacuo. The reaction mixture was dissolved into EtOAc and the layers were separated. The organic layers were dried (MgSO4) and the solvents were removed in vacuo resulting in title compound (756 mg, quantitative) as a brown oil. 1H-NMR (CDCl3): δ 8.44 (s, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 3.05 (s, 3H).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:11][C:10](=[O:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl>[CH2:1]([C@@H:8]1[N:11]([Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:10](=[O:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C[C@H](Cc2ccccc2)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
To a solution of 4(S)-benzylazetidin-2-one (400 mg, 2.48 mmol) in CH2Cl2 (8 mL) was added DIEA (648 μL, 3.72 mmol), followed by tert-butyldimethylsilyl chloride (411 mg, 2.73 mmol). The reaction mixture was stirred for 16 h at room temperature. The CH2Cl2 was evaporated and the residue was purified by flash chromatography (SiO2, 12% EtOAc in hexane) to give 4(S)-benzyl-1-(tert-butyldimethylsilyl)azetidin-2-one (647 mg, 95% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ7.34-7.15 (m, 5H), 3.77-3.70 (m, 1H), 3.25 (dd, J=13.5, 3.5 Hz, 1H), 2.99 (dd, J=15.5 Hz, 5 Hz, 1H), 2.70 (dd, J=15.5, 2.5 Hz, 1H), 2.59 (dd, J=13.5, 11 Hz, 1H), 1.01 (s, 9H), 0.31 (s, 3H), 0.29 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=[C:6]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:9]2=[O:15])[CH:7]=1.[O:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1>>[O:15]=[C:9]1[NH:10][C:11](=[O:14])[CH:12]=[CH:13][N:8]1[C:6]1[CH:7]=[C:2]([C:35]2[CH:36]=[CH:37][O:33][CH:34]=2)[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=1
Reactant: OB(O)c1ccoc1
Reactant: COc1c(Br)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Product: COc1c(-c2ccoc2)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Yield: 45 %

Procedure:
The product from Example 63, Part A (25.9 mg, 0.050 mmol) was reacted with furan-3-yl boronic acid (7.2 mg, 0.064 mmol) as described in Example 63, Part B to give the title compound as an off-white solid (10.6 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ 11.46 (s, 1H) 7.84 (d, J=8.09 Hz, 1H) 7.80 (t, J=1.84 Hz, 1H) 7.68-7.75 (m, 2H) 7.54-7.64 (m, 2H) 7.50 (t, J=6.07 Hz, 1H) 7.35 (d, J=2.57 Hz, 1H) 7.08 (d, J=1.47 Hz, 1H) 6.57 (s, 1H) 5.68 (d, J=8.09 Hz, 1H) 3.47 (s, 2H) 3.30 (s, 3H) 2.96 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44].C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][N:11]([CH2:32][CH2:33][N:34]2[C:38](=[O:39])[C:37]3=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]3[C:35]2=[O:44])[C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
(2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (0.73 g, 1.8 mmol), N-(2-bromoethyl)phthalimide (0.686 g, 2.7 mmol), triethylamine (0.5 ml, 3.6 mmol) and a catalytic amount of potassium iodide was dissolved in dry dimethylformamide (30 ml). The mixture was stirred for 24h at 70° C., cooled to room temperature and evaporated in vacuo. Water (60 ml) was added and extraction with methylene chloride (3×60 ml), drying of the organic phases with magnesium sulphate and evaporation of the solvent in vacuo afforded an oil. Purification twice on silica gel (Eluent 1: Heptane/ethyl acetate (1:1) and eluent 2: Petroleum ether/diethylether (2:1)) gave (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethyl-1-(2-phthalimidoethyl)pyrrolidine (0.64 g, yield: 61%) as an oil.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.C(Cl)Cl.[H][H]>CO.CC(O)=O.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:23])[CH:16]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1)N1CCOCC1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c2ccccc12

Procedure:
A solution of N-(4-((4-nitronaphthalen-1-yl)oxy)pyridin-2-yl)morpholine-4-carboxamide (900 mg, 2.3 mmol) in a mixture of MeOH (140 mL), DCM (140 mL) and AcOH (4 drops) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 25° C., 55 mm, 10% Pt—C Cat-Cart, full hydrogen mode). The reaction mixture was evaporated in vacuo and the residue was partitioned between DCM (50 mL) and saturated aq. NaHCO3 (20 mL). The organic phase was separated and was washed with brine (20 mL), and then dried and evaporated in vacuo to afford the title compound, Intermediate D5, as a brown solid (0.78 g, 90%); Rt 3.65 min (Method 1 basic); m/z 365 (M+H)+ (ES+).
Reaction SMILES: [Al:1].C(Cl)(Cl)(Cl)Cl.[CH:7]([OH:10])([CH3:9])[CH3:8].[O:11](C1C=C(C=CC=1)C=O)[C:12]1[CH:17]=CC=C[CH:13]=1>C1(C)C=CC=CC=1>[CH3:8][CH:7]([O-:10])[CH3:9].[CH3:13][CH:12]([O-:11])[CH3:17].[CH3:8][CH:7]([O-:10])[CH3:9].[Al+3:1]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: [Al]
Reactant: CC(C)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)[O-]
Product: [Al+3]
Reaction time: 3 h

