Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]([NH:20][CH:21]3[C:30]4[C:25](=[C:26]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[CH3:19])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC.[C:40]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:40][N:20]([CH:21]1[C:30]2[C:25](=[C:26]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1)[CH:18]([C:9]1[O:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH3:19]
Reactant: CCOC(=O)COc1cccc2c1CCCC2NC(C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)COc1cccc2c1CCCC2N(C)C(C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Yield: 48.6 %

Procedure:
A solution of 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxynaphthalene (0.24 g), iodomethane (77 mg) and K2CO3 (82 mg) in DMF (5 ml) was stirred for 5 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[N-methyl-N-[1-(4,5-diphenyloxazol-2-yl)ethyl]amino]-1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxynaphthalene (0.12 g). MS (m/z): 511 (M+ +1) IR (Film): 1730 cm-1NMR (CDCl3, δ): 1.29 (3H, t, J=7.1 Hz), 1.63 (3H, d, J=7.1 Hz), 1.58-1.88 (3H, m), 1.95-2.18 (1H, m), 2.26 (3H, m), 2.46-2.68 (1H, m), 2.80-3.00 (1H, m), 4.12 (2H, q, J=7.1 Hz), 4.26 (3H, q, J=7.1 Hz), 4.60 (2H, s), 6.56 (1H, d, J=7.9 Hz), 7.11 (1H, dd, J=7.9, 7.9 Hz), 7.26-7.50 (7H, m), 7.59-7.68 (4H, m)
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1OS(C(F)(F)F)(=O)=O)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.[C:51]1(B(O)O)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(OCC)(=O)C>[F:31][C:30]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[CH:26][C:25]=1[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OS(=O)(=O)C(F)(F)F)nc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2ccccc2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 212.2 %

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-trifluoromethanesulfonyloxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (200 mg) is dissolved in 1,4-dioxane (3 ml), and thereto are added phenyl boronic acid (64 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (22 mg) and cesium carbonate (172 mg), and the mixture is stirred under nitrogen atmosphere at 80° C. overnight. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (192 mg). MS (m/z): 686 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](O)=[O:11])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:26][O:27][NH:28][CH3:29].C(N(CC)CC)C>C(Cl)Cl.CCOCC.CN(C)C=O>[CH3:26][O:27][N:28]([CH3:29])[C:10](=[O:11])[CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C(O)C(Cc1ccc(Cl)cc1)c1ccccc1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-(4-chlorophenyl)-2-phenylpropionic acid (Step B, 14 g, 55 mmol) in CH2Cl2 (125 mL) at 0° C. was added dimethyl formamide (50 μL) and oxalyl chloride (14 g, 0.11 mol) dropwise. The reaction was allowed to warm to room temperature overnight and concentrated to dryness to give the crude acyl chloride, which was used without further purification. Thus, to a solution of the acyl chloride in CH2Cl2 (250 mL) was added N-methoxy-N-methylamine hydrochloride (11 g, 0.11 mol) and triethyl amine (dried over activated molecular sieves, 30 mL, 0.22 mol) at 0° C. After stirring at room temperature for 4 h, the reaction mixture was diluted with ether (500 mL) and successively washed with water, dilute aqueous sodium hydrogen sulfate and brine, dried over anhydrous MgSO4, filtered and concentrated to dryness to give the crude product, which was used without further purification. 1H NMR (500 MHz, CD3OD): δ 7.4-7.1 (m, 9H), 4.38 (br, 1H), 3.48 (s, 3H), 3.35 (dd, 1H), 3.10 (s, 3H), 2.92 (dd, 1H); LC-MS: m/e 304 (3.6 min).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].Cl>CC(O)C>[Br:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Clc1ncnc2cccnc12
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)O
Product: Brc1cccc(Nc2ncnc3cccnc23)c1
Yield: 87 %

Procedure:
Reaction of 4-chloropyrido[3,2-d]pyrimidine (prepared as described in a previous experimental) with 3-bromoaniline in propan-2-ol containing a trace of conc. HCl at 50° C. for 30 min, followed by chromatography of the product on silica gel, gives 4-(3-bromophenyl)aminopyrido[3,2-d]pyrimidine (87% yield). 1H NMR (CDCl3) δ 9.19 (1H, brs), 8.83 (1H, s), 8.80 (1H, dd, J=4.3, 1.5 Hz), 8.29 (1H, brs), 8.19 (1H, dd, J=8.5, 1.5 Hz), 7.83 (1H, m), 7.76 (1H, dd, J=8.5, 4.3 Hz), 7.29-7.27 (2H, m).
Reaction SMILES: Cl.FC1C=CC=C2C=1C=C(C(O)=O)C=N2.Cl.[F:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]2)=[CH:20][CH:19]=1.FC1C=C(C=CC=1)N.C(Cl)(=O)C(Cl)=O.Cl.[CH3:46][C@H:47]1[CH2:52][CH2:51][C@H:50]([NH2:53])[CH2:49][CH2:48]1>ClCCl.CN(C)C=O.C(OCC)(=O)C.CCCCCC>[CH3:46][C@H:47]1[CH2:52][CH2:51][C@H:50]([NH:53][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([F:17])[CH:27]=3)=[O:30])[CH2:49][CH2:48]1
Reactant: C[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1cnc2cc(F)ccc2c1
Agent: Cl
Agent: Nc1cccc(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H](NC(=O)c2cnc3cc(F)ccc3c2)CC1
Reaction time: 8 h

