Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][C:28]2[CH:27]=[C:26]([OH:30])[CH:25]=[CH:24][C:23]=2[C@@H:22]2[C@@H:13]1[C@H:14]1[C@@:18]([CH2:20][CH2:21]2)([CH3:19])[C@@H:17]([OH:31])[CH2:16][CH2:15]1)(C)(=O)=O.[Br-].C[Si](C)(C(C)(C)C)OCCCCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:65]([S:70][CH2:71][CH2:72][CH2:73][SH:74])[CH2:66][CH2:67][CH2:68][CH3:69]>>[CH2:65]([S:70][CH2:71][CH2:72][CH2:73][S:74][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][C:28]2[CH:27]=[C:26]([OH:30])[CH:25]=[CH:24][C:23]=2[C@@H:22]2[C@@H:13]1[C@H:14]1[C@@:18]([CH2:20][CH2:21]2)([CH3:19])[C@@H:17]([OH:31])[CH2:16][CH2:15]1)[CH2:66][CH2:67][CH2:68][CH3:69]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCOS(C)(=O)=O)[C@H]3[C@@H]1CC[C@@H]2O
Reactant: CCCCCSCCCS
Agent: CC(C)(C)[Si](C)(C)OCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCCCSCCCSCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12

Procedure:
The process described in Example 32 was repeated using 7α-(6-mesyloxyhexyl)oestra-1,3,5(10)-triene-3,17β-diol (obtained as described in Example 41 using initially 5-(dimethyl-t-butylsilyloxy)pentyltriphenylphosphonium bromide and 3-n-pentylthiopropanethiol (obtained from trimethylene-1,3-dithiol and pentyl bromide) as starting materials. There was thus obtained as an oil 7α-[6-(3-n-pentylthiopropylthio)hexyl]-oestra-1,3,5(10)triene-3,17β-diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6](=O)[C:5]=12.P(Cl)(Cl)(Cl)(Cl)Cl.[C:22]1([CH3:28])C=CC=CC=1>CN(C)C=O>[CH3:3][N:4]1[CH2:28][CH2:22][N:7]([C:6]2[C:5]3=[CH:1][CH:2]=[CH:3][N:4]3[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=2)[CH2:6][CH2:5]1
Reactant: Cc1ccccc1
Reactant: O=C1Nc2ccccc2Cn2cccc21
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CN1CCN(C2=Nc3ccccc3Cn3cccc32)CC1

Procedure:
A mixture of 2 g. of 5,10-dihydro-11H-pyrrolo[2,1-c]-[1,4]benzodiazepin-11-one (Example 1), 2 g. of phosphorus pentachloride and two drops of N,N-dimethylformamide in 50 ml. of toluene is heated on the steam bath for several hours. The solvent is removed by distillation, 25 ml. of chloroform is added and the mixture evaporated again. The residue is dissolved in 25 ml. of chloroform and this solution slowly added to 10 ml. of N-methylpiperazine in 40 ml. of toluene. This mixture is heated for several hours, finally to the boiling point of toluene, and then evaporated to an oily residue. The residue is taken up in ether (500 ml) and extracted into dilute acetic acid. The aqueous acetic acid layer is made basic with concentrated ammonium hydroxide and the product which precipitates is extracted into ether. The ether solution is dried over anhydrous potassium carbonate, and evaporated to a residue which contains the desired product. When purified by recrystallization it shows m.p. 139°-141° C. (base).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.C([Li])CCC.[Cl-].[NH4+].Cl.[O:47]1CCC[CH2:48]1>CCCCCC.CN(C)C=O>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:14]2[C:13]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:4]=[CH:3][C:2]([CH:48]=[O:47])=[CH:7][N:6]=3)[N:17]=[CH:16][N:15]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C=O)cn2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-[6-{2-(5-bromopyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide (700 mg) in tetrahydrofuran (15 ml) is added dropwise a 1.6M solution of n-butyl lithium in n-hexane (1.46 ml) at -78° C. The mixture is stirred at -78° C. for 15 minutes, and thereto is added dimethylformamide (0.28 ml), and the reaction solution is reacted at the same temperature for 15 minutes. The solution is treated with aqueous ammonium chloride solution, and acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and the residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=100:1~30:1), and recrystallized from diisopropyl ether to give 4-tert-butyl-N-[6-{2-(5-formylpyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl]benzenesulfonamide (198 mg) as crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:21][C@@H:22]1[CH2:24][C@H:23]1[CH3:25])[C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[N:14]=1)[C:9](O)=[O:10].C(N(C(C)C)CC)(C)C.[C:35]([NH:42][NH2:43])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:21][C@@H:22]1[CH2:24][C@H:23]1[CH3:25])[C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:17])=[O:18])[N:14]=1)[C:9]([NH:43][NH:42][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:10]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COCCN(C[C@@H]1C[C@H]1C)c1cc(C(=O)O)cc(N(C)S(C)(=O)=O)n1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCN(C[C@@H]1C[C@H]1C)c1cc(C(=O)NNC(=O)OC(C)(C)C)cc(N(C)S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-{(2-methoxyethyl)[(trans-2-methylcyclopropyl)methyl]amino}-6-[methyl(methylsulfonyl)amino]isonicotinic acid (14.05 g, 37.8 mmol) in DCM (150 mL) was added diisopropylethyl amine (7.91 mL, 45.4 mmol), Boc-hydrazine (6 g, 45.4 mmol), HOAt (1.03 g, 7.6 mmol) and EDC (8.7 g, 45.4 mmol), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc, washed with 10% KHSO4, aq NaHCO3 and brine, dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography (silica, 30% to 70% EtOAc in hexane) to give tert-butyl 2-{2-{(2-methoxyethyl)[(trans-2-methylcyclopropyl)methyl]amino}-6-[methyl(methylsulfonyl)amino]isonicotinoyl}hydrazinecarboxylate. MS M+1=486.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)([O-:9])=[O:8].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])[CH2:18][CH2:17]2)=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(C(Cl)Cl)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 45.8 %

