Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Clc1nc(NCc2ccccc2)c2[nH]cnc2n1
Temperature: 60 °C
Yield: 96.3 %

Procedure:
To a suspension of 2,6-dichloropurine (110 mg, 0.52 mmol) in n-butanol (3 mL), benzylamine (57 mg, 0.52 mmol) and triethylamine (72 mg, 0.79 mmol) was added. The mixture was stirred and heated at 60° C. for 15 min. The resulting precipitate was filtered, washed with water (20 mL) and methanol (10 mL), and air-dried overnight. Compound 4 (130 mg, 95%) was obtained as an off-white solid: mp 262° C.; EI/MS (m/z (relative %)): 259 (19, M+.), 260 (14), 261 (17%), 106 (100), 91 (77); 1H NMR (400 MHz, DMSO) δ 8.15 (s, 1H), 7.25-7.34 (m, 5H), 4.66 (d, J=6 Hz, 2H); 13C NMR (100 MHz, DMSO) δ 155.0 (s) 153.1 (s), 150.7 (s), 140.2 (d, 1JC—H=200 Hz), 139.6 (s), 128.5 (d, 1JC—H=158 Hz, 127.5 (d, 1JC—H=157 Hz), 127.0 (d, 1JC—H=158 Hz) 118.1 (s), 43.4 (t, 1JC—H=139 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:30]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4([NH:41]C(=O)OC(C)(C)C)[CH2:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:49].O1CCOCC1>C(Cl)Cl>[ClH:49].[ClH:49].[ClH:49].[NH2:41][C:37]1([C:34]2[CH:33]=[CH:32][C:31]([N:30]3[C:11]4=[N:12][C:13]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([N:22]6[CH2:27][CH2:26][S:25](=[O:28])(=[O:29])[CH2:24][CH2:23]6)[CH:17]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:36][CH:35]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CCS(=O)(=O)CC6)c5)nc43)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ncccc1-c1nc2ccc(-c3cccc(N4CCS(=O)(=O)CC4)c3)nc2n1-c1ccc(C2(N)CCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
tert-Butyl [1-(4-{2-(2-aminopyridin-3-yl)-5-[3-(1,1-dioxidothiomorpholin-4-yl)phenyl]-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)cyclobutyl]carbamate (29.0 mg, 0.0449 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 2 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (33.2 mg, 85.1%) as pale yellow solid.
Reaction SMILES: [NH:1]1[C:5](=O)[CH:4]=[CH:3][C:2]1=O.[F:8][C:9]([F:26])([F:25])[C:10]1[CH:19]=[C:18]([S:20][CH2:21][C:22]([NH2:24])=[O:23])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>>[C:3]1([C:21]2[C:22](=[O:23])[NH:24][C:22](=[O:23])[C:21]=2[S:20][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:9]([F:8])([F:25])[F:26])[CH:19]=2)[C:4]2=[C:5]3[C:17](=[CH:12][CH:13]=[CH:14]2)[CH2:18][CH2:19][CH2:10][N:1]3[CH:2]=1
Reactant: NC(=O)CSc1cc(C(F)(F)F)nc2ccccc12
Reactant: O=C1C=CC(=O)N1
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1Sc1cc(C(F)(F)F)nc2ccccc12

Procedure:
3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4¶-trifluoromethyl-quinolin-4-yl-sulfanyl)-pyrrole-2,5-dione was prepared according to Example 1, steps 1-6, employing 2-[[2-(trifluoromethyl)-4-quinolinyl]thio]acetamide in place of indole-3-acetamide in step 6. 1H NMR (CDCl3) 400 MHz δ: 8.3(d, 1H, J=7.6 Hz), 8.11(d, 1H, J=8.4 Hz), 8.05(s, 1H), 7.68-7.82(m, 4H), 7.23(s, 1H), 6.83(m, 2H), 4.21(t, 2H, J=6 Hz), 2.92(t, 2H, J=6 Hz), 2.21(m, 2H).
Reaction SMILES: C([O:8][CH2:9][C:10]1[NH:11][C:12]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:21]=2)=[CH:13][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH:29]1([O:28][C:22]2[CH:21]=[C:20]([C:12]3[NH:11][C:10]([CH2:9][OH:8])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=3)[CH:25]=[CH:24][C:23]=2[O:26][CH3:27])[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(-c2ccc(OC)c(OC3CCCC3)c2)[nH]c1COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(OC)c(OC3CCCC3)c2)[nH]c1CO
Temperature: 30 °C
Reaction time: 1.25 h
Yield: 43.3 %

