Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][C:11]1[C:12]([CH3:20])=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:7]#[N:8].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][C:11]1[C:12]([CH3:20])=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:7]#[N:8]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: Cc1c(Nc2c(I)cncc2C#N)ccc2[nH]ccc12
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: Cc1c(Nc2c(C#N)cncc2-c2cc3ccccc3o2)ccc2[nH]ccc12
Temperature: 80 °C
Yield: 18.1 %

Procedure:
To a mixture of 5-iodo-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (200 mg, 0.53 mmol), 2-benzofuranboronic acid (173 mg, 1.07 mmol) and Pd(PPh3)4 (31 mg, 0.027 mmol) in DME (4.0 mL) was added 2.0 M aqueous Na2CO3 (0.8 mL). The resulting mixture was heated at 80° C. for 2 h, cooled to r.t. and filtered. The filtrate was concentrated and purified by HPLC to give 35 mg of 5-(1-benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile 222 as a yellow solid. MS: 365.2 (M+H); HPLC retention time: 11.4 min.(a).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[C:16]([OH:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.CN(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=2[F:14])=[N:6][CH:7]=1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3O)cc2F)cn1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution consisting of 4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-ol Example 476 (50 mg, 0.18 mmol) and DMF (1 mL) was added Cs2CO3 (116 mg, 0.36 mmol). The mixture was stirred at rt for 30 min. Methyl 2-bromoacetate (30 mg, 0.19 mmol) was added and the resultant mixture stirred at rt for 1 hour and then poured into 15 mL of water. The precipitate was collected and washed with water and air dried to give methyl 2-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)oxy)acetate (50 mg, 72%). MS (ESI): mass calcd. for C19H16FN3O3, 353.12; m/z found, 354.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.03 (s, 1H), 7.93 (m, 1H), 7.57 (d, J=13.0, 1H), 7.54 (d, J=9.2, 1H), 7.50 (d, J=7.4, 1H), 7.34 (m, 1H), 7.10-7.02 (m, 2H), 6.70 (s, 2H), 4.89 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([OH:21])=O)[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1>>[CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([NH:22][N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:21])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:16])([F:18])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: NN1CCC(O)CC1
Product: O=C(NN1CCC(O)CC1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid and 1-amino-4-piperidinol (CAN 79414-82-7) as starting materials; LC-MS (UV peak area/ESI) 96.4%, 402.1991 (M+H)+.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[C:17]3[CH:18]=[CH:19][C:20]([CH:22]=C)=[CH:21][C:16]=3[O:15][N:14]=2)[CH2:8]1.CSC>ClCCl>[CH3:4][O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[C:17]3[CH:18]=[CH:19][C:20]([CH:22]=[O:1])=[CH:21][C:16]=3[O:15][N:14]=2)[CH2:8]1
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc2c(N3C[C@H](COC)OC3=O)noc2c1
Solvent: CSC
Solvent: ClCCl
Product: COC[C@H]1CN(c2noc3cc(C=O)ccc23)C(=O)O1
Reaction time: 3 h

Procedure:
A stream of ozone at -40° C. is passed for 2 hours into a solution of 8.0 g (0.029 mol) of (R)-5-(methoxymethyl)-3-(6-ethenyl-1,2-benzisoxazol-3-yl)oxazolidin-2-one in 210 ml of dichloromethane, then the ozone is driven off with a stream of argon, and 10.7 ml (0.15 mol) of dimethyl sulphide are added. The mixture is stirred for 3 hours while allowing the temperature to return to ambient temperature, and then the solvent is evaporated off under reduced pressure. By chromatography of the residue on a silica column with a mixture of 30% ethyl acetate in cyclohexane, 5.0 g of product are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:32])=[O:31]
Reactant: COC(=O)c1ccccc1CSc1cc(Cl)ccc1N
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1CSc1cc(Cl)ccc1NS(=O)(=O)c1cc2ccccc2o1
Yield: 27.8 %