Procedure:
7.1 g (0.048 mol) of dichloroacetyl chloride were added dropwise to a solution of 10 g (0.048 mol) of 1-(4-nitrophenyl)-piperazine and 5 g (0.495 mol) of triethylamine in 100 ml of toluene at room temperature, while stirring. The mixture was subsequently stirred at 20° C. for 3 hours. Working up was then effected by a procedure in which the reaction mixture was washed twice with 100 ml of water each time and the organic phase was separated off, dried and evaporated under reduced pressure. The residue was recrystallized from toluene. 7 g (46% of theory) of 1-(4-nitrophenyl)-4-dichloroacetyl-piperazine were obtained in the form of light yellow crystals of melting point 155° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)=[C:10]2[C:27]([O:29]CC)=[O:28])=[CH:5][CH:4]=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Reaction time: 56 h
Yield: 106 %

Procedure:
To a solution of ethyl (RS)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (0.72 g, 1.7 mmol) in EtOH (30 ml) was added 10% palladium on activated carbon (1 g). The resulting suspension was stirred under an atmosphere of H2 for 56 h and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid (0.70 g, 95%), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:13])=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].B([O-])([O-])[O-].F[N+:19](F)(F)F.F[N+](F)(F)F.F[N+](F)(F)F.N([O-])=O.[Na+].C([O-])(=O)C.[K+].C1OCCOCCOCCOCCOCCOC1>Cl.O.C(Cl)(Cl)Cl>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:2]2[C:3]=1[NH:13][N:19]=[CH:1]2)=[O:6]
Reactant: F[N+](F)(F)F
Reactant: COC(=O)c1ccc(C)c(C)c1N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C)c2cn[nH]c12
Reaction time: 12 h
Yield: 58.9 %

Procedure:
A solution of methyl 3,4-dimethyl-2-aminobenzoate (10 g) in concentrated hydrochloric acid (20 ml) was cooled to 0° C., treated with solution of tetrafluoroammoniumborate (9.4 g) in water (2 ml), a solution of sodium nitrite (7.7 g) in water (2 ml) dropwise, stirred for 2 h, filtered to get a solid. The solid residue was dissolved in chloroform (50 m), treated with potassium acetate (2 mol equivalents) and catalytic amounts of 18-Crown-6, and stirred for 12 h. The reaction mixture was treated with water (50 ml) and extracted with chloroform (2×50 ml). The combined organic layers were dried over sodium sulfate and concentrated. Chromatographic purification (hexane/ethyl acetate 80:20) gave 4-methyl- 1H-indazole-7-carboxylic acid methyl ester (3.2 g). 1H-NMR (400 MHz, CDCl3): 2.68 (s, 3H), 4.00 (s, 3H), 7.02 (d, 1H), 7.97 (d, 1H), 8.15 (s, 1H). LC-MS (methanol): m/z=191 (M+H).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:7]=1[C:8](=[O:21])[C:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=1[C:15]2=[O:20])([O-])=O.CC(O)COC(CO)C.[H][H]>[Pd]>[NH2:3][C:6]1[C:7]2[C:8](=[O:21])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:20])[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Agent: CC(O)COC(C)CO
Agent: [Na+]
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Yield: 87.3 %

