Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5](Br)=[C:6](Br)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)C.Cl.[NH2:24][OH:25].[OH-].[Na+]>>[OH:3][C:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C(Br)=C(Br)c1ccc(Oc2ccccc2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(-c2ccc(Oc3ccccc3)cc2)on1
Yield: 81.7 %

Procedure:
α,β-Dibromo-4-phenoxycinnamic acid ethyl ester (7.0 g), hydroxylamine hydrochloride (1.4 g) and sodium hydroxide (3.3 g) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(c) to obtain the title compound (3.4 g, 83%) as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:16])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].C1(C)C(S(O[CH2:28][CH:29]2[CH2:33][CH:32]=[CH:31][CH2:30]2)(=O)=O)=CC=CC=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:29]1([CH2:28][N:7]2[C:8]([S:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:17])[NH:5][C:6]2=[O:16])[CH2:33][CH2:32][CH2:31][CH:30]=1
Reactant: Cc1ccccc1S(=O)(=O)OCC1CC=CC1
Reactant: CCc1c(Sc2ccccc2)[nH]c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(Sc2ccccc2)n(CC2=CCCC2)c(=O)[nH]c1=O
Yield: 34.3 %

Procedure:
A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione (0.10 g, 0.40 mmol) and (cyclopent-3-en-1yl)methyl toluenesulfonate (0.12 g, 0.40 mmol) in dimethylformamide (10 ml) were heated at 90° C. for overnight in the presence of sodium bicarbonate (41 mg, 0.48 mmol). After the concentration of dimethylformamide under vacuum distillation, the desirable product was obtained as white solid (45 mg) by the separation of column chromatography.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>CO>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:5]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: [H][H]
Reactant: CN1CCC(Oc2ccccc2[N+](=O)[O-])(c2ccccc2)CC1
Solvent: CO
Product: CN1CCC(Oc2ccccc2N)(c2ccccc2)CC1
Yield: 77.8 %

Procedure:
A solution of 1-methyl-4-(2-nitrophenoxy)-4-phenylpiperidine (6.4 g) in methanol (200 ml) was hydrogenated at atmospheric pressure and ambient temperature until the theoretical uptake of hydrogen had occurred (about 2 hours). The catalyst was removed by filtration, the solvent removed under reduced pressure and the residue recrystallised twice from IPE to give the title compound (4.5 g) m.p. 129°-30°.
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]=[C:5]1[N:11]2[CH2:12][CH2:13][C@H:10]2[C:9]2=[C:14]([C:17]([O:19]CC)=O)[N:15]=[CH:16][N:8]2[C:7]2[CH:22]=[CH:23][S:24][C:6]1=2>C(O)C>[O:4]=[C:5]1[N:11]2[CH2:12][CH2:13][CH:10]2[C:9]2=[C:14]([C:17]([NH:2][NH2:3])=[O:19])[N:15]=[CH:16][N:8]2[C:7]2[CH:22]=[CH:23][S:24][C:6]1=2
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ncn2c1C1CCN1C(=O)c1sccc1-2

Procedure:
10 ml of hydrazine hydrate were added to a suspension of 6.0 g (19.8 mmol) of ethyl (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxylate in 50 ml of ethanol and the mixture was heated at reflux for 3 hours. After cooling to 0° the crystals obtained were filtered off and there were obtained 5.6 g (98%) of S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno-[3,2-e][1,4]diazepine-1-carboxylic acid hydrazide as colourless needles of m.p. 260°-263°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:52])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][C:48]([NH:50][NH2:51])=[O:49])[CH2:15]2)=[CH:10][CH:9]=1.CO[CH:55](OC)[N:56]([CH3:58])[CH3:57]>C(Cl)Cl>[CH3:55][N:56]([CH3:58])/[CH:57]=[N:51]/[NH:50][C:48](=[O:49])[CH2:47][C@H:16]1[CH2:15][C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][O:6][CH2:5][C@@H:4]([CH3:52])[CH2:3][O:2][CH3:1])=[CH:13][CH:12]=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:18][N:17]1[S:37]([C:40]1[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=1)(=[O:38])=[O:39]
Reactant: COC(OC)N(C)C
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)NN)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Solvent: ClCCl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)N/N=C/N(C)C)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Temperature: 25 °C

