Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:40])[CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]3[N:37]=[CH:38][N:39]=[C:13]23)[CH2:8][CH2:7]1.[CH3:41]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[F:1][CH2:2][C:3]1([CH2:4][O:5][C@H:6]2[CH2:11][CH2:10][C@H:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]4[N:37]=[CH:38][N:39]=[C:13]34)[CH2:8][CH2:7]2)[CH2:41][O:40]1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)CF)CC2)c2ncnn12
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(CF)CO3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 4′-({4-[trans-4-(3-fluoro-2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.33 g), Dess-Martin periodinane (0.51 g) and acetonitrile (4 mL) was stirred at room temperature for 14 hr. Saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution were added to the reaction mixture. After evaporation of the solvent under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was added to a mixture of trimethylsulfoxonium iodide (0.16 g), sodium hydride (0.030 g) and dimethyl sulfoxide (5 mL) stirred at room temperature for 1 hr in advance, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.17 g, 52%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>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.C(O)CC>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: O
Solvent: CCCO
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccccc4)ccc32)n1)c1ccccc1
Temperature: 25 °C
Yield: 36.3 %

Procedure:
A solution containing 27 mg of 2-[(S)-1-phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine, 22 mg phenyl boronic acid, 42 mg potasium carbonate, 0.7 mg Pd(PPh3)4, 1.5 mL of H2O and 1.5 mL n-propanol was refluxed under nitrogen for 2 hours. The solution was cooled to room temperature, added to 100 mL of ethyl acetate and washed with saturated NaHCO3 and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by MPLC eluting with methanol in methylene chloride to give 8.7 mg of the title compound. RF: 0.55 (5% MeOH in CH2Cl2). 1H NMR (300 MHz, 3:1 CD3OD/CDCl3): δ 1.62 (d, J=6.9 Hz, 3H), 5.17 (q, J=7.0 Hz, 1H), 1H), 7.05 (d, J=5.8 Hz, 1H), 7.2-7.65 (m, 12H), 7.89 (br s, 1H), 8.36 (br s, J=5.6 Hz, 1H), 8.8-8.95 (m, 1H). Mass Spectrum (CH3CN-TFA-NH4HCO2-ESI): 392.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[C:23]([NH:25][CH2:26][C:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2)=[O:24].Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[O:7])=[CH:4][C:3]=1[C:23]([NH:25][CH2:26][C:27]12[CH2:28][CH:29]3[CH2:30][CH:31]([CH2:32][CH:33]([CH2:35]3)[CH2:34]1)[CH2:36]2)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C(=O)C2CCNCC2)ccc1Cl
Yield: 81.5 %

Procedure:
A solution of 4-[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]benzoyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.07 g, Example 76a) in methanol (3 ml) was treated with 4N hydrochloric acid solution in dioxane (1 ml). After 14 h the solvents were removed under reduced pressure and the residue was triturated with diethyl ether to give the title compound as a white powder (0.025 g).
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:21][NH2:22]>CCO>[Br:17][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][CH:15]=1)[O:10][CH2:9][C:8]1[N:7]2[CH:5]([CH3:6])[C:4](=[O:3])[NH:21][N:22]=1
Reactant: NN
Reactant: CCOC(=O)[C@@H](C)N1C(=S)COc2ccc(Br)cc21
Solvent: O
Solvent: CCO
Product: CC1C(=O)NN=C2COc3ccc(Br)cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
To a mixture of (R)-2-(6-bromo-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (75.2 g, 219 mmol) in EtOH (800 mL) was added hydrazine hydrate (98%, 21.9 g, 438 mmol) and the mixture was stirred at ambient temperature overnight. The precipitate was collected by filtration and washed with cold EtOH (3×80 mL) to give 6-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (6 g, 9%) as a yellow solid. The filtrate was concentrated to give 70 g of crude product, which was purified by chromatography on silica gel (eluting with 10-25% EtOAc in petroleum ether) to give a second batch of (R)-6-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (45.9 g, 71%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.53 (brs, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.03 (s, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.69-4.52 (m, 3H), 1.52 (d, J=6.8 Hz, 3H). SFC (Table 1, Method 32) Rt=6.075 min.; [α]D20=−314.92 (C=0.002 g/mL in methanol).
Reaction SMILES: Br[Zn][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=1.[CH2:11]([C:13]1[C:17](I)=[C:16]([CH:19]=[O:20])[NH:15][C:14]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:12]>C1COCC1.CN1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:11]([C:13]1[C:17]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=2)=[C:16]([CH:19]=[O:20])[NH:15][C:14]=1[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH3:12]
Reactant: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1I
Reactant: COc1cccc([Zn]Br)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN1CCCC1
Solvent: C1CCOC1
Product: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1-c1cccc(OC)n1
Temperature: 100 °C

