Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.[CH3:27][O:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][O:38][CH3:39])[C:31]=1[CH3:40]>C(Cl)(Cl)(Cl)Cl>[CH3:27][O:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][O:38][CH3:39])[C:31]=1[CH2:40][Br:1]
Reactant: COCOc1cccc(C(=O)OC)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: COCOc1cccc(C(=O)OC)c1CBr
Reaction time: 3.5 h
Yield: 99.9 %

Procedure:
In a 25 ml round-bottom flask, N-bromosuccinimide (236 mg, 1.3 mmol) and azobis(cyclohexanecarbonitrile) (33 mg, 0.14 mmol) were added to a solution of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester (265 mg, 1.26 mmol) in carbon tetrachloride (6.5 ml). The reaction was heated to reflux with stirring for 3.5 hours. The volatiles were removed in vacuo and the residue purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (9:1) as eluent, which afforded 364 mg (100%) of 2-bromomethyl-3-methoxymethoxy-benzoic acid methyl ester as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH2:5][NH2:6].C(N(CC)CC)C.[Br:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[NH:24][C:23](=[O:30])/[C:22]/2=[CH:31]/OC.O>CN(C)C=O>[Br:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[NH:24][C:23](=[O:30])/[C:22]/2=[CH:31]\[NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1
Reactant: NCc1ccc(O)c(O)c1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
According to general procedure 1, an amount of 3, 4 dihydroxybenzylamine (0.596 g, 4.3 mmol), is dissolved in N,N-dimethylformamide (61 mL). 1.8 ml (12.9 mmol) of triethylamine is added followed by 1.21 g (4.3 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione. After the mixture is stirred at room temperature for 30 min, water (5 mL) is added and the reaction mixture is stirred for 60 min. The precipitate is filtered and washed several times with anhydrous ether. The crude solid is then purified by high performance liquid chromatography to give 910 mg of a white solid. MS (ESI) m/z 389.7 (M+1).
Reaction SMILES: [CH3:1][O-].[Na+].C[O:5][C:6](=O)[CH:7]([CH:13]([CH3:15])C)[NH:8][S:9]([NH2:12])(=[O:11])=[O:10]>CO>[CH2:13]([CH:7]1[NH:8][S:9](=[O:11])(=[O:10])[NH:12][C:6]1=[O:5])[CH2:15][CH3:1]
Reactant: COC(=O)C(NS(N)(=O)=O)C(C)C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC1NS(=O)(=O)NC1=O
Reaction time: 6 h
Yield: 184053 %

Procedure:
A solution of freshly prepared sodium methoxide (6.41 g, from 2.3 g of Na) in 100 ml of methanol was added to a solution of N-(aminosulfonyl)-DL-valine methyl ester (10.5 g; 0.05 mmol) in methanol (150 ml) and the resulting reaction mixture was stirred for 6 hours. The mixture was cooled, neutralized with BIO-RAD® 50W-X8 H+ ion exchange resin, and filtered. The filtrate was concentrated in vacuo to yield a solid residue which was crystallized from methanol/hexane to afford 16.4 g of a crude 4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IV: R1 =H R2 =isopropyl, R3 =H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: Cc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
m-Toluidine (10 ml; 93 mmol) was added to a stirred solution of acetic anhydride (30 ml). The reaction mixture was stirred for 1.5 h at rt., evaporated to dryness, stirred with H2O and filtered to give 13 g product (94%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:24]2[CH:25]=[C:26]([NH:18][C:16]3[N:17]=[C:10]4[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:4][CH:5]=5)=[CH:14][CH:13]=[CH:12][N:11]4[N:15]=3)[CH:27]=[CH:22][CH:23]=2)[CH2:29][CH2:30]1
Reactant: Nc1nc2c(-c3ccc(C(F)(F)F)cc3)cccn2n1
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(C(F)(F)F)cc5)cccn4n3)c2)CC1

