Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:45])([O:16][CH2:17]/[C:18](/[C:35]1[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1)=[C:19](/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)\[CH2:20][O:21][Si](C(C)(C)C)(C)C)[O:2][CH2:3][CH2:4][CH2:5][CH:6]([O:12][N+:13]([O-:15])=[O:14])[CH2:7][O:8][N+:9]([O-:11])=[O:10]>C(#N)C.C1(C)C=CC=CC=1>[C:1](=[O:45])([O:16][CH2:17]/[C:18](/[C:35]1[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:42])=[O:43])=[CH:37][CH:36]=1)=[C:19](/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)\[CH2:20][OH:21])[O:2][CH2:3][CH2:4][CH2:5][CH:6]([O:12][N+:13]([O-:15])=[O:14])[CH2:7][O:8][N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)[Si](C)(C)OC/C(=C(\COC(=O)OCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/CO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.7 %

Procedure:
To a solution of 18 ml of phosgene (1.93 M /toluene) at −78° C. under N2, was added 3 g of 3,4-bis(nitrooxy)butyl alcohol. The resulted mixture was stirred at 25° C. for 24 h. Distillation of excess phosgene was done under low vacuum at 50° C. to afford 4.2 g of the desired compound as an orange oil. The crude compound was used directly in the next reaction. To a solution of 3.5 g of (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-ol, 1.0 g of DMAP and 1.8 mL of Hünig's base in 40 mL of CH2Cl2 at −78° C. was added 3.3 g of 4,5-bis(nitrooxy)pentyl chloridocarbonate. The reaction mixture was stirred for 2 h at 25° C. and then filtered through a pad of silica gel, washed with EtOAc and evaporated. Purification by flash chromatography afforded 5.4 g of the titled compound as a yellowish oil. The compound was used directly in the next step. To a solution of 5.4 g of 4,5-bis(nitrooxy)pentyl (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-yl carbonate in 50 mL of acetonitrile was added 2.5 mL of HF.pyr and the mixture was stirred at 25° C. for 1.5 h. The reaction mixture was diluted with 200 mL of toluene, loaded on silica gel and washed with EtOAc. Purification by flash chromatography afforded 4.6 g of the titled compound as a colorless oil. 1H NMR (acetone-d6, 500 MHz): δ 7.69 (d, 2H), 7.34 (d, 2H), 7.14-7.08 (m, 5H), 5.30 (s, 2H), 5.01 (dd, 1H), 4.73 (dd, 1H), 4.64 (d, 2H), 4.17-4.11 (m, 3H), 4.04 (q, 4H), 3.03 (s, 3H), 1.91-1.81 (m, 4H).
Reaction SMILES: [C:1]([N:8]([CH3:20])[C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:22][O:23][C:24](=[O:37])[C@H:25]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH2:26].OC1C2N=NNC=2C=CC=1.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH3:22][O:23][C:24](=[O:37])[C@H:25]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH:26][C:17](=[O:19])[C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:20]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-BOC-N-methyl-(D)-phenylalanine (2.1 g, 7.5 mmol) [BOC=tert-butyloxycarbonyl] in dry DMF [N,N-dimethylformamide] (15 ml) are added (L)-tryptophan methyl ester hydrochloride (2 g, 7.8 mmol) and hydroxybenztriazole (1.2 g, 8.8 mmol). The mixture is cooled to 0° and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.7 ml, 9.2 mmol) is added dropwise. The reaction mixture is slowly warmed to r.t. (room temperature) and stirring continued for 2 hours. The homogeneous mixture is diluted with ethyl acetate (500 ml) and washed with three portions of water (200 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to give N-BOC-N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester as a white foam. [a]D =+42° (c=1.0, ethanol).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[N:13][OH:14]
Reactant: CC1Cc2ccccc2C1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1Cc2ccccc2C1=NO
Temperature: 60 °C
Yield: 89.8 %

