Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH2:12][N:11]([C:13]2[S:14][CH2:15][C:16](=[O:18])[N:17]=2)[CH2:10]1)=[O:8].[F:20][C:21]([F:45])([F:44])[C:22]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:23]=1[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([CH:34]=O)=[CH:31][CH:32]=2)[CH:27]=[N:26]1>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH2:10][N:11]([C:13]2[S:14][C:15](=[CH:34][C:30]3[CH:29]=[C:28]4[C:33](=[CH:32][CH:31]=3)[N:25]([CH2:24][C:23]3[CH:36]=[CH:37][C:38]([C:40]([F:43])([F:42])[F:41])=[CH:39][C:22]=3[C:21]([F:45])([F:20])[F:44])[N:26]=[CH:27]4)[C:16](=[O:18])[N:17]=2)[CH2:12]1)=[O:8]
Reactant: COC(=O)CCNC(=O)C1CN(C2=NC(=O)CS2)C1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Product: COC(=O)CCNC(=O)C1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1

Procedure:
3-[(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carbonyl)-amino]-propionic acid methyl ester was prepared from 3-{[1-(4-oxo-4,5-dihydro-thiazol-2-yl)-azetidine-3-carbonyl]-amino}-propionic acid methyl ester and 1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde following General Procedure D.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][C:10](=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13].Cl[CH2:18][C:19](=[O:22])[CH2:20][CH3:21].Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[CH3:7][O:8][CH2:9][C:10](=[O:16])[CH:11]([CH2:18][C:19](=[O:22])[CH2:20][CH3:21])[C:12]([O:14][CH3:15])=[O:13]
Reactant: CCC(=O)CCl
Reactant: COCC(=O)CC(=O)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CCC(=O)CC(C(=O)COC)C(=O)OC
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
67.99 g (492 mmol) of potassium carbonate and 1.87 g (8.2 mmol) of benzyltriethylammonium chloride are suspended in 500 ml of acetonitrile. 59.86 g (410 mmol) of methyl 4-methoxyacetoacetate are added thereto while stirring. 65.50 g (615 mmol) of 1-chloro-2-butanone are added dropwise thereto within 30 minutes and the mixture is stirred at 20°-25° C. for 23 hours. The reaction mixture is poured into 1 l of 1N HCl (pH value=1) and extracted 3 times with 700 ml of ethyl acetate each time. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The crude product distils at 115° C./0.05 mbar. There results 49.01 g (55.3%) of methyl 4-methoxy-2-(2-oxobutyl)-acetoacetate.
Reaction SMILES: [CH:1]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)SC1C=CC=CC=1.[Sn](Cl)(Cl)(Cl)Cl.[C:28]1([O:38][Si](C)(C)C)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH:29]=1>ClCCl>[C:17]1([S:16][CH:1]([S:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:29]2[CH2:30][CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]2=[O:38])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)OC1=CCCc2ccccc21
Reactant: c1ccc(SC(Sc2ccccc2)Sc2ccccc2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C1c2ccccc2CCC1C(Sc1ccccc1)Sc1ccccc1
Temperature: -70 °C
Reaction time: 0.67 h
Yield: 64.7 %

Procedure:
Under argon, 6.22 g (23.8 mmol) of triphenyl trithioorthoformate (1,1′,1″-(methanetriyltrisulphanediyl)dibenzene) are dissolved in anhydrous dichloromethane and cooled to −70° C. 23.8 ml (23.8 mmol) of tin(IV) tetrachloride solution (1 M in dichloromethane) and 5.73 g (26.3 mmol) of (3,4-dihydronaphthalen-1-yloxy)trimethylsilane are added in succession, and the mixture is stirred at −70° C. for 40 min. The reaction mixture is poured into ice-water and extracted with dichloromethane. After washing with water, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate) gives 5.80 g of 2-[bis(phenylsulphanyl)methyl]-3,4-dihydronaphthalen-1(2H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[CH:7][NH2:8])=[CH:4][C:3]=1[CH3:11].CO.S([CH2:24][N+:25]#[C-:26])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[N:25]([CH3:26])[CH:24]=[N:8][CH:7]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cc(C=CN)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: Cc1cc(-c2cncn2C)ccc1Br
Yield: 59.9 %

Procedure:
(4-Bromo-3-methylbenzylidene)methylamine (D91, 2.15 g, 10.1 mmol) was dissolved in dry DME (30 ml) and methanol (70 ml) containing tosylmethylisocyanide (3.0 g; 15.4 mmol) and this solution was treated with potassium carbonate (2.8 g, 20.3 mmol). The whole was heated at reflux for 48 hours, cooled and evaporated in vacuo. The residue was partitioned between brine and chloroform (3 times), and the organics combined and dried over Na2SO4. The organics were filtered and evaporated in vacuo then the residue purified by flash silica gel chromatography (with chloroform as eluant) to yield the title compound as an orange gum (1.52 g, 60%).
Reaction SMILES: [C:1]([C:4]1[S:24][C:7]2[CH2:8][CH2:9][CH:10]3[C:15]([C:6]=2[CH:5]=1)=[N:14][N:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:12](=[O:23])[CH2:11]3)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[S:24][C:7]2[CH2:8][CH2:9][CH:10]3[C:15]([C:6]=2[CH:5]=1)=[N:14][N:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1)[C:12](=[O:23])[CH2:11]3)[CH3:2]
Reactant: CC(=O)c1cc2c(s1)CCC1CC(=O)N(c3ccc(C)cc3)N=C21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(N2N=C3c4cc(C(C)O)sc4CCC3CC2=O)cc1
Reaction time: 3 h
Yield: 43.6 %

Procedure:
To a suspension of 1.3 g of 8-acetyl-4,4a, 5,6-tetrahydro-2-(4-methylphenyl)thieno-[2,3-h]cinnolin-3(2H)-one in methanol was added 300 mg of sodium borohydride under ice-cooling and the mixture was stirred for 3 hours. The mixture was concentrated in vacuo until about a half volume of the methanol was evaporated and water was added, and then extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel (SiO2 :30 g) column using a mixed solvent of chloroform and methanol (98:2) as an eluent. The resulting solid was recrystallized from a mixed solvent of ethyl acetate and hexane to give 570 mg of 8-(1-hydroxyethyl)-4,4a,5,6-tetrahydro-2-(4-methylphenyl)thieno-[2,3-h]cinnolin-3(2H)-one as a pale yellow powder, melting at 129°-145° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[CH3:21][N:18]1[CH2:17][CH2:16][N:15]([C@H:12]2[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]2)[CH2:20][CH2:19]1
Reactant: CN1CCN([C@H]2CC[C@@H](N(Cc3ccccc3)Cc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN([C@H]2CC[C@H](N)CC2)CC1

Procedure:
4.1 g (11 mmol) cis-dibenzyl-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-amine are placed in 80 ml of methanol, 0.8 g palladium/charcoal (10%) are added and then the mixture is hydrogenated at 50 psi and 20° C. The reaction mixture is suction filtered through kieselguhr, the mother liquor is concentrated by evaporation. Yield: 1.90 g. The trans-isomer may be prepared analogously.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[CH2:11]([OH:14])[CH2:12][SH:13]>C(#N)C>[OH:14][CH2:11][CH2:12][S:13][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: Brc1ccc2cnccn12
Reactant: OCCS
Solvent: CC#N
Product: OCCSc1ccc2cnccn12
Temperature: 25 °C

Procedure:
2.5 g of 6-bromopyrrolo[1,2-a]pyrazine prepared in Preparation Example 7 was dissolved in 30 ml of acetonitrile; and 1 ml of 2-thioethanol was added thereto. The reaction mixture was refluxed for 12 hours, cooled to room temperature, poured into ice-water and then extracted with ethyl acetate (50 ml×3). The organic layer was concentrated to dryness under a reduced pressure. The residue was chromatographed over silica gel to obtain 1 g of title compound.
Reaction SMILES: [CH3:1][C:2]([CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7][CH2:6]1)([CH3:4])[CH3:3].C[O-].[Na+]>CO>[CH3:4][C:2]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH:11]=[O:12])[CH2:9][CH2:10]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)C1CCC(C=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[C@H]1CC[C@H](C=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the 4-(1,1-dimethylethyl)cyclohexanecarboxaldehyde (862 mg, 5.12 mmol) as obtained above in CH3OH (44 mL) at room temperature was added dropwise sodium methoxide (1.44 mL of 25% by weight, ~4.73M, 6.29 mmol). After stirring for 3 hrs at room temperature, the reaction was quenched by addition of glacial HOAc-ether (1:3) dropwise until the pH was 6-7 followed by addition of a few drops of sat. NaHCO3. The CH3OH was removed under reduced pressure and the residue was partitioned between EtOAc (200 mL deoxygenated by passage of argon) and brine (40 mL). The aqueous layer was extracted with EtOAc (50 mL) and the combined organic extracts were dried (Na2SO4) and concentrated to give crude product (1.6 g). Purification by flash chromatography, eluting with 25% EtOAc/hexane gave trans-4-(1,1-dimethylethyl)cyclohexanecarboxaldehyde (690 mg, 4.1 mmol) in 80% yield.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[O:12][C:11]([NH2:13])=[N:10][N:9]=1.[Cl:14][C:15]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:16]=1[C:17]([N:19]=[C:20]=[O:21])=[O:18]>C(#N)C>[NH2:13][C:11]1[O:12][C:8]([C:4]2[S:5][CH:6]=[CH:7][C:3]=2[NH:2][C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:15]=2[Cl:14])=[O:21])=[N:9][N:10]=1
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: Nc1nnc(-c2sccc2N)o1
Agent: Cl
Solvent: CC#N
Product: Nc1nnc(-c2sccc2NC(=O)NC(=O)c2cc(F)c(F)cc2Cl)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(3-Aminothiophen-2-yl)[1,3,4]oxadiazol-2-ylamine hydrochloride (30 mg) is initially charged in 3 ml of acetonitrile. The equimolar solution of 2-chloro-4,5-difluorobenzoyl isocyanate in acetonitrile is added and stirred at RT. After 3 hours, the solid is filtered off with suction and dried under reduced pressure.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:20]([F:23])([F:22])[F:21])[CH:11]=[C:12](C(OCC)=O)[CH:13]=2)[C:8]([OH:34])([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[C:7]1=[O:35])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C([O-])(O)=O.[Na+].[C:53](OCC)(=[O:55])[CH3:54]>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:20]([F:21])([F:23])[F:22])[CH:11]=[C:12]([CH2:54][CH2:53][OH:55])[CH:13]=2)[C:8]([OH:34])([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[C:7]1=[O:35])[CH3:2]
Reactant: CCOC(=O)c1cc2c(c(C(F)(F)F)c1)C(O)(c1ccc3ccccc3c1)C(=O)N2CCN(CC)CC
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])O
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(CCO)cc2C(F)(F)F
Temperature: 25 °C
Yield: 9 %

Procedure:
To a solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-ethoxycarbonyl-3-hydroxy-3-(2-naphthyl)oxindole (605 mg, 0. 118 mmol) in toluene (1 mL) was added dropwise 1.01 N diisobutylaluminium hydride in toluene (0.36 mL, 0.364 mmol). The mixture was allowed to warm to room temperature over 4 h. Sat. aqueous NaHCO3 and ethyl acetate were added. Insoluble materials were removed by filtration and the organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography with 30:1 to 15:1 chloroform/methanol to give the title compound (5 mg, 9%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([CH2:40][CH2:41][NH2:42])[CH:37]=[CH:38][CH:39]=1>>[Cl:33][C:34]1[CH:35]=[C:36]([CH2:40][CH2:41][NH:42][C:28]2[N:27]=[C:26]([C:22]3[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=3)[CH2:19][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[S:15]([CH3:18])(=[O:16])=[O:17])[CH:31]=[CH:30][N:29]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)CC1
Product: CS(=O)(=O)N(Cc1cccc(-c2ccnc(NCCc3cccc(Cl)c3)n2)c1)C1CCNCC1

Procedure:
Intermediate 30 was coupled with 2-(3-chloro-phenyl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 500. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H), 8.1 (d, 1H) 7.7 (d, 1H) 7.5 (t, 1H), 7.3 (m, 2H), 7.25 (m, 3H), 7.20 (d, 1H), δ 4.6 (s, 2H), δ 3.3 (t, 2H), 3.09 (s, 3H), δ 3.04 (m, 7H), 2.0 (m, 4H).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:37])[C@@H:15]([O:34][CH2:35][CH3:36])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][C:19]=1[CH2:32][CH3:33])[OH:17])C1C=CC=CC=1.[CH3:38][O-:39].[Na+]>CO>[CH3:38][O:39][C:14](=[O:37])[C@@H:15]([O:34][CH2:35][CH3:36])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:20][C:19]=1[CH2:32][CH3:33])[OH:17]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1CC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1CC