Procedure:
Following General Procedure B, the title compound (65 mg, 28%) was prepared from methyl 2-(((2-amino-5-chlorophenyl)thio)methyl)benzoate (150 mg, crude) and benzofuran-2-sulfonyl chloride (104 mg, 0.48 mmol) in pyridine (3 ml).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:6][CH:7]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
By alkylating tert-butyl (3RS,4RS)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate with 2-bromomethyl-naphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-bromophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 495, 497 (M)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:9])([CH3:8])[CH3:7])[N:3]=[CH:2]1.[CH2:10]([NH:12][C:13]([NH:15][C:16]1[S:17][C:18]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:23][C:22](C3C=NC(C(O)(C)C)=NC=3)=[CH:21][C:19]=2[N:20]=1)=[O:14])[CH3:11]>N1C=CC=CC=1>[CH2:10]([NH:12][C:13]([NH:15][C:16]1[S:17][C:18]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:23][C:22]([N:1]3[CH:5]=[C:4]([C:6]([OH:9])([CH3:8])[CH3:7])[N:3]=[CH:2]3)=[CH:21][C:19]=2[N:20]=1)=[O:14])[CH3:11]
Reactant: CC(C)(O)c1c[nH]cn1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)cc(-c3ccccn3)c2s1
Solvent: c1ccncc1
Product: CCNC(=O)Nc1nc2cc(-n3cnc(C(C)(C)O)c3)cc(-c3ccccn3)c2s1
Temperature: 80 °C
Reaction time: 4.67 h

Procedure:
Compound i (74 mg) and Intermediate 1 (100 mg) were suspended in pyridine with 4 Å mol. sieves. The mixture was degassed and flushed with oxygen and Cu(OAc)2.H2O added. The mixture was again degassed and flushed with oxygen then left stirring at 80° C. for 280 min. The reaction was quenched by adding NH4Cl sat. and diluted with EtOAc and H2O. The mixture was extracted with EtOAc and the organics combined, dried (Na2SO4) and evaporated to dryness. Purification by chromatography on silica, eluting with DCM/MeOH (0-10%) followed by reverse phase chromatography on a C18 column eluting with ACN/H2O afforded Compound 11 (7.5 mg).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10]O.S(=O)(=O)(O)O>>[C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1
Yield: 56 %

Procedure:
A solution of benzoic acid (30 g; 0.25 mole in MeOH (80 g; 2.5 mole) and conc. sulphuric acid (2.7 ml) was passed through the CMR (10.5 ml/min.; 141°-5° C.; 760 kPa). Excess MeOH was removed by rotary evaporation and the residue poured into water (250 ml) and the product extracted in CCl4. The organic phase was washed with bicarbonate solution, dried over MgSO4, filtered, evaporated, and the product (18.6 g; 56% yield) distilled under reduced pressure; b.p. 109° C./30 mm of Hg. cf ref.3, where a different method of work-up was used, and a yield of 92% was obtained after 4 hours at reflux.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[S:15])[NH2:14].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[OH:29])=O>CCOC(C)=O>[CH3:6][O:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[S:15][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[OH:29])[N:14]=1
Reactant: COc1ccc(C(=O)CBr)c(O)c1
Reactant: COC(=O)CCCCC(N)=S
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCc1nc(-c2ccc(OC)cc2O)cs1
Temperature: 25 °C
Yield: 165.9 %

