Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:21])([C:4](=[O:20])[CH:5]([N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:3].[CH3:22][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:3][C:2]([CH3:21])([C:4]([CH3:22])([OH:20])[CH:5]([N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:1]
Reactant: C[Mg]Br
Reactant: CC(C)(C)C(=O)C(CCOc1ccccc1)n1cncn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(C)(O)C(CCOc1ccccc1)n1cncn1
Reaction time: 24 h

Procedure:
A solution of 6.0 g of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-6-phenoxy-hexan-3-one in 50 ml of tetrahydrofuran is added dropwise to a solution of 5.4 g of methyl-magnesium bromide in 28 ml of tetrahydrofuran, and after the slight exothermic reaction has subsided the mixture is left to stand for 24 hours at room temperature. It is then poured into 1,000 ml of 10% strength aqueous ammonium chloride solution and the batch is extracted twice with 200 ml of methylene chloride at a time. The organic phase is washed and dried over magnesium sulfate, and the methylene chloride is evaporated off under reduced pressure. 10 ml of diisopropyl ether are added to the residue, and 1.5 g of white crystals, of melting point 118°-120° C., are isolated from this mixture.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([O:24][C:25](=[O:48])[CH2:26][N:27]([CH2:44][CH2:45][CH2:46][CH3:47])[S:28]([C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25](=[O:48])[CH2:26][N:27]([CH2:44][CH2:45][CH2:46][CH3:47])[S:28]([C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:38][CH2:39][CH:40]([NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:41][CH2:42]2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCN(CC(=O)OCc1ccccc1)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCCCN(CC(=O)OCc1ccccc1)S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 18, (butyl-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-amino)-acetic acid benzyl ester, according to the procedure of Example 1 as a white solid; mp 59-64° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.78 (t, 3H), 1.10-1.40 (m, 6H), 1.80-1.95 (m, 2H), 2.60-3.00 (m, 5H), 2.91 (s, 3H), 3.05 (t, 2H), 3.70-3.80 (m, 2H), 4.04 (s, 2H), 4.40-4.50 (m, 1H), 5.20 (s, 2H), 6.80 (d, 1H), 6.95 (d, 2H), 7.00 (d, 2H), 7.18 (d, 1H), 7.30-7.45 (m, 5H), 7.50 (d, 2H); MS (ES) m/z: 689.1 (MH+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:6]=1[CH2:7]O.C1(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:6]=1[CH2:7][N:30]=[N+:31]=[N-:32]
Reactant: OCc1cc(Cl)ccc1OCC(F)(F)F
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 2-(2,2,2-trifluoroethoxy)-5-chlorobenzyl alcohol (1.9 g, 7.9 mmol) in THF (20 mL) at 0° C. was added diphenyl phosphoryl azide (2.2 mL, 10.2 mmol) followed by DBU (1.5 mL, 10.0 mmol). The reaction mixture was allowed to warm to room temperature overnight following which the solvent was removed under reduced pressure. The residue was partitioned between ether and water and the organic layer dried over sodium sulfate. Filtration, concentration and purification by flash chromatography (19:1 hexane/ether) gave the azide as a white solid: 1H NMR (CDCl3) δ7.31 (m, 2H), 6.82 (d, J=8.8 Hz, 1H), 4.40 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=1)#[N:18]>>[C:17]([C:19]1[CH:20]=[C:21]([CH2:25][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:22]=[CH:23][CH:24]=1)#[N:18]
Reactant: COC(=O)c1ccnc(-n2nccc2O)c1
Reactant: N#Cc1cccc(CO)c1
Product: COC(=O)c1ccnc(-n2nccc2OCc2cccc(C#N)c2)c1