Procedure:
A solution of 1 mmol of [(2R,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid hydrazide in 5 ml of CH2Cl2 is treated at RT with 1.1 mmol of N,N-dimethylformamide dimethylacetal and refluxed for 1 h. The mixture is cooled to RT, and concentrated under reduced pressure to afford the title compound as a viscous brown-orange oil. Rt=4.75 (gradient I).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=O)[N:8]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CC(O)=O.CC(N(C)C)=O>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:21]=[CH:20][CH:19]=[C:16]([CH2:17][N:27]4[CH2:28][CH2:29][CH:24]([N:23]([CH3:30])[CH3:22])[CH2:25][CH2:26]4)[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C1CCNCC1
Reactant: O=Cc1cccc(Nc2nccc(-c3ccc(Br)s3)n2)c1
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: CN(C)C1CCN(Cc2cccc(Nc3nccc(-c4ccc(Br)s4)n3)c2)CC1
Yield: 7.1 %

Procedure:
A solution of 3-[4-(5-Bromo-thiophen-2-yl)-pyrimidin-2-ylamino]-benzaldehyde (25 mg, 0.069 mmol) and 4-dimethylaminopiperidine (13.3 mg, 0.104 mmol) in 25% HOAc in DMA was mixed for 2 h and then treated with MP-CNBH3 (2.5 eq.) for 18 h. The reactions were filtered and purified directly by LCMS to afford title compound (2.3 mg, 7%) for 2 steps. MS: m/z 472 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 1.37 (br q, J=11 Hz, 2H), 1.70 (br d, J=12 Hz, 2H), 1.94 (br t, J=11 Hz, 2H), 2.04 (br t, 1H), 2.87 (br d, J=11 Hz, 2H), 3.33 (s, 2H), 6.89 (d, J=7.5 Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 7.33 (dd, J=1, 5 Hz, 1H), 7.37 (m, 1H), 7.55 (br d, J=8 Hz, 1H), 7.86 (m, 1H), 7.89 (br s, 1H), 8.51 (dd, J=1.5, 5 Hz, 1H), 9.68 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=3[CH3:28])[C:22]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:24])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36]
Reactant: Cc1c(F)cc(C(=O)O)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)Nc2ccccc2)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 34.7 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzoic acid (25 mg, 0.05 mmol) in CH2Cl2 (2 mL) were added aniline (0.025 mL, 0.25 mmol) and HBTU (20 mg, 0.053 mmol). The reaction mixture was stirred over night. The reaction mixture was concentrated. Separation via a HPLC with TFA followed by treatment with t-amino SPE cartridge then provided the title compound as a white solid (10 mg, 35%). LC-MS m/z 576 (M+H)+; 1H-NMR (MeOD) δ 2.27 (s, 3H), 2.79 (s, 6H), 3.15 (m, 2H), 3.55 (m, 2H), 4.21 (s, 2H), 7.19 (m, 3H), 7.39 (m, 2H), 7.54 (m, 1H), 7.71 (m, 3H), 7.86 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH2:16]([O:23][C:24]1[CH:40]=[CH:39][CH:38]=[CH:37][C:25]=1[CH2:26][S:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([S:27][CH2:26][C:25]3[CH:37]=[CH:38][CH:39]=[CH:40][C:24]=3[O:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:36][CH:35]=2)[CH:4]=1
Reactant: O=C(Cl)c1ccc(SCc2ccccc2OCc2ccccc2)cc1
Reactant: NCc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1cccnc1)c1ccc(SCc2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a stirred mixture of 3-aminomethylpyridine (324 mg) and triethylamine (1.51 g) in dichloromethane (20 ml) at 0° C. was added 4-[2-benzyloxybenzylthio]benzoylchloride in CH2Cl2 (10 ml) (3 mmol). The mixture was allowed to warm to ambient temperature, washed with saturated aqueous NaHCO3 (3×20 ml), dried (MgSO4), filtered and evaporated. The residue was triturated with diethyl ether (20 ml) and crystallised from ethyl acetate to give N-(3-pyridylmethyl)-4-[2-benzyloxybenzylthio]benzamide (220 mg). (mpt. 108° C.).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[OH:12][C:13]([CH3:34])([CH3:33])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[NH:28][C:29](=[O:32])[O:30][CH3:31]>ClCCl>[OH:12][C:13]([CH3:34])([CH3:33])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:20]([O-:6])=[CH:19][C:18]=2[N:17]=[C:16]1[NH:28][C:29](=[O:32])[O:30][CH3:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Nc1nc2cnc3ccccc3c2n1CC(C)(C)O
Solvent: ClCCl
Product: COC(=O)Nc1nc2c[n+]([O-])c3ccccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.2 %

