Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH3:31])[CH2:24]/[CH:25]=[C:26](\[CH3:30])/[C:27]([O-])=[O:28].[Li+].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[CH3:22][N:23]([CH3:31])[CH2:24]/[CH:25]=[C:26](\[CH3:30])/[C:27]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:28]
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Reactant: C/C(=C\CN(C)C)C(=O)[O-]
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(NC(=O)/C(C)=C/CN(C)C)c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (100 mg, 0.354 mmol) was added tetrahydrofuran (3.54 mL), TEA (74 μl, 0.53 mmol), lithium (2E)-4-(dimethylamino)-2-methylbut-2-enoate (137 mg, 0.920 mmol) and 1-propanephosphonic acid cyclic anhydride (211 μL, 0.354 mmol). The reaction was stirred at 25° C. overnight and then extracted from aqueous sodium hydrogen carbonate (5%) using ethyl acetate (×3). The organic layers were combined and dried with Na2SO4, filtered, and evaporated in vacuo. The crude product was then taken up in 2 mL of methanol and purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. Lyophilization of the desired fractions afforded the title compound as a colorless solid. LRMS (ESI) calc'd for C22H26N5O3 [M+H]+: 408, found 408. 1H NMR (600 MHz, DMSO-D6) 13.06 (bs, 1H), 10.04 (s, 1H), 9.76 (bs, 1H), 8.96 (s, 1H), 8.36 (d, 1H, J=2.8 Hz), 8.08 (s, 1H), 7.85 (dm, 1H, J=9.0 Hz), 7.47 (t, 1H, J=7.8 Hz), 7.36 (dm, 1H, J=7.8 Hz), 6.33 (t, 1H, J=7.2 Hz), 3.98 (apparent t, 1H, J=7.2 Hz), 3.91 (q, 2H, J=7.2 Hz), 2.89 (s, 3H), 2.88 (s, 3H), 2.02 (s, 3H), 0.90 (t, 3H, J=7.2 Hz).
Reaction SMILES: [C:1](=O)([O-])[O-:2].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].C(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:1](=[O:2])[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12
Reactant: COc1ccccc1Nc1ccccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1-n1c(=O)oc(=O)c2ccccc21
Reaction time: 8 h
Yield: 22.1 %

Procedure:
To a suspension of 24.44 g (0.177 mole) of potassium carbonate in 119 ml of toluene and 238 ml of water, stirred at 20°-40° C., was added 28.61 g (0.1176 mole) of 2-(2-methoxyphenylamino)benzoic acid, and phosgene was bubbled through the mixture for a period of 3.5 hours. The reaction was allowed to stand overnight with stirring, and the solid material was collected by filtration. The latter was dissolved in ethyl acetate and added to the toluene layer separated from the filtrate. The solution was washed twice with 200 ml 1N potassium hydroxide and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to yield 7 g of N-(2-methoxyphenyl)isatoic anhydride.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=O)C.[CH:10]([CH:12]=[CH2:13])=[O:11]>O1CCOCC1>[N:1]1[CH:5]=[CH:4][N:3]2[CH2:13][CH2:12][CH:10]([OH:11])[C:2]=12
Reactant: C=CC=O
Reactant: c1c[nH]cn1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: OC1CCn2ccnc21