Procedure:
The title compound was prepared from methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6) and (3-cyanophenyl)methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C18H14N4O3, 335. Found, 335.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:12]1[O:16][CH:13]1[CH2:14][CH3:15].[CH2:17](N(CC)CC)C>>[CH2:14]([CH:13]1[C:12](=[O:16])[C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4][CH2:17]1)[CH3:15]
Reactant: COC(=O)c1ccccc1O
Reactant: CCC1CO1
Reactant: CCN(CC)CC
Product: CCC1COc2ccccc2C(=O)C1=O
Temperature: 150 °C

Procedure:
To a one liter autoclave was added a mixture of 304 g. (2.0 moles) methyl salicylate (III), 4.0 g. triethylamine and 150 g. (2.1 mole) of 1,2-butylene oxide. The reaction mixture was heated under nitrogen at 150° C for 6 hours. The clear brown liquid crude reaction product (444 g.) was then removed from the autoclave and fractionally distilled (4489-84 and 4524-25) through a 3 ft. Vigreaux (Goodloe packed) column after addition of 2 g. sodium acetate to aid hydrolysis. Traces of glycol and catalyst (Et N) were removed at first, but the main fraction (4524-25), 160 g. was identified (NMR, IR) as the pure title compound IX. On standing in air IX solidified and could be recrystallized from cyclohexane as prisms, m.p. 63°-66° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH2:14][CH2:13][CH2:12][C:11](=O)[CH:10]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1.[CH2:38](I)[CH3:39]>>[CH2:38]([S:25][C:11]1[CH2:12][CH2:13][CH2:14][C:9](=[N:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:10]=1)[CH3:39]
Reactant: Cc1ccc(NC2=CC(=O)CCC2)cc1
Reactant: CCI
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CCSC1=CC(=Nc2ccc(C)cc2)CCC1

Procedure:
N-[3-(Ethylsulphanyl)cyclohex-2-en-1-ylidene]-4-methylaniline is prepared from 3-[(4-methyl-phenyl)amino]cyclohex-2-en-1-one by reaction with Lawesson reagent and subsequent alkylation with ethyl iodide analogously to J. Org. Chem. 1984, 49, 3314.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[C:3]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24].[Br:26]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:26][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[C:3]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2cc(COC(C)=O)c(COC(C)=O)c(C)c2cc1OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc2cc(COC(C)=O)c(COC(C)=O)c(CBr)c2cc1OC
Yield: 83.1 %

Procedure:
To a solution of 1-methyl-2,3-bis(acetoxymethyl)-6,7-dimethoxynaphthalene (5.0 g) in carbon tetrachloride (100 ml) are added N-bromosuccinimide (2.8 g) and benzoyl peroxide (150 mg), and the mixture is refluxed for 2 hours. The mixture is allowed to cool, and the insoluble materials are separated by filtration, and the filtrate is concentrated under reduced pressure to give 1-bromomethyl-2,3-bis(acetoxymethyl)-6,7-dimethoxynaphthalene (5.1 g) as crystal.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[O:13]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C(=O)C>[O:13]1[C:17]2([CH2:22][CH2:21][N:20]([C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=3)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1

Procedure:
Ethyl 4-fluorobenzoate (11.65 g, 69.3 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (9.92 g, 69.3 mmol), and triethylamine (9.66 mL, 69.3 mmol) in N,N-dimethylacetamide (80 mL) were stirred at 80° C. for 24 hours. The reaction was cooled, poured into ethyl acetate, washed with 3× water and brine, and concentrated to afford the title compound.
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Br)=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:21][N:22](C=O)C>[C-]#N.[Zn+2].[C-]#N.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:13]1([C:4]2[C:3]([OH:2])=[CH:8][C:7]([N+:9]([O-:11])=[O:10])=[C:6]([CH:5]=2)[C:21]#[N:22])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(C2CCCC2)c(O)cc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 58 %