Procedure:
3-Chloroperoxybenzoic acid (1.83 g of approximately 75% pure material) was added to a stirred solution of methyl [1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]carbamate (1.0 g, 3.18 mmol) in dichloromethane (25 mL), and the reaction was stirred for 24 hours at room temperature. A precipitate formed and was collected by filtration, washed with a minimal amount of dichloromethane, and dried to provide 0.8 g of methyl [1-(2-hydroxy-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinolin-2-yl]carbamate as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]([C:20]([OH:22])=O)[NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:12])[CH:3]=1.[C:23](OC(=O)C)(=O)C.O>N1C=CC=CC=1>[C:20]([CH:9]([NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[O:12])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:22])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C(=O)NC(Cc2cccc(Br)c2)C(=O)O)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)C(Cc1cccc(Br)c1)NC(=O)c1ccc(C)cc1
Reaction time: 3 h

Procedure:
1-Bromo-3-[2-carboxy-2-(p-toluoylamino)ethyl]benzene (16.84 g) was dissolved in 85 ml of pyridine, and 55 ml of acetic anhydride was added and stirred for 3 hours under argon atmosphere at 90–95° C. Water (55 ml) was added dropwise gradually so that the maximum temperature did not exceed 100° C., and the mixture was stirred for 20 minutes at 60–70° C. The reaction solution was cooled, poured into ice-cold water and extracted with ethyl acetate. The resulting solution was washed with 10% hydrochloric acid, water and saturated aqueous sodium hydrogen carbonate solution sequentially and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting crystals were washed with isopropyl ether to provide 13.31 g of the objective compound as brownish crystals. M.p. 106–107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:21])=[C:12]3[CH:18]=[C:17]([CH2:19][OH:20])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[CH:18]=[C:17]([CH2:19][OH:20])[S:16][C:13]=3[N:14]([CH3:24])[CH:15]=2)=[O:9])=[CH:22][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CO)cc2c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(hydroxymethyl)thieno[2,3-b]pyridine-5-carboxamide (0.955 g) from Example No. 34 in DMF (20 mL) is added potassium carbonate (0.567 g) followed by iodomethane (0.20 mL). The reaction is stirred at rt for 1 h. The reaction mixture is partitioned between water (50 mL) and CH2Cl2 (100 mL). The aqueous layer is extracted with CH2Cl2 (100 mL). The organic layer is removed in vacuo and insoluble material in the aqueous layer is filtered off. The resulting solid is recrystallized from ethanol to yield 0.825 g (83%) of the title compound as a white, crystalline solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH2:11][C:12]#[N:13])[CH:5]=1)#[N:2].Cl.N[C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[C:18]([F:24])[C:17]=1[SH:25]>>[F:22][C:21]1[C:16]2[N:2]=[C:1]([CH2:3][C:4]3[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[C:8]([Br:10])[CH:9]=3)[S:25][C:17]=2[C:18]([F:24])=[CH:19][C:20]=1[F:23]
Reactant: N#CCc1cc(Br)cc(CC#N)c1
Reactant: Nc1c(F)c(F)cc(F)c1S
Agent: Cl
Product: N#CCc1cc(Br)cc(Cc2nc3c(F)c(F)cc(F)c3s2)c1
Yield: 16.5 %

Procedure:
The procedure of Example 22-i) was repeated using 1,3-biscyanomethyl-5-bromobenzene (1.9 g, 8.1 mmol) and 2-amino-3,4,6-trifluorothiophenol hydrochloride (1.74 g, 8.1 mmol) and the resultant product was crystallized from isopropyl ether to give 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]-5-bromophenylacetonitrile (532 mg, 18%) as a colorless powder.
Reaction SMILES: Br[C:2]1[C:3]([C:15]([OH:17])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[N:6][CH:7]=1.[OH-].[NH4+:19]>[O-]S([O-])(=O)=O.[Cu+2]>[NH2:19][C:2]1[C:3]([C:15]([OH:17])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[N:6][CH:7]=1
Reactant: O=C(O)c1nc(-c2ccccc2F)ncc1Br
Reactant: [NH4+]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [OH-]
Product: Nc1cnc(-c2ccccc2F)nc1C(=O)O
Temperature: 110 °C
Yield: 53 %