Procedure:
Add THF (50 mL, anhydrous) to a roundbottom flask containing 5-thiocarbamoyl-pentanoic acid methyl ester-(2.63 g, 15.0 mmol) and 2-bromo-1-(2-hydroxy-4-methoxy-phenyl)-ethanone (4.90 g, 15.0 mmol, 75% pure). Heat to reflux under N2 overnight. Cool to room temperature, add EtOAc, wash with saturated NaHCO3 solution, brine, and backextract from each aqueous layer with EtOAc. Dry combined organic layers over MgSO4 and concentrate to get 8 grams of a yellow solid. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes followed by flash chromatography on silica gel eluting with CHCl3 to afford the title compound (2.69 g, 56%). MS (IS) 322 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](OC(=O)C)(=[O:18])[CH3:17].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:16]([NH:1][C:2]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1N
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of methyl 2-amino-4-(trifluoromethyl)benzoate (8.00 g, 0.036 mol), acetic anhydride (11.18 g, 0.109 mol), pyridine (8.62 g, 0.109 mol) and chloroform (20 ml) was stirred at room temperature for 48 h. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The extracts were washed with 1N hydrochloric acid and water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 50% ethyl acetate/n-hexane to give 8.10 g (0.031 mol 86%) of the title compound as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[Mg].II.N([P:18]([Cl:20])Cl)(CC)CC>CCOCC.C1COCC1>[CH3:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[P:18]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9])[Cl:20]
Reactant: Cc1ccc(Br)c(C)c1
Reactant: CCN(CC)P(Cl)Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(P(Cl)c2ccc(C)cc2C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.92 ml (2161 mmol) of 4-bromo-1,3-dimethylbenzene in 3 ml of Et2O were added at 0° C. to a suspension of 0.5 g (20.56 mmol) of magnesium turnings in 7 ml of THF and 7 ml of Et2O and also a crystal of iodine. The mixture was heated to room temperature, stirred further overnight and slowly added dropwise at 0° C. to a solution of 1.5 ml (10.31 mmol) of Et2NPCl2 in 8 ml of THF. The mixture was heated to room temperature and the solvent was subsequently removed under reduced pressure. After adding 60 ml of hexane, the mixture was filtered through Celite under argon and admixed with hydrogen chloride for 1 hour. After degassing, the resulting solids were filtered off under argon and dried. Yield: 1.4 g (58.3% of theory). 1H NMR (400 MHz, CDCl3) δ, 7.40 (d, Jmeta=4.5 Hz, 2H, arom.), 7.2 (m, 4H, arom.), 2.5 (d, JPH=2.0 Hz, 6H, CH3), 2.4 (s, 6H, CH3). 31P NMR (161.974 MHz, CDCl3) δ, 75.6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Product: CCc1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-amino-5-bromo-phenyl)-phenyl-methanone and 102 mg of 4-Ethyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.13 (t, 3H, J=7.6 Hz), 2.54 (q, 2H, 14.8 Hz, 7.6 Hz), 7.08 (d, 2H, J=8.8 Hz), 7.35-7.43 (m, 4H), 7.46 (d, 1H, J=2.4 Hz), 7.55-7.63 (m, 4H), 7.69 (d, 1H, J=8.8 Hz), 9.78 (s, 1H). m/z 445.3 (M++1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10](I)=[CH:11][C:12]=1[C:13]#[N:14])([CH3:4])([CH3:3])[CH3:2].[N:17]1([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][N:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10]([C:26]2[CH:25]=[N:24][C:23]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:28][CH:27]=2)=[CH:11][C:12]=1[C:13]#[N:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(N3CCCCC3)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)Nc1sc(I)cc1C#N
Product: CC(C)(C)OC(=O)Nc1sc(-c2ccc(N3CCCCC3)nc2)cc1C#N

Procedure:
The title compound was prepared from tert-butyl(3-cyano-5-iodo-2-thienyl)carbamate (Example 581 Step 2) (500 g, 1.43 mmol) and 2-piperidin-1-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (658 mg, 2.29 mmol) as described in Example 581, Step 3.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:14]4[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([N:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:21])[N:7]2[C:14]2[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]1=2)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1cc(Cl)c(Cl)cc13
Product: Cc1ccc2c(=O)n3c4cc(Cl)c(Cl)cc4n(C(=O)c4ccccc4)c3nc2c1

Procedure:
6-Benzoyl-3-methyl-8,9-dichlorobenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 3-methyl-8,9-dichlorobenzimidazo[2,1-b]quinazolin-12(6H)one and benzoyl chloride.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][N:15]2[C@@H:10]([CH2:11][O:12][CH2:13][C:14]2=[O:18])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:11]1[C@H:10]2[CH2:9][NH:8][CH2:17][CH2:16][N:15]2[C:14](=[O:18])[CH2:13][O:12]1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)COC[C@H]2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1COC[C@H]2CNCCN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of (R)-4-oxo-hexahydro-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at RT for 2 h then concentrated in vacuo. The resulting residue was azeotroped with toluene then purified by SCX column to give the title compound as a colourless oil (60 mg, 76%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C@@H:7]([CH3:23])[C@H:8]([N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15])[C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)C.[BH4-].[Li+].CCOC(C)=O>C1COCC1>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C@@H:8]([N:14]([CH3:15])[C:16](=[O:17])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C@H:7]([CH3:23])[CH2:6][CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CC[C@@H](C)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](CCCO)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of compound 2.12d (0.6 g, 1.77 mmol) in THF (3.5 mL) was added lithium borohydride (2.0 M in THF, 8.8 mL, 17.7 mmol, 10.0 equiv) and the resulting mixture was stirred at 50° C. for 1 hour. The reaction mixture was cooled at room temperature and EtOAc (2.0 mL) was added. After stirring for 10 minutes, the reaction mixture was quenched by addition of 1.0 N HCl aqueous solution. The phases were separated and the aqueous layer was extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated to give product 2.19.1a (0.54 g) which was used in the next step with no further purification. MS m/z (M+Na) 320.2
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][SH:4].[CH2:6]([CH:8]1[O:10][CH2:9]1)Cl.[OH-].[Na+]>C(O)C>[OH:10][CH:8]1[CH2:9][S:5][CH2:1][CH2:2][CH2:3][S:4][CH2:6]1
Reactant: ClCC1CO1
Reactant: SCCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OC1CSCCCSC1
Reaction time: 8 h
Yield: 43 %