Procedure:
To a microwave vial charged with 4-bromo-2-cyclopentyl-5-nitrophenyl methyl carbonate (102 mg, 0.29 mmol), zinc cyanide (35 mg, 0.30 mmol) and Pd(PPh3)4 (21 mg, 0.02 mmol) under an N2 atmosphere was added DMF (500 μL). The reaction was heated under microwave irradiation at 130° C. for 30 min. The reaction was quenched with saturated aqueous Na2CO3 and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to yield a brown oil. Purification by silica gel chromatography (0-15% ethyl acetate/hexanes) afforded 5-cyclopentyl-4-hydroxy-2-nitrobenzonitrile as a light yellow solid (40 mg, 58% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 11.62 (s, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 3.29-3.24 (m, 1H), 1.99-1.93 (m, 2H), 1.78-1.76 (m, 2H), 1.66-1.57 (m, 4H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CCCCCC.CN(C)C=O>[Br:3][C:4]1[N:5]=[C:6]2[CH:12]=[CH:11][N:10]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:7]2=[N:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cnc2[nH]ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
Sodium hydride (60% in mineral oil, 0.800 g, 20 mmol) was washed with hexane then taken up in 30 mL of N,N-dimethylformamide and cooled to 0-5° C. 2-Bromo-5H-pyrrolo[2,3-b]pyrazine (3.0 g, 15 mmol) was added, then SEMCl (3.5 mL, 20 mmol). The mixture was stirred at room temperature for 3 h, then concentrated. Column chromatography afforded 3.25 g (65%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine.
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH:25]=[O:26])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:27]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:27][C:10]1[N:11]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)(=[O:13])=[O:14])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][C:9]=1[CH:25]=[O:26]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C(F)(F)F)cc2)c1
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C(F)(F)F)cc2)c1Cl
Reaction time: 24 h
Yield: 61.1 %

Procedure:
5-Phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde (300 mg) was dissolved in N,N-dimethylformamide (6 mL), N-chlorosuccinimide (116 mg) was added at room temperature, and the mixture was stirred for 24 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 3% potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→4:1) to give the title compound as colorless crystals (yield 200 mg, 61%).
Reaction SMILES: [H-].COCCO[Al+]O[CH2:9][CH2:10][O:11]C.[Na+].[H-].[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(COC)[O:23]C>CCOCC>[C:15]1([C@H:21]([OH:23])[CH2:9][CH2:10][OH:11])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COCCO[Al+]OCCOC
Reactant: COCCOC
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: OCC[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of commercial (−)-(2S,3S)-2,3-epoxycinnamyl alcohol (10.0 mmol) in dimethoxyethane (50 mL) is added a 3.4 M solution of sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) in toluene (10.5 mmol) dropwise under nitrogen at 0° C. After stirring at room temperature for 3 h, the solution is diluted with ether and quenched with 5% HCl solution. After further stirring at room temperature for 30 min, the white precipitate formed is removed by filtration and boiled with ethyl acetate and filtered again. The combined organic extracts are dried with magnesium sulfate and concentrated to give (R)-3-phenyl-1,3-dihydroxypropane.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH2:2][CH2:3][CH3:4].[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.O=[C:20]([CH2:27][CH2:28][CH3:29])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:1]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH2:27][CH2:28][CH3:29])[NH:13][C:14]2[NH:15][N:16]=[CH:17][C:18]1=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccccc1C=O
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCCc1ccccc1C1C(C(=O)OCC)=C(CCC)Nc2[nH]ncc21