Procedure:
From a mixture of 16.33 g. of aluminum chips, 100 ml. of toluene and 0.1 g. of mercuric chloride and a solution of 11 ml. of carbontetrachloride and 140 ml. of isopropyl alcohol a solution of aluminum isopropylate in toluene is prepared. A solution of 198.2 g. of 3-phenoxybenzaldehyde in 70 ml. of toluene is added, and the reaction mixture is kept at 45° to 50° C. for 3 hours.
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:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:39][C:40]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:41]=1[C:42](Cl)=[O:43]>>[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:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:42](=[O:43])[C:41]1[CH:45]=[CH:46][C:47]([Cl:49])=[CH:48][C:40]=1[Cl:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1Cl)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 85.4 %

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 35a with 91 μl (0.655 mmol) of triethylamine and 78 μl (0.561 mmol) of 2,4-dichlorobenzoyl chloride to give the title compound (240 mg, 86%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.57, FD-MS: M+ =599,601.
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(O)(=O)C.[NH2:23][CH2:24][C:25]1[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:23][CH2:24][C:25]2[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Reactant: COC(=O)COc1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)cc2)cc1

Procedure:
The title compound was prepared following the procedure A using 4-dec-1-ynylbenzaldehyde, methyl [4-(aminomethyl)phenoxy]acetate, acetate salt and DIEA (1 eq.) (purification by flash chromatography on SiO2, DCM/MeOH 95:5) as a pale yellow oil (63%). M+ (ESI): 422.2. HPLC, Rt: 4.3 min (purity: 96.4%). 1H NMR (CDCl3) δ: 7.37 (d, J=8.3 Hz, 2H), 7.28 (m, 4H), 6.88 (d, J=8.6 Hz, 2H), 4.63 (s, 2H), 3.78 (m, 7H), 2.40 (t, J=7.0 Hz, 2H), 1.61 (m, 2H), 1.44 (m, 2H), 1.30 (brs, 8H), 0.90 (t, J=6.8 Hz, 3H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.Cl.[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.[CH2:23]([N:26]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:27][C:28](O)=[O:29])[CH:24]=[CH2:25].C(N(CC)CC)C>ClCCl>[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:28](=[O:29])[CH2:27][N:26]([CH2:23][CH:24]=[CH2:25])[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]
Reactant: C=CCN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(CC(=O)N1CCC[C@H]1C(=O)OC)C(=O)OCc1ccccc1
Yield: 238.9 %

Procedure:
1-(3-Dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDCI) (0.453 g, 2.36 mmol) was added to a solution of proline methyl ester hydrochloride 30 (0.356 g, 2.15 mmol), acid 55 (0.590 mmol, 2.35 mmol) and triethylamine (0.481 g, 4.73 mmol) in dichloromethane (20 cm3) at 0° C. The resultant solution was stirred for 19 h, washed with 2M aqueous hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and the solvent removed to yield an oil which was purified by chromatography (silica gel, hexanes:ethyl acetate, 2:1, 1:1) to afford protected dipeptide 56 (0.508 g, 66%) as a colourless oil. Dipeptide 56 was shown to be a 76:24 trans:cis mixture of conformers by 13C NMR analysis (the ratio was estimated by integration of signals at δ22.0 and 24.5, 24.7, assigned to the Proγ-C atoms of the minor and major conformers respectively). In addition, restricted rotation about the GlyN-CO carbamate bond was also observed resulting in a further 1:1 mixture of conformers: [α]D −54.6 (c 1.17 in CH2Cl2); δH (400 MHz; CDCl3; Me4Si) 1.81-2.14 (4H, m, ProβH2, Proγ-H2), 3.29-3.58 (2H, m, Proδ-H2), 3.64, 3.66, 3.69* (3H, s, OCH3), 3.84-4.20 [4H, m, CH2(allyl), Glyα-H2], 4.40-4.48 (1H, m, Proα-H), 5.07-5.17 (4H, m, OCH2Ph, ═CH2), 5.69-5.81 (1H, m, C(H)═CH2) and 7.24-7.30 (m, 5H, Ph); δC (100 MHz; CDCl3) 22.0* (CH2, Proγ-C), 24.62, 24.73 (CH2, Proγ-C), 28.66, 28.73 (CH2, Proβ-C), 31.1,* 31.3* (CH2, Proβ-C), 45.93, 45.98 (CH2, ProδC), 46.5* (CH2, Proδ-C), 47.5, 48.0 (CH2, Glyα-C), 50.0, 50.6 [CH2, CH2(allyl)], 50.0,* 50.6* [CH2, CH2(allyl)], 52.0, (CH3, OCH3), 52.31,* 52.5* (CH3, OCH3), 58.4,* 58.5* (CH, Proα-C), 58.8 (CH, Proα-C), 67.2, 67.3 (CH2, OCH2Ph), 117.0, 117.5 (CH2, ═CH2), 127.5, 127.7, 127.8, 128.3, (CH, Ph), 133.2, 133.4 (CH, C(H)═CH2) 136.4, 136.5 (quat., Ph), 155.8, 156.3, (quat., NCO2), 167.1 (quat., Gly-CO), 167.4,* 167.5* (quat., Gly-CO). 172.0,* 172.2* (quat., Pro-CO) and 172.3, 172.4 (quat., Pro-CO); m/z (EI+) 360.1676 (M+. C19H24N2O5 requires 360.1685).
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:48])[C@@H:32]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:33][S:34][S:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:48])[C@@H:32]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:33][S:34][S:35][C:36]([CH3:38])([CH3:39])[CH3:37])[C:23]([O:25][CH2:2][C:1]#[N:4])=[O:24])=[O:20])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@H](CSSC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Reaction time: 5 h
Yield: 78 %