Procedure:
Tert-butyl 3-ethyl-5-formyl-4-iodo-1H-pyrrole-2-carboxylate was obtained following the procedures described in Example 1. To a solution of bromo(6-methoxypyridin-2-yl)zinc (0.076 g, 0.30 mmol) in THF (0.6 mL) and N-methylpyrrolidine (0.44 mL) under argon was added Pd(Pt-Bu3)2 (0.002 g, 0.0032 mmol) and tert-butyl 3-ethyl-5-formyl-4-iodo-1H-pyrrole-2-carboxylate (0.070 g, 0.20 mmol). The reaction was heated to 100° C. and refluxed for 20 h under argon. After cooling to ambient temperature, the reaction was filtered through a pad of silica gel and concentrated. The resultant residue purified by normal phase flash chromatography (5-15% ethyl acetate/hexanes). Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CDCl3) δ 9.86 (s, 1H); 7.66 (t, J=7.8 Hz, 1H); 7.02 (d, J=7.1 Hz, 1H); 6.76 (d, J=8.3 Hz, 1H); 3.95 (s, 3H); 2.90 (q, J=7.3 Hz, 2H); 1.61 (s, 9H); 1.23 (t, J=7.3 Hz, 3H). HRMS (ES) exact mass calculated for C18H23N2O4 (M+H+): 331.1656. Found 331.1656.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[N:21][C:22]#[N:23])SC)[N:11]=1.[NH2:27][CH2:28][CH2:29][NH2:30]>C(O)C>[F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:21][C:22]#[N:23])=[N:27][CH2:28][CH2:29][NH2:30])[N:11]=1
Reactant: CSC(=NC#N)NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: NCCN
Solvent: CCO
Product: N#CNC(=NCCN)NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 8 h

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-methylisothioureido)pentyl]-thiazole (0.5 g.) and 1,2-diaminoethane (1.5 ml.) in ethanol (1 ml.) was allowed to stand at room temperature overnight. The mixture was then evaporated to dryness and the residue purified by preparative medium pressure liquid chromatography on silica gel using methanol/chloroform 1:4 v/v as solvent to give 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-[2-aminoethyl]guanidino)pentyl]thiazole as a straw coloured gum. A sample of the salt prepared with maleic acid included the following n.m.r. resonances when examined in d6 dimethylsulphoxide containing tetramethylsilane as an internal standard (δ=0) (δ): 1.5 (multiplet, 6H); 3.0 (multiplet, 4H); 3.3 (multiplet, 2H); 4.1 (multiplet, 2H); 6.5 (singlet, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:5]=1[C:6]([CH:8]([C:16](=[O:18])[CH3:17])C(OC(C)(C)C)=O)=[O:7])([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:1]([C:4]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:5]=1[C:6](=[O:7])[CH2:8][C:16](=[O:18])[CH3:17])([O-:3])=[O:2]
Reactant: CC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)CC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 68.9 %