Procedure:
CuSO4 (with 5H2O, 65 mg) was added to a mixture of the above made 5-bromo-2-(2-fluorophenyl)pyrimidine-4-carboxylic acid (770 mg, 2.59 mmol) and 28% aqueous ammonium hydroxide (12 ml). The reaction was heated in a microwave reactor at 110° C. for 30 min. It was cooled to RT and concentrated in vacuo. The residue was diluted with 1N HCl (20 mL) and extracted with EtOAc 3×. Combined organic extracts were dried over sodium sulfate and filtered and concentrated to give 5-amino-2-(2-fluorophenyl)pyrimidine-4-carboxylic acid (320 mg, 53%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=2)[C:8]2[C:13]([C:14]=1[C:15]([O:17]CC)=[O:16])=[CH:12][C:11]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[CH:37]([O:36][C:33]1[CH:34]=[CH:35][C:30]([N:7]2[C:8]3[C:13](=[CH:12][C:11]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][N:21]=4)=[CH:10][CH:9]=3)[C:14]([C:15]([OH:17])=[O:16])=[C:6]2[C:4]([OH:5])=[O:3])=[CH:31][CH:32]=1)([CH3:39])[CH3:38]
Reactant: CCOC(=O)c1c(C(=O)OCC)n(-c2ccc(OC(C)C)cc2)c2ccc(-c3ccc(C(F)(F)F)cn3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-n2c(C(=O)O)c(C(=O)O)c3cc(-c4ccc(C(F)(F)F)cn4)ccc32)cc1
Temperature: 80 °C

Procedure:
A mixture of 1-(4-isopropoxyphenyl)-5-(5-trifluoromethylpyridin-2-yl)indole-2,3-dicarboxylic acid diethyl ester hydrochloric salt (150 mg, 0.26 mmol, see step (d) above), NaOH (aq, 2 M, 2 mL) and dioxane (3) mL) was heated at 80° C. for 4 h. After cooling, the reaction mixture was acidified with HCl (aq, IM) to pH 5 and filtered. The solid was recrystallised from EtOAc/petroleum ether to afford the title compound. Yield 96 mg (76%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)=[CH:6][C:5]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:4]([F:32])[CH:3]=1.[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][C:4]([F:32])=[C:5]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:6]=2)=[N:10][CH:11]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cn3)c(Cl)cc2F)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc(N)cn3)c(Cl)cc2F)c1
Temperature: 90 °C
Yield: 74.2 %

Procedure:
A suspension of N-{4-chloro-2-fluoro-5-[(5-nitropyridin-2-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (2.28 g, 5.01 mmol), calcium chloride (1.23 g, 10.0 mmol) and reduced iron (840 mg, 15.0 mmol) in ethanol (35 mL)/water (5 mL) was stirred with heating at 90° C. for 12 hr. After the reaction mixture was cooled to room temperature, the insoluble material was filtered off through a pad filled with celite, and washed with ethyl acetate. The filtrate and the washing fluid were combined, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 mL), washed with water (100 mL×2), 5% aqueous sodium hydrogen carbonate solution (100 mL×2) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (1.58 g, 74%) as a beige amorphous substance.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C([Li])CCC.[CH3:24][CH:25]([CH3:31])[CH2:26][CH2:27][C:28](Cl)=[O:29].C([O-])(O)=O.[Na+]>CCCCCC>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:28](=[O:29])[CH2:27][CH2:26][CH:25]([CH3:31])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
(S)-4-Benzyl-2-oxazolidinone (15.1 g, 85.0 mmol) was dissolved in THF (200 mL, 2.5 mol), cooled at −78° C. under nitrogen, and stirred for 10 minutes. 1.6 M of n-butyllithium in hexane (53.1 mL) was added dropwise and stirred for 15 minutes. 4-Methylpentanoyl chloride (12.6 g, 93.5 mmol) was added dropwise, stirred for 30 minutes at −78° C., then warmed to 0° C. for 2 hours. 150 mL of saturated NaHCO3 was added and the mixture was warmed to room temperature for 30 minutes. The mixture was extracted with DCM, washed with Na2 CO3 (5%) and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Excess oxazolidinone was removed using hexanes to provide intermediate (2a) (14.5 g).
Reaction SMILES: [CH:1]1([CH:6]([OH:9])[CH:7]=[CH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:16]=[C:15](Br)[CH:14]=[CH:13][C:12]=1[CH:18]([F:20])[F:19].C([O-])(O)=O.[Na+].O>CN1C(=O)CCC1>[CH:1]1([C:6](=[O:9])[CH2:7][CH2:8][C:15]2[CH:14]=[CH:13][C:12]([CH:18]([F:20])[F:19])=[C:11]([F:10])[CH:16]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1cc(Br)ccc1C(F)F
Reactant: C=CC(O)C1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(CCc1ccc(C(F)F)c(F)c1)C1CCCC1
Temperature: 140 °C
Yield: 33.4 %