Procedure:
N,N-diisopropylethylamine (0.073 mL, 0.421 mmol) and subsequently bromoacetonitrile (0.080 mL, 1.15 mmol) were added to a solution of (S)-2-((tert-butoxycarbonyl)amino)-6-((R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)hexanoic acid (Compound 52) (206 mg, 0.383 mmol) in acetonitrile (0.3 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 5 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-6-((R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)hexanoate (Compound 53) (172.2 mg, 78%).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:10])=[C:7]([CH:18]=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:20](=[O:24])([O:22][CH3:23])[NH2:21].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[C:1]([C:5]1[CH:17]=[CH:16][C:8]([C:9](=[O:10])[N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[C:7]([CH:6]=1)[CH2:18][NH:21][C:20](=[O:24])[O:22][CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(N)=O
Reactant: CCN(CC)C(=O)c1ccc(C(C)(C)C)cc1C=O
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)c1ccc(C(C)(C)C)cc1CNC(=O)OC
Temperature: 130 °C
Yield: 69.9 %

Procedure:
A 25-mL microwave vial equipped with a magnetic stirrer was charged with 102a (1.00 g, 3.83 mmol), methyl carbamate (575 mg, 7.66 mmol), trifluoroacetic acid (871 mg, 7.66 mmol), triethylsilane (888 mg, 7.66 mmol) and acetonitrile (10 mL). The vial was loaded in a Biotage microwave and heated at 130° C. for 1.5 h. After this time, the solution was concentrated in vacuo. The resulting residue was partitioned between methylene chloride (100 mL) and a saturated aqueous sodium bicarbonate (30 mL). The aqueous layer was extracted with methylene chloride (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 60% ethyl acetate/hexanes) to afford a 71% yield (858 mg) of 102b as a colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.42 (s, 1H), 7.29 (m, 1H), 7.12 (d, 1H, J=7.7 Hz), 5.60 (br s, 1H), 4.27 (br s, 2H), 3.65 (s, 3H), 3.57 (q, 2H, J=6.8 Hz), 3.20 (q, 2H, J=6.7 Hz), 1.31 (s, 9H), 1.26 (t, 3H, J=6.7 Hz), 1.09 (t, 3H, J=6.8 Hz); MS (ESI+) m/z 321.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[CH3:13][C:14]([CH3:19])([CH2:17]O)[CH2:15][OH:16]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]3([O:16][CH2:15][C:14]([CH3:19])([CH3:17])[CH2:13][O:12]3)[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(CO)CO
Reactant: O=C1CCCc2c(Br)cncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)COC2(CCCc3c(Br)cncc32)OC1
Temperature: 135 °C
Yield: 88.8 %