Procedure:
The methods of Erickson (J. Med. Chem., 1979, 22, 7, 816–823) were used to prepare a mixture of 5-fluoroquinoline-3-carboxylic acid hydrochloride and 7-fluoroquinoline-3-carboxylic acid hydrochloride from m-fluoroaniline. A mixture of these two acids (500 mg, 2.2 mmole) in dichloromethane (25 mL) was treated with a solution of oxalyl chloride in dichloromethane (1.2 mL of 2 M, 2.4 mmol) followed by dimethylformamide (5 drops). The reaction was stirred overnight, filtered (Gelman Acrodisc CR PTFE 0.45 micron) and concentrated to a solid. The solid was dissolved in dichloromethane (25 mL) and then treated with trans-4-methylcyclohexylamine hydrochloride (330 mg, 2.2 mmol) followed by 4-N,N′-dimethylaminopyridine (1.22 g, 10 mmol). The reaction was stirred 1 hour at ambient temperature. Chromatography of the crude reaction mixture through a Biotage silica cartridge (8×4 cm i.d.) using a gradient of hexane to 30% ethyl acetate (in hexane) afforded three fractions. Recrystallization of fraction A from hot heptane afforded 30 mg of N-(trans-4-methylcyclohexyl)-7-fluoroquinoline-3-carboxamide (423):
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][C:25](OC)=[O:26])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>CCCCCC.O1CCCC1.[Cl-].[Na+]>[O:26]=[C:25]([CH2:24][CH2:23][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([O:14][CH3:13])[CH:16]=1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COC(=O)CCc1ccc(OC)c(OC)c1
Reactant: COP(C)(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(CCC(=O)CP(=O)(OC)OC)cc1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
To a mixture cooled at -78° C. of 50 ml of 2.1M n-butyl lithium solution in hexane and 100 ml of tetrahydrofuran, was added dropwise 12.4 g of dimethyl methylphosphonate. The mixture was stirred at -78° C. for 30 minutes, and thereafter 22.4 g of methyl 3-(3,4-dimethoxyphenyl)propionate [synthesized from 3,4-dimethoxycinnamic acid in 2 steps: (a) esterification (HCl--CH3OH) and (b) reduction (Pd/C--H2)] and 100 ml of tetrahydrofuran were added dropwise to the mixture. Then, the reaction was continued at -78° C. for 22 hours. The reaction mixture was poured in 500 ml of saturated aqueous sodium chloride solution. After neutralization and extraction with dichloromethane, the extract was dried and concentrated to give crude product. By purification of the crude product by means of column chromatography (silica gel/hexane:ethyl acetate=1:4), 9.0 g of the above caption compound was obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)=[O:3].C=CC1C=C[NH+]=CC=1.[Br-:26].[Br-].[Br-]>CO>[F:17][C:14]([F:15])([F:16])[C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][Br:26])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1
Reactant: [Br-]
Reactant: CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C=Cc1cc[nH+]cc1
Solvent: CO
Product: O=C(CBr)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 91.8 %

