Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:12])=[CH:8][C:9]=2[CH3:11])[C:4]([CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:3]1.[H-].[Na+].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[S:30](Cl)(=[O:32])=[O:31].[OH-].[Na+]>C1COCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][S:30]([C:24]3[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=3[F:22])(=[O:32])=[O:31])=[CH:8][C:9]=2[CH3:11])[C:4]([CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:3]1
Reactant: Cc1cc(O)cc2c(C3CCN(C)CC3)cn(C)c12
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OS(=O)(=O)c2c(F)cccc2F)cc2c(C3CCN(C)CC3)cn(C)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A suspension of 1,7-dimethyl-3-(1-methylpiperdin-4-yl)-5-hydroxy-1H-indole (1.0 eq, 1.98 mmol, 0.511 g) in THF (5.0 mL) at room temperature was added 60% sodium hydride (1.2 eq, 2.37 mmol, 0.095 g). After stirring five minutes 2,6-difluorobenzenesulfonyl chloride (1.1 eq, 2.18 mmol, 0.384 g) was added. The reactions were stirred at room temperature for 3 hours. The reaction was treated with water (25 mL) and 1N sodium hydroxide (2 mL) then extracted with ethyl acetate (2×25 mL). The organic phases were combined, washed with water (25 mL) then brine (25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to an oil. This material was subjected to radial chromatography, 4 mm plate, eluting with 9:1 chloroform:2M ammonia in methanol. Fractions containing product were combined, concentrated in vacuo to afford an oil. The title compound was crystallized from diethyl ether to afford 0.592 g (59%) of the title compound: mp=139° C.; Mass spectrum (ion spray): m/z=439 (M+1); 1H NMR (DMSOd6): 7.95-7.85 (m, 1H), 7.43-7.37 (m, 2H), 7.05 (s, 1H), 6.84 (d, J=2.20 Hz, 1H), 6.64 (d, J=1.46 Hz, 1H), 3.96 (s, 3H), 2.79 (m, 2H), 2.64 (s, 3H), 2.50-2.40 (m, 1H), 2.19 (s, 3H), 1.96 (m, 1H), 1.92 (m, 1H), 1.69-1.56 (m, 2H), 1.53 (m, 1H), 1.44 (m, 1H); Calculated for C22H26N2F2O3S: C, 60.89; H, 5.57; N, 6.45. Found: C, 60.67; H, 5.64; N, 6.54.
Reaction SMILES: [CH2:1](OS(OCC)(=O)=O)[CH3:2].[CH3:10][N:11]([CH3:30])[S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]([OH:20])=[O:19])(=[O:14])=[O:13].[ClH:31]>[OH-].[Na+]>[ClH:31].[CH2:1]([N:27]1[CH2:26][CH2:25][N:24]([C:23]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[S:12](=[O:13])(=[O:14])[N:11]([CH3:30])[CH3:10])[CH2:29][CH2:28]1)[CH3:2]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)ccc1N1CCNCC1
Reactant: CCOS(=O)(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCN1CCN(c2ccc(C(=O)O)cc2S(=O)(=O)N(C)C)CC1

Procedure:
16 Grams of diethylsulfate were added dropwise, at room temperature, while being mixed in a vibro-mixer, to a solution of 31.5 g of 3-dimethylsulfamoyl-4-(piperazine-1-yl)-benzoic acid (0.1 mole), which had been prepared according to Example 15, in 0.3 l of 1N NaOH. The mixture was allowed to react for another 3 hours while being mixed in the vibro-mixer. Subsequently the solution was acidified with 5N HCl, and the separated hydrochloride was recrystallized from ethanol and water.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]1(/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCC/C=C\c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)CCC/C=C\c1ccccc1

Procedure:
A solution of methyl (Z)-6-phenyl-5-hexenoate (2.0 g) in dioxan (20 ml) and 10% sodium carbonate solution (20 ml) was heated under reflux for 6 hours and evaporated to low volume. The residue was diluted with water, washed with ether, acidified and extracted with ether. The extract was dried and evaporated to give (Z)-6-phenyl-5-hexenoic acid.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:11]1([C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][CH:2]=2)[C:6]([OH:8])=[O:7])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: O=C(O)c1cccc(-c2ccccc2)c1
Temperature: 50 °C
Yield: 98.4 %