Procedure:
A mixture of crude t-butyl 2-(2-nitro-4-trifluoromethylbenzoyl)-3-oxobutanoate (9.1 g) and 4-toluenesulphonic acid (0.1 g) in dry, toluene (100 ml) was stirred and heated at reflux for 3 hours. The cooled mixture was extracted with aqueous sodium hydroxide solution (2M, 2×50 ml) and water (2×50 ml). The combined aqueous extracts were acidified to pH 1 and extracted with ether (3×100 ml). The combined organic layers were washed with water (50 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from petroleum spirit (bp 60°-80° C.) to give 1-(2-nitro-4-trifluoromethylphenyl)-butan-1,3-dione (4.6 g) as an off white solid mp 80°-81° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[N:9]=[N:8][N:7]([CH2:17][Si:18]([CH3:19])([CH3:20])[CH3:21])[C:6]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1c(-c2ccccn2)nnn1C[Si](C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)Cn1nnc(-c2ccccn2)c1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
To a solution of 5-pyridin-2-yl-3-trimethylsilanylmethyl-3H-[1,2,3]triazole-4-carboxylic acid ethyl ester (1.67 g, 5.49 mmol) in dry THF (17 mL) was added portionwise lithiumaluminiumhydride (0.24 g, 6.31 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 1 h. Then water (240 μL) and NaOH (15%, 240 μL) was added followed by water (720 μL). The precipitate was then filtered off and the filtrate evaporated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) afforded the title compound (379 mg, 26%) as a white solid. MS: m/e=263.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][OH:12]>CCOC(C)=O.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][OH:12])=[C:2]([F:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CO)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(CO)c(F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 44.5 %

Procedure:
To a stirred solution of (2-fluoro-4-nitrophenyl)methanol (3.0 g, 1.0 eq.) in EtOAc (30 mL) was added 10% Pd—C and the reaction mixture was stirred under H2 gas balloon at RT for 6 h. The reaction mixture was passed through a celite pad and the solvent evaporated. The residue was purified by neutral alumina column using PE/EtOAc (3:2) as eluent to get (4-amino-2-fluorophenyl)methanol (1.1 g, 48%) as a solid; TLC system: EtOAc/PE (1:1), Rf: 0.3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].[CH3:11][N:12](C)C=O>[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>[OH:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[C:11]#[N:12]
Reactant: COc1ccc(Br)c(O)c1
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: COc1ccc(C#N)c(O)c1
Temperature: 95 °C
Yield: 16 %