Procedure:
0.1 Gram of a 5% palladium on carbon catalyst and 10 grams of a 20% aqueous sodium hydroxide solution were added to a mixture of 12.8 grams of 5-nitrotetrahydroanthraquinone and 170 grams of dipropylene glycol in an autoclave, into which was fed hydrogen, until the pressure reached 25 kg/cm2, for hydrogenation of the 5-nitro compound at 120° C. with agitation. Hydrogen was absorbed in the starting 5-nitro compound in an amount of 2mols per mol of the 5-nitro compound. After completion of the hydrogenation, the resultant solution was subjected to filtration under hot conditions at 120° to 130° C. to remove the catalyst therefrom. To the resultant filtrate was added 350 grams of water for dilution to obtain crystals which were separated by filtration, washed with water and dried to yield 9.7 grams of 1-aminoanthraquinone having a purity of 96.7%.
Reaction SMILES: F[P:2]123[N:12]4[CH2:13][CH2:14][N:3]1[CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][N:9]3[CH2:10][CH2:11]4.[OH-:15].[Na+]>>[O:15]=[P:2]12[N:9]3[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][N:3]1[CH2:4][CH2:5][N:6]2[CH2:7][CH2:8]3
Reactant: [OH-]
Reactant: FP123N4CCN1CCN2CCN3CC4
Agent: [Na+]
Product: O=P12N3CCNCCN1CCN2CC3

Procedure:
A 100 mg sample of 13-fluoro-1,4,7,10-tetraaza-13-phosphatetracyclo[5.5.1.04,13.010,13 ]tridecane was dissolved in 0.5 ml of 1N sodium hydroxide by heating to near boiling. This mixture was cooled, filtered and evaporated. The white residue was then sublimed at 150°-180° and 0.1 mm pressure to give 90 mg of 13-oxo-1,4,7,10-tetraaza-13-phosphatricyclo[5.5.1.04,13 ]tridecane and leaving 10- 20 mg of residue. The sublimate was kept under dry nitrogen and melted at 215°-217° to a clear colorless melt. On exposure to moist air this solid picked up water of hydration without softening. The hydrated sample softened at 90° and slowly lost water up to 160° where the sample frothed and then darkened and totally melted in the range of 200°-210°. The anhydrous sample was used for nmr and mass spectra.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F-:12]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: [F-]
Solvent: CC#N
Product: O=S(=O)(F)c1ccc(Br)cc1
Reaction time: 5 h

Procedure:
To a solution of 4-bromophenylsulfonyl chloride (2 g, 7.83 mmol) in acetonitrile (10 mL), was added fluoride on Amberlyst A-26 (Aldrich Chemical Company, 7.5 g, 21.6 mmol F−). After agitation for 5 hours at room temperature, the mixture was filtered. The solvent was removed under reduced pressure to give 4-bromophenylsulfonyl fluoride (1.5 g) (confirmed by IR spectroscopy).
Reaction SMILES: [C]=O.[F:3][CH2:4][C:5]1([CH2:27][F:28])[CH:10]=[C:9](OS(C(F)(F)F)(=O)=O)[C:8]2[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:7]=2[O:6]1.[C:29]([O-:32])(=[O:31])C.[K+]>CN(C)C(=O)C>[F:3][CH2:4][C:5]1([CH2:27][F:28])[CH:10]=[C:9]([C:29]([OH:32])=[O:31])[C:8]2[CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:7]=2[O:6]1
Reactant: O=S(=O)(OC1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21)C(F)(F)F
Reactant: CC(=O)[O-]
Agent: [C]=O
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21