Procedure:
A stirred suspension of 1 g (3.9 mmol) of 3,5-bis(trifluoromethyl)acetophenone (Lancaster, Windham, N.H., USA) in dry methanol (20 mL) and 1 g (15 mmol, 2.6 eq) of poly(4-vinyl pyridinium tribromide)(Aldrich, Milwaukee, Wis. , USA) was protected from moisture with dry nitrogen, and heated at reflux for 70 min. The polymer was filtered from the cooled solution and washed with methanol and twice with dichloromethane. The solvents were removed in vacuo to give 1-[3,5-bis(trifluoromethyl)phenyl]-2-bromoethan-1-one (1.2 g, 92%). 1H-NMR (DMSO-d6; 300 MHz) δ8.43 (m, 2H), 8.12 (m, 1H), 4.46 (s, 3H).
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH2:23]([C:30]1[N:31]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)[N:32]=[C:33]2[C:38]=1[C:37](=[O:39])[N:36]([CH3:40])[C:35](=[O:41])[N:34]2CC1C=CC(OC)=CC=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O.C1COCC1>[CH2:23]([C:30]1[N:31]([CH2:51][C:52]2[CH:53]=[CH:54][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:56][CH:57]=2)[N:32]=[C:33]2[C:38]=1[C:37](=[O:39])[N:36]([CH3:40])[C:35](=[O:41])[NH:34]2)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(Cn2c(=O)n(C)c(=O)c3c(Cc4ccccc4)n(Cc4ccc(-c5ccccc5)cc4)nc32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4ccccc4)cc3)c(Cc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of ammonium cerium (IV) nitrate (204 mg, 0.371 mmol) in water (0.6 mL) is added to a solution of 3-benzyl-2-(biphenyl-4-ylmethyl)-7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (40.3 mg, 0.0743 mmol) in THF (2 mL). The resulting orange solution is stirred at room temperature overnight. Another batch of CAN (204 mg, 0.371 mmol) is added and the mixture is stirred for 3 hours, and then the third batch of CAN (204 mg) is added, and the mixture is stirred at r.t. overnight. The reaction mixture is evaporated to dryness. The residue is treated with brine, and extracted with methylene chloride five times. The organic phase is combined and concentrated. The residue is purified by chromatography to give 11.6 mg product as white solids (Yield: 36.9%). 1H NMR (400 MHz, acetone-d6) δ 3.27 (s, 3H), 4.51 (s, 2H), 5.33 (s, 2H), 7.13-7.62 (m, 14H), 10.26 (s, 1H). MS (FAB) m/z 423.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[N:4]([CH3:17])[CH:3]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(#N)C>[Cl:1][C:2]1[C:6]2[N:7]([C:20](=[O:21])[CH2:19][Cl:18])[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[N:4]([CH3:17])[CH:3]=1
Reactant: Cn1cc(Cl)c2c1C(=O)Nc1ccccc1N2
Reactant: O=C(Cl)CCl
Solvent: CC#N
Product: Cn1cc(Cl)c2c1C(=O)Nc1ccccc1N2C(=O)CCl
Yield: 63 %

Procedure:
First, 3-chloro-1-methyl-1,4,9,10-tetrahydropyrrolo[3,2-b]-[1,5]benzodiazepin-10-one (1.7 g, 6.86 mmol), is refluxed for 1 hour in a mixture with acetonitrile (50 ml) and chloroacetyl chloride (4.0 ml, 52.9 mmol). The mixture is concentrated in vacuo, the residue is taken up in water (20 ml) and filtered and the solid residue is chromatographed using dichloromethane/cyclohexane/ethyl acetate (1:2:1 v/v) as eluant. A wine-red solid is isolated from the eluate, yielding colorless crystals (1.4 g) of mp. 284°-285° C. (D) after purification with tert.butyl methyl ether.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:16][C:15]=3[CH3:34])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:35][NH2:36].CO>CC(O)CC>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:34])=[C:14]([NH:13][C:11]([C:9]2[S:8][C:6]3=[N:7][C:2]([NH:36][CH3:35])=[CH:3][N:4]=[C:5]3[CH:10]=2)=[O:12])[CH:19]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Reactant: CN
Solvent: CCC(C)O
Solvent: CO
Product: CNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Yield: 12 %