Procedure:
A mixture of 2-methyl-1-indanone (10 g, 0.0684 mol) and hydroxylamine hydrochloride (9.5 g, 0.1368 mol) in ethanol was stirred at 60° C., and a solution of sodium acetate (16.8 g, 0.2052 mol) in water added. The resulting mixture was then heated at reflux for 90 minutes, then cooled and the solid filtered. The crude product was washed with water and filtered to give 2-methyl-indan-1-one oxime (9.9 g, yield 81%), mp. 82-91° C., in 90% purity.
Reaction SMILES: S(=O)(=O)(O)O.C(=O)=O.[Br:9][C:10]1[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=1[O:12][CH:13]([CH3:17])[C:14](=O)[CH3:15]>CC(C)=O>[CH3:17][C:13]1[O:12][C:11]2[C:10]([Br:9])=[CH:21][CH:20]=[CH:19][C:18]=2[C:14]=1[CH3:15]
Reactant: CC(=O)C(C)Oc1ccccc1Br
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: Cc1oc2c(Br)cccc2c1C
Reaction time: 0.08 h
Yield: 91.4 %

Procedure:
25 ml of concentrated sulphuric acid are introduced into a 100 ml three-necked flask equipped with a thermometer and a 10 ml dropping funnel and cooling is carried out to between -15 and 0° C. with a bath of solid carbon dioxide in acetone. 3-(2-Bromophenoxy)-2-butanone (5 g, 20.6 mmol) is added dropwise and stirring is continued for 5 min. The mixture is poured onto crushed ice and then extraction is carried out with ethyl acetate (3×80 ml). The organic phases are combined, dried over magnesium sulphate and concentrated. The residue is purified by silica column chromatography (elution solvent: cyclohexane). 4.24 g (Yield: 91%) of 2,3-dimethyl-7-bromobenzofuran are obtained--M.p.: 33° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([O:13][C:14](C)(C)C)=[O:12])[C:4]=2[CH:3]=1.[Li]CCCC.[CH2:29]1[CH2:33][O:32][CH2:31][CH2:30]1>O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH:9]3[CH:14]([C:31]4[O:32][CH:33]=[CH:29][CH:30]=4)[O:13][C:11](=[O:12])[N:10]3[C:4]=2[CH:3]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: [Li]CCCC
Solvent: O
Product: O=C1OC(c2ccco2)C2c3ccccc3Oc3ccc(Cl)cc3N12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A stirring solution of 1 (2.0 g, 6.04 mmol) in 40 mL of THF was cooled to -78° C. followed by the addition of n-BuLi (1.6M, 4.32 mL, 6.91 mmol). The mixture was stirred at -78° C. for 30 minutes and treated with furalaldehyde (670 mg, 6.97 mmol) and then slowly warmed to room temperature and diluted with 16 mL of water. The mixture was then extracted with ether (200 mL×2) and the combined extracts were washed with brine (saturated, 50 mL) and dried (Na2SO4). The extracts were concentrated to give the crude product (2.5 g), which was purified by HPLC with 20% EtOAc/heptane to yield Compounds 13, 14a and 14b as follows:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]([CH3:13])[CH3:12].[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]([N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[C:24]1[CH:25]=[CH:26][C:21]([O:20][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)=[CH:22][CH:23]=1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cnc2c(Cl)ncnc21
Reactant: OB(O)c1ccc(OC2CCCCO2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)n1cnc2c(-c3ccc(OC4CCCCO4)cc3)ncnc21
Temperature: 25 °C