Procedure:
[3-(4-Methyl-piperazin-1-yl)-phenyl]-[8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.270 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a yellow solid (0.043 g, 35%). MP=234-236° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, J=7.0 Hz, 1H), 8.15 (d, J=7.7 Hz, 2H), 7.76 (d, J=8.2 Hz, 2H), 7.62 (d, J=7.2 Hz, 1H), 7.48 (s, 1H), 7.25-7.19 (m, 1H), 7.02-6.97 (m, 1H), 6.92 (d, J=7.3 Hz, 1H), 6.83 (s, 1H), 6.59 (d, J=7.8 Hz, 1H), 3.30-3.25 (m, 4H), 2.62-2.57 (m, 4H), 2.37 (s, 3H). MS=435 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cncc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cncc(C)c2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (370 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4N hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine as a pale-yellow oil (yield 256 mg, 88%). A solution of the obtained 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (78 mg) in ethanol (2 mL) and concentrated under reduced pressure. The residue was recrystallized from ethanol-water to give the title compound as a white solid (yield 288 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:16])[C:9]=1[NH:10]2.[OH-].[K+].[C:19]1([CH:25]=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH:25](=[C:7]1[CH2:6][CH2:5][C:4]2[C:3]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:15])[C:2]=3[Cl:1])[NH:10][C:9]=2[C:8]1=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Cl)c(Cl)c21
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2ccccc2)CCc2c1[nH]c1ccc(Cl)c(Cl)c21
Temperature: 80 °C
Yield: 103.8 %

Procedure:
To a solution of 5,6-dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (intermediate 5a) (0.8 g, 1.97 mmol) in MeOH (10 mL), KOH (0.055 g, 0.98 mmol) followed by PhCHO (1.0 g, 9.42 mmol) were added. The reaction mixture was heated to 80° C. for 12 h cooled to room temperature during which a solid precipitated out which was filtered and dried in vacuo to give the title compound as a light yellow solid (0.7 g, 70%). 1H NMR (500 MHz, CDCl3, δ in ppm) 9.25 (bs, 1H), 7.80 (s, 1H), 7.45-7.42 (m, 4H), 7.39-7.35 (m, 2H), 7.31 (d, J=9.0 Hz, 1H), 3.44 (t, J=6.0 Hz, 2H), 3.28 (t, J=6.0 Hz, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH2:1].[OH-].[Li+].[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:10](=[O:11])[O:9][CH2:8]2>O1CCCC1.CO.O>[Br:4][C:5]1[CH:14]=[CH:13][C:12]([CH2:10][OH:11])=[C:7]([CH:6]=1)[C:8]([OH:1])=[O:9]
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(Br)ccc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (11.80 g, 281.6 mmol) was added at room temperature over several minutes to a solution of 5-bromophthalide (20.0 g, 93.88 mmol) in a 2:1:1 solution of tetrahydrofuran/methanol/water (570 mL) and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and azeotropically dried with benzene to give 5-Bromo-2-hydroxymethyl-benzoic acid as a white solid. The material was used without further purification: 1H NMR (300 MHz, CDCl3+CD3OD) δ 7.89 (d, J=8.3 Hz, 1H), 7.67 (d, J=1.9 Hz, 1H), 7.50 (dd, J=8.3, 1.9 Hz, 1H), 3.99 (s, 2H); ESI MS (negative mode) m/z 229 [C8H7BrO3−H]−. Sodium hyride (15.0 g, 375 mmol, 60% dispersion in mineral oil) was added in small portions over the course of 0.5 h at room temperature to a solution of 5-Bromo-2-hydroxymethyl-benzoic acid in tetrahydrofuran (235 mL) containing bromoacetic acid (14.35 g, 103.2 mmol) and sodium iodide (1.41 g, 9.4 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and poured into water and then extracted with diethyl ether. The aqueous phase was acidified with 10% hydrochloric acid to pH 3-4 and extracted several times with ethyl acetate. The combined ethyl acetate phases were washed with water and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated to yield -Bromo-2-carboxymethoxymethyl-benzoic acid as a white solid. The material was used without further purification: 1H NMR (300 MHz, CD3OD) δ 7.93-7.86 (m, 2H), 7.55-7.50 (m, 1H), 4.98 (s, 2H), 4.23 (s, 2H); ESI MS (negative mode) m/z 287 [C10H9BrO5−H]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[CH:20](OCC)[CH:21]([CH3:29])[CH:22](OCC)OCC)C>CC(O)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2=[C:13]3[N:12]([N:11]=[C:10]2[CH2:9]1)[CH:22]=[C:21]([CH3:29])[CH:20]=[N:16]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Reactant: CCOC(OCC)C(C)C(OCC)OCC
Solvent: O
Solvent: CC(=O)O
Product: Cc1cnc2c3c(nn2c1)CN(C(=O)OC(C)(C)C)C3
Temperature: 50 °C
Reaction time: 20 h
Yield: 57.2 %