Procedure:
Zinc cyanide (1.282 g, 0.770 mmol) and 2-bromo-5-methoxy-phenol (3 g, 14.18 mmol) were taken into dimethylformamide (15 mL) and the mixture was degassed with argon for 45 min. To this was added tetrakis(triphenylphosphine)palladium (993 mg, 0.852 mmol), and the reaction mixture was sealed after being degassed for 30 min. After heated at 95° C. for 2 d, the reaction mixture was cooled to room temperature and worked up with water and diethyl ether. The ethereal extracts were washed with brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 0-25% ethyl acetate in hexanes yielded 2-hydroxy-4-methoxy-benzonitrile (334 mg, 16%).
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7](I)[CH:6]=1.[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15]>O1CCCC1>[Cl:15][C:14]1[N:13]=[C:20]([Cl:21])[N:19]=[C:17]([C:7]2[CH:6]=[C:5]([Cl:4])[CH:10]=[CH:9][C:8]=2[CH3:11])[N:16]=1
Reactant: Cc1ccc(Cl)cc1I
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Alternatively, to a mixture of magnesium (1.46 g, 60.0 mmol) and tetrahydrofuran (100 ml) was added a small crystal of iodine followed by 4-chloro-2-iodo-toluene (12.62 g, 50 mmol). The mixture was heated under gentle reflux in an argon atmosphere for 6 hours and then cooled to −78° C. A solution of cyanuric chloride (7.84 g, 42.5 mmol) in tetrahydrofuran (45 ml) was added over 25 minutes. After stirring at −78° C. for 1 hour, the mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture, cooled in an ice bath, was quenched by slow addition of hydrochloric acid (1 M, 15 ml). The mixture was diluted with water (150 ml) and extracted with dichloromethane (3×125 ml). The combined extracts was washed with water (150 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (7:93) to provide 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine (10.2 g, 87% yield) as a white powder.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1.O>ClCCl>[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:20]([CH:3]=[O:4])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: Fc1ccc(-c2cc3cccc(Cl)n3n2)cc1
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
N,N-Dimethylformamide (100 mL) was cooled to 0° C. and treated with phosphorous oxychloride (5.7 mL, 60.8 mmol). After the addition was complete, the mixture was warmed to room temperature and stirred for 1 hour. To this was added 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (10.0 g, 40.5 mmol) and the resultant solution was stirred overnight. Water was added, followed by dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from diethyl ether and hexanes to give 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (10.6 g, 95%) as a fluffy white solid. 1H NMR (CDCl3): δ 10.07 (s, 1 H), 8.37 (d, 1 H), 7.78 (m, 2 H), 7.48 (t, 1 H), 7.20 (m, 3 H); 19F NMR (CDCl3) δ −111.25; MS m/z 275 (M+1); Anal. Calcd for C14H8ClFN2O: C, 61.22; H, 2.94; N, 10.20. Found: C, 61.34; H, 2.90; N, 10.15; mp 212–213° C. (decomp.).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9]1[C:18]([N+:19]([O-])=O)=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=1)=O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>ClCCl.[NH4+].[O-][V](=O)=O.[Pt]>[O:2]=[C:3]1[NH:19][C:18]2[CH:17]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[N:10][C:9]=2[N:6]2[CH2:7][CH2:8][C@@H:5]12
Reactant: COC(=O)c1cnc(N2CC[C@H]2C(=O)OC)c([N+](=O)[O-])c1
Agent: O=[V](=O)[O-]
Agent: [Pt]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)c1cnc2c(c1)NC(=O)[C@@H]1CCN21
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
(S)-methyl 6-(2-(methoxycarbonyl)azetidin-1-yl)-5-nitronicotinate (0.90 g, 3.05 mmol) was dissolved in dichloromethane (Volume: 15.24 ml) and to this solution was added triphenyl phosphite (9.46 mg, 0.030 mmol), ammonium metavanadate (0.021 g, 0.183 mmol) and Pt/C (5% wt.) (0.119 g, 0.030 mmol). The reaction mixture was hydrogenated at 100 psi at 25° C. for 2 h. LCMS showed complete conversion of the starting material to the corresponding amine, but no cyclization product was observed. The reaction mixture was filtered through a short plug of celite and the plug and precipitate were washed well with dichloromethane (30 mL) and methanol (20 mL). The combined filtrates were concentrated in vacuo (LC: CR1) and dissolved in AcOH (5 mL) (LC: AA-rt). This solution was heated to 80° C. for 5 min (LCMS—AA-90C-5 min—complete conversion to the desired product) and concentrated in vacuo. The residue was crystallized with ethyl ether (20 mL) and sonicated until a fine suspension was obtained The precipitate was filtered off and dried in vacuum to afford (S)-methyl 6-oxo-6,6a,7,8-tetrahydro-5H-azeto[1,2-a]pyrido[3,2-e]pyrazine-3-carboxylate (0.5840, 2.504 mmol, 82% yield) as a light pink solid. [M+H] calc'd for C11H11N3O3, 234; found, 234.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[I:17]I>O>[C:1]([C:5]1[CH:11]=[C:10]([I:17])[CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)c1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cc(I)ccc1N
Temperature: 0 °C
Reaction time: 16 h