Procedure:
In analogy to the procedure described in example 1 b], (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one was treated with sodium methoxide in methanol to give (2S,3R)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester as colorless liquid. According to 1H-NMR spectroscopy, one single diastereomer was obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([C:32]1[CH:33]=[CH:34][C:35]2[C:36]([CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)=[C:37]3[C:43]4[CH:44]=[CH:45][C:46]([O:48][CH3:49])=[CH:47][C:42]=4[CH:41]=[C:40]([C:50]([OH:52])=O)[CH2:39][N:38]3[C:53]=2[CH:54]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.Cl.[CH3:63][N:64]1[CH2:70][CH:69]2[NH:71][CH:66]([CH2:67][CH2:68]2)[CH2:65]1>CN(C=O)C.O>[CH:55]1([C:36]2[C:35]3[CH:34]=[CH:33][C:32]([C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])=[CH:54][C:53]=3[N:38]3[CH2:39][C:40]([C:50]([N:71]4[CH:66]5[CH2:67][CH2:68][CH:69]4[CH2:70][N:64]([CH3:63])[CH2:65]5)=[O:52])=[CH:41][C:42]4[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=4[C:37]=23)[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]1
Reactant: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Reactant: CN1CC2CCC(C1)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)C=C(C(=O)N1C3CCC1CN(C)C3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
HATU (680 mg, 1.8 mmol) was added to a stirring solution of 10-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (670 mg, 1.37 mmol) and 3-methyl-3,8-diazabicyclo[3.2.1]octane di HCl salt (560 mg, 2.81 mmol) in DMF (6 mL) and TEA (1.2 mL, 8.2 mmol) and the reaction was stirred for 30 min (complete by LCMS). The reaction mixture was diluted with water (˜35 mL) (precipitate formed) and stirred ON. The precipitate was collected by filtration, flushed with water and dried under high vacuum at 55° C. to yield tert-butyl 13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (775 mg, 1.30 mmol, 95% yield) as a light yellow solid. The material was used without further purification. 1HNMR (300 MHz, CDCl3) δ ppm 1.14-3.95 (m, 24H), 1.59 (s, 9H), 3.86 (s, 3H), 4.21-5.26 (m, 2H), 6.82 (s, 1H), 6.88 (d, J=2.6 Hz, 1H), 7.01 (dd, J=8.8, 2.6 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.66 (dd, J=8.4, 1.1 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 8.02 (br s, 1H). LC-MS retention time: 3.72 min; m/z 596 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[K].[CH3:11][C@@H:12]([CH2:15][CH:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:17])[CH:13]=O.CO.O>C1COCC1.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC.C1(C)C=CC=CC=1>[CH3:11][CH:12]([CH2:15][C@H:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:17]=[CH:11][CH2:12][CH2:15][CH3:16])[CH3:13]
Reactant: CC(C[C@H](C)C=O)NC(=O)OC(C)(C)C
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Br-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCC=C[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 173.5 %