Procedure:
Compound 52B (165 mg, 0.84 mmol) in toluene (5 ml) was treated sequentially with 4-(tetrahydro-2H-pyran-2-yloxy)phenylboronic acid (280 mg, 1.26 mmol), tetrakis(triphenylphosphine)palladium(0) (48.6 mg, 0.042 mmol) and sodium carbonate (2N aq.) (1.26 ml, 2.52 mmol). The reaction vessel was purged with nitrogen and heated at reflux overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography on silica gel eluting with a gradient of 0 to 5% MeOH in CH2Cl2: 1H NMR (300 MHz, DMSO-d6) δ ppm 8.92 (1H, s), 8.83 (2H, m), 8.74 (1H, s), 7.22 (2H, m), 5.63 (1H, t), 4.92 (1H, septet), 3.79 (1H, ddd), 3.60 (1H, m), 1.82 (4H, m), 1.60 (6H, d), 1.55 (2H, m).
Reaction SMILES: [H-].[Na+].Cl[C:4](Cl)(Cl)[CH2:5][O:6][C:7]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:53])[C@@H:16]([NH:32][C:33](=[O:52])[C@@H:34]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:19]=2)[NH:10]1)=[O:8].[CH2:56](O)[CH2:57]C=C>O1CCCC1>[CH2:5]([O:6][C:7]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:53])[C@@H:16]([NH:32][C:33](=[O:52])[C@@H:34]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:19]=2)[NH:10]1)=[O:8])[CH2:4][CH:56]=[CH2:57]
Reactant: C=CCCO
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)C(=O)N2CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCOC(=O)[C@@H]1CCCN(C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC(=O)[C@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)N1
Temperature: 50 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
Sodium hydride (6 mg, 0.139 mmol) was added to a solution of (S)-1-{(S)-2-[(S)-2-tert-butoxycarbonylamino-3-(4-methoxy-phenyl)-propionylamino]-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (570 mg, 0.698 mmol) and 3-buten-1-ol (601 μL, 6.98 mmol) in tetrahydrofuran (10 mL) and the reaction stirred at 50° C. under nitrogen for 18 h. The reaction was cooled and the mixture passed through a plug of silica gel (eluting twice with ethyl acetate, 50 mL) to afford the title compound (438 mg, 85%) as a colourless oil (438 mg, 85%). 1H NMR (300 MHz, CDCl3) δ0.20 (s, 6H), 1.00 (s, 9H), 1.10-140 (m, 2H), 1.40 (s, 9H), 1.72-1.86 (m, 2H), 2.33-2.46 (m, 3H), 2.60-3.05 (m, 5H), 3.50 (d, 11.4 Hz, 1H), 3.80 (s, 3H), 4.15-4.35 (m, 4H), 4.95 (br s, 1H), 5.09-5.19 (m, 2H), 5.60-5.70 (m, 1H), 5.71-5.87 (m, 1H), 6.42 (d, J=8.0 Hz, 1H), 6.62-6.80 (m, 3H), 6.82 (d, J=8.7 Hz, 2H), 7.07-7.16 (m, 3H). LCMS (m/z) 739.40 [M+H], Tr=5.82 min.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N:31]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[N:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C1COCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([N:31]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCN(Cc2ccccc2)CC1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 73.3 %

Procedure:
To a solution of diisopropylamine (153 mg, 1.5 mmol) in THF (20 mL) was added n-BuLi (2.5 M, 0.6 mL) at −75° C. under N2. After 5 min, ethyl 1-benzylpiperidine-4-carboxylate (247 mg, 1.0 mmol) was added and the resulting mixture then stirred at −70° C. for 10 min, before adding di-tert-butyl azodicarboxylate (345 mg, 1.5 mmol). The reaction was stirred for 30 min, then quenched with aqueous NH4Cl (10 mL) and extracted with EA (10 mL×3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product (350 mg, 72%) as an off-white solid. MS (ESI, m/e) [M+1]+ 478.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]([NH2:14])[CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29]([C:35]3[N:36]=[C:37]4[C:43]([C:44](O)=[O:45])=[CH:42][N:41]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[C:38]4=[N:39][CH:40]=3)=[N:30][N:31]2[CH3:34])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]([NH:14][C:44]([C:43]2[C:37]3[C:38](=[N:39][CH:40]=[C:35]([C:29]4[C:28]5[C:32](=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=5)[N:31]([CH3:34])[N:30]=4)[N:36]=3)[N:41]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH:42]=2)=[O:45])[CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(N)C1CN(C(=O)OC(C)(C)C)C1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a solution of 3-(1-amino-ethyl)-azetidine-1-carboxylic acid tert-butyl ester (crude from step 3, 63 mg, 0.31 mmol) in DMF (2 mL) were added N,N-diisopropylethylamine (69 μL, 0.39 mmol), 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.26 mmol), and HATU (110 mg, 0.29 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 30% to 60% EtOAc/hexanes to afford 158 mg (94%) of 3-(1-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-azetidine-1-carboxylic acid tert-butyl ester as a white foam. 1H NMR (CDCl3, 300 MHz): δ (ppm) 9.23 (s, 1H), 8.36 (t, J=4.3 Hz, 2H), 8.18 (d, J=9.1 Hz, 1H), 7.52 (s, 1H), 7.24-7.29 (m, 1H), 5.73 (s, 2H), 4.57-4.68 (m, 1H), 4.18 (s, 3H), 3.87-4.08 (m, 3H), 3.79 (dd, J=8.7, 6.0 Hz, 1H), 3.55-3.65 (m, 2H), 2.73 (br. s., 1H), 1.39 (s, 9H), 1.36 (d, J=6.8 Hz, 6H), 0.89-1.01 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].Br[CH2:15][C:16]([C:18]1[CH:22]=[C:21]([CH3:23])[S:20][C:19]=1[CH3:24])=O>>[CH3:24][C:19]1[S:20][C:21]([CH3:23])=[CH:22][C:18]=1[C:16]1[N:2]=[C:1]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[S:3][CH:15]=1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Reactant: Cc1cc(C(=O)CBr)c(C)s1
Product: COC(=O)c1ccc(-c2nc(-c3cc(C)sc3C)cs2)cc1
Yield: 64 %