Procedure:
To a solution of imidazole (2 mL, 30.26 mmol) and acetic acid (0.12 mL, 2.12 mmol) in dry dioxane (20 mL) under N2 was added acrolein (3.03 mL, 45.39 mmol) in 1 portion and the resultant solution heated to reflux for 4 hr. The reaction mixture was concentrated in vacuo and the yellow-brown residue was purified by column chromatography, (elution with 25% methanol in DCM) to give the title product; 1H NMR (500 MHz, DMSO) delta 2.25 (1H, ddt, J=13.06, 7.90, 3.94, 3.94 Hz), 2.70-2.87 (1H, m), 3.85 (1H, ddd, J=10.72, 8.51, 4.26 Hz), 4.03 (1H, ddd, J=10.72, 7.80, 6.23 Hz), 4.86 (1H, dd, J=7.09, 3.00 Hz), 5.58 (1H, br. s.), 6.94 (1H, s), 7.06 (1H, d, J=0.95 Hz); LC-MS: m/z=+124.9 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1>>[F:33][C:29]1[CH:28]=[C:27]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])[CH:32]=[CH:31][CH:30]=1
Reactant: Fc1cccc(Br)c1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3cccc(F)c3)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and 1-bromo-3-fluorobenzene
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:15].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.O>[C:1]1([C:7]2[CH:12]=[C:11]([Br:15])[CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [Br-]
Reactant: COc1ccccc1-c1ccccc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Br)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-phenylanisole (18.27 g, 0.099 mol) in CH2Cl2 (350 mL) was added pyridinium tribromide (34.88 g, 0.109 mol). The resulting mixture was allowed to stir at RT overnight. The mixture was diluted with CH2Cl2 and H2O and the layers were separated, the aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were washed with H2O, brine and dried with MgSO4. The mixture was filtered and the solvents evaporated to give 2-phenyl-4-bromoanisole as a reddish oil (26.05 g, 100%). 1H NMR (300 MHz, CDCl3): δ 3.75 (s, 3H), 6.82 (d, J=8.7 Hz, 1H), 7.28–7.43 (m, 5H), 7.45–7.49 (m, 2H).
Reaction SMILES: C([CH2:4][NH:5][C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([O:23][CH2:24][CH3:25])[C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=2)=[CH:9][N:10]=1)(=O)C.[OH-].[Na+]>CO.O>[CH2:24]([O:23][C@@H:18]([CH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[S:7][C:6]([NH:5][CH3:4])=[N:10][CH:9]=2)=[CH:16][CH:15]=1)[C:19]([OH:21])=[O:20])[CH3:25]
Reactant: CCO[C@@H](Cc1ccc(-c2cnc(NCC(C)=O)s2)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCO[C@@H](Cc1ccc(-c2cnc(NC)s2)cc1)C(=O)O

