Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].Br[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:30][O:29][C:27]1[CH:28]=[C:23]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[CH:24]=[N:25][CH:26]=1
Reactant: COc1cncc(Br)c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cncc(N2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)c1
Temperature: 100 °C
Yield: 25 %

Procedure:
A 10 mL pressure tube was charged with spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.28 g, 1.0 mmol), 3-bromo-5-methoxypyridine (0.26 g, 1.4 mmol), palladium (II) acetate (0.038 g, 0.2 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.14 g, 0.24 mmol), cesium carbonate (0.46 g, 1.4 mmol) and 1,4-dioxane (1.2 mL). The reaction mixture was heated at 100° C. for 25 min under microwave irradiation and allowed to cool to ambient temperature. The mixture was diluted with dichloromethane (20 mL) and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo and the residue purified by column chromatography eluted with a 0% to 15% gradient of ethyl acetate in hexanes to afford 1′-(5-methoxypyridin-3-yl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.097 g, 25%) as a brown solid: 1H NMR (300 MHz, CDCl3) δ8.37 (d, J=6.2 Hz, 2H), 7.39-7.34 (m, 1H), 7.32-7.24 (m, 2H), 7.18-7.09 (m, 1H), 6.95 (d, J=7.9 Hz, 1H), 6.53 (s, 1H), 6.25 (s, 1H), 5.88 (d, J=6.2 Hz, 2H), 4.89 (ABq, 2H), 3.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.0, 156.3, 156.0, 149.1, 142.5, 141.9, 138.9, 137.3, 131.9, 129.1, 129.0, 128.2, 124.5, 119.2, 118.5, 109.6, 103.0, 101.6, 93.7, 80.7, 58.5, 56.0; MS (ES+) m/z 389.3 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][CH2:6][C:7](OCC)=[O:8])#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:1]([CH2:3][C:4]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:5][CH2:6][CH2:7][OH:8])#[N:2]
Reactant: CCOC(=O)CCC(CC#N)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCC(CCCO)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a stirred solution of ethyl 5-cyano-4,4-diphenylpentanoate (2 g) in tetrahydrofuran (25 ml) was added lithium aluminum hydride (0.37 g) in small portions under ice-cooling. After completion of addition, the mixture was further stirred for 30 minutes. While the reaction mixture was stirred under ice-cooling, water (0.9 ml), 15% aqueous sodium hydroxide (2.7 ml), and water (0.9 ml) were added in the order mentioned. The insoluble matter that separated out was filtered off and the filtrate was extracted with ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness. The group was purified by silica gel column chromatography to provide the title compound (1.3 g) as colorless syrup.
Reaction SMILES: [CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[N:7](/[CH:33]=[C:34](/[C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)\[CH3:35])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CC(=CBr)c1ccncc1
Reactant: CCN1CCc2[nH]c3ccccc3c2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3ccccc3n2/C=C(\C)c2ccncc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (150 mg, 0.65 mmol) was dissolved in DMF. Copper (I) iodide (14 mg, 0.13 mmol), L-proline (12 mg, 0.065 mmol) and potassium phosphate (275 mg, 1.3 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-Bromoprop-1-en-2-yl)pyridine (195 mg, 0.9 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). The product was further purified by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.70 (d, 2H), 8.0 (d, 2H), 7.60 (d, 2H), 7.30 (m, 2H), 7.20 (t, 1H), 4.40 (m, 1H), 3.90 (m, 1H), 3.60 (m, 1H), 3.50 (q, 2H), 3.36 (m, 1H), 3.20 (m, 2H), 2.10 (s, 3H), 1.50 (t, 3H).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[K].[C:6]([NH:11][C:12](=[S:16])[O:13][CH2:14][CH3:15])(OCC)=[O:7].C(N(CC)CC)C>CO>[C:3]([C:2]1[S:16][C:12]([O:13][CH2:14][CH3:15])=[N:11][C:6]=1[OH:7])#[N:4]