Procedure:
To 280 ml of ethanol solution containing 3.15 g (7.0 mmol) of ethyl 2-benzyloxymethyl-5-(3-cyclopentoxy-4-methoxyphenyl)-1H-pyrrol-3-carboxylate obtained in Reference example 47-(c) was added 600 mg of 10% palladium-active carbon, and the mixture was stirred under 1 atm hydrogen atmosphere at room temperature for 11 hours. Then, the mixture was stirred at 30° C. for 1.25 hours, and further at 40° C. for 13 hours. After completion of the reaction, the reaction suspension was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3→1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 1.09 g of the title compound as a yellowish oil. (Yield: 43%)
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.N1C=CC=CC=1.[CH3:19][O:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:19][O:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](=[O:29])(=[O:30])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
250 ml of dichloromethane is combined with 9.38 g (52.37 mmol) of 4-fluoro-2-trifluoromethylaniline and 6 ml (14.3 mmol) of pyridine. The mixture is cooled with ice water and under agitation and exclusion of moisture, 13.52 g (57.62 mmol) of 2-chlorosulfonylbenzoic acid methyl ester is added in small increments. The mixture is agitated overnight, washed with 2N hydrochloric acid and water, the dichloromethane solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized from ethyl acetate/hexane. The title compound melts at 143°-145° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[Br:14]Br>CO>[Br:14][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N+:8]([O-:10])=[O:9])[N:4]=1
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: BrBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1nc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0° C., and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0° C. for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification: MS (ES) m/z 219.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8].[F:11][C:12]1[CH:24]=[C:23](F)[C:22]([F:26])=[CH:21][C:13]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:23]2[C:22]([F:26])=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[C:12]([F:11])[CH:24]=2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(F)c(OCc2cnc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
To a solution of (5,6-dichloropyridin-3-yl)methanol (275 mg, 1.55 mmol) in DMSO (5 mL) were added tert-butyl 2,4,5-trifluorobenzoate (Preparation 97, 300 mg, 1.30 mmol), and potassium carbonate (535 mg, 3.88 mmol) and the mixture stirred for 18 hours at room temperature under a nitrogen atmosphere. Water (10 mL) was added and the mixture extracted with EtOAc (3×20 mL). The combined organics were washed with water (20 mL) and concentrated in vacuo to yield the title compound (490 mg, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([OH:18])=[O:17])=[N:8]2)=[C:4]([CH3:21])[CH:3]=1.OS(O)(=O)=O.[CH2:27](O)[CH3:28]>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([O:18][CH2:27][CH3:28])=[O:17])=[N:8]2)=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Cn1nc(C(=O)O)c2ccccc21
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nn(Cc2ccc(Cl)cc2C)c2ccccc12
Temperature: 25 °C

Procedure:
To a suspension of 1-(4-chloro-2-methylbenzyl)-1H-indazole-3-carboxylic acid, prepared as described in J. Med. Chem. (1976) 19, 778-783, (120 g; 0.4 mol) in absolute ethanol (850 ml), stirred at room temperature, was cautiously added concentrated H2SO4 (15 ml). The mixture was then refluxed for 9 hours. The reaction was then completed by cooling the mixture to room temperature. The solid thus formed was filtered off under cold conditions (10° C.) and washed thoroughly on the filter with water. 126 g of ethyl 1-(4-chloro-2-methylbenzyl)-1H-indazole-3-carboxylate were thus obtained, and were used in the following reaction without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#N)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].CN(C)C=O.[BH4-].[Na+].[CH3:24][O:25][CH2:26]CCl>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:24][O:25][CH3:26])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: COCCCl
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
2.37 G. of 1-acetamido-2-nitro-4-thiocyanatobenzene in 10 ml. dimethylformamide is treated at 20°-25° C under nitrogen, with 0.38 g. of sodium borohydride. After one hour 1.6 ml. of chloroethyl methyl ether is added, and the mixture kept at 20°-30° C for a further three hours. Water is then added and the product filtered off. Recrystallization from cyclohexane gives 1-acetamido-2-nitro-4-methoxyethylthiobenzene.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5](=[CH:14][C:15]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[O:16])[NH:4][C:3]1([CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[S:44](Cl)(=[O:46])=[O:45]>>[O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([S:44]([C:40]3[S:39][CH:43]=[CH:42][CH:41]=3)(=[O:46])=[O:45])[CH2:10][CH2:9]2)[C:5](=[CH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)=[O:16])[NH:4][C:3]1([CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCNCC2)cc1
Product: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCN(S(=O)(=O)c3cccs3)CC2)cc1