Procedure:
The title compound was prepared from 2-butylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:27])[C:12]=2[N:14]2[CH2:18][CH2:17][C@H:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15]2)[NH:7][CH:6]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)[Cl:36]>>[ClH:36].[NH2:19][C@H:16]1[CH2:17][CH2:18][N:14]([C:12]2[C:11]([Br:27])=[CH:10][N:9]=[C:8]3[NH:7][CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:13]=23)[CH2:15]1
Reactant: ClCCl
Reactant: CC(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c12
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@H](N)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
(S)-tert-Butyl 1-(3-acetamido-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.250 g, 0.570 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 0-50% water:ACN). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (S)—N-(4-(3-aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide hydrochloride (0.21 g, 90% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.17 (s, 1H), 7.24 (s, 1H), 4.10-4.05 (m, 1H), 3.95-3.84 (m, 2H), 3.79-3.70 (m, 2H), 2.37-2.32 (m, 1H), 2.07 (s, 3H), 2.02-1.96 (m, 2H). LCMS (APCI+) m/z 338, 340 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][C:6]2[NH:7][C:8]([S:10][C:11]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=3[N+:19]([O-])=O)=[N:9][C:5]=2[CH:4]=1.[Cl-].[NH4+].C(O)C.O>[Fe].CCOCC>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][C:6]2[NH:7][C:8]([S:10][C:11]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=3[NH2:19])=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(Sc2nc3cc(OC)c(OC)cc3[nH]2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: COc1ccc(N)c(Sc2nc3cc(OC)c(OC)cc3[nH]2)c1

Procedure:
The product of step (a) above (6.3 g), iron powder (6.3 g) and ammonium chloride (6.3 g) were stirred together with ethanol (63 ml) and water (120 ml) and heated under reflux for 1 hour. The hot mixture was filtered and the residue washed with hot ethyl acetate (500 ml). The combined filtrates were separated and the aqueous phase extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine, then dried and evaporated to leave a foam. Upon trituration with ether the sub-title compound was formed as a grey solid, MS MW bp 331.
Reaction SMILES: CN(C)C=O.[CH2:6]([C:13]1[C:18](Br)=[CH:17][CH:16]=[C:15]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:26]([C:28]1([OH:36])[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1)#[CH:27].C(N(CC)CC)C>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(OCC)(=O)C>[CH2:6]([C:13]1[C:18]([C:27]#[C:26][C:28]2([OH:36])[CH:33]3[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]3)[CH2:29]2)=[CH:17][CH:16]=[C:15]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: CCOCCOc1ccc(Br)c(Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCCOc1ccc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
7 ml of N,N-dimethylformamide was added to a mixture of 2-benzyl-3-bromo-6-(2-ethoxyethyl)oxypyridine, 601 mg of 3-ethynyl-3-quinuclidinol, 406 mg of tetrakis(triphenylphosphine)palladium(0), 220 mg of cuprous iodide and 1.7 ml of triethylamine, followed by heating under stirring at 80° C. in an oil bath for one hour in a nitrogen atmosphere. After cooling as it was, ethyl acetate was added thereto. The mixture was filtered through Celite, and it was washed with aqueous ammonia. The organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using ethyl acetate/hexane as an eluent for separation and purification, to give 247 mg of the target compound.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[C:3]([CH:8]=O)=[CH:2]1.C1CCN2C(=[N:14]CCC2)CC1.S1C=CC=C1.[C:26]([O:32][C:33](C(F)(F)F)=O)([C:28](F)(F)F)=[O:27]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:5]1[S:1][CH:2]=[C:3]2[C:4]=1[CH:6]=[C:28]([C:26]([O:32][CH3:33])=[O:27])[N:14]=[CH:8]2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=Cc1cscc1C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: c1ccsc1
Product: COC(=O)c1cc2cscc2cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.1 %