Reactant: N#CCCl
Reactant: CCOC(=O)NC(=S)OCC
Agent: [K]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOc1nc(O)c(C#N)s1
Reaction time: 2 h

Procedure:
22.8 g of chloroacetonitrile were added dropwise with stirring at room temperature to a suspension of 61.5 g of the potassium salt of ethyl N-carbethoxy-thiocarbamate [described by Guha et al, Indian Chem. Soc., Vol. 6 (1929), p. 570] in one liter of methanol and after stirring the mixture for 2 hours, 30 g of triethylamine were added thereto. The mixture was stirred for another 48 hours and was then refluxed for 2 hours and filtered. The filtrate was concentrated to dryness and the residue was added to sodium hydroxide solution. The resulting solution was washed with ethyl ether, acidified with hydrochloric acid and extracted with ethyl ether. The extracts were dried and evaporated to dryness and the residue was crystallized from petroleum ether to obtain 26.4 g of 5-cyano-4-hydroxy-2-ethoxy-thiazole melting at 132°C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(OP(OCC)OCC)C.[H-].[Na+].[CH3:26][O:27][CH2:28][O:29][C:30]1[C:37]([CH3:38])=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[CH3:39]>CN(C=O)C.C(OCC)(=O)C>[CH3:26][O:27][CH2:28][O:29][C:30]1[C:37]([CH3:38])=[CH:36][C:33](/[CH:34]=[CH:2]/[C:3]2[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:32][C:31]=1[CH3:39]
Reactant: COCOc1c(C)cc(C=O)cc1C
Reactant: CCOC(=O)c1cccc(CCl)c1
Agent: CCOP(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(/C=C/c2cc(C)c(OCOC)c(C)c2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
Ethyl 3-(chloromethyl)benzoate (1.192 g, 6 mmol) and triethylphosphite (1.273 mL, 7.2 mmol) were heated to 150° C. for 4 hours. The reaction mixture was cooled to 0° C. and then DMF was added. NaH (60% in oil, 0.252 g, 6.3 mmol) was added to the solution at 0° C. After stirring for 20 minutes, the solution of 4-(methoxymethoxy)-3,5-dimethylbenzaldehyde (4-MOMO-3,5-dimethylbenzaldehyde; 0.583 g, 3 mmol) in DMF was added to the mixture dropwise at 0° C. After 18 hours, the mixture was diluted with ethyl acetate (EtOAc) and the solution was washed with 10% citric acid and brine. After drying on Na2SO4, the organic layer was filtered and concentrated under reduced pressure. The compound was purified by column chromatography (9.5:0.5 Hexane:EtOAc) to afford (E)-ethyl 3-[4-(methoxymethoxy)-3,5-dimethylstyryl]-benzoate (0.726 g, 71%).
Reaction SMILES: O=[C:2]([CH2:21][CH3:22])[CH2:3][CH:4]([P:13]([O:18][CH2:19][CH3:20])(=[O:17])[O:14][CH2:15][CH3:16])[P:5]([O:10][CH2:11][CH3:12])(=[O:9])[O:6][CH2:7][CH3:8].CC1C(C2(C3C(C)=C(Br)C(O)=C(C(C)C)C=3)OS(=O)(=O)C3C2=CC=CC=3)=CC(C(C)C)=C(O)C=1Br.[CH2:58]([NH2:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH2:58]([NH:65][CH:2]([CH2:21][CH3:22])[CH2:3][CH:4]([P:13]([O:18][CH2:19][CH3:20])(=[O:17])[O:14][CH2:15][CH3:16])[P:5]([O:10][CH2:11][CH3:12])(=[O:9])[O:6][CH2:7][CH3:8])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: CCOP(=O)(OCC)C(CC(=O)CC)P(=O)(OCC)OCC
Reactant: NCc1ccccc1
Agent: Cc1c(C2(c3cc(C(C)C)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(C(C)C)c(O)c1Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOP(=O)(OCC)C(CC(CC)NCc1ccccc1)P(=O)(OCC)OCC
Reaction time: 96 h

Procedure:
To a stirred solution of tetraethyl 3-oxopentane-1,1-bisphosphonate (0.50 g, 1.4 mmol) in methanol (5 ml) was added a small amount of bromothymol blue and benzylamine (0.75 g, 7.0 mmol). Acetic acid was added dropwise until the solution turned yellow (pH=6), and NaCNBH3 (57 mg, 0.9 mmol) was added. The resulting yellow solution was stirred at room temperature for 2 days, at which time more NaCNBH3 (20 mg) was added. After stirring a total of 4 days, the reaction was quenched by adding concentrated HCl until the pH was less than 1, and the solvents were removed in vacuo. The residue was taken up in water (10 ml) and washed with diethyl ether (2×20 ml). The aqueous layer was made basic (pH greater than 10) by the addition of solid KOH, saturated with NaCl, and extracted with dichloromethane (5×25 ml). The combined extracts were dried (Na2SO4) and concentrated to give tetraethyl 3-benzylaminopentane-1,1-bisphosphonate. This material was hydrolyzed by heating at reflux in concentrated HCl (6 ml) for 20 hours. The volatiles were removed under vacuum, the residue dissolved in water (10 ml) and concentrated under vacuum to give 0.49 g of Compound No. 159 as a hygroscopic foam.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32]>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:1]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:17])=[O:18])[CH:13]=[CH:12][C:11]=1[O:20][C:31](=[O:32])[N:30]([CH3:34])[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: CS(=O)(=O)c1ccc(O)c(C(=O)OCc2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)Oc1ccc(S(C)(=O)=O)cc1C(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
A mixture of 1 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid benzyl ester, 1.5 mmol of N-methylmorpholine and 0.2 mmol of 4-dimethylaminopyridine in 4 ml of dimethylformamide was treated with 1.3 mmol of N,N-dimethyl-carbamoylchloride. The reaction mixture was stirred at 60° for 48 hours, concentrated in vacuo and the residue taken up in 5 ml of water. Acidification with diluted hydrochloric acid and extraction with ethyl acetate yielded a crude product which was purified by chromatography (SiO2; ethyl acetate/cyclohexane 1.1). MS (m/e): 378.3 (MH+, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].Br[C:25]1[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.CCO.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>[CH3:1][O:2][C:3]([C:5]1[C:14]([C:25]2[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=2)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: Cn1cncc1Br
Reactant: COC(=O)c1cc2ccccc2cc1B1OC(C)(C)C(C)(C)O1
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2ccccc2cc1-c1cncn1C
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a mixture of methyl-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthoate (Preparation 13) (15.37 g, 49.3 mmol) and 5-bromo-1-methyl-1H-imidazole (9.06 g, 49.3 mmol) in toluene/EtOH (350 mL/36 mL) were added Pd(PPh3)4 (11.37 g, 9.84 mmol), Na2CO3 (20.9 g, 197.2 mmol) and water (106 mL). The mixture was degassed, purged with N2, and heated to reflux for 20 hours. It was then cooled to RT, neutralized with HCl (1.0 N, 100 mL), and concentrated in vacuo. The residue was partitioned between water (300 mL) and EtOAc (1 L). The organic layer was washed with water (2 L) and brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting crude material was submitted to flash chromatography (1.5% MeOH/CHCl3), furnishing the title compound as a light-yellow solid (9.5 g, 72%). 1H NMR (CDCl3): 8.53 (s, 1H), 7.99 (d, J=8.1, 1H), 7.80 (d, J=8.1, 1H), 7.77 (s, 1H), 7.56 (m, 1H), 7.54 (m, 1H), 7.54 (s, 1H), 6.94 (s, 1H), 3.73 (s, 3H), 3.29 (s, 3H). (ESI) m/z (M+H)+=267.11.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][S:8]([CH2:11][C@H:12]([NH:16][C@@H:17]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:18]([F:21])([F:20])[F:19])[C:13]([OH:15])=O)(=[O:10])=[O:9])[CH:2]=1.[CH:29]1([NH:32][C:33](=[O:41])[CH:34]([OH:40])[C@@H:35]([NH2:39])[CH2:36][CH2:37][CH3:38])[CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH4+].[Cl-]>C(#N)C.C(OCC)(=O)C>[CH:29]1([NH:32][C:33](=[O:41])[CH:34]([OH:40])[C@@H:35]([NH:39][C:13](=[O:15])[C@@H:12]([NH:16][C@@H:17]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:18]([F:21])([F:20])[F:19])[CH2:11][S:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:10])[CH2:36][CH2:37][CH3:38])[CH2:31][CH2:30]1