Procedure:
A mixture of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (5 g; 22.3 mmol; 1 eq.) and 1,1,3,3-tetraethoxy-2-methylpropane (4.32 mL; 22.3 mmol; 1 eq.) in AcOH (50 mL) was stirred at 50° C. for 20 hours then diluted with water (250 mL). The precipitate was filtered off and dried to afford the title compound (3.5 g, 57%) as a pale beige solid. 1H NMR (DMSO-d6) δ 8.98-8.95 (m, 1H), 8.43 (d, J=2.1 Hz, 1H), 4.61-4.54 (m, 4H), 2.31 (s, 3H), 1.47 (s, 9H). HPLC (max plot) 99.7%; Rt 3.27 min. UPLC/MS: (MS+) 275.0 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21]C(=O)C)=[N:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][C:27]([O:29]C)=[O:28]>>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([N:14]([CH2:26][C:27]([OH:29])=[O:28])[S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=2)(=[O:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CC(=O)Nc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Reactant: COC(=O)CBr
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc(N)nc2)cc1

Procedure:
prepared by reaction of N-[5-(4-tert-butyl-benzenesulfonylamino)-pyridin-2-yl]-acetamide with methyl bromoacetate
Reaction SMILES: [C:1]([C:3]([C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH3:20])=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH3:8])[C:4]([O:6]C)=[O:5])#[N:2].[OH-].[K+].Cl>CCO.O.C(OCC)(=O)C>[C:24]([O:23][C:21]([N:13]1[C:14]2[C:10](=[C:9]([C:3]([C:1]#[N:2])([CH3:8])[C:4]([OH:6])=[O:5])[C:17]([O:18][CH3:19])=[CH:16][C:15]=2[CH3:20])[CH:11]=[CH:12]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)C(C)(C#N)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(C#N)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-(2-cyano-1-methoxy-1-oxopropan-2-yl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 155-D) (0.35 g, 0.940 mmol) was dissolved in EtOH (4.70 ml), cooled to 0° C. and added 10% KOH (2.64 ml, 4.70 mmol) and stirred for 1 hour. At this point, the reaction was placed in an ice bath and quenched with 1 N HCl (4.70 ml, 4.70 mmol). The reaction was diluted with water and ethyl acetate. The layers were separated and the ethyl acetate layer was removed, dried over Na2SO4 and concentrated to obtain the title compound which was used directly in the next reaction without purification. MS (ESI+) m/z 359.4 (M+H).
Reaction SMILES: [S:1]1[CH2:6][C:5](=O)[CH2:4][C:3](=[O:8])[CH2:2]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[NH2:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>C(O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[N:21]3[N:22]=[CH:23][CH:24]=[C:20]3[NH:19][C:5]3[CH2:6][S:1][CH2:2][C:3](=[O:8])[C:4]2=3)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Nc1cc[nH]n1
Reactant: O=C1CSCC(=O)C1
Solvent: CCO
Product: O=C1CSCC2=C1C(c1ccc(F)c(Br)c1)n1nccc1N2
Temperature: 25 °C
Yield: 11.8 %