Procedure:
3,4-Thiophene dicarboxaldehyde (1.0 g, 7.13 mmol) is dissolved in CH2Cl2 (40 ml) and chilled to 0° C. C153 (1.88 g, 7.85 mmol) is dissolved in CH2Cl2 (30 ml) and combined with DBU (1.1 ml, 7.85 mmol). This solution is added dropwise to the chilled thiophene solution after stirring for 5 min. The reaction mixture is stirred at 0° C. for 1 h and then overnight at rt. The volatiles are removed in vacuo and the crude material is chromatographed over 68 g slurry-packed silica eluting with 70% EtOAc/hexane. The appropriate fractions are combined and concentrated to yield 2.09 g of the carbinol intermediate as a white foam. The intermediate is dissolved in CHCl3 (50 ml) and treated with DBU (1.32 ml, 8.8 mmol) and TFAA (1.24 ml, 8.8 mmol) in a drop-wise fashion. The reaction is stirred overnight at rt and is then quenched with saturated NaHCO3 solution (50 ml). The layers are separated, and the aqueous layer is extracted with CHCl3 (2×50 ml). The combined organics are dried over MgSO4, filtered, and concentrated to a yellow oil. This oil is chromatographed over 50 g slurry-packed silica, eluting with 90% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 1.2 g (88%) of methyl thieno[3,4-c]pyridine-6-carboxylate as a yellow solid. MS (EI) m/z: 193 (M+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([P:8]([N:29]([CH2:33][CH2:34][Cl:35])[CH2:30][CH2:31][Cl:32])([O:10][CH2:11][CH2:12][S:13]([CH2:16][C@@H:17]([C:26]([OH:28])=[O:27])[NH:18]C(OC(C)(C)C)=O)(=[O:15])=[O:14])=[O:9])[CH2:5][CH2:6][Cl:7].Cl.C(OCC)C>C(OCC)(=O)C>[Cl:32][CH2:31][CH2:30][N:29]([P:8]([N:4]([CH2:3][CH2:2][Cl:1])[CH2:5][CH2:6][Cl:7])([O:10][CH2:11][CH2:12][S:13]([CH2:16][C@@H:17]([C:26]([OH:28])=[O:27])[NH2:18])(=[O:14])=[O:15])=[O:9])[CH2:33][CH2:34][Cl:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](CS(=O)(=O)CCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: N[C@@H](CS(=O)(=O)CCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
3-[[2-[[Bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfonyl]-N-tert-butoxycarbonyl-L-alanine, 1.82 g (2.91 mmol), was dissolved in 18 mL ethyl acetate, and to this solution was added hydrogen chloride, 1.75 mL of 2 M solution in diethyl ether (3.5 mmol); and the resulting mixture stirred under nitrogen overnight at room temperature. HPLC analysis of the reaction mixture showed that the reaction was incomplete (20.8% product), so an additional 0.9 equivalents of hydrogen chloride solution was added and the reaction mixture stirred for an additional 4 days, resulting in the formation of a slurry. HPLC analysis of the reaction mixture showed 99.7% product and 0.3% starting material. The slurry was filtered under nitrogen, washed with ethyl acetate, and dried under nitrogen for 3 hours to give 3-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfonyl]-L-alanine, compound 70A, as the hydrochloride salt, off-white solid, 0.90 g (55% yield). HPLC analysis of the product showed a purity of 99.7%. 1H NMR: δ 8.50-9.10 (bs, 3H), 4.43 (m, 1H), 4.32 (m, 2H), 3.93-3.97 (m, 1H), 3.70-3.80 (m, 11H), 3.34 (m, 8H). 13C NMR: δ 168.2, 58.0, 57.9, 53.8, 53.7, 53.0, 48.3, 48.3, 47.1, 42.3. 31P NMR: δ 17.5 (s, 1P). Mass spectrum: m/z 526 [C13H26Cl4N3O6PS+H]+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[N:25]([C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]3[CH2:14][CH2:13]3)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:24][CH2:23]2
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Br)c2c(c1)CCN2
Agent: Cl
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 138-140° C.; 1H NMR (300 MHz, CDCl3): δ 6.94 (s, 1 H), 6.89 (d, J=2.2 Hz, 1H), 6.75 (d, J=2.5 Hz, 1 H), 4.34-4.24 (m, 2 H), 4.10-4.01 (m, 1 H), 3.76 (s, 3 H), 3.09 (t, J=7.9 Hz, 2 H), 1.91-1.74 (m, 2 H), 1.06-0.98 (m, 1 H), 0.95-0.86 (m, 3 H), 0.79-0.72 (m, 1 H), 0.53-0.44 (m, 2 H), 0.35-0.24 (m, 1 H); HRMS (CI) calcd for C19H22N3O2BrCl (M+H)+: 438.0584; found m/z 438.0570.