Reactant: O=C(O)[C@H](CS(=O)(=O)Cc1cccnc1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCC[C@H](NC(=O)[C@H](CS(=O)(=O)Cc1cccnc1)N[C@@H](c1ccc(F)cc1)C(F)(F)F)C(O)C(=O)NC1CC1

Procedure:
A mixture of 3-(pyridin-3-ylmethanesulfonyl)-2-(R)[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionic acid (420 mg, 1 mmol), 3(S)-amino-2-hydroxyhexanoic acid cyclopropylamide (186 mg, 1 mmol) prepared as described in PCT application publication No. WO-02/18369 as compound xiii, HBTU (455 mg, 1.2 mmol), and NMM (0.44 mL, 4 mmol) in acetonitrile was stirred at room temperature overnight. Sat. NH4Cl (10 mL) and ethyl acetate (10 mL) were added and after 20 min the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried with MgSO4, filtered and the filtrated was concentrated under the reduced pressure to give 2-hydroxy-3(S)-{3-(pyridin-3-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)-ethylamino]propionylamino}-hexanoic acid cyclopropylamide which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=1)[CH:31]=O>>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=1)[CH2:31][NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:7]2[C:6]3[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=[N:9][C:8]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: Fc1ccc(Br)cc1CNc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 5-bromo-2-fluorobenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 517.9.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:39](O)=[O:40].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:39]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)=[O:40]
Reactant: O=CO
Reactant: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCN(C=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide hydrochloride (494) (60 mg, 0.11 mmol) was dissolved in 3 mL DMF. To it were added formic acid (25 mg, 0.55 mmol), DIEA (200 μL, 1.10 mmol) and then PyBOP (115 mg, 0.22 mmol). The mixture was stirred at RT for 1 hour, quenched with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC to isolate the title compound, (R)-5-(4-(1-formylpiperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide (496), as HCl salt (37 mg). LC-MS (ESI): m/z (M+1) 536.2. UV: λ=261, 329, 337 nm.
Reaction SMILES: Br[C:2]1[C:3]([OH:25])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C@@H:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13])[N:8]=[CH:7]2.[N+:26]([O-])([O-:28])=[O:27].[Na+].O>O1CCCC1.C(O)(=O)C>[OH:25][C:3]1[C:2]([N+:26]([O-:28])=[O:27])=[C:10]2[C:6]([CH:7]=[N:8][N:9]2[CH2:11][C@@H:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:13])=[CH:5][CH:4]=1
Reactant: C[C@@H](Cn1ncc2ccc(O)c(Br)c21)NC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](Cn1ncc2ccc(O)c([N+](=O)[O-])c21)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A solution of the product from Step B (3.76 g, 9.3 mmol) in tetrahydrofuran (20 mL) and acetic acid (10 mL) was cooled in an ice bath, sodium nitrate (1.93 g, 27.9 mmol) was added and the reaction mixture was stirred for 1 h followed by warming to room temperature and stirring for one hour. Water (150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with a saturated aqueous solution of sodium bicarbonate (2×100 m), dried over magnesium sulfate, filtered, and evaporated to an oil (2.87 g). This residue was purified by chromatography (silica gel, hexane/ethyl acetate) to give a tan foam (2.44 g, 71%): LC/MS m/z 371. This was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.[CH2:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39]>ClCCl>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[O:29][C:5]1[CH:4]=[CH:3][C:2]([N:1]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[CH:7][C:6]=1[C:8]1[C:9]2[CH:18]=[CH:17][N:16]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=3)(=[O:20])=[O:21])[C:10]=2[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(N)ccc4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCS(=O)(=O)N(c1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)c1)S(=O)(=O)CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 181.4 %