Procedure:
A reaction mixture of 4-bromo-6,7-dihydro-5H-isoquinolin-8-one (intermediate B-11 [C], 5.0 g, 22 mmol), 2,2-dimethyl-propane-1,3-diol (2.8 g, 26.5 mmol) and toluene-4-sulfonic acid (85 mg, 0.44 mmol) in toluene (100 mL) was heated at 135° C. for 12 hours. After cooling to room temperature, it was concentrated under reduced pressure to give a residue which was extracted between EtOAc and water. The organic layer was washed with brine, dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product (6.1 g, 88.9%) as a light yellow solid. MS: 312.2 & 314.2 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][O:29][CH2:30][CH3:31])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:33]=1>>[CH2:30]([O:29][CH2:28][C@@:10]12[CH2:9][N:8]([S:38]([C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)(=[O:40])=[O:39])[CH2:17][CH2:16][C:15]1=[CH:14][C:13]1[N:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:19]=[CH:20][C:12]=1[CH2:11]2)[CH3:31]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cccnc1)C2

Procedure:
The title compound was prepared by the method of Preparation 1c using (R)-4a-ethoxymethyl-1-(4-fluorophenyl)-1,4,4a,5,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-6-carboxylic acid tert-butyl ester and pyridine-3-sulfonyl chloride. LCMS (Method C): 469 (M+H)+, Retention time 11.1 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=C2C(O)=O)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:22].C[CH2:24][O:25][C:26]([CH3:28])=[O:27]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:22])[C:10]([CH3:15])=[C:28]2[C:26]([O:25][CH3:24])=[O:27])=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCOC(C)=O
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2)CC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=C(C)N(C)C(=O)CC1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
The product from Example 4, Step 2 (1.0 g, 3.6 mmol, 1.0 equiv) was dissolved in DMF (36 mL) and cooled to 0° C. Sodium Hydride (144 mg, 60% in mineral oil, 3.6 mmol, 1.0 equiv) was added, followed by iodomethane (222 μL, 3.6 mmol, 1.0 equiv). The reaction was allowed to warm to room temperature and stirred for 2 hours. Additional portions of NaH (72 mg, 1.8 mmol, 0.50 equiv) and iodomethane (111 μL, 1.8 mmol, 0.50 equiv) were added and the reaction was stirred for one hour. The reaction mixture was diluted with water and EtOAc. The phases were separated and the organic phase was washed twice with satd. NaCl, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (linear gradient 10→50% EtOAc/Hexanes) to afford 470 mg of the title compound (45%) as an off-white powder. MS (ES+) m/e 294 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:6][N:5]=[C:4]([N:16]=CN(C)C)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1>CCO>[NH2:16][C:4]1[N:3]=[C:2]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)[C:7]([S:8]([NH:11][C:12]([CH3:13])([CH3:14])[CH3:15])(=[O:9])=[O:10])=[CH:6][N:5]=1
Reactant: CN(C)C=Nc1ncc(S(=O)(=O)NC(C)(C)C)c(Cl)n1
Reactant: Cc1cccc(N)c1
Solvent: CCO
Product: Cc1cccc(Nc2nc(N)ncc2S(=O)(=O)NC(C)(C)C)c1
Yield: 85 %

Procedure:
To a mixture of 4-chloro-2-[[(dimethylamino)methylene]amino]-N-(1,1-dimethylethyl)-5-pyrimidinesulfonamide, prepared according to the process of Example 1, Step 6 (44.62 g, 0.139 mol) in EtOH (1800 mL) was added metatoluidine (59.8 g, 0.558 mol) and heated to reflux for 10 hours. After cooling, the solvent was removed in vacuo and the residue extracted into EtOAc (1 liter). The solution was twice washed with 1N HCl washed with water and then with saturated NaCl. The organics were dried over MgSO4 and evaporated in vacuo to give a colorless solid, m.p. 174°-178° C. in 85% yield. Used without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2CC#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([OH:25])(=[O:24])[CH3:23].S(=O)(=O)(O)O.O>O>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:8]=2[CH2:23][C:22]([OH:25])=[O:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: N#CCc1c(-c2ccccc2)cccc1-c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1c(-c2ccccc2)cccc1-c1ccccc1
Yield: 76 %

Procedure:
A mixture of [1,1′;3′,1″]terphenyl-2′-yl-acetonitrile (0.78 g, 2.9 mmol) in 28 mL of 10:3:1 acetic acid/sulfuric acid/water was refluxed for 2 days The reaction mixture was cooled and diluted with water. The aqueous was extracted with diethyl ether, dried over magnesium sulfate and concentrated to give 1,1′:3′,1″-terphenyl-2′-ylacetic acid as a tan solid (0.64 g, 76%): MS (ESI) m/z 287.1 (M−H); MS (ESI) m/z 575.2 (2M−H); MS (ESI) m/z 333 (M+FA−H); HRMS calcd for C20H16O2, 288.1150. Found (ESI+), 289.12244; 1H NMR (DMSO-d6): δ 3.30 (s, 2H), 7.30-7.50 (m, 13H), 12.07 (br s, 1H); Anal. Calcd for C20H16O2: C, 83.31; H, 5.59. Found: C, 83.02; H, 5.35.