Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[O-].[Na+].[CH3:4][O:5][C:6]1[C:7]([CH:20]=[N:21][OH:22])=[CH:8][C:9]2[C:10]([CH3:19])([CH3:18])[CH2:11][CH2:12][C:13]([CH3:17])([CH3:16])[C:14]=2[CH:15]=1.[C:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1)#[CH:24]>>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([C:23]2[O:22][N:21]=[C:20]([C:7]3[C:6]([O:5][CH3:4])=[CH:15][C:14]4[C:13]([CH3:16])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:18])([CH3:19])[C:9]=4[CH:8]=3)[CH:24]=2)=[CH:26][CH:27]=1)#[N:30]
Reactant: COc1cc2c(cc1C=NO)C(C)(C)CCC2(C)C
Reactant: C#Cc1ccc(C#N)cc1
Agent: [Na+]
Agent: [O-]Cl
Product: COc1cc2c(cc1-c1cc(-c3ccc(C#N)cc3)on1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.5 %

Procedure:
17.2 g of a 10% strength aqueous sodium hypochlorite solution were added dropwise at 10°-15° C. to a solution of 5.0 g (19 millimoles) of 5,6,7,8-tetrahydro-3-methoxy-5,5,8,8-tetramethyl-2-naphthaldoxime and 2.4 g (19 millimoles) of 4-ethynylbenzonitrile. The mixture was stirred for 1.5 hours at room temperature. Thereafter, the reaction mixture was poured onto water, the phases were separated and the aqueous phase was extracted again with methylene chloride The combined organic extracts were washed with sodium bisulfite solution, dried over sodium sulfate and evaporated down. The residue was digested in hot methanol, the mixture was allowed to cool and the crystals were filtered off under suction and dried to give 5.4 g of the title compound of melting point 202°-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([Cl:46])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:9]=1.Br[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][CH2:55][CH2:56][NH:57][C:58](=[O:60])[CH3:59]>>[C:58]([NH:57][CH2:56][CH2:55][CH2:54][C:49]1[CH:48]=[CH:53][CH:52]=[CH:51][C:50]=1[C:28]1[CH:29]=[CH:30][C:25]([CH:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][O:4][C:3]3[C:2]([Cl:1])=[CH:44][C:43]([CH3:45])=[CH:42][C:41]=3[Cl:46])=[CH:13][CH:12]=2)[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[C:26]([CH3:40])[CH:27]=1)(=[O:60])[CH3:59]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Reactant: CC(=O)NCCCc1ccccc1Br
Product: CC(=O)NCCCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl {3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and N-[3-(2-bromophenyl)propyl]acetamide (V.15) as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 100% in 15 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12]C1C=CC=CC=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CN(C)C=O
Product: Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A mixture of 1-bromo-4-fluoro-3-nitrobenzene (2270 mg, 10.01 mol), aniline (3 ml) and DMF (20 ml) was heated at 100° C. under an atmosphere of Nitrogen for 7 h. The mixture was then concentrated in vacuo, and the residue triturated with heptane (30 ml) to give the desired product. 1H NMR (400 MHz, CDCl3) δ=7.11 (d, 1H, J=9.2 Hz), 7.25-7.29 (m, 3H), 7.40-7.45 (m, 3H), 8.35 (d, 1H J=2.4 Hz) and 9.45 firs, 1H).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[N:8][N:7]([CH2:17][CH3:18])[C:6](=[O:19])[C:5]=1[N+:20]([O-])=O)(=[O:3])[CH3:2].N[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[N:8][N:7]([CH2:17][CH3:18])[C:6](=[O:19])[C:5]=1[NH:20][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)(=[O:3])[CH3:2]
Reactant: Nc1cccc2cccnc12
Reactant: CCn1nc(-c2cccc(Cl)c2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2cccc(Cl)c2)c(C(C)=O)c(Nc2cccc3cccnc23)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
To a stirred solution of 100 mg (0.311 mmol) of 5-acetyl-2-ethyl-4-nitro-6-(3-chlorophenyl)pyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 8-aminoquinoline (67 mg, 0.467 mmol) was added. The resulting mixture was stirred at room temperature for two hours. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 2:1) to yield the title compound (65 mg, 50% yield).
Reaction SMILES: C(OC([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N1C(C2C=CC=CC=2)=C2C(CCNC(C)C2)=N1)(C)C>>[CH:19]([N:13]1[C:12]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:11]2[C:15]([CH2:16][CH:17]([CH3:18])[NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:20])[CH3:21]
Reactant: CC1Cc2nn(C(C)C)c(OS(=O)(=O)C(F)(F)F)c2CCN1C(=O)OC(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: CC1Cc2c(nn(C(C)C)c2-c2ccccc2)CCN1
Product: CC1Cc2nn(C(C)C)c(-c3ccccc3)c2CCN1
Yield: 64.3 %

