Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C:13](O)([CH2:18][O:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:14]([F:17])([F:16])[F:15])(=O)=O)=CC=1.C(=O)([O-])[O-]>ClCCl>[CH3:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([O:19][CH2:18][C:13]2([C:14]([F:17])([F:16])[F:15])[CH2:12][O:11]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)(COS(=O)(=O)c2ccc(C)cc2)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A solution of the 3,3,3-trifluoro-2-hydroxy-2-({[(4-methyl phenyl) sulfonyl]oxy}methyl)propyl 4-methylbenzenesulfonate (186.5 g, 398.5 mmol) in dichloromethane (2500 ml) was stirred under nitrogen whilst polymer supported carbonate resin (ex Fluka, ca. 3.5 mmoles carbonate/g resin) (232 g) was added. The mixture was stirred at room temperature overnight. The resin was filtered off and the resin was washed with dichloromethane. The combined filtrate and washings were concentrated under reduced pressure to give the title compound (116.2 g) as a brown oil.
Reaction SMILES: COCCOC.Br[C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)c1ncccc1Br
Reactant: CC(C)(C)OC(=O)NCc1ccccc1B(O)O
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: COCCOC
Solvent: ClCCl
Product: CCOC(=O)c1ncccc1-c1ccccc1CNC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
150 ml of 1,2-dimethoxyethane were aerated with argon, and 874 mg (0.75 mmol) of Pd(PPh3)4 and 3.45 g (15 mmol) ethyl 3-bromopyridine-2-carboxylate were added. After 10 min, 5.53 g (22.5 mmol) of 2-(tert-butoxycarbonylaminomethyl)phenylboronic acid and finally 15 ml of a 2M sodium carbonate solution were added. The mixture was heated to reflux for 18 h under argon, diluted with dichloromethane after cooling and washed with water. The organic phase was dried, concentrated and purified by chromatography on silica gel. 3.4 g (66%) of a viscous oil were obtained. MS (ES+): m/z=357 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][O:19][C:20](=[O:45])[C@:21]([CH2:41][CH2:42][C:43]#[N:44])([CH3:40])[NH:22][C:23](=[O:39])[C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>ClCCl>[CH3:18][O:19][C:20](=[O:45])[C@:21]([CH2:41][CH2:42][C:43]#[N:44])([CH3:40])[NH:22][C:23](=[O:39])[C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30].[CH3:18][O:19][C:20](=[O:45])[C@:21]([CH2:41][CH2:42][C:43]#[N:44])([CH3:40])[NH:22][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: COC(=O)[C@@](C)(CCC#N)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@](C)(CCC#N)NC(=O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
p-Chlorobenzoyl chloride (0.91 g) and triethylamine (0.91 ml) were added at 5° C. to a solution of 0.85 g of isomer (i) of the 2-(2-cyanoethyl)alanine methyl ester in dichloromethane (20 ml), and the resulting mixture was stirred at 0°-5° C. for 2 hours. The reaction mixture was then washed with water (20 ml) and the organic layer was dried over magnesium sulphate. The solvent was distilled off and the residue was purified by silica gel Lobar column chromatography (eluent: 1/1 cyclohexane/ethyl acetate; flow rate: 12 ml/minute), giving 1.13 g of isomer (i) of the desired product as a colourless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][C:26]([NH:31]CC=C)=[CH:25][C:24]=2[O:35][CH3:36])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]>CC#N.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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][C:26]([NH2:31])=[CH:25][C:24]=2[O:35][CH3:36])=[CH:21][CH:22]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: C=CCNc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)c(OC)c1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cc(N)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 2 h
Yield: 82.2 %

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(4-allylamino-2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (0.93 g) was dissolved in MeCN/water (40 mL of 84:16) under N2. Wilkinson's catalyst (79 mg ) was added and the mixture was brought to boiling. After 2 h, more catalyst (170 mg ) was added and the reaction continued for another 6 h. The solvent was evaporated and the residual water coevaporated with MeCN. The residue was purified by preparative TLC (silica gel; eluent: hexane/AcOEt 2:1 to 1:2) to give N-(2,6-dichlorobenzoyl)-4-(4-amino-2,6-dimethoxyphenyl)-L-phenylalanine methyl ester(708 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])O[C:6]2=[O:11].Cl.[NH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]>>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[N:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:11]
Reactant: O=C1OC(=O)c2c(O)cccc21
Reactant: COC(=O)CN
Agent: Cl
Product: COC(=O)CN1C(=O)c2cccc(O)c2C1=O
Yield: 18.6 %

