Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[O:14])[CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([C:13]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14])[CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: COC(=O)CCNC(=O)[C@@H](CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)[C@@H](CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Reaction time: 3 h
Yield: 76.9 %

Procedure:
To a solution of (R)-3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoic acid (22.1 mg, 0.060 mmol) in THF (0.6 mL) and methanol (0.1 mL), aqueous 1M NaOH (0.12 mL, 0.12 mmol) is added at room temperature. After stirring for 3 hours, additional aqueous 1M NaOH (0.12 mL, 0.12 mmol) is added. The reaction mixture is allowed to stir for 30 minutes and quenched with 0.5 mL of aqueous 1M HCl and 0.5 mL of brine. The mixture is extracted twice with ethyl acetate, and the organic layer is concentrated under reduced pressure to give (R)-3-(biphenyl-4-ylmethyl)-4-(2-carboxyethylamino)-4-oxobutanoic acid (16.4 mg). HPLC retention time=1.04 minutes (condition A); MS (m+1)=356.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.13-2.31 (m, 3H) 2.59-2.65 (m, 1H) 2.81-2.90 (m, 2H) 3.12-3.27 (m, 2H) 7.26 (d, 2H, J=8 Hz) 7.34 (t, 1H, J=7.4 Hz) 7.45 (t, 2H, J=7.7 Hz) 7.57 (d, 2H, J=8.1 Hz) 7.63-7.65.
Reaction SMILES: CC([N:5]([C:9]([CH3:32])([CH3:31])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[C:28]3[CH:27]([CH2:29][CH3:30])[O:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:29]([CH:27]1[C:28]2[C:20]([O:19][C:16]3[N:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C:9]([CH3:32])([CH3:31])[NH2:5])=[CH:18][CH:17]=3)=[CH:21][CH:22]=[CH:23][C:24]=2[CH2:25][O:26]1)[CH3:30]
Reactant: CCC1OCc2cccc(Oc3ccc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cn3)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1OCc2cccc(Oc3ccc(NC(=O)C(C)(C)N)cn3)c21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl[2-({6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate (Intermediate 148, 36.5 mg, 0.066 mmol) was dissolved in Dichloromethane (3 mL) to give a colourless solution. The reaction mixture was cooled at 0° C. and TFA (1.5 mL, 19.47 mmol) was added at that temperature. The reaction mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was evaporated in vacuo affording and the residue was charged on a 2 g SCX cartridge. It was then flushed with 15 mL of MeOH followed by 15 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated in vacuo affording the title compound (17.2 mg) as colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:42]([O:44][C:45]([O:47][CH2:48][O:49][C:50](=[O:71])[C@@:51]([CH2:69][OH:70])([CH3:68])[CH2:52][C@H:53]([NH2:67])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:57][CH:56]=1)=[O:46])[CH3:43]>CN(C=O)C>[CH2:42]([O:44][C:45]([O:47][CH2:48][O:49][C:50](=[O:71])[C@@:51]([CH2:69][OH:70])([CH3:68])[CH2:52][C@H:53]([NH:67][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:54][C:55]1[CH:56]=[CH:57][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:59][CH:60]=1)=[O:46])[CH3:43]
Reactant: CCOC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)OCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8.2 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid ethoxycarbonyloxymethyl ester (51 mg, 120 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (5 mg; purity 90%). MS m/z [M+H]+ calc'd for C26H30N4O7, 511.21. found 511.6.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:21][NH2:22]>>[F:19][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([F:18])[CH:15]=1)[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:21][NH2:22])=[O:2])[CH2:6][CH2:7]1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2cc(F)cc(F)c2)CC1
Reactant: NN
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](Oc2cc(F)cc(F)c2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(3,5-difluoro-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.148 g, 0.548 mmol) and hydrazine hydrate (0.106 ml, 2.19 mmol) was heated at 120° C. for 18 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated.
Reaction SMILES: [CH3:1][C:2]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[F:17])([CH3:7])[C:3]([NH:5][NH2:6])=O.FC(F)(F)C(O)=O.[CH2:25]([N:27]=[C:28](SC)[N:29]1[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]1)[CH3:26].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:25]([N:27]1[C:3]([C:2]([CH3:7])([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=2[F:17])[CH3:1])=[N:5][N:6]=[C:28]1[N:29]1[CH2:30][CH2:31][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:34]1)[CH3:26]
Reactant: CC(C)(Oc1c(F)cc(F)cc1F)C(=O)NN
Reactant: CCN=C(SC)N1CCC(C(=O)OCC)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCN(c2nnc(C(C)(C)Oc3c(F)cc(F)cc3F)n2CC)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
2-methyl-2-(2,4,6-trifluorophenoxy)propanohydrazide (500 mg) and trifluoroacetic acid (0.08 ml) were added to a solution of ethyl 1-[(ethylimino)(methylsulfanyl)methyl]piperidine-4-carboxylate (600 mg) in toluene (10 ml), followed by stirring at 120° C. for 8 hours. An aqueous saturated sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate and the solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (using basic silica:hexane:ethyl acetate=100:0 to 50:50 to 0:100) to obtain ethyl 1-{4-ethyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}piperidine-4-carboxylate (254 mg), as a colorless solid.
Reaction SMILES: CO[CH:3]1[CH:7]=[CH:6][CH:5](OC)[O:4]1.[NH2:10][CH:11]([CH2:17][SH:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(#N)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>[NH2:10][CH:11]([CH2:17][S:18][C:5]1[O:4][CH:3]=[CH:7][CH:6]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COC1C=CC(OC)O1
Reactant: CCOC(=O)C(N)CS
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Product: CCOC(=O)C(N)CSc1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To 16.25 g (125 mmol) of 2,5-dimethoxy-2,5-dihydrofuran and 23.20 g (125 mmol) of ethyl 2-amino-3-mercaptopropanoate in 100 ml dry acetonitrile was added approximately 0.15 g of tosyl chloride. The mixture was stirred 1 hour at room temperature under nitrogen during which time complete solution was attained which became very dark. The mixture was concentrated in vacuo, taken up in ethyl acetate, then extracted with aqueous NaHCO3 solution followed by saturated NaCl solution. The organic portion was dried over MgSO4, filtered then concentrated to 50 ml. The concentrate was then chromatographed to give 8.35 g (31.0%) of the title compound as a dark oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:21][C:22]4[NH:27][C:26](=[N:28][NH:29][C:30](OCC)=[O:31])[CH2:25][O:24][C:23]=4[N:35]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CN(C=O)C.ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:21][C:22]4[N:27]5[C:30](=[O:31])[NH:29][N:28]=[C:26]5[CH2:25][O:24][C:23]=4[N:35]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)NN=C1COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(n[nH]c3=O)CO4)cc2)CCC1
Yield: 34.2 %

Procedure:
A solution of Ethyl 2-(6-(4-(1-(tert-butoxycarbonylamino)cyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-ylidene)hydrazinecarboxylate (24 mg, 0.04 mmol) in dry DMF (1 mL) was heated at 200° C. for 10 min under microwave irradiation. The reaction mixture was diluted with dichloromethane, filtered on celite and concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (method G, gradient 5 to 95% 0.1% FA/ACN in 0.1% FA/H2O) to give the title compound (7 mg, 32%). 1H NMR (500 MHz, CDCl3): 9.18 (1H, br s), 8.54 (1H, s), 7.32 (2H, d), 7.28-7.26 (5H,m), 7.22-7.20 (2H,m), 5.32 (2H, s), 5.07 (1H, br s), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[CH3:26][NH2:27]>C(O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([NH:27][CH3:26])[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: CN
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Solvent: CCO
Product: CNc1nc2c(s1)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O

Procedure:
The product from example 44 step (viii) (0.05 g) was heated with 40% aq. Methylamine (4 ml) in ethanol (1 ml) for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was collected, dried (MgSO4) and solvent evaporated under reduced pressure. The residue was triturated with ethyl acetate/iso-hexane mixtures and the title product collected by filtration as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH2:24]([O:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:25]>>[CH2:24]([O:26][C:27]1[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[S:10][C:9]([C:15]5[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)=[N:8][C:7]=4[C:6]=3[CH:23]=2)=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:25]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CCOc1ncccc1B(O)O
Product: CCOc1ncccc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Yield: 27 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 2-ethoxypyridin-3-ylboronic acid were reacted to give 283 (0.045 g, 27%). 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J=2.2, 1H), 8.15 (dd, J=4.9, 1.8, 1H), 7.92 (s, 1H), 7.65 (dd, J=7.3, 1.8, 1H), 7.55 (dt, J=11.2, 5.6, 1H), 7.13 (d, J=8.4, 1H), 7.02-6.93 (m, 1H), 5.84 (dt, J=13.2, 6.6, 1H), 4.55-4.39 (m, 4H), 3.45 (t, J=5.0, 2H), 1.59 (d, J=6.6, 6H), 1.38 (t, J=7.0, 3H). MS (ESI(+)): m/z 434.1 (M+H)
Reaction SMILES: N1CCCCC1.[CH:7]1([O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=2[O:21][CH3:22])[CH2:11][CH2:10][CH2:9][CH2:8]1.C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.Cl>C1(C)C=CC=CC=1>[CH:7]1([O:12][C:13]2[CH:20]=[CH:19][C:16](/[CH:17]=[CH:26]/[C:27]([NH:29][C:30]3[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=3[C:32]([OH:34])=[O:33])=[O:28])=[CH:15][C:14]=2[O:21][CH3:22])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COc1cc(C=O)ccc1OC1CCCC1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC1CCCC1
Yield: 67.8 %

Procedure:
Piperidine (0.45 mL, 4.5 mmol) was added to a suspension of 4-cyclopentyloxy-3-methoxybenzaldehyde (1.0 g, 4.5 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.92 g, 4.1 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-{[3-(4-cyclopentyloxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino}benzoic acid (1.06 g, 67%) as a pale yellow crystalline solid; mp 96-98° C.; δH (400 MHz, DMSO-d6) 1.46 (m, 2H, CH2), 1.67-1.71 (m, 4H, CH2), 1.90 (m, 2H, CH2), 3.81 (s, 3H, OCH3), 4.82 (t, J=5.6 Hz, 1H, OCH), 6.76 (d, J=15.6 Hz, 1H, CH═CHCO), 6.94 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.19 (dd, J5′,6′=8.4, J5′,6′=1.6 Hz, 1H, H6′), 7.35 (d, J2′,6′=1.6 Hz, 1H, H2′), 7.54 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 HZ, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.28 (s, 1H, NH), 13.59 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 23.7, 32.3, 55.7, 79.5, 110.9, 114.0, 116.5, 119.7, 120.3, 122.5, 122.6, 127.0, 131.1, 134.0, 141.1, 141.7, 149.0, 149.6, 164.2, 169.5; HRMS (ESI) calculated for C22H23NO5 [M+Na]+ 404.1468. found 404.1468; vmax 747, 1261, 1506, 1584, 1659, 2964, 3524 cm−1.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].CI.[O:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:17][O:13][CH2:14][C@H:15]1[CH2:16][CH2:14][C@@H:15]2[C@@H:17]([CH2:16]2)[O:13]1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Product: COC[C@H]1CC[C@H]2C[C@H]2O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The product (4.63 g) obtained by the reaction in 2) was dissolved in tetrahydrofuran (50 ml), potassium bis(trimethylsilyl)amide (0.5N toluene solution, 80 ml) was added to the solution at −78° C. After stirring at same temperature for 10 minutes, methyl iodide (2.93 ml) was added. After heating the mixture to 0° C., it was stirred for 1 hour, quenched with a saturated aqueous solution of ammonium chloride and then diluted with diethyl ether. An organic layer was separated, washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the title compound (3.7 g).
Reaction SMILES: C(O[CH:9]([O:32]CC1C=CC=CC=1)[C:10]([N:12]([CH2:23][O:24]CC1C=CC=CC=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[O:11])C1C=CC=CC=1.FC(F)(F)C(O)=O>[Pd].ClCCl>[OH:32][CH:9]1[O:24][CH2:23][N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[C:10]1=[O:11]
Reactant: O=C(C(OCc1ccccc1)OCc1ccccc1)N(COCc1ccccc1)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C(O)OCN1c1cccc(C(F)(F)F)c1
Reaction time: 5 h
Yield: 56.2 %

Procedure:
A mixture of 2,2-dibenzyloxy-N-benzyloxymethyl-N(3-trifluoromethylphenyl)-acetamide (0.27 g, prepared as described in Step 4), 10% palladium on carbon (50 mg), trifluoroacetic acid (1 ml) and dichloromethane (50 ml) was stirred under an atmosphere of hydrogen for five hours. It was filtered through Hyflo Supercel™, evaporated under reduced pressure and chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant to give the title compound (0.07 g) as a waxy solid, m.p. 75°-76° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].[C:13]([O:17][C:18]([NH:20][C:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C:21]1([C:24](=[O:25])[NH:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)=[O:5])[CH2:22][CH2:23]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NCC(=O)c2ccc(Br)cc2)CC1
Reaction time: 18 h
Yield: 89.6 %

