Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:19][S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:26]3[CH2:27][CH2:28][N:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:24][CH2:25]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]

Procedure:
Starting materials: 1-(3-methoxy-4-nitrophenyl)piperidin-4-one (INTERMEDIATE 18) and 1-(methylsulfonyl)piperazine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[CH:17]=[C:16]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[CH:17]=[C:16]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2cc(F)ccc2c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)c2cc(F)ccc2c1
Reaction time: 16 h
Yield: 62.3 %

Procedure:
10% Palladium on carbon (0.09 g) was added to a deoxygenated solution of 4-(7-fluoro-3-methoxycarbonylmethyl-naphthalen-1-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (which may be prepared as described above; 0.64 g, 1.6 mmol) in ethanol (30 mL) in a Parr shaker vessel. The mixture was hydrogenated at 60 psi for 16 h and then filtered through a pad of celite. The celite was washed with ethanol (2×5 mL) and the combined filtrates were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100-200 mesh), using 20% ethyl acetate/hexanes as eluent, to give 4-(7-fluoro-3-methoxycarbonylmethyl-naphthalen-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.40 g, 62%) as a sticky colorless solid. MS cald. for C23H29FNO4 [(M+H)+] 402, obsd. 402.4.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:29]([O:31][C:32](=[O:37])[CH:33](Br)[CH2:34][CH3:35])[CH3:30]>CN(C=O)C.O.[Na+].[Cl-]>[CH2:29]([O:31][C:32](=[O:37])[CH:33]([O:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:21][CH:20]=1)[CH2:34][CH3:35])[CH3:30]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(O)cc1
Reactant: CCOC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
A solution of 4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenol in dry DMF (3.0 mL) under argon was treated with Cs2CO3 (483 mg, 1.5 mmol) then 2-bromobutyric acid ethyl ester (350 μL, 2.4 mmol). The reaction mixture was stirred at 55° C. for 18 h, was allowed to cool to room temperature, diluted with H2O, saturated with NaCl, and partitioned with ethyl acetate. The organic layer was washed with NaHCO3 then brine, dried (Na2SO4), and concentrated in vacuo to give a yellow oil (394 mg). The product was purified by radial chromatography using a 1 mm plate and 0-2% ethyl acetate in CH2Cl2 to give a yellow oil (216 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 1.07 (t, 3H, J=7.33 Hz), 1.22-1.26 (m, 3H), 1.91-1.99 (m, 2H), 2.37 (s, 3H), 2.96 (t, 2H, J=6.60 Hz), 4.18-4.25 (m, 5H), 4.44 (t, 1H, J=6.35 Hz), 6.81 (s, 4H), 7.42-7.48 (m, 3H), 7.98-8.00 (m, 2H); MS (ES) m/e 410.2 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[O:8])[CH2:3][CH2:2]1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:27]([C:23]1[CH:22]=[C:21]([CH2:20][N:1]2[CH2:6][CH2:5][CH:4]([C:7]([N:9]3[CH2:18][CH2:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:10]3)=[O:8])[CH2:3][CH2:2]2)[CH:26]=[CH:25][CH:24]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: O=C(C1CCNCC1)N1CCc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(C1CCN(Cc2cccc([N+](=O)[O-])c2)CC1)N1CCc2ccccc2C1
Reaction time: 15 h
Yield: 119.8 %

