Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[C:16]([Si:20]([CH3:45])([CH3:44])[O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1/[CH:32]=[C:33](/[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=1[F:43])\[C:34]#[N:35])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:32]([C:26]2[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=2[O:24][CH2:23][CH2:22][O:21][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:45])[CH3:44])[C:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=2[F:43])([C:34]#[N:35])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1/C=C(\C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(Cl)ccc2OCCO[Si](C)(C)C(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Yield: 18.4 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl}-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (3.7 g, 8 mmol) prepared in Example 84a, AgF (1.0 g, 8 mmol), and triethylamine (2.8 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl}-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.0 g, 18%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](OC)=[O:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[OH-].[NH4+:30]>C1COCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:25])[NH2:30])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(C#N)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cccc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Yield: 49 %

Procedure:
A solution of the 9-[(3-cyanophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (114 mg, 0.32 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 7 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 40 mg (49%) of the 9-[(3-cyanophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.7 (d, 1H, J=8 Hz), 7.6 (s, 1H), 7.5-7.4 (m, 3H), 7.3 (t, 1H, J=8 Hz), 7.25 (d, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), and 5.75 (s, 2H). IR (KBr, cm−1) 3430, 3347, 2231, 1628, and 1601. MS (ES) m/e 340, 342.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:8]1([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH2:1][Br:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(-c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(-c2ccccc2)c1

Procedure:
A mixture of 3-methylbiphenyl (5.23 g, 31.1 mmol), N-bromosuccinimide (5.56 g, 31.2 mmol), benzoyl peroxide (135 mg, 0.56 mmol), and carbon tetrachloride (150 ml) is refluxed for 17 h. The mixture is concentrated in vacuo and the residue is purified by flash column chromatography (hexane) to give 3-phenylbenzyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:21][N:22]2C(=O)C3C(=CC=CC=3)C2=O)=[N:14][C:15]=1[O:16][CH2:17][CH:18]([CH3:20])[CH3:19].O.NN>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:21][NH2:22])=[N:14][C:15]=1[O:16][CH2:17][CH:18]([CH3:19])[CH3:20]
Reactant: COc1ccc(F)c(-c2ccc(CN3C(=O)c4ccccc4C3=O)nc2OCC(C)C)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(F)c(-c2ccc(CN)nc2OCC(C)C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.2 %

Procedure:
To a solution of 2-((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methyl)-1H-isoindole-1,3(2H)-dione (228 mg) in ethanol (3.0 ml) was added hydrazine monohydrate (3.0 mL), and the mixture was stirred at room temperature for 20 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (152 mg) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]#[N:33]>>[Cl:25][C:26]1[CH:27]=[C:28]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)[CH:29]=[CH:30][C:31]=1[C:32]#[N:33]
Reactant: N#Cc1ccc(B(O)O)cc1Cl
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: N#Cc1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1Cl
Yield: 43.2 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 3-chloro-4-cyanophenylboronic acid (available from Combi-Blocks Inc.; 73 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 3′-chloro-4′-cyano-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (42 mg, 43%). 1H NMR (400 MHz, DMSO-d6) δ 13.40 (br s, 1H) 8.44-8.55 (m, 2H), 8.34 (d, J=1.8 Hz, 1H), 8.28 (dd, J=8.0, 2.0 Hz, 1H), 8.07-8.13 (m, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.81 (d, J=1.3 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.56 (dd, J=8.0, 1.5 Hz, 1H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH2:6]2)=O.[C:10]([CH2:12]C(O)=O)#[N:11].[OH-].[NH4+].CN(C)C=O>C1C=CC=CC=1>[C:10]([CH2:12][CH:1]=[C:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH2:6]2)#[N:11]
Reactant: O=CC1CC2CCC1C2
Reactant: N#CCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: N#CCC=C1CC2CCC1C2
Yield: 78.7 %

Procedure:
A stirred solution of 95 g (0.77 mol) of 2-formylbicyclo[2.2.1]heptane, 65 g (0.76 mol) of cyanoacetic acid, 2 ml of ammonium hydroxide (58%), 132 ml of dimethylformamide, and 170 ml benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the evaluation of carbon dioxide ceased (approx. 24 hrs.). Upon completion, the reaction was cooled and the solvent removed under reduced pressure. The residual oil was distilled under vacuum to give 88 g (79% yield) of 2-(2-cyanoethylidene)-bicyclo[2.2.1]heptane: b.p. 72-80° C/1 mm; ir 2960, 2870, 2260, 1685, 1450, 1420, 1305, 920; nmr 1.15-2.8 (10H, m), 2.96 (2H, m) 4.9-5.4 (1H, m); ms 147.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[OH:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][NH:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: CC(C)(CO)CNS(=O)(=O)c1ccc(N)cc1
Product: CC(C)(CO)CNS(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1