Procedure:
4-Hydroxyisobenzofuran-1,3-dione (600 mg, 3.66 mmol) and methyl 2-aminoacetate hydrochloride (505 mg, 4.02 mmol) were finely dispersed on Montmorillonite K10 (powder, Sigma-Aldrich) (1.2 g) and the solid mixture was reacted under microwave irradiation at 150° C. for 30 minutes. Montmorillonite was washed with MeOH and the solvent was evaporated under vacuum. The crude was purified by preparative HPLC (Method 1) recovering the title compound (160 mg, 0.680 mmol, 19% yield). MS/ESI+ 236.1 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:20])=[CH:13][CH:14]=2)[C:9]1([CH2:23][CH3:24])[CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OCC)(=O)C.[F:39][C:40]([F:46])([F:45])[S:41](Cl)(=[O:43])=[O:42]>[Cl-].[Na+].O>[C:1]([O:5][C:6]([NH:7][C@@H:8]1[C:9]([CH2:21][CH3:22])([CH2:23][CH3:24])[C:10]2[CH:11]=[C:12]([O:20][S:41]([C:40]([F:46])([F:45])[F:39])(=[O:43])=[O:42])[CH:13]=[CH:14][C:15]=2[CH2:16][C@H:17]1[O:18][CH3:19])=[O:25])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC1(CC)c2cc(O)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCC1(CC)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
A mixture of trans-(1,1-diethyl-7-hydroxy-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (195.0 g, 0.558 mol), triethylamine (160 mL, 1.1 mol) and ethyl acetate (2000 mL) was stirred at room temperature for 15 min and cooled to 0° C. followed by slow addition of trifluoro-methanesulfonyl chloride (150 g, 0.89 mol) keeping the internal temperature below 4° C. The resulting slurry was stirred at 0° C. for 1 h. Additional triethylamine (16 mL) followed by additional trifluoromethanesulfonyl chloride (15.0 g) was added slowly maintaining a temperature below 5° C. The reaction mixture was stirred at room temperature for an additional hour. Diluted brine (1.0 L) was added and the reaction mixture was stirred for 10 min at room temperature. The layers were separated; the organic layer was washed with diluted NaHCO3 (1.0 L) and then concentrated to ˜350 mL by rotary evaporation at 28° C. and stirred at room temperature for 30 min. Heptane (700 mL) was added and the resulting slurry was stirred at room temperature for 30 min, cooled to 4° C. and stirred for 1 h. The solids were filtered, washed with heptane, and then dried under vacuum to yield the title compound (193.0 g, >97% purity). The filtrate was concentrated, slurried in an isopropyl acetate and heptane mixture (1:3, 60 mL) over 30 min, filtered and dried to yield additional product (45.0 g, >97% purity).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:18]=[C:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:9]=[C:10]([NH2:11])[N:5]2[N:4]=1.C1(C2[O:27]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.C(OC(=O)C)C.CO>ClCCl>[CH3:1][S:2]([C:3]1[N:18]=[C:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:9]=[C:10]([NH2:11])[N:5]2[N:4]=1)=[O:27]
Reactant: CSc1nc2cc(-c3ccccn3)cc(N)n2n1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CS(=O)c1nc2cc(-c3ccccn3)cc(N)n2n1
Yield: 56 %

Procedure:
8.66 g (0.034 mol) 2-Methylsulfanyl-7-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine in 850 ml dichloromethane were oxidised with a solution of 17.6 g (0.067 mol) 3-phenyl-2-(phenylsulfonyl)oxaziridine in 150 ml dichloromethane overnight. Chromatography on aluminiumoxide (dichloromethane/ methanol 97:3) and on silicagel (ethylacetate/methanol 9:1) yielded 5.2 g (57%) 2-methanesulfinyl-7-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, MS m/e (%):274 (M+H+,100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].CO>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#CCc1ccc(F)c(Cl)c1
Solvent: CO
Solvent: C1CCOC1
Product: Cl
Product: NCCc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 145 %