Procedure:
A first solution of 1,3-propanedithiol (10.82 grams, 0.10 moles, commercially available from Alfa Aesar; Ward Hill, Mass.) and ethanol (45 milliliters) was placed in a 60-milliliter syringe. A second solution of epichlorohydrin (9.25 grams, 0.10 moles) and ethanol (45 milliliters) was placed in a second 60-milliliter syringe. Both solutions were slowly added dropwise to a mixture of sodium hydroxide (8.80 grams, 0.22 moles) and ethanol (250 milliliters) at room temperature over 10 hours. After stirring for an additional 8 hours, the reaction mixture was concentrated under vacuum, and then diluted with ethyl acetate (200 milliliters). The organic phase was washed with water (200 milliliters) and saturated sodium chloride in water (100 milliliters) and dried over magnesium sulfate. The solvent was removed under reduced pressure to give the crude product that was purified by column chromatography over silica gel using a mixture of ethyl acetate in hexane (30/70 parts by weight). The product was isolated as an oil. (6.99 grams, 43% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([C:36]([N:38]=[C:39]=[S:40])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:39]([NH:38][C:36](=[O:37])[C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=2)=[S:40])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (79 mg, yield 96%).
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9](O)=[O:10])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>ClCCl>[C:9]([Cl:16])(=[O:10])/[CH:8]=[CH:7]/[C:6]1[CH:5]=[CH:4][C:3]([OH:12])=[CH:2][CH:1]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)/C=C/c1ccc(O)cc1

Procedure:
To a solution of coumaric acid (36.3 g) in dichloromethane (1.03 L) were added oxalyl chloride (45.2 mL) and N,N-dimethylformamide (0.6 mL). After foaming calmed down, the mixture was heated to reflux for 3 hours. The reaction mixture was concentrated to give the title compound. The obtained compound was used for the next reaction without being purified.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](OCC)=[O:12])=[N:9][N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:5]2=[N:6][CH:7]=1.[NH3:24]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([NH2:24])=[O:12])=[N:9][N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:5]2=[N:6][CH:7]=1
Reactant: N
Reactant: CCOC(=O)c1nn(Cc2ccccc2F)c2ncc(F)cc12
Solvent: CO
Product: NC(=O)c1nn(Cc2ccccc2F)c2ncc(F)cc12

Procedure:
1.00 g (3.152 mmol) of the compound obtained in example 25A was stirred in 10 ml of a 7N solution of ammonia in methanol at RT for three days. This was followed by concentration under reduced pressure. This gave 908 mg (99% of theory) of the title compound.
Reaction SMILES: [N:1]1([CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].I[CH3:31]>CN(C)C=O>[CH3:31][N:13]1[C:14]2[C:9](=[CH:8][C:7]([CH:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][C:12]1=[O:17]
Reactant: CI
Reactant: O=c1ccc2cc(C(c3cccc(C(F)(F)F)c3)n3cncn3)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)ccc2cc(C(c3cccc(C(F)(F)F)c3)n3cncn3)ccc21
Temperature: 25 °C
Yield: 28 %

Procedure:
A mixture of compound 3 (10 g) in N,N-dimethylformamide (100 ml) was stirred at room temperature under N2. Sodium hydride (0.51 g) was added portionwise and the mixture was stirred for 15 minutes. The mixture was cooled, iodomethane was added dropwise and the reaction mixture was stirred for 12 hours. The solvent was evaporated and the residue was partitioned between CH2Cl2 and water. The separated organic layer was dried over MgSO4, filtered and the filtrate evaporated. The oily residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 98/2/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from methyl ethyl keton/diethyl ether, yielding 2.9 g(28%) (±)-1methyl-6-[1H-1,2,4-triazol-1-yl[3-(trifluoromethyl)phenyl]methyl]-2(1H)-quinolinone (compound 12; mp. 186.7° C.). In a similar manner, the following compounds were prepared: