Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[O:9]1[CH2:13][CH2:12][C@@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:11]2[CH2:12][CH2:13][O:9][CH2:10]2)[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(Br)cc[nH]1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1cc(Br)ccn1[C@H]1CCOC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
A mixture of 4-bromo-1H-pyridin-2-one (0.50 g), (R)-toluene-4-sulfonic acid tetrahydrofuran-3-yl ester (0.40 g), potassium carbonate (0.80 g), and dimethylsulfoxide (5 mL) was stirred at 80° C. overnight. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by HPLC on reversed phase (acetonitrile/water) to afford the title compound [besides, 4-bromo-2-[(S)-tetrahydro-furan-3-yloxy]-pyridine was isolated in 0.36 g (56% of theory)]. Yield: 0.11 g (16% of theory); LC (method 3): tR=2.18 min; Mass spectrum (ESI+): m/z=244/246 (Br) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9](NC1CCN(C2SC(C#N)=C(O)N=2)CC1)=[O:10].Cl.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:37]([CH2:39][O:40][CH3:41])[N:38]=2)[CH2:30][CH2:29]1>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:37]([CH2:39][O:40][CH3:41])[N:38]=2)[CH2:30][CH2:29]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3nc(O)c(C#N)s3)CC2)c(Cl)c1Cl
Reactant: CCOC(=O)c1sc(N2CCC(N)CC2)nc1COC
Agent: Cl
Product: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1COC

Procedure:
The title compound was prepared from 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3) and ethyl 2-(4-aminopiperidin-1-yl)-4-(methoxymethyl)-1,3-thiazole-5-carboxylate hydrochloride (Intermediate 36) in a manner analogous to Example 29.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].Cl.[CH3:31][O:32][C:33]([C@H:35]1[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[CH3:31][O:32][C:33]([C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=3)=[O:11])=[CH:21][C:22]=2[F:29])[CH2:37][CH2:36]1)=[O:34]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](NC(=O)c2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccccc3Cl)cc2F)CC1

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with trans-4-amino-cyclohexylcarboxylic acid methyl ester hydrochloride using BOP reagent in tetrahydrofuran to give the title compound as a light yellow foam, MS (ESI+): m/z=553.3 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O=S(Cl)Cl.[CH:14](O)([CH3:16])[CH3:15]>>[CH:14]([O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH2:1])([CH3:16])[CH3:15]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC(C)O
Solvent: O=S(Cl)Cl
Product: CC(C)C[C@H](N)C(=O)OC(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of L-Leucine (1 g, 1 eq.), SOCl2 (1.7 ml, 3 eq.) in isopropanol (15 ml) was stirred under microwave irradiation at 100° C. for 1 hour. Solvent was then evaporated, the residue filtered and Et2O was added to give L-Leucine isopropyl ester as a yellow oil in 71% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 0.88 (dd, J=6.41 Hz and J=2.14 Hz, 6H), 1.22 (t, J=6.03 Hz, 6H), 1.60-1.75 (m, 3 H), 3.82 (t, J=7.10 Hz, 1H), 4.97 (m, 1H), 8.61 (s, 2H).
Reaction SMILES: [CH:1]1([C:4]2(O)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][CH2:7][C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=3)[CH2:3][CH2:2]1.C(O)(=O)C.[BrH:24]>C(Cl)Cl>[Br:24][CH2:3][CH2:2][CH:1]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2
Reactant: OC1(C2CC2)c2ccccc2CCc2ccccc21
Reactant: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: BrCCC=C1c2ccccc2CCc2ccccc21
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
In a 100-mL round bottom flask, 5-cyclopropyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ol (0.130 g, 0.0006 mol) was added with 1 mL acetic acid. The solid was allowed to dissolve at which point the reaction mixture was chilled to 10° C. Then a solution of 33% hydrobromic acid (0.5 mL hydrobromic acid and 0.5 mL acetic acid; total 1 mL) was added to the flask. The reaction was allowed to stir for an additional 30 min. while reaction progress was monitored by HPLC. Then the reaction mixture was transferred to a separatory funnel and DCM (100 mL) added. The organic layer collected and washed with H2O (1×100 mL) and dried over Na2SO4 for 2 hrs. The resulting product was purified by flash column chromatography on silica gel using MeOH/DCM (Biotage 25M column). The product was confirmed by 1H NMR and LC/MS. (Yield ˜62%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1)#[N:10].C([O-])([O-])=O.[K+].[K+].CCOCC>CCO.C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C#N)cc2)cc1
Reactant: Nc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Solvent: ClCCl
Product: N#Cc1ccc(CCSc2cccc(N)c2)cc1
Yield: 48.8 %

Procedure:
3-Aminothiophenol (0.87 g; 7.0 mmol), 4-toluenesulfonic acid-2-(4-cyano-phenyl) ethyl ester (2.0 g; 6.6 mmol; from step (i) above) and K2CO3 (1 g) were stirred in a mixture of EtOH (10 mL) and CH2Cl2 for 4 hours. Addition of ether, washing with brine and 2M aqueous NaOH, drying (MgSO4), evaporation of the solvent and flash chromatography (SiO2; Et2O:hexane (1:1)) afforded 0.82 g (49%) of the sub-title compound.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[N:26]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:25]3[N:26]=[C:22]([CH3:21])[S:23][CH:24]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2csc(C)n2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.87 min.; [M+H]+: 423.22 g/mol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24][CH2:25][C:26](Cl)=[O:27].C(=O)(O)[O-].[K+]>C(#N)C.O>[Cl:24][CH2:25][C:26]([NH:12][C:11]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(CCl)Nc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
To 7.7 g (25 mmol) of 3,4-dibenzyloxyaniline in 50 ml of 1:1 acetonitrile/water at 0° C. was added chloroacetyl chloride (3.0 ml) while keeping the pH at 6.5 with saturated aqueous potassium bicarbonate. When the pH remained constant for 15 minutes, an additional 3 ml of chloroacetyl chloride was added in small portions while maintaining the pH at 6.5. When the pH remained constant for 15 minutes, the acetonitrile was evaporated, and the resulting aqueous solution was filtered. The precipitate was washed thoroughly with water to yield, upon drying in vacuo, 8.98 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH:23](B(O)O)[CH2:22][CH2:21][CH2:20]2)[C:12]1=[O:27].C([O-])(=O)C.[Na+].[OH-].[Na+]>COCCOC.O>[C:1]([C:3]1[CH:4]=[C:5]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][C:12](=[O:27])[C:13]23[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: O=C1Nc2ccccc2C12CCCC2B(O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(-c2ccc3c(c2)C2(CCCC2)C(=O)N3)ccc1F
Temperature: 25 °C
Yield: 10.5 %

Procedure:
A solution of 3-cyano-4-fluoro-bromobenzene (0.63 g, 3.1 mmol), and tetrakis(triphenylphosphine)paladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.0 g, 4.7 mmol) and sodium acetate (1.0 g, 9.4 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.10 g, 10%) as white crystals. mp: 264-266° C.; 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.3 (dd, 1H, J=2.4, 3.7 Hz), 8.1-8.0 (m, 1H), 7.6-7.5 (m, 2H), 7.5 (dd, 1H, J=1.9, 6.3 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS [M−H]−=305.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[NH:7][CH2:6][CH2:5]2.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)=[CH:25][N:24]=1.C(N(CC)CC)C.O>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:12])[F:13])[N:7]([C:30](=[O:31])[NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)=[N:24][CH:25]=1)[CH2:6][CH2:5]2
Reactant: O=C(Nc1ccc(OCc2ccccn2)nc1)Oc1ccccc1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCC2
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccc(OCc3ccccn3)nc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A mixture of indoline (D13, 0.30 g, 1.49 mmol), phenylcarbamate (D3, 0.48 g, 1.5 mmol) and triethylamine (0.20 ml, 1.5 mmol) in dry acetonitrile (10 mL) was warmed briefly to ensure complete solution of reactants, then stirred overnight at room temperature. The mixture was poured into water (50 ml) and the precipitate was filtered off, washed with water and dried. The crude product was chromatographed on silica gel (25 g) eluted with 4% methanol/dichloromethane. Eluted product was recrystallised from dichloromethane/methanol to give the title compound (0.35 g, 55%), m.p. 219-20° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21](I)[CH:20]=4)[CH2:14][CH2:13]3)[N:11]([CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[C:10](=[O:31])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]([Sn](CCCC)(CCCC)CCCC)[CH:33]=[CH2:34]>CN(C=O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:34]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][N:15]1[CH2:16][CH2:17][C:12]2([N:11]([CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[C:10](=[O:31])[N:9]=[C:8]2[NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:13][CH2:14]1)[CH:33]=[CH2:32]
Reactant: C=CCCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1cccc(I)c1)CC2
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1cccc(CC=C)c1)CC2
Temperature: 90 °C