Procedure:
A solution of 3,5-thiopyrandione (0.13 g, 1 mmol), 3-bromo-4-fluorobenzaldehyde(0.203 g, 1 mmol), and 3-aminopyrazole (0.082 g, 1 mmol) in ethanol (2 mL) was heated at reflux for 24 hours. After the reaction mixture was allowed to cool to ambient temperature, the volatiles were evaporated at reduced pressure and the resulting residue was chromatographed on silica gel, eluting with 5% ethanol/methylene chloride to provide 0.045 g (12%) of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:33][C@@H:32]([C:34]3[CH:45]=[CH:44][C:37]4[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=4[CH:35]=3)[O:31][C:30]2=[O:46])[CH:15]=[CH:16][CH:17]=1.C(O)(C)C>ClCCl>[CH3:42][C:39]1([CH3:43])[O:38][C:37]2[CH:44]=[CH:45][C:34]([C@H:32]3[O:31][C:30](=[O:46])[N:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][C:14]4[CH:13]=[C:12]([NH:11][C:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=5)=[O:10])[CH:17]=[CH:16][CH:15]=4)[CH2:33]3)=[CH:35][C:36]=2[CH2:41][O:40]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Reactant: O=C=Nc1cccc(I)c1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc(I)c5)c4)C(=O)O3)ccc2O1
Reaction time: 5 h
Yield: 76.6 %

Procedure:
3-Iodophenylisocyanate (500 mg) was added to a solution of (5R)-3-{6-[2-{[(3-aminophenyl)methyl]oxy}ethoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (700 mg) in dichloromethane (14 ml) and the mixture was stirred at 20° under nitrogen for 5 h. Isopropanol (14 ml) was added and the mixture was stirred for 16 h. The solvent was evaporated in vacuo to give a residue that was purified by Biotage. Elution with EtOAc-PE (2:1) gave the title compound (800 mg). LCMS RT=4.02 min, ES+ve 744 (MH)+.
Reaction SMILES: [NH2:1][C@:2]12[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]1)[CH2:4][C:3]2=[O:11].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[C:12]1([NH:1][C@:2]23[C:8]([CH3:9])([CH3:10])[C@H:5]([CH2:6][CH2:7]2)[CH2:4][C:3]3=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(N)C(=O)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)[C@@H]2CC[C@@]1(Nc1ccccc1)C(=O)C2
Temperature: 40 °C
Reaction time: 25 h
Yield: 16 %