Procedure:
According to the procedure of Example 13, the title compound of 40B (36 mg, 0.071 mmol) and thiophene-2-sulfonyl chloride (16 mg, 0.085 mmol) were reacted to generate the title compound (9 mg, 0.014 mmol,19% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[C:32]1(B(O)O)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:40]4[C:41]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:37]=[CH:38][CH:39]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)[CH3:6])[CH3:2]
Reactant: OB(O)c1cccc2ccccc12
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccc5ccccc45)cc3)oc2C)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl-propionic acid ethyl ester (0.907 mmol) (see Ex. 2, part B) and 1-naphthaleneboronic acid (0.998 mmol) in toluene:ethanol (18.2 mL of a 1:1 solution) was treated with Na2CO3(aq) (0.906 mL of a 2M solution). A nitrogen atmosphere was applied, Pd(PPh3)4 (52.5 mg) was added, and the orange mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (20 mL) and H2O (30 mL). The layers were separated, and the aqueous phase was back-extracted with ethyl acetate (2×10 mL). Combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (20 g SiO2, 3:7 ethyl acetate:hexanes) to give the desired product in 87% as an orange oil; Rf=0.46 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=8 Hz, 2H), 7.92-7.82 (m, 3H), 7.59-7.40 (m, 6H), 6.81-6.72 (m, 4H), 4.22-4.17 (m, 4H), 2.98 (t, 2H), 2.38 (s, 3H), 1.46 (s, 6H), 1.22 (t, 3H); MS (EI) 536.3 (M+H)+.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][C:35]1([CH3:39])[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:37]4[CH2:38][C:35]([NH2:34])([CH3:39])[CH2:36]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CC1(N)CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CC1(N)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 68.3 %

Procedure:
To 350 mg of N,N-dimethylformamide were added 80 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-amino-3-methylazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 40 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol to obtain 64 mg of the title compound as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH3:10])[CH:7]=1.Cl[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:21]=2[N:20]=1>O1CCOCC1>[Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:19]3[NH:20][C:21]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:22]=4[N:23]=3)[C@H:13]([CH3:17])[CH2:12]2)=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH3:10])[CH:7]=1
Reactant: COCc1cnc(N2CCN[C@H](C)C2)c(Cl)c1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Solvent: C1COCCO1
Product: COCc1cnc(N2CCN(c3nc4cc(C(F)(F)F)ccc4[nH]3)[C@H](C)C2)c(Cl)c1

Procedure:
A mixture of (3R)-1-(3-chloro-5-methoxymethyl-pyridin-2-yl)-3-methyl-piperazine from step (b) above (153 mg, 0.6 mmol) and 2-chloro-6-trifluoromethyl-1H-benzoimidazole (153 mg, 0.48 mmol, Example 1c) in dioxane (2 mL) reacted under the conditions of Example 3c to give the title compound. MS (ESI, pos. ion) m/z: 440 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14](C(F)(F)F)([C:18]([F:21])([F:20])[F:19])[C:15](O)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30][N:31](C)[CH:32]=O>>[CH3:30][N:31]([CH3:32])[C:15](=[O:16])[CH:14]([O:13][CH2:12][C:11]1[CH:26]=[CH:27][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[C:18]([F:21])([F:20])[F:19]
Reactant: O=C(O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CN(C)C(=O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)C(F)(F)F
Temperature: 100 °C