Procedure:
In the same manner as in Example 74, methyl 4-thiocarbamoylbenzoate was reacted with 3-bromoacetyl-2,5-dimethylthiophene to obtain methyl 4-[4-(2,5-dimethyl-3-thienyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 64%. Pale yellow pritsms. Melting point: 109 to 110° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[OH:25])=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[CH2:26](O)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[O:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2O)c1
Reactant: OCCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A mixture of 5-chloro-2-hydroxy-[1,1′;2′,1″]terphenyl-3″-carboxylic acid ethyl ester (100 mg, 0.28 mmol), phenethyl alcohol (31 mg, 0.25 mmol), triphenyl phosphine (74 mg, 0.28 mmol), diisopropyl azodicarboxylate (57 mg, 0.28 mmol) in THF (6 ml) was stirred at room temperature overnight. The mixture was then poured into water and extracted with ether, the organic layers were dried over MgSO4 and evaporated. The residue was chromatographed through an SPE column using iso-hexane to yield the title compound (95 mg, 80%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13]C)[CH:8]=1)=[O:5].Br>C(O)(=O)C>[F:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5]
Reactant: COc1cc(NC(=O)c2ccc(C(F)(F)F)cc2F)ccn1
Agent: Br
Solvent: CC(=O)O
Product: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1F
Temperature: 100 °C
Reaction time: 6 h
Yield: 76.6 %

Procedure:
To 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(trifluoromethyl)benzamide (1.00 g, 3.18 mmol) in acetic acid (6.0 mL) was added HBr (33% in acetic acid) (3.9 mL of 33% w/v, 15.91 mmol) and the mixture stirred at 100° C. for 6 hours. Additional HBr (2 mL, 33% in acetic acid) was added and the mixture was stirred at room temperature overnight. The mixture was then heated at 100° C. for 2 hours before it was cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with water and brine (2×), dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid was slurried in methyl-tert-butyl ether and filtered to give 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (19) (731 mg, 76%). ESI-MS m/z calc. 301.05, found 301.3 (M+1)+; Retention time: 1.35 minutes (3 minute run). 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 10.70 (s, 1H), 7.96-7.85 (m, 2H), 7.75 (d, J=8.2 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 6.81 (d, J=1.9 Hz, 1H), 6.41 (dd, J=7.2, 2.1 Hz, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]=[N:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:5]2=1.[O:20]([CH2:27][CH:28]1[CH2:30][O:29]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:30][CH:28]([OH:29])[CH2:27][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6]1[CH:11]=[N:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:5]2=1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(Br)cc12
Reactant: c1ccc(OCC2CO2)cc1
Product: CCOC(=O)c1cc2c3cc(Br)ccc3n(CC(O)COc3ccccc3)c2cn1