Procedure:
A three-necked 50-ml flask (equipped with a reflux condenser, a thermometer, and a CO introducing pipe connected with a balloon charged with carbon monoxide gas) was charged with 1.0 g (2.4 mmol) of trifluoromethanesulfonic acid 2,2-bis(fluoromethyl)-6-(trifluoromethyl) -2 H- 1-benzopyran-4-yl ester, 0.95 g (9.7 mmol) of potassium acetate, and 10 ml of N,N-dimethylacetamide. Under stirring of the mixture, predetermined amounts of reagents were added, as shown in Table. Then, the reaction was conducted under conditions shown in Table. After that, the reaction mixture was subjected to the same post-treatments as those of Example 5. As a result, 2,2-bis(fluoromethyl)-6-(trifluoromethyl)-2 H- 1-benzopyran-4-carboxylic acid was obtained, as shown by yield in Table.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[N:3]=1.[NH2:13][C@H:14]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:15][OH:16]>C1COCC1>[F:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([NH:13][C@@H:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:15][OH:16])=[N:3][C:2]=1[F:1]
Reactant: N[C@@H](CO)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc(F)c(F)nc1F
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(F)nc1N[C@H](CO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,3,6-trifluoro-5-nitropyridine (1.2 g, 6.7 mmol) in THF (40 ml) was cooled to 0° C. (R)-2-amino-2-(4-fluorophenyl)ethanol (1.0 g, 6.7 mmol) was then added and the reaction was stirred at 0° C. for 30 minutes. The reaction was quenched with water (50 ml) and then extracted with DCM (2×75 ml). The combined organic fractions were dried over
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][CH3:3].[Br:7][C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13](Cl)[S:14][C:10]=2[CH:9]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>C1(C)C=CC=CC=1>[Br:7][C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([CH:2]([CH3:3])[C:1]([O:5][CH3:6])=[O:4])[S:14][C:10]=2[CH:9]=1
Reactant: CCC(=O)OC
Reactant: Clc1nc2ccc(Br)cc2s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)c1nc2ccc(Br)cc2s1
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To a solution of methyl propionate (0.088 mL, 0.89 mmol) and 6-bromo-2-chlorobenzo[d]thiazole (221 mg, 0.89 mmol) in degassed toluene (5 mL) at brine/ice bath temperature was slowly added 1.0 M NaHMDS in THF (2.22 mL, 2.22 mmol). After the addition was complete, the reaction was stirred for 10 min. The mixture was then quenched with sat′d NH4Cl (15 mL) then extracted with EtOAc (2×20 mL). The organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexane to give Compound R1a (198 mg, 0.66 mmol, 74% yield) as a yellow solid. LCMS=1.0 min using analytical method (M), 302.0 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=1.8 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.58 (dd, J=8.7, 1.9 Hz, 1H), 4.30 (q, J=7.3 Hz, 1H), 3.78 (s, 3H), 1.75 (d, J=7.3 Hz, 3H).
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)C.[O:17]=[C:18]1[N:29]([C@H:30]2[CH2:35][CH2:34][CH2:33][C@H:32]([CH:36]=O)[CH2:31]2)[C:21]2=[C:22]3[CH:28]=[CH:27][NH:26][C:23]3=[N:24][CH:25]=[C:20]2[NH:19]1.O>O1CCCC1>[O:17]=[C:18]1[N:29]([C@H:30]2[CH2:35][CH2:34][CH2:33][C@H:32](/[CH:36]=[CH:7]/[C:6]([OH:5])=[O:16])[CH2:31]2)[C:21]2=[C:22]3[CH:28]=[CH:27][NH:26][C:23]3=[N:24][CH:25]=[C:20]2[NH:19]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C[C@H]1CCC[C@H](n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C/[C@H]1CCC[C@H](n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of sodium hydride (60% in oil) (7 mg) in tetrahydrofuran (1 ml) was added dropwise ethyl(diethoxyphosphoryl)acetate (53 μl). After stirring at ambient temperature for 5 minutes, trans-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexanecarbaldehyde (50 mg) was added and stirred at ambient temperature for overnight. The reaction mixture was poured into water, and extracted with EtOAc and tetrahydrofuran. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by preparative thin layer chromatography eluting with dichloromethane:methanol=10:1. The fractions containing desired compound were combined and evaporated. The residue was dissolved in dioxane (250 μl), and 1M NaOH solution (176 μl) was added, then stirred at 110° C. for 2 hours. After cooling to the ambient temperature, 1M HCl (176 μl) and pH 4 buffer (5 ml) was added to the reaction mixture. Resulting precipitates were collected by filtration and washed with water to give (2E)-3-[trans-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexyl]acrylic acid (11.0 mg) as a brown powder.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:27]=[C:26]([CH3:28])[C:20]([O:21][CH2:22][CH2:23][CH2:24][NH2:25])=[C:19]([CH2:29][CH3:30])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:33](O)(=[O:36])[CH2:34][OH:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:27]=[C:26]([CH3:28])[C:20]([O:21][CH2:22][CH2:23][CH2:24][NH:25][C:34](=[O:35])[CH2:33][OH:36])=[C:19]([CH2:29][CH3:30])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CO
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCNC(=O)CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.2 %