Procedure:
A mixture of 7 g (28.6 mmol) of 2-[(4-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline, 6.8 g (31.5 mmol) of α-bromo-3-nitrotoluene and 6 g (43 mmol) of potassium carbonate in 140 ml of acetone is stirred for 15 h. The solvent is evaporated off, water and dichloromethane are added and the organic phase is separated off, neutralized, dried and evaporated. 13 g of a yellow oil are obtained, and this is purified by chromatography on a silica column, eluting with a 98:2 dichloromethane/methanol mixture. After recrystallization in ether, 9.6 g of product are obtained, this being used without further purification in the following stage.
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1B(O)O.Br[C:23]1[CH:36]=[CH:35][C:34]2[C:25](=[CH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH:24]1[C:25]2[C:34](=[CH:33][C:32]3[C:27]([CH:26]=2)=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:35]=[CH:36][C:23]=1[C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=1
Reactant: Brc1ccc2cc3ccccc3cc2c1
Reactant: OB(O)c1ccc2c3ccccc3c3ccccc3c2c1
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: COCCOC
Product: c1ccc2cc3cc(-c4ccc5c6ccccc6c6ccccc6c5c4)ccc3cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
Under an argon atmosphere, 7.79 g of triphenylene-2-boronic acid piconal ester, 5.14 g of 2-bromoanthracene, 0.462 g of tetrakis(triphenylphosphine)palladium (0), 30 mL of 1,2-dimethoxyethane and 15 mL of a 2M sodium carbonate aqueous solution were placed in a flask, and refluxed with stirring for 8 hours. After cooling to room temperature, deposited crystals were collected by filtration. The resulting solid was subjected to repeated recrystallization with toluene-hexane and washing to obtain 6.07 g (yield: 75%) of 2-(2-anthryl)triphenylene.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][C:2]1=[O:12].[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:13][N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][C:2]1=[O:12]
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c2c(ccc1=O)C(=O)CCC2

Procedure:
3.36 g (0.0206 mol) of 7,8-dihydro-2,5(1H,6H)-quinolinedione are stirred with 5.69 g (2×0.0206 mol) of powdered anhydrous potassium carbonate and 1.92 ml (1.5×0.0206 mol) of methyl iodide in 35 ml of dimethylformamide for 16 hours at ambient temperature. The mixture is then suction filtered, the solvent is evaporated off in vacuo and the residue is recrystallised from chloroform/ethyl acetate. Melting point: 203°-205° C., Yield: 3.1 g (84.9% of theory).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH3:24])[C:11]2[C:16]([CH:17]=1)=[C:15]([O:18][CH3:19])[C:14]([O:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)(=O)=O.[NH:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:24][N:10]1[C:11]2[C:16](=[C:15]([O:18][CH3:19])[C:14]([O:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)[CH:17]=[C:9]1[CH2:8][CH2:7][CH2:6][N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:6][CH2:7][CH2:8][C:9]2[N:10]([CH3:24])[C:11]3[C:16]([CH:17]=2)=[C:15]([O:18][CH3:19])[C:14]([O:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=3)[CH2:27][CH2:26]1
Reactant: COc1cc2c(cc(CCCOS(C)(=O)=O)n2C)c(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc2c(cc(CCCN3CCCN(CCCc4cc5c(OC)c(OC)c(OC)cc5n4C)CC3)n2C)c(OC)c1OC

Procedure:
2-(3-Methanesulfonyloxypropyl)-1-methyl-4,5,6-trimethoxyindole (130 mg) and homopiperazine (18 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH2:18]1[O:24][P:22]([OH:25])(=[O:23])[CH2:21][O:20][C@H:19]1[CH2:26][N:27]1[C:32](=[O:33])[N:31]=[C:30]([NH2:34])[CH:29]=[CH:28]1>>[CH3:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:25][P:22]1([O:24][CH2:18][C@H:19]([CH2:26][N:27]2[C:32](=[O:33])[N:31]=[C:30]([NH2:34])[CH:29]=[CH:28]2)[O:20][CH2:21]1)=[O:23]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: Nc1ccn(C[C@H]2COP(=O)(O)CO2)c(=O)n1
Product: CCCCCCCCCCCCCCCCOP1(=O)CO[C@@H](Cn2ccc(N)nc2=O)CO1
Yield: 55 %

Procedure:
The title compound was prepared using the same procedure as described for Example 1 using 1-bromohexadecane and cyclic cidofovir.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:35])[CH:4]([C:9]1[CH:10]=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=2)[N:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: C=C(C)CC(C(=O)OC)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 92.1 %