Procedure:
p-Iodo-benzoic acid (4.96 g, 20 mmol), phenyl boronic acid (2.68 g, 22 mmol), Na2CO3 (6.36 g, 60 mmol) and Pd(OAc)2 (44 mg) were dissolved in 80 ml water and heated to 50° C. for 1 hour. Filtered and washed EtOAc, then acidified with 1 M HCl and extracted into EtOAc, dried with Na2SO4, evaporated and recrystallised from EtOAc and heptane to yield 3.9 g of meta-phenyl benzoic acid as a white solid. 2-(3-Biphenyl-3-yl-ureido)-4-chloro-benzoic acid was then prepared according to method E (m.p. 181-183° C.).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:30]([NH:32][CH2:33][CH2:34][OH:35])[CH3:31]>>[CH2:30]([N:32]([CH2:22][CH2:21][CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:29])([F:1])[F:28])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:33][CH2:34][OH:35])[CH3:31]
Reactant: CCNCCO
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: CCN(CCO)CCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1, Methanesulfonic acid 5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and 2-Ethylaminoethanol were converted to yield 2-(Ethyl-[5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amino)-ethanol as light yellow oil, MS: 433 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][O:8][C@@H:9]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=1)[CH2:10][CH2:11][N:12]([CH2:36][CH2:37][CH3:38])[C:13](=[O:35])[NH:14][C@@H:15]([CH2:28][C@H:29]1[CH2:34][CH2:33][CH2:32][O:31][CH2:30]1)[CH2:16][N:17](C)[C:18](=O)OCC[Si](C)(C)C)=[O:4].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:45][C:41]1[CH:40]=[C:39]([C@H:9]([O:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[O:2][CH3:1])[CH2:10][CH2:11][N:12]([CH2:36][CH2:37][CH3:38])[C:13](=[O:35])[NH:14][C@@H:15]([CH2:28][C@H:29]2[CH2:34][CH2:33][CH2:32][O:31][CH2:30]2)[CH2:16][NH:17][CH3:18])[CH:44]=[CH:43][CH:42]=1
Reactant: CCCN(CC[C@@H](OCCNC(=O)OC)c1cccc(Cl)c1)C(=O)N[C@@H](C[C@H]1CCCOC1)CN(C)C(=O)OCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CC[C@@H](OCCNC(=O)OC)c1cccc(Cl)c1)C(=O)N[C@H](CNC)C[C@H]1CCCOC1
Yield: 105.6 %

Procedure:
2-(trimethylsilyl)ethyl (S)-2-(3-((R)-3-(2-(methoxycarbonylamino)ethoxy)-3-(3-chlorophenyl)propyl)-3-propylureido)-3-((R)-tetrahydro-2H-pyran-3-yl)propyl(methyl)carbamate (31 mg) was treated with (V/V) 20% TFA/CH2Cl2 (2 mL) for 1 hr. The excess reagent was evaporated and the crude material was purified via preparative HPLC to afford the desired product (25.7 mg). LC-MS (3 min) tR=1.36 m/z=527. 1H NMR (CD3OD) d 7.25-7.35 (m, 4H), 4.30 (t, 1H), 4.10 (m, 1H), 3.89 (dd, 1H), 3.83 (m, 1H), 3.63 (s, 3H), 3.36-3.42 (m, 4H), 3.27 (m, 3H), 3.05-3.17 (m, 3H), 2.97 (t, 1H), 2.71 (s, 3H), 1.82-1.92 (m, 3H), 0.91 (t, 3H).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.O.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:17]3[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: C1CCNCC1
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Powdered potassium hydroxide (144.4 g) was added carefully to a mechanically stirred mixture of 6-fluoroindole (49.23 g, 0.364 mol) and piperidine monohydrate (111.93 g, 0.728 mol) in methanol (1500 ml) The mixture was then heated under reflux under nitrogen for 18 h and then more potassium hydroxide (40 g) was added and the reaction mixture heated under reflux for a further 4 h. The reaction mixture was allowed to cool to room temperature and poured onto ice-water (3000 ml) and stirred for 1 h and the precipitated solid isolated by filtration and dried at 50C in vacuo to give a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1([C:11](=[O:14])[CH2:12]Br)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:15][O:16][P:17]([O:20]C)[O:18][CH3:19]>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]([C:8]1([C:11](=[O:14])[CH2:12][P:17]([O:18][CH3:19])([O:16][CH3:15])=[O:20])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C1(C(=O)CBr)CC1
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C1(C(=O)CP(=O)(OC)OC)CC1
Yield: 59 %