Procedure:
A solution of 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (4.35 g, 8.34 mmol) in dichloromethane (50 mL) was cooled to 0° C. To this solution was added ethanesulfonyl chloride (2.37 mL, 25.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 80% ethyl acetate/hexanes) to provide N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-N-(ethylsulfonyl)ethanesulfonamide (5.34 g, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:5]=[CH:4][C:3]=1[OH:18].C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27].C(OC=CC)=CC>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC.CC(=O)CC>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:5]=[C:4]([CH:25]=[CH:26][CH3:27])[C:3]=1[OH:18]
Reactant: C=CCBr
Reactant: O=C(c1ccccc1F)c1ccc(O)c(Cl)c1Cl
Agent: CC=COC=CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CC=Cc1cc(C(=O)c2ccccc2F)c(Cl)c(Cl)c1O

Procedure:
A mixture of 2,3-dichloro-4-(2-fluorobenzoyl)phenol (98 g., 0.343 mole), K2CO3 (94 g., 0.68 mole), allyl bromide (37 ml., 0.425 ml.) and 750 ml. of 2-butanone was heated at reflux for 4 hours. After cooling the 2-butanone was partially evaporated and the residue distributed between methylene chloride and aqueous NaCl. The organic layer was dried and evaporated to give 105 g. of the intermediate propenyl ether as a liquid. This material was dissolved in an equal volume of diphenyl ether and heated at 250° for 3.5 hours. The cooled reaction mixture was diluted with hexane and washed several times with 1N aqueous KOH. The combined aqueous washes were acidified with 6N HCl and the resulting mixture extracted with methylene chloride. The methylene chloride solution was dried (MgSO4) and evaporated to a residue. Trituration with hexane gave 73 g. of solid product, m.p. 83°-84° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([CH3:9])[CH3:8])(=[O:4])[NH:2][NH2:3].C(OCC)(=O)NN.[C:17](Cl)([Cl:19])=[O:18]>C(OCC)C>[CH3:8][CH:7]([CH3:9])[CH2:6][O:5][C:1]([NH:2][NH:3][C:17]([Cl:19])=[O:18])=[O:4]
Reactant: CC(C)COC(=O)NN
Reactant: O=C(Cl)Cl
Agent: CCOC(=O)NN
Solvent: CCOCC
Product: CC(C)COC(=O)NNC(=O)Cl

Procedure:
Example 1 was repeated but substituting iso-butyl carbazate (24.75 g, 0.6 mole) for the ethyl carbazate and using phosgene (20 ml, 0.3 mole) in diethyl ether. 2-(2-methylpropyloxycarbonyl)hydrazinecarbonyl chloride was isolated as a viscous oil (31 g, 84%) whose ir spectrum was similar to that of 2-ethoxycarbonylhydrazinecarbonyl chloride.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([S:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14])[C:8]#[CH:9].O.[OH-].[Na+]>O1CCCC1>[CH2:7]([S:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[CH2:13][OH:14])[C:8]#[CH:9]
Reactant: C#CCSc1ccccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCSc1ccccc1CO
Temperature: 25 °C
Yield: 82281.1 %

Procedure:
To a slurry of LiAlH4 (6.5 g; 0.17 mmol) in 250 ml of tetrahydrofuran (THF) at 0° C. was added 2-(2-propynylthio)benzoic acid (28.8 g; 0.15 mmol). The reaction mixture was allowed to warm to room temperature. To the reaction mixture was added 6.5 ml of water, then 6.5 ml of 15% NaOH and 13.0 ml of water. The mixture was filtered through diatomaceous earth (Celite,) and concentrated to afford 22 g of the subtitle compound.