Procedure:
A solution of 2-[2,6-bis-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-4-methyl-pent-4-enoic acid methyl ester (280 mg, 0.57 mmol), Pd/C (10%, 30 mg) in methanol (10 mL) was hydrogenated for 4 h. The mixture was filtered through Celite, washed with methanol, and evaporated. The residue was dissolved in CH2Cl2, filtered and evaporated to give the product as a white solid (260 mg, 92%). 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=8.29 Hz, 4H), 7.76 (d, J=8.29 Hz, 4H), 7.73 (s, 2H), 3.82 (t, J=7.72 Hz, 1H), 3.72 (s, 3H), 2.11 (dt, J=7.72, 13.94 Hz, 1H), 1.76 (dt, J=6.92, 13.66 Hz, 1H), 1.49-1.62 (m, 1H), 0.97 (d, J=6.40 Hz, 6H). MS m/e 496.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](N)=[CH:5][CH:4]=1.[I-:10]>>[I:10][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: [I-]
Reactant: COc1ccc(N)cc1
Product: COc1ccc(I)cc1

Procedure:
diazotizing p-anisidine to produce a diazotization product and reacting the diazotization product with an aqueous iodide solution to produce 4-iodoanisole;
Reaction SMILES: C(OC[C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[OH:28])[S:20][CH:21]=2)[C:7]=1[C:31]([OH:33])=[O:32])(=O)C.C1(C(OC(C2N3C(SCC=2)C(NC(=O)CC2N=C(C4C=CC=CC=4O)SC=2)C3=O)=O)C2C=CC=CC=2)C=CC=CC=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)CCl>[OH:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[S:20][CH:21]=[C:17]([CH2:16][C:15]([NH:14][CH:10]2[C:9](=[O:30])[N:8]3[CH:11]2[S:12][CH2:13][CH:6]=[C:7]3[C:31]([OH:33])=[O:32])=[O:29])[N:18]=1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Agent: O=C(Cc1csc(-c2ccccc2O)n1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCSC12
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1csc(-c2ccccc2O)n1)NC1C(=O)N2C(C(=O)O)=CCSC12
Yield: 100 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8c (184 mg, 0.316 mmol), Et3SiH (0.505 mL, 3.16 mmol), and trifluoroacetic acid (0.972 mL, 12.6 mmol) in dry ClCH2CH2Cl (4 mL) at 0° C. under nitrogen to give 9c (132 mg, 100%) as a white solid after crystallization from THF/Et2O/hexane. mp 185° C. (dec); IR (KBr) 3700-2800 (br), 3291, 1768, 1710, 1659, 1230 cm-1 ; 1H NMR (DMSO-d6) δ3.48 (1H, dd, J=19.0 and 6.0 Hz), 3.59 (1H, dd, J=19.0 and 2.6 Hz), 3.75 (2H, s, CH2), 5.01 (1H, d, J=4.9 Hz), 5.72 (1H, dd, J=8.2 and 4.9 Hz), 6.45 (1H, dd, J=6.0 and 2.6 Hz), 6.88 (1H, t, J=7.8 Hz), 6.96 (1H, d, J=7.8 Hz), 7.25 (1H, t, J=7.8 Hz), 7.41 (1H, s), 7.94 (1H, d, J=7.8 Hz), 9.08 (1H, d, J=8.2 Hz, NH), 11.30 (1H, s, OH), 13.14 (1H, br s, CO2H); FDMS m/z 417 (M+), 418 (M+ +1); Anal. Calcd for C18H15N3O5S2. (C4H8O) 0.20: C, 52.28; H, 3.87; N, 9.73. Found: C, 52.41; H, 3.62; N, 9.71
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH:17]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH3:16])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:37][N:38]1C2C=CC=CC=2N=N1.NO>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]([CH3:16])[CH:17]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:33])[O:34][CH2:35][CH3:36])=[CH:25][CH:26]=2)[C:18]([NH:38][OH:37])=[O:19])(=[O:14])=[O:13])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)O)c2ccc(OCCCNC(=O)OCC)cc2)cc1
Agent: NO
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)NO)c2ccc(OCCCNC(=O)OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To [{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino}(4-{3-[(ethoxycarbonyl)amino]propoxy]phenyl)acetic acid (0.35 g, 0.67 mmol) and 1-(3-dimethyl aminopropyl) 3-ethyl carbodiimide (0.2 g, 1.01 mmol) in DMF (8 ml), 1-hydroxybenzotriazole (0.13 g, 0.95 mmol) was added and the reaction was stirred at room temperature for 2 h. Hydroxylamine (0.23 ml of 50% in water, 3.71 mmol) was added and the reaction was stirred overnight. After evaporating the solvent, the residue was extracted with ethyl acetate and water, the organic layer was washed with saturated NaHCO3, water and brine, dried over Na2SO4, and concentrated. The residue was purified with preparative TLC plates (eluting with ethyl acetate:methanol (85:15) to provide 0.1 g of ethyl 3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxyamino)-2-oxoethyl]phenoxy}propylcarbamate as a yellow solid. mp 60-62° C. Electrospray Mass Spec 532 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>N1C=CC=CC=1>[CH:16]1([C:19]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:7])=[CH:14][CH:15]=2)=[O:20])[CH2:18][CH2:17]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1ccc(OC(=O)C2CC2)cc1