Procedure:
Potassium hexamethyldisilazane (10.8 mL of a 1.85M solution in THF, 20 mmol) was added over 15 minutes to a stirred mixture of n-butyl triphenyl-phosphonium bromide (7.99 g., 20 mmol) and THF (75 mL) at 0°. After addition was complete, the mixture was stirred at 0° for 30 minutes and then a solution of (S)-2-methyl-4-(tert. butoxycarbonylamino) pentanal (2.04 g, 9.48 mmol) in toluene (10 mL) was added over 15 minutes. The reaction mixture was stirred at 0° for 30 minutes, 20°-25° for 30 minutes and then at 40° for 18 hours. Methanol (1 mL) then H2O (5 mL) were added and solvents removed under reduced pressure at 40°. The residue was partitioned between ethyl acetate and a dilute solution of Rochelle's salt. The ethyl acetate extract was washed with brine, dried (Na2SO4), filtered and concentrated. Flash chromatography of the residue over silica gel and elution with 10% ethyl acetate 90% hexane gave 2.10 g of product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][CH2:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=O)=[CH:16][CH:15]=1)=[O:4].[Cl:25][C:26]1[CH:35]=[CH:34][C:29]([CH2:30][NH:31][CH2:32][CH3:33])=[CH:28][CH:27]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]([CH2:32][CH3:33])[C:20](=[O:22])[CH2:19][O:18][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][S:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:3]([O:2][CH3:1])=[O:4])=[CH:24][CH:23]=2)=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)O)cc1
Reactant: CCNCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCN(Cc1ccc(Cl)cc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
[4-(2-{[2-(Methoxycarbonyl)phenyl]thio}ethyl)phenoxy]acetic acid (0.200 g, 0.577 mmol) was dissolved in DMF (10 ml), N-(4-chlorobenzyl)-N-ethylamine (0.108 g, 0.635 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.204 g, 0.635 mmol) and N-ethyl-N,N-diisopropylamine (0.157 g, 1.212 mmol) were added. The solution was stirred overnight at room temperature. Water (100 ml) was added and the water phase was extracted with diethyl ether (3×20 ml). The organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×, 10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by flash chromatography (started with isocratic heptane/EtOAc 30/70 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the solvent was removed by evaporation to give 0.085 g of methyl 2-{[2-(4-{2-[(4-chlorobenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}benzoate (yield 29.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][C@@H:6]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[O:7][C@H:8]2[CH2:14][NH:15][CH:16]=[O:17].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O.C(O)(=O)C>[CH2:24]([N:21]1[CH2:20][CH2:19][CH:18]([C@@H:6]2[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:12]([CH3:13])[C:3]=3[O:2][CH3:1])[C@H:8]([CH2:14][NH:15][CH:16]=[O:17])[O:7]2)[CH2:23][CH2:22]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1c(C)ccc2c1C[C@@H](C1CCNCC1)O[C@H]2CNC=O
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(Cl)Cl
Product: COc1c(C)ccc2c1C[C@@H](C1CCN(Cc3ccccc3)CC1)O[C@H]2CNC=O
Yield: 112.6 %

Procedure:
Stir a suspension of N-((1R,3S)-5-methoxy-6-methyl-3-(4-piperidinyl)-1-isochromanylmethyl)formamide (0.5 g, 1.6 mmol), benzaldehyde (0.16 g, 1.5 mmol), acetic acid (0.9 g and dichloroethane (13 mL) for 5 min. Add sodium triacetoxyborohydride (0.5 g, 2.3 mmol) and stir at room temperature for 4 h. Cool the reaction in an ice bath and and water (18 mL), and then make the make the mixture basic by the addition of 50% aqueous NaOH. Extract the mixture with dichloromethane, filter the biphasic mixture through Celite, separate the phases and reextract the aqueous with dichloromethane. Combine the extracts, wash with H2O, dry over MSO4, filter and concentrate under vacuum to obtain 0.69 g of a brown oil. Purify the crude oil by preparative HPLC on a silica gel cartridge (35 g) and use 2% diethylamine(Et2NH)-EtOAc followed by 10% Et2NH-EtOAc. Combine like fractions and concentrate to obtain 0.34 g of the title compound
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][CH2:12][O:13][C:14]1[C:18](=O)[C:16](=[O:17])[C:15]=1[O:20]CC>C(O)C>[CH2:12]([O:13][C:14]1[C:15](=[O:20])[C:16](=[O:17])[C:18]=1[NH:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])[CH3:11]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: N#Cc1cccc(O)c1N
Solvent: CCO
Product: CCOc1c(Nc2c(O)cccc2C#N)c(=O)c1=O

Procedure:
A solution of 2-amino-3-hydroxybenzonitrile (1.00 g, 0.0075 mol) and diethyl squarate (1.10 ml, 0.0075 mol) in dry ethanol (20 ml) was heated at 85° C. for three days. During the course of the reaction, a tan precipitate forms. The solid is filtered through a Buchner funnel, washed with cold ethanol, adsorbed on silica gel, and flash chromatographed using hexane/ethyl acetate (2:1) as the eluant to give 3-ethoxy-4-(2-hydroxy-6-cyanophenyl)amino-3-cyclobutene-1,2-dione, 0.50 g (0.0019 mol, 26%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]([F:16])([F:15])[C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1>CS(C)=O.C(OCC)(=O)C>[N:1]([CH2:11][C:10]1[CH:9]=[CH:8][C:7]([C:6]([F:5])([F:15])[F:16])=[CH:14][CH:13]=1)=[N+:2]=[N-:3]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium azide (2.30 g, 35.4 mmol) was added to a solution of 4-(trifluoromethyl)benzyl bromide (4.26 g, 17.8 mmol) dissolved in dimethyl sulfoxide (15 mL) and stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure to afford the title compound. The crude product was used in the next step without further characterization.