Procedure:
Borane-tetrahydrofuran complex solution (1 M in THF, 132 mL, 132 mmol) was added dropwise over 30 min at 0-5° C. to a solution of 3-chloro-4-fluoro-phenylacetonitrile (4.37 g, 25.8 mmol) in THF (40 mL), then the reaction mixture was stirred at RT for 20 min and refluxed for 21 h. The reaction mixture was then cooled to 0° C., and methanol (30 mL) was added at 2-5° C. over 45 minutes. After refluxing for 1 h the reaction mixture was concentrated, the residue dissolved in dichloromethane and the amine extracted twice with 1 M aq. hydrochloric acid solution. The combined aqueous phases were then treated with concentrated aq. sodium hydroxide solution to adjust the pH to 12, then extracted twice with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate, filtered and concentrated, leading to a colorless oil (4.3 g). This was dissolved in diethyl ether (125 mL), treated with hydrogen chloride solution (2.6 M in diethyl ether), and stirred at RT for 1 h. The precipitate was then collected by filtration to afford the title compound (3.93 g, 73%) White solid, MS (ISP) 174.1 (M−Cl)+.
Reaction SMILES: [ClH:1].Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10](F)[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=1.[CH3:21][O:22][C:23]1[N:28]=[N:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[Cl:1][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH2:3][NH:29][C:26]3[N:27]=[N:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[C:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:6]=2)[CH:9]=1
Reactant: COc1ccc(N)nn1
Reactant: Fc1ccc(-c2nc3ccc(F)cn3c2CCl)cc1
Reactant: Cl
Product: COc1ccc(NCc2c(-c3ccccc3)nc3ccc(Cl)cn23)nn1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine hydrochloride and 6-methoxypyridazin-3-amine compound. M/e+ 366 for C19H17ClN5O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.16 (t, J=0.7 Hz, 1H), 7.68 (dd, J=8.4, 1.4 Hz, 2H), 7.52 (d, J=9.5 Hz, 1H), 7.39 (m, 3H), 7.16 (dd, J=9.5, 1.8 Hz, 1H), 6.84 (q, J=9.5 Hz, 2H), 5.07 (d, J=4.7 Hz, 2H), 4.06 (s, 3H), 1.62 (bs, 1H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11]OS(C)(=O)=O)[S:7][C:6]=2[CH:17]=1.[CH3:18][NH:19][CH3:20]>CO>[CH3:18][N:19]([CH3:20])[CH2:11][CH2:10][C:8]1[S:7][C:6]2[CH:17]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[CH:9]=1
Reactant: Cc1ccc2cc(CCOS(C)(=O)=O)sc2c1
Reactant: CNC
Solvent: CO
Product: Cc1ccc2cc(CCN(C)C)sc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
In a closed pressure vessel methanesulfonic acid 2-(6-methyl-benzo[b]thiophen-2-yl)-ethyl ester from the previous step was taken up in MeOH (30 mL) and a 40% solution of dimethylamine in MeOH (30 mL) was added. The mixture was stirred for 2 hours at 90° C., cooled down to room temperature and concentrated in vacuo to afford 3.55 g of dimethyl-[2-(6-methyl-benzo[b]thiophen-2-yl)-ethyl]-amine (97%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C1(C)C=CC(S(O[CH2:17][C@H:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>>[CH3:23][C:20]1([CH3:24])[O:19][C@@H:18]([CH2:17][N:4]2[CH:3]=[C:2]([I:1])[CH:6]=[N:5]2)[CH2:22][O:21]1
Reactant: Ic1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](Cn2cc(I)cn2)O1
Temperature: 100 °C

Procedure:
A mixture of 4-iodopyrazole (1.00 g, 5.16 mmol), (R)-(−)-(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl p-toluenesulfonate (1.624 g, 5.671 mmol), Cs2CO3 (2.52 g, 7.73 mmol) and DMF (8 mL, 100 mmol) was heated to 100° C. for 2 h. The solution was extracted with EtOAc, and washed with water (2×). The organic layer was concentrated in vacuo and purified via column chromatography, eluting with 2-10% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=309.00 (100) [MH+]. HPLC: tR=1.32 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20](F)[C:11]=1[C:12]([NH:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])=O.O.C(OCC)(=O)C>O1CCCC1>[CH:1]1([C:20]2[CH:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:10]([F:9])[C:11]=2[C:12]2[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(F)c(C(=O)NC(C)(C)CO)c(F)c1
Reactant: Cl[Mg]C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(F)c(C2=NC(C)(C)CO2)c(C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclohexylmagnesium chloride (22 mL, 2M in diethyl ether, 44 mmol) was added slowly to an ice-cooled solution of the compound from preparation 2 (9.64 g, 40 mmol) in tetrahydrofuran (100 mL), and the solution then stirred at room temperature for 2 hours. Water (10 mL) was added, the mixture poured into ethyl acetate, and washed with a solution of ethylenediaminetetracetic acid disodium salt (24 g) in water (200 mL), then 1N sodium hydroxide solution (100 mL) and brine. The organic solution was dried (MgSO4) and evaporated under reduced pressure to afford the title compound as a colourless oil, 12.4 g.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][C:20]=3[C:29](=[O:31])[NH2:30])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>CN(C=O)C.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:28][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][C:20]=3[C:29](=[O:31])[NH2:30])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Oc2ccccc2)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(Oc2ccccc2)c1
Reaction time: 0.05 h
Yield: 65.3 %