Procedure:
The title compound was prepared from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-(3-hydroxy-2,2-dimethyl-propyl)benzenesulfonamide according to Procedure J: mp>250° C.; 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.52 (d, J=6.7 Hz, 2H), 3.06 (bs, 2H), 4.43 (bs, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.32 (t, J=6.7 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.3 Hz, 1H), 8.07 (d, J=12.2 Hz, 1H), 9.26 (s, 1H), 10.91 (s, 1H), 11.16 (d, J=12.3 Hz, 1H); APCI-MS: m/z 457 (M−H)−. Anal. Calcd for C21H22N4O4S2: C, 55.01; H, 4.84; N, 12.22; S, 13.98. Found: C, 54.90; H, 4.86; N, 12.25; S, 13.94.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:10][O:11][C:12](=[O:16])[C@@H:13]([CH3:15])[NH2:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:10][O:11][C:12](=[O:16])[C@@H:13]([CH3:15])[NH:14][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C)N
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H](C)NCc1ccccc1
Temperature: 22 °C
Reaction time: 19 h

Procedure:
Benzaldehyde (19 mL, 19 g, 0.18 mol) was added to a solution of D-alanine methyl ester hydrochloride (25 g, 0.18 mol) in dry CH2Cl2 (300 mL). The solution was stirred at 22° C. for 19 h. The reaction mixture was cooled with an ice-water bath and solid sodium triacetoxyborohydride (46 g, 0.22 mol) was added in portions over ˜15 min. The cooling bath was removed and the milky white solution was stirred at 22° C. for 7 h. The solvent was removed by rotary evaporation under reduced pressure and the resulting slush was partitioned between EtOAc (˜100 mL) and 1 N HCl (˜400 mL). The aqueous layer was extracted with EtOAc (˜50 mL). The aqueous layer was adjusted to pH ˜10 with 1 N NaOH (˜50 mL) and the milky aqueous layer was extracted immediately with EtOAc (3×250 mL). The combined organic layers were washed with brine (˜250 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford N-benzyl-D-alanine methyl ester A51(28 g, 80%) as a colorless semi-solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10](#[N:16])[CH:11]([CH2:13][C:14]#[N:15])[OH:12]>C(O)C.N1CCCCC1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:13]([C:14]#[N:15])[CH:11]([OH:12])[C:10]#[N:16]
Reactant: O=Cc1ccccc1F
Reactant: N#CCC(O)C#N
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=Cc1ccccc1F)C(O)C#N

Procedure:
2-Fluorobenzaldehyde (15.8 ml) was dissolved in ethanol (100 ml) and to the stirred solution was added malonitrile (9.9 g). The solution was heated to reflux, the heating discontinued and piperidine (4 drops) was added. Once the vigorous reaction had diminished, the solution was heated for 15 minutes and then chilled. Crystals of product were filtered off and washed with ethanol, m.p. 122° C.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.CON(C)[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([CH3:23])[CH:17]=1>C1COCC1>[CH3:23][C:18]1[CH:17]=[C:16]([C:15]([C:11]2[N:7]([CH3:6])[N:8]=[N:9][CH:10]=2)=[O:24])[CH:21]=[C:20]([CH3:22])[N:19]=1
Reactant: CON(C)C(=O)c1cc(C)nc(C)c1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cnnn2C)cc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of n-BuLi (3.8 mL, 9.5 mmol, 2.5 M solution in hexane) was added slowly to a solution of 1-methyl-1H-1,2,3-triazole (0.83 g, 10 mmol) in THF (48 mL) at −50° C. After addition, stirring was continued for an additional 30 minutes and N-methoxy-N,2,6-trimethylisonicotinamide (0.97 g, 5.0 mmol, Intermediate 29: step a) dissolved in THF (12 mL) was slowly added. An additional 2 mL of THF was used to complete the quantitative addition. The mixture was stirred at −50° C. for 5 minutes then warmed to room temperature and stirred overnight. The solution was quenched with saturated aqueous NH4Cl. H2O was added and layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified using flash column chromatography (0 to 100% EtOAc/DCM) to provide the title compound.
Reaction SMILES: Cl.[Br:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[NH:6][CH:7]=1>CC(O)=O.Br>[Br:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)[NH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(Br)c[nH]2)cc1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: Oc1ccc(-c2nc(Br)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A suspension of 10 (2.6 g, 0.0091 mol) in AcOH (10 ml) and 48% HBr (40 ml) was heated at reflux for 10 hours. After stirring overnight at room temperature the solution was concentrated to dryness and the residue stirred overnight with saturated NaHCO3. The mixture was filtered to yield 1.36 g (65%) of 11.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=4)=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:26])[CH3:25].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[N:21][CH:22]=4)=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2ccc3oc(-c4ccc(Cl)cc4)nc3c2)cn1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2ccc3oc(-c4ccc(Cl)cc4)nc3c2)cn1
Temperature: 80 °C
Reaction time: 40 h
Yield: 41.2 %

Procedure:
To 5-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)pyridin-2-amine (96.5 mg, 0.30 mmol) in dry pyridine (3 mL) at room temperature was added acetyl chloride (26 μL, 0.36 mmol), and stirred at 80° C. for 40 h. After cooling, the mixture was poured into water to give a precipitate, which was filtered off. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 20:80 v/v to afford 45 mg (41%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)[CH:7]=1.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26](O)=[O:27]>>[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26]([NH:14][C:12]1[CH:11]=[N:10][N:9]([CH2:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=1)=[O:27]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: Nc1cnn(Cc2cc(Cl)ccc2OCc2ccccc2)c1
Product: O=C(Nc1cnn(Cc2cc(Cl)ccc2OCc2ccccc2)c1)c1c(F)cccc1Cl

Procedure:
The title compound was prepared in a similar fashion to the preparation of example 16, replacing 1-[(2,4-dichlorophenyl)methyl]-1H-pyrazol-4-amine with 1-({5-chloro-2-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-4-amine (for a preparation see intermediate 9) and replacing 2,6-dichlorobenzoic acid with 2-chloro-6-fluorobenzoic acid (Aldrich); LCMS (System 3): MH+=470, tRET=1.28 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[C:11]1[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH:12]=1.[N:19]([Sn:22]([CH3:25])([CH3:24])[CH3:23])=[N+:20]=[N-:21]>C1(C)C=CC=CC=1>[CH3:17][C:14]1([CH3:18])[CH2:15][CH2:16][C:11]([C:3]2[CH:4]=[C:5]([CH2:8][C:9]3[N:19]([Sn:22]([CH3:25])([CH3:24])[CH3:23])[N:20]=[N:21][N:10]=3)[CH:6]=[CH:7][C:2]=2[NH2:1])=[CH:12][CH2:13]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CC1(C)CC=C(c2cc(CC#N)ccc2N)CC1
Solvent: Cc1ccccc1
Product: CC1(C)CC=C(c2cc(Cc3nnnn3[Sn](C)(C)C)ccc2N)CC1
Temperature: 25 °C
Yield: 53 %

Procedure:
A mixture of [4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-acetonitrile (as prepared in the previous step, 417 mg, 1.73 mmol) and azidotrimethylstannane (428 mg, 2.08 mmol) in toluene (8 mL) was heated at reflux for 40 h. The reaction was allowed to cool to room temperature and then filtered. The precipitate was washed with 20 mL of toluene and dried under vacuum to afford 410 mg (53%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C16H21N5, 284.1 (M-SnMe3+2H), found 284.1.
Reaction SMILES: [CH2:1]([N:8](C)[CH:9]1[CH2:15][O:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]1)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[CH3:1][NH:8][CH:9]1[CH2:15][O:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]1
Reactant: CN(Cc1ccccc1)C1COCCN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CNC1COCCN(C(=O)OC(C)(C)C)C1
Reaction time: 22 h

Procedure:
A solution of tert-butyl 6-(benzyl(methyl)amino)-1,4-oxazepane-4-carboxylate (0.795 g (2.48 mmol) 107.2 in MeOH (20 mL) was treated with 5% Pd/C (0.26 g) and HCO2H (1 mL). The black suspension was stirred under a 60 PSI H2 atmosphere for 22 hr. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuo to remove volatiles. The residue was diluted with EtOAc and washed with sat′d NaHCO3, dried over MgSO4, filtered, and concentrated to yield 0.tert-butyl 6-(methylamino)-1,4-oxazepane-4-carboxylate (0.17 g) 107.3 as a clear viscous oil that was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.82-3.60 (m, 5H), 3.59-3.48 (m, 1H), 3.47-3.33 (m, 3H), 3.26 (dd, J=6.5, 14.6 Hz, 1H), 2.93-2.82 (m, 2H), 2.46 (s, 3H), 1.48 (s, 9H); LCMS (ESI) m/z: 231.10 [M+H]−.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH:5]1([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH:30]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[C:1]([C:2]1[CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:12]2=[C:11]([CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[C:19]3[CH:18]=[CH:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=3[N:13]2[CH:3]=1)#[N:4]
Reactant: C=CC#N
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)[nH]c2c1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C=C(C#N)Cc1ccccc1-3
Temperature: 100 °C

Procedure:
Acrylonitrile (2 mL of 1.52 M in 1,4-dioxane, 3.04 mmol) was added to methyl 3-cyclohexyl-2-(2-formylphenyl)-1H-indole-6-carboxylate (200 mg, 0.55 mmol) in a microwave vial. The vial was sealed and Triton® B (50□L, 0.11□mol) was added via syringe. The vial was heated in a microwave apparatus for 1 hr at 100° C. The solution was concentrated and the residue dissolved in methylene chloride. The solution was applied to a silica gel thick layer plate. The plated was eluted with hexanes-ethyl acetate (8:2). The product containing band was extracted with methylene chloride-methanol (3×). The combined extracts were concentrated and the residue recrystallized from methanol to afford the titled compound as a tan solid. MS m/z 397 (MH); 1H NMR (300 MHz, CHLOROFORM-D) □ ppm 1.16–2.25 (m, 10 H) 2.90–3.10 (m, 1 H) 3.20–3.34 (m, 1 H) 3.60–3.75 (m, 1 H) 3.95 (s, 3 H) 7.28–7.49 (m, 4 H) 7.76 (s, 1 H) 7.86–7.97 (m, 2 H) 8.13 (s, 1 H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13]=O>Cl>[CH2:13]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]([C:10]([OH:12])=[O:11])[NH:1]1
Reactant: C=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: O=C(O)C1Cc2ccccc2CN1
Reaction time: 16 h

Procedure:
A mixture of phenylalanine (40 g), formaldehyde (37% w/v in water, 91 ml) and concentrated hydrochloric acid (310 ml) was stirred and heated to reflux for 4 hours and then stored at ambient temperature for 16 hours. The precipitate was filtered off, washed with cold water and with acetone to give 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (11 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:26])[O:17][CH2:18][CH:19]1[CH2:22][N:21]([C:23](=[O:25])[CH3:24])[CH2:20]1)([O-])=O.C([O-])=O.[NH4+]>CO.C1COCC1.[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:26])[O:17][CH2:18][CH:19]1[CH2:22][N:21]([C:23](=[O:25])[CH3:24])[CH2:20]1
Reactant: CC(=O)N1CC(COC(=O)Nc2cc(-c3cccs3)ccc2[N+](=O)[O-])C1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N1CC(COC(=O)Nc2cc(-c3cccs3)ccc2N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.7 %

Procedure:
To a solution of (1-acetylazetidin-3-yl)methyl (2-nitro-5-(thiophen-2-yl)phenyl)carbamate (0.15 g, 0.40 mmol, 1 eq.) in MeOH/THF (5 mL/5 mL) was added Zinc powder (0.13 g, 2.00 mmol, 5 eq.) and ammonium formate (0.20 g, 3.20 mmol, 8 eq.). The reaction was stirred at room temperature for 3 h. The reaction was filtered through Celite and the solids washed with MeOH. The filtrate was concentrated under reduced pressure then diluted with water. The obtained solid was filtered and dried. The crude product was purified by column chromatography (silica gel, 5% MeOH/CH2Cl2) to obtain (1-acetylazetidin-3-yl)methyl (2-amino-5-(thiophen-2-yl)phenyl)carbamate (0.030 g, 22% yield). ESI+ MS: m/z 346 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 8.74 (bs, 1H), 7.50 (bs, 1H), 7.34 (d, J=5.0 Hz, 1H), 7.24-7.14 (m, 2H), 7.08-7.01 (m, 1H), 6.72 (d, J=8.0 Hz, 1H), 5.14 (bs, 2H), 4.30-4.10 (m, 3H), 3.95-3.80 (m, 2H), 3.68-3.55 (m, 1H), 2.95-2.85 (m 1H), 1.74 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)CC)C>C(#N)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: O=C(Cl)c1cc(I)ccc1Cl
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(I)ccc2Cl)n1
Temperature: 150 °C
Yield: 21.6 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 2-chloro-5-iodobenzoyl chloride (0.159 g, 0.528 mmol) and triethylamine (0.5 mL, 6.81 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.019 g (22% yield) of pure product: MS (ES) m/z 570 (M+1).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(O[C:25]([CH3:28])([CH3:27])[CH3:26])(=O)C.Cl(O)(=O)(=O)=O.[OH-].[Na+]>O.C(OCC)(=O)C>[C:1]([NH:11][C@H:12]([C:18]([O:20][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](CCCCN)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 25 g of Nα-CBZ-L-lysine from Sigma, where CBZ is benzyloxycarbonyl, 250 mL of t-butyl acetate and 14 mL of 70% perchloric acid was vigorously mixed until all solids were dissolved. After stirring overnight, 375 mL of ethyl acetate was added followed by 250 mL of water. The pH of the aqueous layer was raised to 5.5 with 20% NaOH whereupon the organic phase was separated. The aqueous phase was extracted with the ethyl acetate solution and the pH again raised to 10.5 whereupon it was again extracted with 200 mL of fresh ethyl acetate. The organic extracts were combined, washed with saturated brine, dried over Na2SO4 and concentrated. The residue was dried overnight under high vacuum to yield 23.2 g of a colorless, viscous material.