Procedure:
The title compound (102 mg) was prepared as in Example 263 using 260 mg of 2-isopropyl-7-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (as outlined in Example 308 replacing cyclopentyl hydrazine with isopropyl hydrazine) and 101 mg of phenylboronic acid. The reaction sequence also yielded 2-isopropyl-5-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. MS (ESI): exact mass calculated for C17H23N3, 269.19; found, m/z 270.5 [M+H]+. 1H NMR (600 MHz, CD3OD): 7.58-7.52 (m, 3H), 7.36-7.35 (m, 2H), 4.43 (m, 1H), 3.65-3.57 (m, 1H), 3.51-3.48 (m, 1H), 3.23-3.11 (m, 3H), 2.87-2.82 (m, 2H), 2.76-2.73 (m, 1H), 1.48 (d, J=6.4 Hz, 3H), 1.43-1.40 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1.[CH:34](=O)[CH3:35].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH2:34][CH3:35])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNCc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(Cl)c(Cl)c1

Procedure:
4-Amino-5-chloro-N-((1-(3-(3,4-dichlorobenzylamino)propyl)-piperidin-4-yl)methyl)-2-methoxybenzamide (2.0 g) as starting compound, acetaldehyde (0.27 ml) and sodium cyanoborohydride (0.3 g) were reacted and treated in the same manner as in Example 136 to give 0.7 g of 4-amino-5-chloro-N-((1-(3-(N-(3,4-dichlorobenzyl)-N-ethylamino)propyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][CH2:11][C:10]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][OH:17].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[CH2:1]([O:8][C@H:9]1[CH2:12][CH2:11][C@H:10]1[NH:14][CH2:15][CH2:16][OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC1OCc1ccccc1
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: OCCN[C@@H]1CC[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(benzyloxy)cyclobutanone (prepared according to the method of P. Bisel et al., Eur. J. Org. Chem. 1998, 4, 729-733; 2.35 g, 13.3 mmol) and 2-aminoethanol (1.63 g, 26.7 mmol) in dichloromethane (47 mL) was treated with acetic acid (0.76 mL, 13.3 mmol) and sodium triacetoxyborohydride (5.95 g, 26.7 mmol) and stirred at room temperature for 16 hours. Aqueous sodium hydroxide solution (1 N, 100 mL) was added and the mixture was extracted with dichloromethane (2×100 mL). The combined organic layers were washed with aqueous sodium hydroxide solution (1 N, 100 mL), dried over magnesium sulfate and concentrated in vacuo to afford the product as a colorless oil. Yield: 2.9 g, 13 mmol, 98%. 1H NMR (400 MHz, CDCl3) δ 7.28-7.39 (m, 5H), 4.51 (AB quartet, JAB=11.7 Hz, ΔνAB=61.1 Hz, 2H), 4.13-4.18 (m, 1H), 3.54-3.58 (m, 2H), 3.32-3.39 (m, 1H), 2.72-2.78 (m, 2H), 2.5 (v br s, 2H), 2.05-2.14 (m, 1H), 1.83-1.98 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:21]#[N:22])=[CH:4][C:3]=1[NH:23][C:24]1[N:29]=[C:28]([N:30]([CH:40]2[CH2:42][CH2:41]2)CC2C=CC(OC)=CC=2)[C:27]2=[N:43][CH:44]=[C:45]([C:46]#[N:47])[N:26]2[N:25]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:16][C:17]([F:20])([F:19])[CH2:18]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:21]#[N:22])=[CH:4][C:3]=1[NH:23][C:24]1[N:29]=[C:28]([NH:30][CH:40]2[CH2:41][CH2:42]2)[C:27]2=[N:43][CH:44]=[C:45]([C:46]#[N:47])[N:26]2[N:25]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC(NC5CC(F)(F)C5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCC(NC3CC(F)(F)C3)CC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 11.9 %