Procedure:
40% Methanolic Triton B (0.054 mL, 0.12 mM) was added to a solution of the 9-[(3-phenoxyphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (39.5 mg, 0.10 mM) in 3 mL DMF at room temperature. After 3 minutes, t-butyl bromoacetate (54.8 mg, 0.27 mM) was added and the resultant mixture stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, once with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 33.0 mg (65%) of the {9-[(3-phenoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.5-6.8 (m, 15H), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.8 (s, 2H), and 1.45 (s, 9H). IR (KBr, cm−1) 3450, 1748, 1670, 1582, 1486, 1246, 1225, and 1151. MS (ES) m/e 523.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[NH:8][C:7]=2[CH:15]=1.Cl[CH2:17][CH2:18][CH2:19][O:20][CH3:21].[F-].[K+].[I-].[K+]>C(#N)C>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]=2[CH:15]=1
Reactant: CC1(C)Oc2ccc(CO)cc2NC1=O
Reactant: COCCCCl
Agent: [F-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(CO)cc21

Procedure:
A suspension of 2.270 g of 6-hydroxymethyl-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one in 180 ml of acetonitrile is admixed with 2.410 ml of 1-chloro-3-methoxypropane, 9.844 g of potassium fluoride on alumina and 0.036 g of potassium iodide. The reaction mixture is heated to reflux over 30 hours and filtered through Hyflo, and the filtrate is concentrated. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (3:1 EtOAc-heptane); Rt=3.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH2:44]([N:46]([C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=1)[CH2:47][CH2:48][NH2:49])[CH3:45]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:49][CH2:48][CH2:47][N:46]([CH2:44][CH3:45])[C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=2)=[O:42])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Reactant: CCN(CCN)c1cccc(C)c1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1OC)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1-ethyl-N1-(3-methylphenyl)-1,2-ethanediamine (84 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (140 mg, yield 85%).
Reaction SMILES: Cl.O1CCOCC1.[C:8]1([CH3:43])[C:9]([C:14]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:20][CH:19]([NH:34]C(OC(C)(C)C)=O)[C:18]2=[O:42])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1>C(O)C>[C:8]1([CH3:43])[C:9]([C:14]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([C:28](=[O:33])[C:29]([CH3:31])([CH3:32])[CH3:30])[CH2:20][CH:19]([NH2:34])[C:18]2=[O:42])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccccc1C(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)CN(C(=O)C(C)(C)C)c2ccccc21
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccccc1C(=O)CN1C(=O)C(N)CN(C(=O)C(C)(C)C)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
4N HCl-dioxane solution (5 ml) was added to 1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (540 mg) in ethanol (5 ml), and the mixture was stirred at 50° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with methylene chloride. The extract was dried over anhydrous sodium sulfate, to thereby obtain 411 mg of the titled compound.
Reaction SMILES: C([O:4][C:5]1[CH:17]=[CH:16][C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH:6]=1)=CC.Cl[C:19]1[CH:24]=CC=C[C:20]=1Cl>[Pd].C(OCC)(=O)C>[OH:4][C:5]1[CH:17]=[CH:16][C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]=1[CH2:20][CH2:19][CH3:24]
Reactant: CC=COc1ccc2oc3ccccc3c2c1
Reactant: Clc1ccccc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(O)ccc2oc3ccccc3c12
Temperature: 25 °C

Procedure:
A solution of 2-propenyloxydibenzofuran (0.9 grams) in ortho-dichlorobenzene 8 mL) was refluxed for 22 hours. Mixture was cooled to room temperature and was chromatographed over silica gel to afford the intermediate which was hydrogenated over 10% Pd/C catalyst (90 mg) in ethyl acetate for 18 hours. The reaction was filtered through Celite and all volatiles were removed to afford the title compound.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8]=[O:9].[CH2:10]1[CH2:14][O:13][CH2:12][CH2:11]1>>[CH2:8]([O:9][CH2:14][C:10]#[C:11][CH2:12][OH:13])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: [Li]CCCCCC
Reactant: C=O
Product: OCC#CCOCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
The crude alkyne I1 (81.9 g, 560 mmol) was dissolved in 500 ml of THF and cooled to −78° C. A 2.5M solution of n-hexyl lithium (250 ml, 625 mmol) was added dropwise over a period of 2 hours, so that the temperature did not exceed −70° C. Stirring was continued for 3 hours at −78° C. and then solid paraformaldehyde (20.18 g, 672 mmol) was added. The dry ice-bath was removed and the reaction allowed to warm up to room temperature over night (approx. 20 hours). The mixture was diluted with 600 ml of TBME and extracted with 400 ml of an ammonium chloride solution (20%). The aqueous layer was extracted once more with 200 ml of TBME and the combined organic fractions were washed three times with 400 ml of a brine, dried over anhydrous sodium sulfate and evaporated to give an orange liquid. Yield: 87.9 g (89%).