Procedure:
A solution of 16 3.42 g (13.0 mmol) and trimethylphosphite (1.95 mL, 2.05 g, 16.5 mmol) in toluene (45 mL) was refluxed for 15 hours. The solvent and remaining trimethyl phosphite were then distilled off, and the residue was purified by column chromatography (2-10% isopropanol/hexane) to give 2.26 g (7.74 mmol; 59% yield) of 17. 1H NMR (500 MHz, CDCl3) δ 0.95 (3H, t, J=7.3 Hz), 1.39 (2H, m), 1.57-1.67 (6H, m), 3.75 (2H, d, JH-P=22.1 Hz), 3.78 (6H, d, JH-P=11.1 Hz), 4.15 (2H, t, J=6.7 Hz). 13C NMR (125 MHz, CDCl3) δ 13.7, 19.2, 20.6, 30.5, 35.3, 39.8, 40.8, 52.9 (d, JC-P=6.0 Hz), 170.8, 197.0 (d, JC-P=6.3 Hz). MS (EI) m/z 292 (15, M+), 264 (17), 236 (21), 218 ((45), 191 (18), 163 (22), 150 (59), 126 (100); exact mass (ESI) calculated for C12H21O6PNa ([M+Na]+) 315.0973, found 315.0963.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[S:13]([N:11]1[CH2:10][CH2:9][N:8]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=2)[C@@H:7]([CH2:6][N:37]2[CH2:38][CH2:39][NH:34][C:35](=[O:40])[CH2:36]2)[CH2:12]1)(=[O:14])=[O:15]
Reactant: O=C1CNCCN1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCNC(=O)C2)cc1)C(F)(F)F
Temperature: 130 °C
Yield: 44.7 %

Procedure:
((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (100 mg, 0.189 mmol, Intermediate B) was combined with piperazin-2-one (18.9 mg, 0.189 mmol, Alfa-Aesar) and potassium carbonate (78 mg, 0.57 mmol, Sigma-Aldrich, St. Louis, Mo.) in acetonitrile (1.89 mL) and heated at 130° C. for 30 min. After the reaction was allowed to cool to room temperature, the mixture was diluted with EtOAc and the solids were removed by filtering through a 0.2 μm millipore Millex-FG filter (Millipore, Billerica, Mass.). After concentration of the filtrate, the crude residue was purified by silica gel chromatography (0 to 7% MeOH in CH2Cl2) followed by purification via reverse-phase HPLC (Phenomenex Gemini-NX 10μ, 110 Å, AXIA packed column, 100×50 mm, 60 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10 min gradient). The collected fractions were partitioned between CH2Cl2 and saturated aqueous NaHCO3 and then the organic extracts were dried (Na2SO4), filtered and concentrated. The residue was taken up in MeOH and was passed through an AccuBond SPE SCX cartridge eluting with 2M ammonia in MeOH to give the title compound (45 mg) as a mixture of two isomers.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]([OH:31])[CH2:19][C:20]([N:22]2[CH2:29][CH2:28][C:25]3([CH2:27][CH2:26]3)[C@H:24]([OH:30])[CH2:23]2)=[O:21])[C:13](=[O:32])[C@@H:12]1[CH3:33])=O)C1C=CC=CC=1.Cl>>[OH:31][C@@H:18]([CH2:19][C:20]([N:22]1[CH2:29][CH2:28][C:25]2([CH2:26][CH2:27]2)[C@H:24]([OH:30])[CH2:23]1)=[O:21])[CH2:17][N:14]1[CH2:15][CH2:16][NH:11][C@@H:12]([CH3:33])[C:13]1=[O:32]
Reactant: C[C@H]1C(=O)N(C[C@@H](O)CC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)OCc1ccccc1
Agent: Cl
Product: C[C@@H]1NCCN(C[C@@H](O)CC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Yield: 64 %