Procedure:
0.6 g (1.6 mmol) of methyl 3-{4-[2-(acetylmethylamino)thiazol-5-yl]phenyl}-2(S)-ethoxypropanoate in 25 ml of methanol and 2.4 ml (2.4 mmol) of aqueous 1M sodium hydroxide solution are heated at 60° C. for 18 hours. The reaction medium is cooled, diluted with water, acidified to pH 4-5 and then extracted with ethyl acetate and n-butanol. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is used in step h without purification.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([CH2:45][NH:46][C:47]([NH:49][CH2:50][CH2:51][N:52]([CH:56]1[CH2:60][CH2:59][CH2:58][CH2:57]1)[CH:53]([CH3:55])[CH3:54])=[O:48])=[N:25][C:26]=2[NH:30][CH2:31][CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH:56]1([N:52]([CH:53]([CH3:54])[CH3:55])[CH2:51][CH2:50][NH:49][C:47]([NH:46][CH2:45][C:24]2[N:23]=[C:22]3[C:27]([N:28]=[CH:29][N:21]3[C@H:6]3[C@H:5]([OH:4])[C@H:9]([OH:10])[C@@H:8]([C:14]4[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=4)[O:7]3)=[C:26]([NH:30][CH2:31][CH:32]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:25]=2)=[O:48])[CH2:57][CH2:58][CH2:59][CH2:60]1
Reactant: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNC(=O)NCCN(C(C)C)C5CCCC5)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNC(=O)NCCN(C(C)C)C5CCCC5)nc43)[C@H](O)[C@@H]2O)n1
Yield: 29.6 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(acetoxy)-2-{2-({[({2-[cyclopentyl(isopropyl)amino]ethyl}amino)carbonyl]amino}methyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3-furanyl acetate (Preparation 45) (135 mg, 0.16 mmol) and sodium carbonate (5 mg, 0.05 mmol) in methanol (5 ml) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:conc. aqueous ammonia (95:5:0.5 by volume) gradually changing to dichloromethane:methanol:conc. aqueous ammonia (90:10:1 by volume). Product containing fractions were evaporated and the resulting solid was dried under vacuum to afford the title compound as a white powder (35 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1)=[O:15].Br[CH2:28][C:29]1([CH:36]=[CH:35][CH:34]=[CH:33][CH:32]1[C:37]([F:40])([F:39])[F:38])CBr>C1COCC1.CS(C)=O>[Cl:11][C:12]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH2:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:38])([F:39])[F:40])[N:18]=1)=[O:15]
Reactant: O=C(Nc1cc[nH]n1)c1c(Cl)cccc1Cl
Reactant: FC(F)(F)C1C=CC=CC1(CBr)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2ccccc2C(F)(F)F)n1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 M lithium bis(trimethylsilyl)amide (100 μl, 0.1 mmol, Aldrich) was slowly added to a solution of 2,6-dichloro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 44)(26 mg, 0.1 mmol) in THF (400 μl). The resulting solution was then transferred to a solution of 1-(bromomethyl)-2-(trifluoromethyl)benzyl bromide (24.7 mg, 0.1 mmol, Apollo Scientific Limited) in THF (200 μl) and stirred for 2 h under nitrogen at ambient temperature. The mixture was diluted with DMSO (0.6 ml) and purified by MDAP using the Sunfire C18 column (Method D) using Acetonitrile-Water with a TFA modifier. The solvent was removed under a stream of nitrogen to give the title compound (27 mg); LCMS (System 4) MH+=415, tRET=3.11 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][N:29](CC3C=CC=CC=3)[CH3:30])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][N:29]([C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])[CH3:30])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCn1cc(-c2ccc(F)c(F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1)Cc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CC#N
Product: CN(CCn1cc(-c2ccc(F)c(F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Yield: 82 %

Procedure:
Charge 4-[1-[2-(benzyl-methyl-amino)-ethyl]-4-(3,4-difluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.8 g; 0.0035 mol; 1.0 equiv) in ACN (40 mL) under nitrogen and add benzyl chloroformate drop wise at 0° C. Stir the reaction for 30 min and bring to RT. Stir at RT for 1.5 h. After completion, quench the reaction with saturated sodium bicarbonate solution and extract in EA. Wash with water and brine, dry over anhydrous sodium sulfate and evaporate off the solvent under vacuum. Purify on silica column using 15% EA/hexane to get the title compound (1.6 g; 82%). (ES+): m/z=555 (M+H).
Reaction SMILES: C([N:8]([CH2:32][CH2:33][O:34][C:35]([CH3:38])(C)C)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:16]=2[CH:31]=1)=[O:10])C1C=CC=CC=1.Br.C(=O)(O)[O-:41].[Na+]>C(O)(=O)C>[C:35]([O:34][CH2:33][CH2:32][NH:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:16]=2[CH:31]=1)=[O:10])(=[O:41])[CH3:38]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)N(CCOC(C)(C)C)Cc3ccccc3)ccc21
Reactant: O=C([O-])O
Agent: Br
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCCNC(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Reaction time: 72 h