Procedure:
To a solution of 3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)propan-1-amine (200 mg, 0.458 mmol), glycolic acid (52 mg, 0.687 mmol) and DIPEA (178 mg, 1.37 mmol) in DMF (5 mL), TBTU (191 mg, 0.596 mmol) is added. The mixture is stirred at rt for 18 h before it is diluted with EA (50 mL) and washed twice with sat. aq. NaHCO3 solution (50 mL) followed by brine (50 mL). The org. extract is dried over Na2SO4, filtered, and concentrated. The crude product is purified by prep. HPLC to give the title compound (116 mg) as a pale yellow oil; LC-MS: tR=1.14 min, [M+H]+=495.25; 1H NMR (CD3OD): δ 7.85 (s, 1H), 7.83 (s, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 4.01 (s, 2H), 4.00 (s, 3H), 3.94 (t, J=6.1 Hz, 2H), 3.57 (t, J=6.9 Hz, 2H), 3.24-3.31 (m, 1H), 2.77 (q, J=7.6 Hz, 2H), 2.38 (s, 3H), 2.05-2.16 (m, 4H), 1.86-1.96 (m, 4H), 1.72-1.82 (m, 2H), 1.31 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:11]([N:10]1[C:5]2[C:4]([Cl:21])=[N:3][C:2]([NH2:1])=[N:7][C:6]=2[CH:8]=[CH:9]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc2ccn(Cc3ccccc3)c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Temperature: 116 °C
Yield: 25.6 %

Procedure:
A mixture of 2-amino-5-benzyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (1.1 g, 7.4 mmol) and POCl3 (7 mL, 74 mmol) was heated at 116° C. for 3 h. Upon completion of the reaction, the reaction mixture was poured into ice and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography, eluting with CH2Cl2/Acetone (3:1), afforded the product as a white solid (490 mg, 40%).
Reaction SMILES: [Cl-:1].[NH2:2][C@H:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.[O-]S(C(F)(F)F)(=O)=O.[N:29]1([S:34](N2C=C[N+](C)=C2)(=[O:36])=[O:35])[CH:33]=[CH:32][N:31]=[CH:30]1>CC#N>[Cl-:1].[N:29]1([S:34]([NH:2][C@H:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4][N+:5]([CH3:8])([CH3:6])[CH3:7])(=[O:36])=[O:35])[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: COC(=O)C[C@@H](N)C[N+](C)(C)C
Reactant: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](C[N+](C)(C)C)NS(=O)(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (R)-2-amino-4-methoxy-N,N,N-trimethyl-4-oxobutan-1-aminium chloride (35 mg) in anhydrous MeCN (5 mL) is treated with triethyl amine (2.5 equiv.) and 3-(Imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium triflate (1.5 equiv.). The reaction mixture is stirred at ambient temperature for 16 h then concentrated under reduced pressure and the resulting residue is purified on silica gel using MeOH/DCM (0->80%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([O:27]C)=[O:26])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[NH:17][CH2:16][CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1.CO.[OH-].[Na+]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([OH:27])=[O:26])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[NH:17][CH2:16][CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNc1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNc1ccccc1-3
Yield: 76.7 %

Procedure:
A solution of methyl 13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-carboxylate (45.8 mg, 0.12 mmol) in THF/MeOH (1:2, 3 mL) and 1N aqueous NaOH (0.5 mL) was heated at 50° C. for 5 h. The reaction solution was concentrated to remove volatile organics, neutralized with TFA (0.04 mL) and purified by preparative HPLC (MeOH/H2O with TFA buffer) to yield 13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-carboxylic acid (33 mg, 0.092 mmol, 76%) as white solid. 1HNMR (500 MHz, MeOD) δ 8.25 (s, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.79 (dd, J=8.5, 1.2 Hz, 1H), 7.63-7.52 (m, 3H), 7.50-7.46 (m, 1H), 4.44 (br s, 2H), 3.92-3.86 (m, 2H), 3.03 (tt, J=12.4, 3.1 Hz, 1H), 2.21-2.10 (m, 2H), 1.97-1.80 (m, 5H), 1.54-1.36 (m, 2H). LCMS: m/e 361 (M+H)+, ret time 1.88 min, column C, 2 minute gradient, start at 0% B.