Procedure:
In analogy to intermediate 12E, (S)-4-[(S)-2-hydroxy-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester was hydrogenated without aqueous HCl to give the titled compound in 64% yield as off-white waxy solid. MS: 326.21 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:36][C:37]1[CH:49]=[CH:48][C:40]([C:41]([NH:43][CH:44]2[CH2:47][O:46][CH2:45]2)=[O:42])=[CH:39][C:38]=1[O:50][CH3:51].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C(Cl)Cl.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].CO>[F:34][C:32]1([F:35])[CH2:33][CH:30]([O:29][C:4]2[C:5]3[C:10]([C:11]4[CH:20]=[CH:19][C:14]([C:15](=[O:16])[NH:17][CH3:18])=[CH:13][CH:12]=4)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=3[N:7]=[C:2]([NH:36][C:37]3[CH:49]=[CH:48][C:40]([C:41]([NH:43][CH:44]4[CH2:45][O:46][CH2:47]4)=[O:42])=[CH:39][C:38]=3[O:50][CH3:51])[N:3]=2)[CH2:31]1
Reactant: COc1cc(C(=O)NC2COC2)ccc1N
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CC(F)(F)C4)c23)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Nc4ccc(C(=O)NC5COC5)cc4OC)nc(OC4CC(F)(F)C4)c23)cc1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
A mixture of 4-(2-chloro-4-(3,3-difluorocyclobutoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide (1 equiv), 4-amino-3-methoxy-N-(oxetan-3-yl)benzamide (1 equiv), and cesium carbonate (3 equiv) in 1,4-dioxane (0.1 M) was degassed with N2 for 10 min. Then (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.2 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv), were added to this mixture. The mixture was stirred at 140° C. for 1.5 h. After cooling to room temperature, the reaction mixture was purified using silica gel chromatography (0-100% ethyl acetate in hexane then 0-20% MeOH in DCM) to afford the title compound (78.3% yield). MS (ESI) m/z 709.4 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:22](I)[CH3:23]>CN(C)C=O.C(OCC)C.O>[CH2:22]([O:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1)[CH3:23]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCOc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-hydroxy-3-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (10 g, 38 mmol) in dimethylformamide (70 mL) was added sodium hydride (60% dispersion in oil, 1.5 g) and the resulting mixture stirred for 0.5 h. Ethyl iodide (3.6 mL, 45 mmol) was added and the mixture stirred for 12 h at 70° C. The mixture was cooled to room temperature and diluted with diethyl ether (200 mL) and water (200 mL), the layers were separated and the aqueous portion extracted with diethyl ether (200 mL). The combined organic extracts were washed with brine (200 mL) and sodium hydroxide solution (2N, 200 mL) and then evaporated to give a yellow oil.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[CH2:12]([O:19][CH:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([O:19][CH:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCCCCCC(CCCCCO)OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCCCCC(CCCCC=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
PCC (9.7 g, 45 mmol) was added in portions to a solution containing 6-benzyloxy-1-tetradecanol (7.5 g, 30 mmol) in methylene chloride (100 ml) at RT. The black mixture was stirred for 2 hours, then filtered through a bed of silica gel using hexane:ethyl acetate (90:10). The corresponding aldehyde, 6-benzyloxy-tetradecanal, was produced at a yield of 6.1 g (81%). This aldehyde compound was mixed with carbethoxymethylene triphenylphosphorane (10 g, 29 mmol) in 100 ml of methylene chloride at RT. The mixture was allowed to stir overnight, after which the solvent was removed and replaced with hexane. Solid precipitates were removed by filtration. Following chromatography on silica gel using hexane:ethyl acetate at a ratio of 90:10, the corresponding ester was detected at 8.4 g scale (90%). The chemical shift of the ester, 8-benzyloxyhexadec-2-enoate ethyl ester, is as follows: 1H-NMR (CDCl3) δ 0.89 (m, 6H, CH3), 1.2-1.5 (m, 20H, CH2), 2.2 (m, 2H, CH2—C═), 3.35 (m, 2H, CH2O), 4.2 (q, 2H, MeCH2—O), 4.55 (dd, 2H, CH2—O), 5.8 (d, 1H, CH═C), 6.95 (d,t 1H, CH═C), 7.35 (m, 5H, benzyl).
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][S:9][CH2:8]1.CN(P(N(C)C)(N(C)C)=O)C.[CH3:23][N:24]1[N:28]=[N:27][C:26]([C:29]2[CH:39]=[C:38]([CH3:40])[C:32]([O:33][CH2:34][CH2:35][CH2:36]Br)=[C:31]([CH3:41])[CH:30]=2)=[N:25]1.[Cl-].[NH4+]>C1COCC1>[CH3:6][N:7]1[CH:11]=[C:10]([CH2:36][CH2:35][CH2:34][O:33][C:32]2[C:31]([CH3:41])=[CH:30][C:29]([C:26]3[N:27]=[N:28][N:24]([CH3:23])[N:25]=3)=[CH:39][C:38]=2[CH3:40])[S:9][CH2:8]1
Reactant: CN1C=CSC1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC1=CN(C)CS1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 27.7 %