Procedure:
200 mg (0.4 mM) of 1-benzyl-1-(2-tert.butoxyethyl)-3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]urea are heated on a steam-bath for 10 minutes in 3 ml of a 33% solution of hydrogen bromide in glacial acetic acid and then left to stand at room temperature for 3 days. The mixture is neutralised with sodium bicarbonate and extracted several times with methylene chloride. The methylene chloride extracts are combined, dried over sodium sulphate, filtered and concentrated. The residue is purified in a pressure column (0.2-0.4 atmospheres of nitrogen) on 15 g of silica gel (particle size 0.04-0.06 mm) using ethyl acetate as the eluting agent and crystallised from ethyl acetate/ether, there being obtained 2-[3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7yl]ureido]ethyl acetate which melts at 196°-198° C.
Reaction SMILES: [P:1](=[S:5])([OH:4])([OH:3])[SH:2].[O-2].[Zn+2:7]>>[P:1]([O-:4])([O-:3])([S-:5])=[S:2].[Zn+2:7].[P:1]([O-:4])([O-:3])([S-:5])=[S:2].[Zn+2:7].[Zn+2:7]
Reactant: OP(O)(=S)S
Agent: [O-2]
Agent: [Zn+2]
Product: [O-]P([O-])(=S)[S-]
Temperature: 65 °C

Procedure:
To a three neck flask was added 204.3 g of the dithiophosphoric acid mixture from Example 3, lot RJT-543-244, and 27.1 g of zinc oxide. The mixture was heated to 65° C. and mixed at this temperature for four hours. The temperature was then increased to 100° C. The temperature was then gradually increased to 110° C. under vacuum while distilling off any water produced from the reaction. After mixing at 110° C. for 1 hour while under vacuum, the final product was filtered with diatomaceous earth.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][S:10][C:5]2=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[Li]CCCC.[Cl:23]N1C(=O)CCC1=O.[NH4+].[Cl-]>C1COCC1>[Cl:23][C:9]1[S:10][C:5]2[C:6](=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:8]=1
Reactant: Cc1ccc2sccc2n1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc2sc(Cl)cc2n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81.7 %

Procedure:
To a solution 5-methylthieno[3,2-b]pyridine (3.60 g, 24 mmol) and N,N-diisopropylamine (100 uL) in THF (80 mL) at -78° C. was added dropwise 16 mL of n-BuLi (1.6M, 25.6 mmol). The mixture was stirred at -78° C. for 20 min and then transfered via a cannula to a solution of N-chlorosuccinimide (4.5 g, 34 mmol) in THF (300 mL) at -10° C. The mixture was stirred at -10° C. for 30 min. Saturated NH4Cl solution was then added and the product was extracted with EtOAc, dried over MgSO4, and concentrated to an oil. Chromatography of the crude oil on silica gel (eluted with 15% EtOAc in hexane) yielded 3.60 g (81%) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:5][NH:4][C:3]1=[O:6].O.[C:8]1([CH2:14][C:15](O)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>O1CCCC1>[C:8]1([CH2:14][C:15]([NH:1][C@H:2]2[CH2:5][NH:4][C:3]2=[O:6])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N[C@H]1CNC1=O
Reactant: O=C(O)Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N[C@H]1CNC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
(S)-3-Amino-2-azetidinone (0.86 g) is suspended in 40 ml of tetrahydrofuran and 5 ml of water is added. A solution of phenylacetic acid (1.36 g) in 10 ml of tetrahydrofuran is added, followed by N-ethyl-N'-(3-dimethylamino)propylcarbodiimide, hydrochloride (1.92 g). The solution is adjusted to pH 4 by the addition of 2N hydrochloric acid and stirred for 1 hour at room temperature. The tetrahydrofuran is removed by evaporation and the remaining suspension is filtered to yield 1 g of (S)-3-[[(phenylmethyl)carbonyl]amino]-2-azetidinone, melting point 182° C., dec.
Reaction SMILES: [Cl:1][C:2]1[C:14]([F:15])=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:9]=4[C:10]([CH3:17])([CH3:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:24][C:25]1([CH3:32])[O:29][C@@H:28]([CH2:30]O)[CH2:27][O:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:14]([F:15])=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:21]=[CH:20][C:19]([O:22][CH2:30][C@H:28]5[CH2:27][O:26][C:25]([CH3:32])([CH3:24])[O:29]5)=[CH:18][C:9]=4[C:10]([CH3:17])([CH3:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1c(F)c(Cl)ccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4c(F)c(Cl)ccc4c2C3=O)O1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
3-Chloro-4-fluoro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S2-3, 20.0 mg, 0.061 mmol) was dissolved in THF (0.25 mL), added with ((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (9.8 μL, 0.079 mmol), triphenylphosphine (20.7 mg, 0.079 mmol) and diethyl azodicarboxylic acid (35.9 μl, 0.079 mmol), and then stirred at 40° C. for 5 hr. The reaction solution was concentrated under reduced pressure, and the resulting residues were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the intermediate, 3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-4-fluoro-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one. This compound was dissolved in THF (0.10 mL) and MeOH (0.08 ml), added with sulfuric acid (0.5 M, 0.045 ml), and then stirred at 60° C. for 1 hr. The reaction solution was added with saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The yellow solid obtained after concentration under reduced pressure was washed with methylene chloride/hexane solvent and filtered to obtain the title compound (4.3 mg, 18%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[CH2:14]([O:21][C:22]([NH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](O)=[O:28])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]([NH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:28])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC1CCc2ccccc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Product: CC(C)(CC(=O)NC1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1