Procedure:
To a solution of (1S,4R)-1-amino-7,7-Dimethyl-bicyclo[2.2.1]heptan-2-one (compound 1) (1.0 g, 6.5 mmol) and phenyl boronic acid (2.0 equivant) in methylene chloride (43 mL, 0.15 M) was added copper acetate Cu(OAc)2 (1.0 equivant) and triethylamine (2.0 equivant). The reaction mixture was stirred for 25 h at 40° C., then filtered with Celite and washed with ethyl acetate. The combined organic extracts were purified by column chromatography with EA/hexane (1/8) as eluent to give white solid (0.23 g, 16%). 1H NMR (400 MHz, CDCl3) δ7.15-7.08 (m, 2H), 6.81-6.73 (m, 3H), 4.13 (br, 1H), 2.49-2.35 (m, 2H), 2.16-2.01 (m, 3H), 1.52-1.40 (m, 2H), 1.21 (s, 3H), 0.90 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:30])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([CH2:26][CH3:27])=[C:22]([CH2:24][CH3:25])[CH:23]=3)[O:15][N:14]=2)=[CH:8][C:7]=1[CH2:28][CH3:29].[C:31](O)(=[O:34])[CH2:32][OH:33].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CC(=O)OCC>[CH2:24]([C:22]1[CH:23]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:9]3[CH:10]=[C:11]([CH3:12])[C:6]([O:5][CH2:4][CH:3]([OH:30])[CH2:2][NH:1][C:32](=[O:33])[CH2:31][OH:34])=[C:7]([CH2:28][CH3:29])[CH:8]=3)[N:17]=2)[CH:19]=[N:20][C:21]=1[CH2:26][CH3:27])[CH3:25]
Reactant: CCc1cc(-c2nc(-c3cc(C)c(OCC(O)CN)c(CC)c3)no2)cnc1CC
Reactant: O=C(O)CO
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCc1cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(CC)c3)no2)cnc1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of (RS)-1-amino-3-{4-[5-(5,6-diethyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propan-2-ol (99 mg, 0.24 mmol), glycolic acid (18.5 mg, 0.244 mmol) and Hünig's base (78 mg, 0.61 mmol) in DCM (5 mL) is added PyBOP (126.7 mg, 0.24 mmol) and the mixture is stirred at rt for 30 min. The mixture is diluted with EA, washed with sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude product is purified by chromatography on prep. TLC plates eluting with DCM:MeOH 10:1 to give N—((RS)-3-{4-[5-(5,6-diethyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide (90 mg) as an oil; LC-MS: tR=0.88 min, [M+1]+=469.25.
Reaction SMILES: P(Br)(Br)Br.[CH3:5][S:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]O.[C-:15]#[N:16].[Na+]>C1(C)C=CC=CC=1.O.C(O)C>[CH3:5][S:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][C:15]#[N:16]
Reactant: [C-]#N
Reactant: CSc1ccccc1CO
Agent: BrP(Br)Br
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CSc1ccccc1CC#N
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Phosphorus tribromide (75 g) in toluene (50 ml) was added to a stirred mixture of 2-methylthiobenzyl alcohol (42.5 g) in toluene (25 ml) over 10 minutes at 5° C. The mixture was then stirred at 40° C. for 1 hour, water (100 ml) was added and stirring continued at ambient temperature for 1 hour. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic layers yielded an oil. The oil (58.6 g) was dissolved in a 1:2 mixture of water and ethanol and sodium cyanide (26.5 g) was added over 15 minutes. The mixture was stirred at 50° C. for 1.5 hours then poured onto water (500 ml) and extracted with ethyl acetate. The extract yielded 2-methylthiophenylacetonitrile.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][NH:11][CH3:12])[CH:8]=2)[CH:3]=[CH:2]1.Cl.Cl.[CH3:15][N:16]1[CH2:22][C:21]2[CH:23]=[C:24](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)[CH:25]=[N:26][C:20]=2[NH:19][C:18](=[O:32])[CH2:17]1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][N:11]([CH3:12])[C:29](=[O:31])/[CH:28]=[CH:27]/[C:24]3[CH:25]=[N:26][C:20]4[NH:19][C:18](=[O:32])[CH2:17][N:16]([CH3:15])[CH2:22][C:21]=4[CH:23]=3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNCc1ccc2cc[nH]c2c1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(=O)Nc2ncc(/C=C/C(=O)N(C)Cc3ccc4cc[nH]c4c3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a solution of (1H-indol-6-ylmethyl)methylamine (98 mg, 0.6 mmol), (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid dihydrochloride (160 mg, 0.5 mmol) HOBt (81 mg, 0.5 mmol) and diisopropylethylamine (0.41 mL, 2 mmol) in DMF (12 mL) was added EDC hydrochloride (114 mg, 0.6 mmol). The mixture was stirred overnight at room temperature. Water (75 mL) was added and the solution stirred for 1 hr. The precipitate was collected by filtration and triturated with hexanes to afford (E)-N-(1H-indol-6-ylmethyl)-N-methyl-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamide (89 mg, 37%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 11.03-11.01 (m, 1H), 10.33-10.30 (m, 1H), 8.52 (d, J=7.6 Hz, 1H), 8.13 (d, J=2.4 Hz, 1H), 7.60-7.22 (m, 5H), 6.92-6.86 (m, 1H), 6.37 (s, 1H), 4.88-4.68 (2×s, 2H), 3.78-3.74 (m, 2H), 3.08-2.89 (2×s, 3H), 2.36-2.33 (2×s, 3H); ESI MS m/z 390 [C22H23N5O2+H]+.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:19][C:20]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[Br:30]N1C(=O)CCC1=O>ClC1C=CC=CC=1.C(OCC)(=O)C>[Br:30][CH2:29][C:28]1[C:20]([Cl:19])=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23]
Reactant: Cc1cccc(C(=O)O)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(CBr)c1Cl
Temperature: 85 °C

Procedure:
Benzoyl peroxide (1.33 g) was added to a suspension of 2-chloro-3-methylbenzoic acid (25 g) and N-bromosuccinimide (28.7 g) in chlorobenzene (250 mL) and the resulting mixture was heated to 85° C. for 4 h. The mixture was diluted with ethyl acetate (100 mL) and washed with 10% aqueous brine (3×100 mL). The organic layer was dried over magnesium sulphate, filtered and evaporated. The beige solid was recrystallised from ethyl acetate (˜75 mL)/isohexane (˜250 mL) to give the subtitled compound as a white solid. Yield 25.3 g.