Procedure:
Prepared from 6.0 g of 4-hydroxybenzophenone and 4.1 ml of cyclopropanecarbonyl chloride in 70 ml of pyridine. Recrystallized from ethyl acetate-ethanol-water mixture; M.P.~81°-81.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[C:9](=O)[NH:10][CH:11]([C:12]([F:15])([F:14])[F:13])[C:5]=2[O:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>C(Cl)Cl>[Cl:22][C:9]1[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH:11]([C:12]([F:15])([F:14])[F:13])[N:10]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1noc2c1-c1ccccc1C(=O)NC2C(F)(F)F
Solvent: ClCCl
Product: Cc1noc2c1-c1ccccc1C(Cl)=NC2C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.7 %

Procedure:
To a round bottomed flask was added 1-methyl-4-(trifluoromethyl)-4H-benzo[c]isoxazolo[4,5-e]azepin-6(5H)-one (86 mg, 0.305 mmol), DCM (2 mL), and PCl5 (102 mg, 0.488 mmol). The solution was stirred at room temperature for 30 min before addition of more PCl5 (˜0.5 eq). The solution was stirred at room temperature for 4 h before pouring onto an ice-saturated aqueous NaHCO3 mixture. The layers were separated and the aqueous phase was extracted with DCM. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford the titled compound (52.9 mg, 0.176 mmol). LC/MS m/z 301 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][N:16]1[CH2:17][CH2:18][N:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([C:5]3[S:6][C:2]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:3][CH:4]=3)[CH:12]=2)[CH2:14][CH2:15]1
Reactant: OB(O)c1ccccc1
Reactant: CN1CCN(c2ccnc(-c3ccc(Br)s3)c2)CC1
Product: CN1CCN(c2ccnc(-c3ccc(-c4ccccc4)s3)c2)CC1

Procedure:
The title compound was prepared by treating 1-[2-(5-bromo-thiophen-2-yl)-pyridin-4-yl]-4-methyl-piperazine with phenylboronic acid under conditions as described in Example 26.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[C:13]([OH:15])=[O:14].C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1>[NH2:19][C:18]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[NH:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(NCc2ccccc2Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)O)cc1NCc1ccccc1Cl
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A mixture of 3-[(2-chlorophenyl)methyl]amino-4-nitrobenzoic acid (6 g, 19.6 mmol), tetrahydrofuran (60 mL) and 5% sodium bicarbonate solution (50 mL) was treated portionwise with sodium hydrosulfite (4 g). The resulting clear solution had a pH of 6.29 that was adjusted to pH 7.15 by the addition of solid sodium bicarbonate. Additional sodium hydrosulfite was added (12 g) over several hours, and the mixture was stirred overnight. The tetrahydrofuran phase was separated, concentrated and triturated with ether/methylene chloride/hexane to afford 5.07 g of solid. Crystallization from methanol followed by washing with cold dilute aqueous methanol provided 4.79 g (88%) of pink-to-white crystals of 4-amino-3-[(2-chlorophenyl)methyl]aminobenzoic acid; mp 176°-177° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][C:4]2[CH:15]=[N:16][NH:17][C:3]1=2.[H-].[Na+].I[CH3:22]>CN(C=O)C>[CH3:22][N:17]1[C:3]2[C:2]([CH3:18])([CH3:1])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:5][C:4]=2[CH:15]=[N:16]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1Cc2cn[nH]c2C(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2c1C(C)(C)CN(C(=O)OC(C)(C)C)C2
Reaction time: 0.5 h