Procedure:
Prepared from 3-amino-2,3,4,5-tetrahydro-1H[1]benzazepin-2-one (Example 1, Step A) and 3-benzyloxycarbonylamino-3-methylbutanoic acid (Example 1, Step E) by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.38 (s,3H), 1.39 (s,3H), 1.82 (m,1H), 2.52 (s,2H), 2.5-3.0 (m,3H), 4.51 (m,1H), 5.07 (br s,2H), 5.58 (br s,1H), 6.68 (d,7 Hz, 1H), 6.96 (d,8 Hz, 1H), 7.1-7.4 (m,8H), 7.62 (br s, 1H). FAB-MS: calculated for C23H27N3O4 409; found 410 (M+H,100%).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[F:10][C:11]([F:15])([F:14])[CH2:12]I>[Pt](=O)=O>[F:10][C:11]([F:15])([F:14])[CH2:12][N:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[N:2]1
Reactant: c1cc2cn[nH]c2cn1
Reactant: FC(F)(F)CI
Agent: O=[Pt]=O
Product: FC(F)(F)Cn1ncc2c1CNCC2

Procedure:
1H-Pyrazolo[3,4-c]pyridine was alkylated with 1,1,1-trifluoro-2-iodoethane, then reduced via hydrogenation over platinum(IV) oxide to afford 1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[C:4]([C:8]#[N:9])[N:5]([CH3:7])[CH:6]=1.[Si:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:3]([CH3:10])=[C:4]([C:8]#[N:9])[N:5]([CH3:7])[CH:6]=2)=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Reactant: Cc1c(Br)cn(C)c1C#N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2)cn(C)c1C#N
Temperature: 100 °C

Procedure:
4-Bromo-1,3-dimethyl-1H-pyrrole-2-carbonitrile (2.03 g, 10.2 mmol) and 4-[(tert-butyldimethylsilyl)oxy]aniline (3.41 g, 15.3 mmol) are dissolved in toluene (40 mL). The solution is degassed with nitrogen for 10 minutes. Sodium tert-butylate (1.18 g, 12.2 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.17 g, 0.41 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.187 g, 0.2 mmol) are then added. The mixture is heated at 100° C. for 30 minutes and then cooled to ambient temperature. Water (50 mL) and Celite (6 g) are added. The suspension is filtered over Celite, and the filtrate is diluted with MTBE. The phases are separated and the aqueous phase is extracted with MTBE (2×50 mL). The combined organic phases are dried over Na2SO4 and filtered. The residue is purified by chromatography over silica gel using ethyl acetate and heptane as eluants followed by reverse-phase chromatography using methanol and water as eluants. The product obtained is lyophilised to provide the expected compound in the form of a solid.