Procedure:
A solution of 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionic acid (2.06 g.) in dimethylformamide (10 ml.) is added dropwise at 0° C. under argon to a stirred suspension of sodium hydride (216 mg. of a 60% dispersion in oil from which the oil has been washed with light petroleum) in dimethylformamide (15 ml.). The mixture is heated at 100° C. for 18 hours, cooled, and evaporated in vacuo. The residue is mixed with water and the solid obtained (1.8 g.) is washed with water and dried, then chromatographed in toluene on a column of silica (60 g.). The column is washed with toluene (900 ml.) until no more material is eluted, and then with ether. The ether is evaporated and the solid (0.4 g.) is crystallised from light petroleum to give (±)-N,N-dimethyl-2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoropropionamide, m.p. 103°-107° C. (212 mg.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH:18][C:19]([C:21]2[N:22]([CH3:30])[N:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=2)=[O:20])[C:3]=1[N+:31]([O-])=O.O.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:31][C:3]1[C:4]([NH:18][C:19]([C:21]2[N:22]([CH3:30])[N:23]=[C:24]([C:26]([CH3:28])([CH3:27])[CH3:29])[CH:25]=2)=[O:20])=[N:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:17])[F:16])=[N:7][C:2]=1[CH3:1]
Reactant: Cc1nc(-c2ccccc2C(F)(F)F)nc(NC(=O)c2cc(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccccc2C(F)(F)F)nc(NC(=O)c2cc(C(C)(C)C)nn2C)c1N
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid [6-methyl-5-nitro-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amide (226 mg, 0.490 mmol, prepared as described in the previous step) in ethanol (10 mL) and water (5 mL) was treated with ammonium chloride (262 mg, 4.90 mmol) and iron powder (137 mg, 2.45 mmol), and the mixture was heated to 50° C. for 4 h. Ethanol was removed in vacuo, and the resulting residue was diluted with water (20 mL) and extracted twice with EtOAc (30 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Isco system: Flow rate=20 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 10 min, then 1:99 to 1:4 v/v over 40 min) to yield 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid [5-amino-6-methyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amide as an off-white solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C21H23F3N6O: 433.2 (M+H). Measured: 433.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[CH3:15][O:14][C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:16][CH3:17])[N:5]=[CH:4][CH:3]=[C:2]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2)=[O:13]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: COC(=O)c1cc2c(Cl)ccnc2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc2c(Oc3ccc4[nH]ccc4c3)ccnc2cc1OC
Temperature: 130 °C
Reaction time: 5 h
Yield: 29.8 %

Procedure:
After mixing methyl 4-chloro-7-methoxyquinoline-6-carboxylate (described in WO0050405, p.34, 8.5 g, 33.77 mmol), 5-hydroxyindole (7 g), diisopropylethylamine (8.9 ml) and N-methylpyrrolidone (8.9 ml), the mixture was heated and stirred at 130° C. for 5 hours and then at 150° C. for 8 hours. After standing to cool, the solution was adsorbed onto silica gel and purified with a silica gel column (hexane-ethyl acetate system). Ethanol, diethyl ether and hexane were added to the obtained yellow oil, and crystals precipitated after a period of standing. The crystals were filtered out, washed with diethyl ether and hexane and then dried by aspiration to obtain light yellow crystals (3.506 g, 10.06 mmol, 29.80%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.O>CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[C:9]1[N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(Br)n2Cc1ccccc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(N1CCCC1)n2Cc1ccccc1
Temperature: 100 °C
Yield: 94.9 %

Procedure:
Compound 35 (500 mg, 1.05 mmol) obtained in Example 35 was dissolved in N,N-dimethylformamide (15 mL), to the solution were added potassium carbonate (430 mg, 3.11 mmol, 3.0 equivalents) and pyrrolidine (260 μL, 3.11 mmol, 3.0 equivalents), and then the mixture was stirred with heating at 100° C. for 3.5 hours. To the reaction solution was added water, the mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=99:1 to 97:3), and to the residue were added acetone and diethyl ether. The deposited crystals were collected by filtration to obtain the title compound (467 mg, 95%) as white crystals.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:19]2[NH:20][C:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)([C:24]([NH:26][CH3:27])=[O:25])[CH2:22][O:23][C:18]=2[CH:17]=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:27][NH:26][C:24]([C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[N:20]2[C:2](=[O:4])[NH:13][C:14]3=[CH:15][CH:16]=[CH:17][C:18](=[C:19]23)[O:23][CH2:22]1)=[O:25]
Reactant: CNC(=O)C1(c2ccccn2)COc2cccc(N)c2N1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reaction time: 1 h
Yield: 249.8 %

Procedure:
Triphosgene (10 mg, 0.04 mmol) was added to a solution of 5-amino-N-methyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide (30 mg, 0.1 mmol) in tetrahydrofuran (3 mL) and N,N-diisopropylethylamine (40 μL, 0.2 mmol) at room temperature and was stirred for 1 h. The reaction mixture was then partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give crude N-methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide as a semisolid (0.031 g, 100%). LCMS calculated for C16H15N4O3 (M+H)+: m/z=311.1. found: 311.1.