Procedure:
Following Representative Procedure 1, the title compound ethyl 6-bromo-9-(2-hydroxy-3-phenoxypropyl)-9H-pyrido[3,4-b]indole-3-carboxylate was prepared from ethyl 6-bromo-9H-pyrido[3,4-b]indole-3-carboxylate and phenoxymethyloxirane in 71% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]([NH2:20])=O)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1N.C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:9])[C:12]3[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:17])[N:21]3[CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[N:20]=[C:18]23)=[CH:4][CH:3]=1
Reactant: NC(=O)C1(c2ccc(F)cc2)OC(=O)c2ccccc21
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(O)(c2ccc(F)cc2)C2=NC3CCCCC3N12
Yield: 41.8 %

Procedure:
A mixture of 1-(4-fluorophenyl)-3-oxo-1,3-dihydro-2-benzofuran-1-carboxamide (5 g) (Step 1 of Example 2), trans 1,2-diaminocyclohexane (8.3 g), and toluene (75 mL) was heated at reflux for 66 h in a flask equipped with a water separator. The mixture was evaporated to dryness and the residual gum was extracted with hexane. The residue was chromatographed over silica gel and eluted with 10% methanol in methylene. Crystallization from ethyl acetate afforded the title compound (2.7 g) as a white solid m.p. 203-205° C.
Reaction SMILES: [N:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][N:11]3[C:19](Cl)=[C:18]4[C:13]([N:14]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:15](=[O:23])[N:16]([CH3:22])[C:17]4=[O:21])=[CH:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[C:30]1([OH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[N:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][N:11]3[C:19]([O:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:18]4[C:13]([N:14]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:15](=[O:23])[N:16]([CH3:22])[C:17]4=[O:21])=[CH:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(-n4cncn4)cc3)cc21
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Oc3ccccc3)n(Cc3ccc(-n4cncn4)cc3)cc21
Temperature: 150 °C
Yield: 58.6 %

Procedure:
Crude 6-(4-(1H-1,2,4-triazol-1-yl)benzyl)-5-chloro-1-isobutyl-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (12 mg, 0.029 mmol), phenol (14 mg, 0.15 mmol) and Cs2CO3 (29 mg, 0.087 mmol) are placed in a microwave vial, and then dioxane (0.25 mL) is added. The vial is sealed and heated in a Biotage microwave instrument at 150° C. for 3 h. The reaction mixture is then purified with a semi-preparative HPLC to give 8.0 mg of product as off-white solid (purity: 97%). MS (ESI) m/z 471.2 [M+H]+.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[Br:15][CH2:16][CH2:17]C(O)=O>C1(C)C=CC=CC=1>[C:11]([O:10][C:6](=[O:5])[CH2:17][CH2:16][Br:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: O=C(O)CCBr
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCBr
Yield: 80.4 %

Procedure:
28 g (138 mmol) N,N-dimethylformamide di-tert-butyl acetal was slowly added during 50 min to a solution of 5.3 g (34.5 mmol) 3-bromo-propionic acid in 50 ml toluene. The reaction was heated for further 30 min, cooled and extracted with H2O/toluene (2×), aqueous saturated NaHCO3 and aqueous saturated NaCl. The organic phase was dried over Na2SO4 and carefully (low boiling point of the product) evaporated to give 5.8 g (80%) of 3-bromo-propionic acid tert butylester [U. Widmer, A convenient preparation of tert-butyl esters. Synthesis (1983), Issue 2, 135-6].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>>[C:12]1([CH2:11][CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:25])[N:3]=[CH:4]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)c1c(N)ncn1CCc1ccccc1
Reactant: O=C(O)c1cccnc1
Product: NC(=O)c1c(NC(=O)c2cccnc2)ncn1CCc1ccccc1

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 2.00 g (8.69 mmol) of 4-amino-1-(2-phenylethyl)-5-imidazolecarboxamide prepared in the same manner as in Example 56 and nicotinic acid instead of 3-pyridylacetic acid hydrochloride to obtain crude 1-(2-phenylethyl)-4-(3-pyridylcarbonylamino)-5-imidazolecarboxamide.