Procedure:
To a solution of 4-(cyclohexylamino)-8-(3-iodobenzyl)-1-pent-4-en-1-yl-1,3,8-triazaspiro[4.5]dec-3-en-2-one (920 mg, 1.72 mmol, intermediate I.1.d.1) and trans-bis(triphenylphosphine)palladium(II) chloride (121 mg, 0.17 mmol) in degassed DMF (11.5 mL) was added allyl tri-n-butyltin (0.61 mL, 1.98 mmol) in one portion. The reaction mixture was stirred at 90° C., sealed, for 16 h, diluted with EtOAc, washed with aqueous LiCl twice, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (90 g silica gel, EtOAc) to give the desired product. LRMS (M+1)=449.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([CH:22]=1)[NH:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)=[O:7].[N:28]1([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[CH3:1][N:2]([CH3:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([CH:22]=1)[NH:14][C:15]1[CH:20]=[C:19]([NH:36][CH2:35][CH2:34][CH2:33][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[N:18]=[CH:17][N:16]=1)=[O:7]
Reactant: NCCCN1CCCC1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1Nc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1Nc1cc(NCCCN2CCCC2)ncn1

Procedure:
A mixture of 4-[5-(3-dimethylaminobenzamido)-2-methylanilino]-6-chloropyrimidine (0.114 g), 3-pyrrolidin-1-ylpropylamine (0.95 ml), N,N-di-isopropylethylamine (0.063 ml) and n-butanol (2 ml) was stirred and heated to reflux for 18 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 10:1 mixture of ethyl acetate and methanol as eluent. There was thus obtained the title compound (0.124 g); NMR Spectrum: (DMSOd6) 1.59 (m, 6H), 2.15 (s, 3H), 2.34 (m, 6H), 2.93 (s, 6H), 3.14 (m, 2H), 6.72 (m, 1H), 6.89 (m, 1H), 7.2 (m, 4H), 7.3 (m, 1H), 7.5 (m, 1H), 7.72 (m, 1H), 7.96 (m, 1H), 8.16 (s, 1H), 10.02 (s, 1H); Mass Spectrum: M+H+ 474.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7](O)=[O:8])=[O:4].OC(C(F)(F)F)=O.[I:20][C:21]1[CH:34]=[CH:33][C:24]2[NH:25][C:26]([C@@H:28]3[CH2:32][CH2:31][CH2:30][NH:29]3)=[N:27][C:23]=2[CH:22]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[I:20][C:21]1[CH:34]=[CH:33][C:24]2[NH:25][C:26]([C@@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:10]([CH3:12])[CH3:11])=[N:27][C:23]=2[CH:22]=1
Reactant: Ic1ccc2[nH]c([C@@H]3CCCN3)nc2c1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(I)ccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a mixture of (S)-2-methoxycarbonylamino-3-methyl-butyric acid (68 mg, 0.39 mmol) and (S)-5-iodo-2-(pyrrolidin-2-yl)-1H-benzo[d]imidazole-TFA salt (100 mg, 0.32 mmol) in anhydrous DMF (2 mL) is added DIPEA (0.25 mL, 1.43 mmol) followed by HATU (142 mg, 0.37 mmol). The reaction mixture is stirred for 4 hours at room temperature. Ice is added and the product is extracted with EtOAc. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated in vacuum. The residue is purified by flash column chromatography on silica gel (EtOAc/MeOH 0% to 10%) to give methyl ((S)-1-((S)-2-(5-iodo-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (150 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:35][CH3:36])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=2[O:31]COC)(=[O:11])=[O:10])[CH:8]=1)#[N:2].Cl>C(O)(C)C.O1CCCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:35][CH3:36])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:28])=[O:29])=[CH:17][C:16]=2[OH:31])(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: COCOc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(-c2ccccc2S(C)(=O)=O)cc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a suspension of 14.89 g of 5-cyano-N-[2-(2′-methane-sulfonyl-3-methoxymethoxybiphenyl-4-yl)ethyl]-2-methoxy-benzenesulfonamide in a mixture of 30 mL of isopropanol and 90 mL of tetrahydrofuran was added 11.7 mL of concentrated hydrochloric acid. After being stirred at 50° C. for 2 hours, the reaction mixture was diluted with 50 mL of water, and extracted with 150 mL of ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: ethylacetate-methanol) to give 10.22 g of 5-cyano-N-[2-(3-hydroxy-2′-methanesulfonylbiphenyl-4-yl)ethyl]-2-methoxybenzenesulfonamide, colorless and amorphous.
Reaction SMILES: [F:1][C:2]1[C:10]([N:11]2C(=O)C3=CC=CC=C3C2=O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:22])[NH:6]2.O.NN.C(NN)(=O)C1C(=CC=CC=1)C(NN)=O>CO>[NH2:11][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([CH3:22])=[CH:4]2
Reactant: Cc1cc2c(F)c(N3C(=O)c4ccccc4C3=O)ccc2[nH]1
Agent: NN
Agent: NNC(=O)c1ccccc1C(=O)NN
Solvent: CO
Solvent: O
Product: Cc1cc2c(F)c(N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
4-Fluoro-2-methyl-5-phthalimidoindole (1.2, 4 mmol) was dissolved in methanol (30 ml). Hydrazine monohydrate (260 μl, 5.3 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 hours. The solvent was evaporated off and the residue taken up in methylene chloride. The phthalhydrazide by-product was removed by filtration and the filtrate purified by flash chromatography 0.5% methanol in methylene chloride. Evaporation of the solvent gave a white solid which contained traces of phthalhydrazide. Further purification was done by dissolving it in ethyl acetate, washing the organic phase with NaOH 2N and brine, drying over MgSO4. Rotary evaporation of the solvent gave 5-amino-4-fluoro-2-methylindole (500 mg, 76%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([OH:14])[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]([OH:14])[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=1
Reactant: Cc1nc2c(O)cc([N+](=O)[O-])cc2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(O)cc(N)cc2o1