Procedure:
n-BuLi (2.5M, 1.33 ml, 3.33 mmol) was added slowly at -78° C. to a solution of 3-methyl-thiazole (300 mg, 3.03 mmol) in 8 ml of THF under nitrogen. After stirring at -78° C. for 15 min, HMPA (1.08 g, 6.06 mmol) was added and the resulting mixture was stirred for 10 min. To the above mixture was added at -78° C. 3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propylbromide (985 mg, 3.03 mmol) in 5 ml of THF. The mixture was allowed to warm to 20° C. and stirred for 3 h. Saturated ammonium chloride solution was added and the aqueous layer was extracted with ether (3×), and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (15 cm column, ethyl acetate/hexane, 1/8-3/1) to afford 290 mg (28%) of 3-methyl-5-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]thiazole.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].NC1C(OC)=C(NS(C)(=O)=O)C=C(C(C)(C)C)C=1.[N:31]([C:34]1[CH:35]=[C:36]([CH:57]=[CH:58][C:59]=1C)[C:37]([NH:39][C:40]1[CH:45]=[C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:43]=[C:42]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[C:41]=1[O:55][CH3:56])=[O:38])=[N+:32]=[N-:33].NC1C=C(C=CC=1)C(O)=O.N(C1C=C(C=CC=1C)C(O)=O)=[N+]=[N-]>>[N:31]([C:34]1[CH:35]=[C:36]([CH:57]=[CH:58][CH:59]=1)[C:37]([NH:39][C:40]1[CH:45]=[C:44]([C:46]([CH3:47])([CH3:48])[CH3:49])[CH:43]=[C:42]([NH:50][S:51]([CH3:54])(=[O:52])=[O:53])[C:41]=1[O:55][CH3:56])=[O:38])=[N+:32]=[N-:33].[N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3]
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Agent: Nc1cccc(C(=O)O)c1
Product: COc1c(NC(=O)c2cccc(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
3-Azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-benzamide was prepared from 3-azido benzoic acid and N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in the same manner as 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide (Example 15). 3-Azido benzoic acid was prepared from 3-amino benzoic acid in the same manner as 3-azido-4-methyl benzoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][O:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:16]23)[CH:21]=1.[OH-].[NH4+]>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH:12][C:13]2[CH:14]=[C:15]3[C:19]4=[C:20]([CH2:22][O:23][CH2:24][CH2:25][N:18]4[C@H:17]4[CH2:26][CH2:27][NH:28][CH2:29][C@@H:16]34)[CH:21]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: Brc1cnc2ccccc2c1
Agent: [NH4+]
Agent: [OH-]
Product: c1ccc2ncc(Nc3cc4c5c(c3)[C@@H]3CNCC[C@@H]3N5CCOC4)cc2c1

Procedure:
Using 3-bromoquinoline and following the procedures described in EXAMPLE 56, Part C, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into (7bR,11aS)-N-(3-quinolinyl)-1,2,7b,8,9,10,11,11a-octahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indol-6-amine, bis-trifluoroacetic acid salt. This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to afford the title compound of EXAMPLE 114. 1H NMR(CDCl3) δ: 8.60 (d, 1H, J=2.9 Hz), 7.95 (d, 1H, J=1.9 Hz), 7.60-7.55 (m, 1H), 7.50-7.38 (m, 3H), 6.88 (d, 1H, J=1.9 Hz), 6.81 (s, 1H), 5.99 (s, 1H), 5.85 (broad s, 1H), 4.61 (ABq, 2H, JAB=14.7 Hz), 4.23 (app d, 1H, J=12.4 Hz), 3.74 (app t, 1H), 3.43 (broad s, 1H), 3.30-3.00 (m, 4H), 2.75 (app t, 1H), 2.65-2.55 (m, 1H), 2.20-1.90 (m 3H). LRMS (ES)+: 373.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:31]C)[N:6]2[CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:23][CH:22]=1.Cl.[CH3:34]O>O1CCOCC1>[CH3:34][O:30][C:28](=[O:29])[CH2:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][CH2:18][CH2:17][CH2:16][N:6]2[C:5](=[O:31])[NH:4][C:3]3[C:7]2=[N:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][C:2]=3[NH2:1])=[CH:26][CH:25]=1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCNCc3ccc(CC(=O)O)cc3)c2n1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3ccc(CC(=O)OC)cc3)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product from step (viii) (13 g) was dissolved in methanol (100 ml) and 4N—HCl in dioxane (10 ml) added. The reaction mixture was stirred at rt for 24 h. The resultant was concentrated under reduced pressure and aqueous NaHCO3 added to pH 8. The suspension was filtered and the solid collected and dried under reduced pressure to give the subtitle compound. Yield 11 g.