Procedure:
2.10 g (8.36 mmol) tert. butyl 7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylate were placed in 25 mL DMF. While cooling with ice, 350 mg (8.75 mmol) sodium hydride (55%) were added. The reaction mixture was stirred for 30 min, then 0.540 mL (8.67 mmol) iodomethane were added and the mixture was stirred for 1 h at 0° C. The reaction mixture was concentrated to dryness by rotary evaporation and the residue was mixed with water and extracted with EtOAc. The organic phase was dried, filtered and concentrated to dryness by rotary evaporation. The residue was purified by HPLC. The product-containing fractions were combined and organic solvent was eliminated by rotary evaporation. The aqueous residue was extracted with DCM. The organic phase was dried, filtered and concentrated to dryness by rotary evaporation.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[I:9](O)(=O)(=O)=O.S(=O)(=O)(O)O.II>C(O)(=O)C.O>[I:9][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([NH2:8])=[N:5][CH:6]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: Cc1ccnc(N)c1
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(N)ncc1I
Temperature: 80 °C
Yield: 389.6 %

Procedure:
To a stirred solution of 4-methyl-pyridin-2-ylamine (30 g, 278 mmol, 1 eq) in acetic acid (167 mL) was added periodic acid (12.7 g, 55.6 mmol, 0.2 eq) followed by addition of sulphuric acid (4.8 mL, 90.8 mmol, 0.34 eq), water (33.3 mL) and iodine (28.7 g, 111.1 mmol, 0.4 eq) at room temperature. Resulting reaction mixture was heated at 80° C. for 6 hours. After complete consumption of starting material, reaction mixture was cooled and poured into sodium thiosulfate solution (200 mL), reddish oil was settled down at the bottom. Reaction mixture was decanted from reddish oil and filtrate was basified with 50% sodium hydroxide solution (100 mL), yellow colored solid was formed. Resulting solid was extracted with diethyl ether (2×200 mL) and dried over sodium sulfate. Organic layer was concentrated under reduced pressure to afford brown semi solid (60 g, crude). Crude was purified by column chromatography using silica gel (100-200 mesh). Desired compound was eluted at 15% EtOAc in hexane to get title compound as faint brown solid (50.7 g, 78%). 1H NMR (400 MHz, CDCl3) δ: 2.27 (s, 3H), 4.46 (bs, 2H), 6.44 (s, 1H), 8.24 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:11])[C:7]=1[CH:8]([F:10])[F:9].Br[C:22]([C:24]([F:27])([F:26])[F:25])=[CH2:23].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:11][C:6]1[CH:5]=[C:4]([C:22]([C:24]([F:27])([F:26])[F:25])=[CH2:23])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH:8]([F:9])[F:10]
Reactant: CC1(C)OB(c2cc(Cl)c(C(F)F)c(Cl)c2)OC1(C)C
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(C(F)F)c(Cl)c1)C(F)(F)F
Temperature: 70 °C
Yield: 63 %

Procedure:
A mixture of 2-(3,5-dichloro-4-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (0.58 g, 1.8 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (0.45 g, 2.5 mmol), Cs2CO3 (1.8 mL, 2M, 3.6 mmol) and Pd(PPh3)2Cl2 (38 mg) in THF (10 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel eluted with hexanes to give 1,3-dichloro-2-(difluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (0.33 g; yield 62%) as colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.381 (s, 2H), 7.045 (t, J=53.0 Hz, 1 H), 6.049 (s, 1 H), 5.820 (s, 1 H) ppm.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[CH:18]=2)=O)=[CH:9][CH:8]=1)[CH3:4].Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[OH:35]/[N:34]=[C:15](/[C:17]1[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[CH:18]=1)\[CH2:14][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([C:6]([NH:5][C@@H:3]([CH3:4])[CH2:2][OH:1])=[O:32])=[CH:12][CH:11]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@@H](C)CO)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@@H](C)CO)cc1

Procedure:
In analogy to example 151, step 3, N—((S)-1-hydroxypropan-2-yl)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid, MS (ESI+): m/z=448.2 [M+H]+.