Procedure:
A mixture of 1-cyclopentyl-2-propen-1-ol (34 g, 0.266 mol), 2-fluoro-4-bromo-difluoromethyl benzene, (40 g, 0.177 mol, 1.5 equiv), and NaHCO3 (17.8 g, 0.212 mol, 1.2 equiv) in anhydrous NMP (200 mL) was heated to 140° C. for 1 h, resulting in complete conversion by TLC. The reaction mixture was poured into water and extracted with CH2Cl2. The organic layer was separated, washed with brine and dried over anhydrous Na2SO4. After the removal of the solvent, the residue was purified by column chromatography using hexanes/ethyl acetate, and the product-containing fractions combined and concentrated. The residue was fractionally distilled through a Vigreux column to give 16 g (33%) of the desired product (bp 100° C./0.2 Torr).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])[CH2:15]2)[C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[K+]>C(O)(C)C.O>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])[CH2:15]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(C)cccc1CO[C@@H]1CCC[C@H](OCc2nc(-c3ccc(C)cc3)oc2C)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(-c2nc(CO[C@H]3CCC[C@@H](OCc4cccc(C)c4C(=O)O)C3)c(C)o2)cc1
Temperature: 95 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
from methyl methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-cyclohexyloxymethyl]benzoate: 97.1 g (165 mmol) of methyl methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]benzoate are dissolved in a mixture of 640 ml of isopropanol and 80 ml of water. 47.7 g (809 mmol) of potassium hydroxide are added in portions. The reaction is stirred at 95° C. for 24 hours. Subsequently, the solvent is removed fully under reduced pressure and the residue is taken up in 800 ml of tert-butyl methyl ether and 800 ml of water. Addition of hydrochloric acid (2 M) acidifies the mixture. After phase separation, the organic phase is washed four times with 200 ml each time of water. The organic phase is concentrated under reduced pressure and the residue is stirred with a little diisopropyl ether. The solid is filtered and dried under reduced pressure. 2-methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-cyclohexyloxymethyl]benzoic acid is obtained in 57% yield as a crystalline solid.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]3[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])[CH2:9][CH2:8]1)=[O:6].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.[I-].[K+]>CC(N(C)C)=O>[Cl:33][C:29]1[C:28]([F:34])=[C:27]([CH:32]=[CH:31][CH:30]=1)[NH:26][C:17]1[C:16]2[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH:10]3[CH2:9][CH2:8][N:7]([C:5](=[O:6])[NH:4][CH2:3][CH2:2][N:35]4[CH2:39][CH2:38][CH:37]=[CH:36]4)[CH2:12][CH2:11]3)[CH:15]=2)[N:20]=[CH:19][N:18]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)NCCCl)CC1
Reactant: C1CCNC1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)NCCN2C=CCC2)CC1
Temperature: 80 °C
Yield: 35.6 %

Procedure:
A mixture of 6-{[1-(N-(2-chloroethyl)carbamoyl)piperidin-4-yl]oxy}-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline (204 mg, 0.4 mmol), pyrrolidine (0.14 ml, 1.6 mmol) and potassium iodide (134 mg, 0.8 mmol) in dimethylacetamide (3 ml) was heated at 80° C. for 4 hours. After cooling and evaporation of the solvents under vacuum, the residue was partitioned in water, dichloromethane and extracted with dichloromethane. The organic layer was washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvents under vacuum, the residue was purified by chromatography on silica gel (eluant: 3% to 4% 7N methanolic ammonia in dichloromethane) to give the title compound as a white solid (77 mg, 36%).