Procedure:
In a 500 mL round-bottomed flask was combined 2-tert-butylaniline (7.46 g, 50 mmol) and sodium bicarbonate (7.56 g, 90 mmol) in water (50 mL). The mixture was cooled to 0° C. and iodine (12.69 g, 50.0 mmol) was added portion-wise over 20 minutes. The mixture was stirred for 16 hours at room temperature, partitioned between ethyl acetate and 10% aqueous sodium thiosulfate and stirred vigorously for 20 minutes. The ethyl acetate layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a dark oil that was purified on an Isco 120 g silica cartridge eluting with ethyl acetate/hexane (0% to 10%) to give the title compound.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:3].[NH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][C:11]1=[O:17]>O>[CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH:3][C:13]1[CH2:14][CH2:15][NH:10][C:11](=[O:17])[CH:12]=1
Reactant: O=C1CCNC(=O)C1
Reactant: CN(N)c1ccccc1
Solvent: O
Product: CN(NC1=CC(=O)NCC1)c1ccccc1
Yield: 89.6 %

Procedure:
1-Methyl-1-phenylhydrazine (21.6 g) was added to a suspension of 2,4-piperidinedione (20.0 g) in industrial methylated spirit (100 ml) at 20°-25° under nitrogen. The resultant solution was stirred for 3 h at room temperature. Water (300 ml) was added and the resulting suspension was filtered to give the title compound (34.4 g) as a solid, m.p. 180.5°-182°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[S-:11][S-:12].[Na+].[Na+]>O>[CH:5]1[CH:4]=[C:3]([N+:8]([O-:10])=[O:9])[C:2]([S:11][S:12][C:2]2[C:3]([N+:8]([O-:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: [S-][S-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccccc1SSc1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 95 %

Procedure:
1300 parts of water containing 150 parts of castor oil ethoxylate and 250 parts of 1-chloro-2-nitrobenzene are charged to a reactor and heated to 60° C. with thorough mixing. Simultaneous addition is then made of 2268 parts of disulfide solution (preparation as described in Example 1) and 2250 parts of 1-chloro-2-nitrobenzene in separate streams. The rate of addition is 400 parts per hour. When the total amount of chloronitrobenzene has been added, the remaining amount of disulfide is added at a rate of 100 parts per hour. The reaction is slightly exothermic and the temperature is kept in the range from 60°-65° C. by cooling. During the reaction, both the continuously added chloronitrobenzene and the resultant disulfide are continuously dispersed in the reaction mixture. This is done by constant and intensive mixing. Agglomerates are comminuted with a dismembrator. After the total amount of disulfide has been added as well, stirring is continued until the reaction mass consists of individual yellow crystals and of a colourless to tea-coloured mother liquor. The batch is then cooled to 40° C. and filtered. The product is washed with cold water until the washings are colourless, affording 2,2'-dinitrodiphenyl disulfide which contains about 5% of by-products. The yield is 95%.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O)C.S(=O)(=O)(O)O.OO.[C:21]([OH:24])(=[O:23])[CH3:22]>>[CH2:5]([C:4]1[CH:3]=[CH:11][CH:10]=[C:9]2[NH:8][C:7](=[O:12])[O:24][C:21](=[O:23])[C:22]=12)[CH3:6]
Reactant: CC(=O)O
Reactant: CCc1ccc2c(c1)C(=O)C(=O)N2
Agent: O=S(=O)(O)O
Agent: OO
Product: CCc1cccc2[nH]c(=O)oc(=O)c12
Temperature: 25 °C

Procedure:
5-Ethylisatin (70 g), acetic acid (200 ml) and concentrated sulfuric acid (0.8 ml) were charged in a 500 ml two-necked flask, followed by stirring at room temperature. Then, 50 ml of aqueous 30% hydrogen peroxide was added dropwise and, after stirring at 60° to 65° C. for additional one hour, the mixture was cooled. The deposited solid was filtered, washed with water and dried under vacuum to obtain 6-ethylisatoic anhydride. Crude yield: 35 g