Procedure:
A solution of 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (0.049 mmol, 24 mg) and methylamine 33% in MeOH (0.049 mmol, 500 μL, 4.61 mg) in butan-2-ol (500 μL) was stirred at 150° C. for 5 h. The reaction mixture was concentrated under reduced pressure and purified with HPLC to give the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-(methylamino)thieno[2,3-b]pyrazine-6-carboxamide (96a) (3 mg, 12%). NMR (400 MHz, DMSO-d6) 1.75 (s, 6H), 2.24 (s, 3H), 2.89 (d, J=4.7 Hz, 3H), 7.28 (d, J=8.2 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.62 (dd, J=8.2 Hz and 2.0 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.83 (m, 2H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.11 (s, 1H), 8.25 (s, 1H), 10.08 (s, 1H), 10.33 (s, 1H). (m/z)=485 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:10]([N+:13]([O-:15])=[O:14])=[C:9]([F:11])[C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(C(=O)O)c(Cl)cc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(C(=O)O)c(Cl)c([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
2-Chloro-4-fluoro-5-methylbenzoic acid (2.0 g) was added to concentrated sulfuric acid (20 ml) to dissolve it, and potassium nitrate (1.07 g) was added portionwise to the solution under ice cooling. After the addition, the temperature of the reaction mixture was given back to room temperature to conduct stirring overnight. The reaction mixture was poured into ice water and extracted with diethyl ether. After an organic layer was collected and dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound (2.25 g) as a reddish brown oil.
Reaction SMILES: [N+](=[C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-]>ClCCl.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.[Rh+2].[Rh+2]>[N+:16]([C:12]1[CH:11]=[C:10]([C:3]23[CH2:9][CH:8]2[CH2:7][O:6][C:4]3=[O:5])[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: C=CCOC(=O)C(=[N+]=[N-])c1cccc([N+](=O)[O-])c1
Agent: [Rh+2]
Agent: CCCCCCCC(=O)[O-]
Solvent: ClCCl
Product: O=C1OCC2CC12c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of commercially available rhodium(II) octanoate dimer (Rh2(C7H16CO2)4) CAS-no. [73482-96-9] (440 mg, 565 μmol, Eq: 0.00941) in dichloromethane (180 ml) at 50° C. was added a solution of allyl 2-diazo-2-(3-nitrophenyl)acetate (intermediate B4a) (14.85 g, 60.1 mmol, Eq: 1.00) in dichloromethane (38 ml) via syringe pump within 18 h. Refluxing was continued for 30 min, the solvent was evaporated and the crude material was purified by flash chromatography (silica gel, 70 g, 0% to 100% EtOAc in heptane) to give (1SR,5RS)-1-(3-nitrophenyl)-3-oxabicyclo[3.1.0]hexan-2-one (12 g, 54.7 mmol, 91.1% yield) as a light brown solid. [cf. Adv. Synth. Catal. 2001, 343, 299 for an enantioselective version of this reaction]. MS (ISP): m/z=237.1 [(M+NH4)+].
Reaction SMILES: Cl[C:2]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](OCC2C(OC)=CC=C(F)C=2F)=[CH:17][C:3]=1[NH:4]C1C([N+]([O-])=O)=C(OC)N=C(Cl)N=1.C1(=O)NC(=O)C2=CC=CC=C12.[K].Cl>CN1CCCC1=O>[CH3:22][O:21][C:19]1[CH:20]=[CH:2][C:3]([NH2:4])=[CH:17][CH:18]=1
Reactant: COc1cc(Cl)c(Nc2nc(Cl)nc(OC)c2[N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F
Agent: Cl
Agent: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN1CCCC1=O
Product: COc1ccc(N)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 330.9 %

Procedure:
To a solution of 2-chloro-N-(2-chloro-6-methoxy-5-nitropyrimidin-4-yl)-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.33 g) in 1-methyl-2-pyrrolidone (5 mL) was added potassium phthalimide (0.26 g), and the mixture was stirred at 65° C. for 2 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate=2/1), and collected by filtration. The collected solids were dried under reduced pressure to give 2-chloro-N-[6-methoxy-5-nitropyrimidin-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-4-yl]-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.26 g). To this material were added tetrahydrofuran (8 mL), methanol (3 mL) and 10% platinum-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. To the suspension of the residue in tetrahydrofuran (6 mL) was added triphosgene (50 mg) at room temperature. To the mixture was added sodium hydride (55%, 64 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/9) to give 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-7,9-dihydro-8H-purin-8-one (0.1 g). This material was dissolved in tetrahydrofuran (3 mL). To the solution was added hydrazine monohydrate (0.039 mL), and the reaction vessel was equipped with a reflux condenser, and the mixture was stirred at 90° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate) to give the title compound (71 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[CH:12]1([C:15]2[C:16]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([C:16]3[C:15]([CH:12]4[CH2:14][CH2:13]4)=[CH:20][C:19]([C:21]([F:24])([F:22])[F:23])=[CH:18][N:17]=3)[CH2:26][CH2:27]2)=[O:8])=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: O=C(O)c1ccc(Br)nc1
Agent: Cl
Product: O=C(c1ccc(Br)nc1)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 106.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 27 and using 6-bromonicotinic acid (667 mg) and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine hydrochloride (1.2 g) described in Preparation Example 76, the title compound (1.6 g) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=1.C1N=CN([C:18](N2C=NC=C2)=[O:19])C=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:18]1=[O:19]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCCNc1ccccc1N
Solvent: C1CCOC1
Product: COCCn1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
The residue 109B (422 mg, 2.54 mmol) was dissolved in THF (7.5 mL). CDI (494 mg, 3.05 mmol) in THF (7.6 mL) was added slowly via addition funnel. After addition the mixture was stirred overnight at room temperature, solvent was removed under vacuum. The residue was purified by column chromatography (5% MeOH/DCM) to give the product 1-(2-methoxyethyl)-1H-benzo[d]imidazol-2(3H)-one (109C) as an orange solid (449 mg, 92%). ESI-MS:m/z 193.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[S:28][CH:29]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[S:28][CH:29]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15 mg (0.03 mmol) of the compound from example 20A are dissolved in 0.7 ml of dry DMF, and 10 mg (0.04 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 11 mg (0.14 mmol) of sodium bicarbonate are added. The reaction mixture is stirred at RT for 8 h. The mixture is then poured into 2 ml of saturated aqueous sodium bicarbonate solution, and the aqueous phase is extracted three times with in each case 5 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, and the solvent is removed on a rotary evaporator.