Procedure:
To a round bottom flask charged with 2-((2-chloro-5-cyano-3-(4-((3,3-difluorocyclobutyl)amino)piperidin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (34.9 mg, 0.053 mmol) in dichloromethane (530 μl) was added anisole (116 μl, 1.060 mmol), followed by the slow addition of trifluoroacetic acid (408 μl, 5.30 mmol). The reaction mixture was stirred at room temperature 2 d. Excess TFA was removed in vacuo. The crude residue was taken up in MeOH and free based using a Phenomenex Strata 1 g SCX column. The crude solid was purified via preparative LC/MS and provided 2-((2-chloro-5-cyano-3-(4-((3,3-difluorocyclobutyl)amino)piperidin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (3.4 mg).
Reaction SMILES: [Li][CH3:2].C[Si](Cl)(C)C.[CH3:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[C:12](/[C:19](/[CH3:26])=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:13]=[CH:14][CH:15]=2)[N:10]=1>CCOCC.C(Cl)Cl>[CH3:26][C:19]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[C:9]([CH3:8])[CH:18]=[CH:17]2)([CH3:2])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: [Li]C
Reactant: CCOC(=O)/C=C(/C)c1cccc2ccc(C)nc12
Agent: C[Si](C)(C)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CC(C)(C)c1cccc2ccc(C)nc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a mixture of Cu(I)I (2.42 g, 12.7 mmol) in ether (5 mL) was added a solution of 1.6 M MeLi (15.9 ml, 25.4 mmol) in ether at 0° C. and the mixture was stirred at 0° C. for 10 minutes. The solvent was removed under reduced pressure and cold DCM (10 mL) was added. The solvent was removed under reduced pressure. Cold DCM (40 mL) was added and the mixture was cooled to −78° C. TMSCl (1.54 mL, 12.7 mmol) was added, followed by a solution of (Z)-ethyl 3-(2-methylquinolin-8-yl)but-2-enoate (0.81 g, 3.17 mmol) in DCM (10 mL). The reaction mixture was warmed to 0° C. and stirred at 0° C. for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution. The organic layers was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (7:1 hexane/ethyl acetate) to give ethyl 3-methyl-3-(2-methylquinolin-8-yl)butanoate (0.66 g, 76.8%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([CH2:12][CH3:13])[OH:11])[S:7][C:6]=2[C:14]=1[Cl:15].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:16][C:3]1[C:2]([Cl:1])=[C:14]([Cl:15])[C:6]2[S:7][C:8]([CH:10]([OH:11])[CH2:12][CH3:13])=[CH:9][C:5]=2[CH:4]=1)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CCC(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2cc(C(O)CC)sc2c(Cl)c1Cl
Reaction time: 3 h

Procedure:
To a mixture of 6,7-dichloro-5-hydroxy-α-ethylbenzo[b]thiophene-2-methanol and 200 ml of 2-butanone is added a mixture of 7.35 g of ethyl bromoacetate in 100 ml of 2-butanone, followed by 7.4 g of potassium carbonate and 3.3 ml of sieve-dried dimethylformamide. The reaction mixture is stirred at 95°-100° for 3 hrs, allowed to cool and filtered. To the filtrate is added 100 ml of water and the mixture is extracted with ethyl ether. The organic layers are washed, dried over anhydrous magnesium sulfate, filtered and the solvent removed to give an oil which solidifies on cooling. Recrystallization from ethyl ether and hexane gives 10 g of ethyl[ (6,7-dichloro-2-(1-hydroxypropyl]benzo[b]thien-5-yl]oxy]acetate, mp 69°-70°.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:17][S:18][CH3:19])[CH:10]=[CH:9]1)=O)(C)(C)C.C[O-].[Na+]>CO>[CH3:19][S:18][CH2:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[NH:8][CH:9]=[CH:10]2
Reactant: CSCc1cccc2ccn(C(=O)OC(C)(C)C)c12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSCc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.16 g (4.18 mmol) of the compound from Example 7A were introduced into 23 ml of methanol, 26 ml (113 mmol) of a 25% strength methanolic sodium methanolate solution were added, and the mixture was stirred at RT overnight. Then ice-water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate gradient) to result in 549 mg (74% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:29][CH2:28][C@@H:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]1>CN1C(=O)CCC1>[C:31]([NH:30][C@@H:27]1[CH2:28][CH2:29][N:25]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:21])[CH3:22])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:26]1)(=[O:33])[CH3:32]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CC(=O)N[C@@H]1CCNC1
Solvent: CN1CCCC1=O
Product: CC(=O)N[C@@H]1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Yield: 108.5 %

Procedure:
In a 2 mL microwave vial were placed N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 80 mg, 0.24 mmol) and (R)-N-(pyrrolidin-3-yl)acetamide (62 mg, 0.48 mmol). To the sealed vial were then added NMP (2 ml), and the mixture was then heated in the microwave at 100° C. for 15 minutes. After cooling to room temperature, the reaction mixture was filtered by syringe filter and was then directly purified by preparatory HPLC (20-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white powder (110 mg, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ=10.84 (s, 1 H), 8.24 (d, J=6.3 Hz, 1 H), 8.01 (d, J=2.3 Hz, 1 H), 8.00-7.95 (m, 2 H), 7.65-7.59 (m, 2 H), 6.90 (s, 1 H), 6.28 (d, J=2.3 Hz, 1 H), 4.41-4.31 (m, 1H), 4.19 (br. s., 1 H), 3.96 (br. s., 2 H), 2.19 (dd, J=5.8, 12.6 Hz, 1 H), 2.01-1.91 (m, 1 H), 1.83 (s, 3 H), 1.46 (s, 6 H); ESI-MS: m/z 423.4 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]=[C:17]=[O:18])[C:5]=1CC1OC=CC=1)=[C:2]=[O:3].N(CC/C(/C([O-])=O)=C(/CCN=C=O)\C([O-])=O)=C=O.N(CCOC(=O)OCCN=C=O)=C=O>>[C:12]1([N:16]=[C:17]=[O:18])[CH:13]=[CH:14][CH:15]=[C:4]([N:1]=[C:2]=[O:3])[CH:5]=1
Reactant: O=C=Nc1cccc(N=C=O)c1Cc1ccco1
Agent: O=C=NCC/C(C(=O)[O-])=C(/CCN=C=O)C(=O)[O-]
Agent: O=C=NCCOC(=O)OCCN=C=O
Product: O=C=Nc1cccc(N=C=O)c1

Procedure:
methylene-bis(4-phenylisocyanate); 2,6-diisocyanatobenzylfuran; bis(2-isocyanato-ethyl)fumarate; bis(2-isocyanato-ethyl)carbonate;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[CH3:13]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([O:9][CH3:13])=[O:8]
Reactant: CO
Reactant: O=C(O)C=Cc1cccc(Br)c1
Product: COC(=O)C=Cc1cccc(Br)c1
Yield: 81 %

Procedure:
Reaction of 3-bromocinnamic acid (22.72 g) with methyl lodide (21.3 g) as described in Example 1 gave the title ester (19.5 g, 81%) as a white solid mp (methanol) 62°-65° C.
Reaction SMILES: [CH:1]([N:4]=[CH:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:8])([CH3:3])[CH3:2]>O1CCOCC1.[Pt]>[CH:1]([NH:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:8])([CH3:2])[CH3:3]
Reactant: CC(C)N=CCC(C)c1ccccc1-c1ccccc1
Agent: [Pt]
Solvent: C1COCCO1
Product: CC(C)NCCC(C)c1ccccc1-c1ccccc1

Procedure:
A solution of 2.65 g of 1-isopropylimino-3-p-biphenylyl-butane (obtainable from 3-p-biphenylyl-butanal and isopropylamine) in 25 ml of dioxane is hydrogenated, over 0.2 g of platinum, at 20° and normal pressure until hydrogen absorption ceases. The mixture is filtered and evaporated to give 1-isopropylamino-3-p-biphenylyl-butane.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[C:12]([O:16][C:17]([N:19]1[CH2:23][C@@H:22]([OH:24])[CH2:21][C@H:20]1[C:25]([OH:27])=[O:26])=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN(CC)CC>CC#N.CCOC(C)=O.C([O-])(O)=O.[Na+].[Cl-].[Na+].O>[OH:24][C@@H:22]1[CH2:23][N:19]([C:17]([O:16][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:18])[C@H:20]([C:25]([O:27][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=2)=[O:4])=[O:26])[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)OCC(=O)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 83.7 %

Procedure:
To a solution of 2-bromo-1-(4-bromophenyl)ethanone (3.6 g, 12.98 mmol) and (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.0 g, 8.65 mmol) in MeCN (50 mL) was added Et3N (1.8 mL, 12.98 mmol). After 3 h, the solution was diluted with EtOAc, sat. NaHCO3, brine, dried over MgSO4, and concentrated. The residue was taken on crude to yield product (3.1 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([OH:24])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O[K])(C)(C)C>C1COCC1.O>[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([O:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11][CH3:12])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
Dissolve 1-fluoro-2-methoxy-4-nitro-benzene (118 g, 689 mmol) and 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (125 g, 724 mmol) in THF (800 mL) and cool to 0° C. To the above solution under a nitrogen atmosphere, add dropwise a 1M solution of tBuOK (1 L, solution in THF). After addition is complete, stir the dark brown solution for 30 min at 0° C., then dilute with water (1 L) over a 10 min period. Stir the mixture for 5 min, then extract with MTBE twice. Combine the organic solutions and wash with brine (2×700 mL), then dry and concentrate. Dry the solid in vacuo at 45° C. for 20 h to obtain 216 g (95%) of the title compounds as a yellow solid. 1H NMR (300 MHz, CDCl3) δ1.42 (s, 9H), 3.80 (s, 3H), 4.04 (m, 2H), 4.18 (m, 2H), 4.76 (m, 1H), 6.17 (dd, 1H, J=2.4, 8.5), 6.30 (d, 1H, J=2.6), 6.47 (d, 1H, J=8.5).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:23][C:24]#[C:25][CH3:26])[CH2:10][N:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[C:12](=[O:15])[CH2:13]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O.CCCCCC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:9]([CH2:23][C:24]#[C:25][CH3:26])[CH2:10][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:12](=[O:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCC(CN(C(=O)CCl)c1cccc(Cl)c1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCC1CN(c2cccc(Cl)c2)C(=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the chloroacetamide from Step H (1.68 g, 4.23 mmol) in 15 mL of dry DMF at 0° C. was added Cs2CO3 (3.08 g, 9.48 mmol). The solution was stirred for 30 minutes, then allowed to warm to room temperature. After 14 hours, the reaction was poured into 50% EtOAc/hexane, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. This material was purified by silica gel chromatography (20-40% EtOAc/hexane) to yield the titled product.
Reaction SMILES: CC1C=CC=CC=1S([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]2[NH:22][N:23]=[CH:24][C:14]=2[CH2:13][CH2:12]1)(=O)=O>C(O)(=O)C>[NH:22]1[C:15]2[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:11][CH2:12][CH2:13][C:14]=2[CH:24]=[N:23]1
Reactant: Cc1ccccc1S(=O)(=O)N1CCc2cn[nH]c2-c2ccccc21
Solvent: CC(=O)O
Product: c1ccc2c(c1)NCCc1cn[nH]c1-2
Temperature: 60 °C

Procedure:
A mixture of 1.0 g of 1,4,5,6-tetrahydro-6-[(2-methylphenyl)sulfonyl]pyrazolo[4,3-d][1]benzazepine in 60 ml of 40% (V/v)H2SO4 in glacial acetic acid is heated at 60° C. for 12 hours or until the tosyl group is removed. The mixture is poured into 100 ml ice and water with cooling. Solid NaOH is added portionwise (temperature kept below 30° C.) with efficient stirring and the pH brought to 8. The mixture is extracted with ethyl acetate and the extract dried (Na2SO4) and the solvent removed to give a solid.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[O:15][C@@H:14]([C:16]([N:18]([CH:34]2[CH2:36][CH2:35]2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:21]=2)=[O:17])[CH2:13][N:12]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:11]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-].[C]>[CH:34]1([N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:21]=2)[C:16]([C@@H:14]2[O:15][C@H:10]([CH2:9][OH:8])[CH2:11][N:12]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:13]2)=[O:17])[CH2:36][CH2:35]1
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](COCc3ccccc3)O2)C2CC2)ccc1OC
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COCCCOc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](CO)O2)C2CC2)ccc1OC
Yield: 107 %

Procedure:
20% Palladium hydroxide-carbon (dry) (22 mg) was added to a solution of tert-butyl(2S,6R)-2-[(benzyloxy)methyl]-6-({cyclopropyl[4-methoxy-3-(3-methoxypropoxy)benzyl]amino}carbonyl)morpholin-4-carboxylate (220 mg) in methanol and the mixture was stirred under normal pressure of hydrogen atmosphere at room temperature for 6 hours. After filtration of insoluble materials through Celite, the filtrate was concentrated to give tert-butyl(2R,6S)-2-({cyclopropyl[4-methoxy-3-(3-methoxypropoxy)benzyl]amino}carbonyl)-6-(hydroxymethyl)morpholin-4-carboxylate (200 mg) as a pale yellow oil.