Procedure:
To a solution of 6-nitro-4-hydroxy-2-methylbenzoxazole (5.1 g, 0.026 mole) in THF (100 ml) and methanol (50 ml) were added about 0.5 g of 10 percent palladium on carbon. The mixture was placed on the Parr-shaker apparatus and hydrogenated two hours. At this time hydrogen uptake was complete (6.3 psi, 0.079 mole). The catalyst was removed and the solvents were removed under reduced pressure. The resulting off-white solid (4.1 g, 97.0 percent) was collected and dried. TLC showed the product to be pure. A ninhydrin test for amines was positive. A silver test for hydroxylamine was negative.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([C:14]([CH3:18])([CH3:17])[CH2:15][CH3:16])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[C:27]1([C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N+]=[N-])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH:33]([OH:4])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[NH2:1][C:2]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:18])[CH2:15][CH3:16])=[CH:10][C:6]=1[C:7]([O-:9])=[O:8]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2N)c(C(=O)O)c1
Solvent: Cc1ccccc1
Product: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2N)c(C(=O)[O-])c1
Product: OC(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
2-(amino-4-trifluoromethylphenoxy)-5-(1,1-dimethylpropyl)benzoic acid (150 mg, 0.0004 mol) was dissolved in toluene and diphenyldiazomethane was added. The mixture was heated to 50° C., under argon, and stirred for 4 h. The solvents were evaporated and the residue was flash chromatographed (silica gel, ethyl acetate/hexane) to yield the title compound. 1H NMR (250 MHz, CDCl3) δ7.98 (d, 1H), 7.45 (dd, 1H), 7.24 (s, 10H), 6.83-6.98 (m, 4H), 6.65 (d, 1H), 3.93 (s, 2H), 1.64 (s, 2H), 1.29 (s, 6H), 0.69 (t, 3H).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C([Mg:14][Cl:15])(C)C.[Li+].[Cl-]>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([Mg:14][Cl:15])=[CH:3][C:4]=1[F:10])#[N:7]
Reactant: CC(C)[Mg]Cl
Reactant: N#Cc1ccc(I)cc1F
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc([Mg]Cl)cc1F
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-iodo-2-fluorobenzonitrile (2.5 g, 10.12 mmol) in 10.12 ml THF under argon, a solution of isopropylmagnesium chloride. LiCl in THF (10.12 ml, 13.16 mmol) was added at 0° C. The reaction mixture was stirred at this temperature for 5 min to afford the title compound, which was used immediately in the next step as a stock solution (˜0.5M in THF).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-])=O)=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[O:13]1CC[CH2:15][CH2:14]1.C(OC(=O)C)(=O)C>C(O)C.[Pd].C(OCC)(=O)C>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:10][C:14](=[O:13])[CH3:15]
Reactant: COc1cccc(C)c1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc(C)c1NC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
To a solution of 3-methyl-2-nitroanisole (10.00 g, 59.8 mmol) in ethanol (60 mL)-tetrahydrofuran (60 mL) is added a 10% palladium on carbon (50% wet, 2.00 g), and the mixture is subjected to hydrogenation, and stirred at room temperature for 1.5 hour. After the reaction is completed, the reaction solution is filtered through celite, and the solvent is evaporated under reduced pressure. To a solution of the residue in ethyl acetate (110 ml) is added acetic anhydride (9.0 mL, 95.2 mmol), and the mixture is refluxed for 5 hours. The reaction solution is cooled with ice, and the precipitated solid is collected by filtration, and washed with hexane to give the title compound (9.28 g, yield: 87%).