Procedure:
2-Amino-1-(4-bromo-phenyl)-ethanone HCl (2.5 g, 10 mmol) in DMF (30 mL) was treated with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid (1.97 g, 9.8 mmol), HATU (4.02 g, 10.5 mmol), and DIPEA (5.6 mL, 31.1 mmol). The mixture was stirred for 18 hours and concentrated. The mixture was diluted with EtOAc (25 mL), and washed with saturated NaHCO3 (3 10 mL), H2O (10 mL), and brine (10 mL). The solution was dried over MgSO4 and subjected to a 80 g SiO2 COMBIFLASH column (0-100% EtOAc-hexanes gradient) to afford {1-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-cyclopropyl}-carbamic acid tert-butyl ester (3.49 g, 90%). This material (3.49 g, 8.8 mmol) in xylenes (20 mL) was treated with ammonium acetate (3.4 g, 44 mmol). The reaction was stirred at 130° C. in a sealed tube for 18 hours. The mixture was concentrated and suspended in dicholormethane (100 mL) and washed with saturated NaHCO3 (50 mL). The solution was dried over MgSO4 to afford crude {1-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester, which was used without further purification: MS (ESI) m/z 379 [M+H]+.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[CH:13]1([NH:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH2:23])[CH2:15][CH2:14]1>CC#N>[CH:13]1([N:16]2[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[NH:23][C:6]2=[O:7])[CH2:15][CH2:14]1
Reactant: Nc1cnccc1NC1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=c1[nH]c2cnccc2n1C1CC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
CDI (CAS 530-62-1) (151.8 g, 936 mmol) was added to a solution of the intermediate 5-c (133 g, 891.4 mmol) in CH3CN (1800 mL) at 0° C. The reaction was allowed to warm to 10° C. and stirred for 1 hour. The solid was collected by filtration, then washed with CH3CN (200 mL) to afford compound 5-d as a white powder (101 g, 65%).
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCO
Reactant: O=C1CCC(O)N1
Product: CCCCCCCCCCOC1CCC(=O)N1
Reaction time: 24 h

Procedure:
3 g of 5-hydroxy-pyrrolidin-2-one and 1.5 g of Amberlite resin IR 120H in 60 cm3 of n-decanol are agitated at 60° C. for 3 hours. The resin is filtered off and the solvent is eliminated by distilling at 60° C. under 0.4 mm of Hg. The residue is taken up in 50 cm3 of n-hexane, kept for 24 hours at -5° C./-10° C., separated, and 3.5 g of the expected product is obtained, m.p. 44°-46° C. After re-crystallizing from n-hexane, m.p. 48°-49° C.
Reaction SMILES: [OH:1][CH:2]([CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3]([OH:5])=O.[NH2:11][C@H:12]([C:14]([C:16]1([NH2:35])[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]([CH3:33])[C:17]1=[O:34])=[O:15])[CH3:13]>>[CH:6]1([CH:2]([OH:1])[C:3]([NH:11][C@H:12]([C:14]([C:16]2([NH2:35])[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=3[N:18]([CH3:33])[C:17]2=[O:34])=[O:15])[CH3:13])=[O:5])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reactant: O=C(O)C(O)C1CCCC1
Product: C[C@H](NC(=O)C(O)C1CCCC1)C(=O)C1(N)N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using (±)-α-hydroxycyclopentylacetic acid (Example P) and 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-1H-1,4-benzodiazepin-2-one (Example 8-B), the title compound was prepared as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[C:5]#[N:6].Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCO.CCOC(C)=O>[NH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)ccc1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
To a solution of 3-methyl-4-nitrobenzonitrile (2 g, 12.3 mmol) in 100 mL of EtOH is added SnCl2 (13.9 g, 61.7 mmol). The resulting solution is refluxed. After 2 hours, the solution is cooled to ambient temperatures. The solution is poured into 150 mL of ice water. The pH of the solution is adjusted to >7 with a solution of saturated NaHCO3. The solution is diluted with EtOAc and the resulting mixture is filtered through Celite. The filtered solution is separated. The organic layer is dried over MgSO4, filtered and concentrated to give the title compound (1.57 g, 8.7 mmol) as an off-white solid.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:35]>CN(C=O)C.O>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:16]=[CH:15][C:14]=3[N:13]([CH3:35])[C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3ccc(S(=O)(=O)c4ccccc4)cc3c2CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCN(C(=O)c1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
A 0° mixture of 3-benzoyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Step II, 1.61 g, 3.74 mmol) in dry DMF (18 mL) is treated with sodium hydride (60% in oil, 165 mg, 4.11 mmol). After 30 min, the mixture is treated with iodomethane (256 μL, 4.11 mmol) and allowed to slowly warm to 20–25° under nitrogen over 16 hr. The resultant mixture is diluted with H2O and filtered. The residual solid is triturated with refluxing methanol, isolated, and dried in the vacuum oven at 50° to give the desired indole, mp=254–255°.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[O:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1F>>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[O:9][CH:6]1[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]2[CH:12]=[CH:11][O:10][C:5]1=2
Reactant: CN1CCC(O)c2occc2C1
Reactant: Fc1cccc(Cl)c1Cl
Product: CN1CCC(Oc2cccc(Cl)c2Cl)c2occc2C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-5,6,7,8-tetrahydro-4H-furo[3,2-c]azepin-8-ol (Reference Example 21) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.