Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]1([NH:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([N:30](C(OC5C=CC=CC=5)=O)[C:31](=[O:39])OC5C=CC=CC=5)[CH:25]=4)=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)=[O:13])[CH2:10][CH2:9]1.C1(NC(N2C3C(=CC(OC4C=CN=C(NC(N5CCC(N6CCCC6)CC5)=O)C=4)=CC=3)C=C2)=O)CC1>CN(C)C=O>[CH:8]1([NH:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:5]5[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]5)=[O:39])[CH:25]=4)=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)=[O:13])[CH2:10][CH2:9]1
Reactant: OC1CCNCC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Agent: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCC(N2CCCC2)CC1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCC(O)CC1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
N,N-Dimethylformamide (5 ml) and 4-hydroxypiperidine (433 mg, 4.29 mmol) were added to a mixture (470 mg) of phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate and phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate obtained in Example 68; the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated to yield the title compound as white crystals (220 mg, 0.51 mmol, 39%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([C:18](C)([CH3:20])[CH3:19])=[N:11]3)=[CH:9][C:4]=2[N:3]=[CH:2]1.C(OCC)(OCC)OCC.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([CH:18]([CH3:20])[CH3:19])=[N:11]3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)c1cc(C(=O)O)n(-c2ccc3ocnc3c2)n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(OCC)OCC
Product: CC(C)c1cc(C(=O)O)n(-c2ccc3ocnc3c2)n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of tert-butyl 1-(4-hydroxy-3-nitrophenyl)-3-isopropyl-1H-pyrazole-5-carboxylate (0.27 g, 0.78 mmol) in ethyl acetate/methanol (1:1, 10 mL) was added palladium on carbon (30 mg) and the mixture was hydrogenated (50 psi) overnight under Parr. The solution was filtered and washed with methanol. The combined filtrate was concentrated to afford tert-butyl 1-(3-amino-4-hydroxyphenyl)-3-isopropyl-1H-pyrazole-5-carboxylate. The crude tert-butyl 1-(3-amino-4-hydroxyphenyl)-3-isopropyl-1H-pyrazole-5-carboxylate was treated with 25% TFA in CH2Cl2 (2 mL) and stirred overnight at RT. The solvent was evaporated to obtain 1-(benzo[d]oxazol-5-yl)-3-tert-butyl-1H-pyrazole-5-carboxylic acid. To a solution of 1-(benzo[d]oxazol-5-yl)-3-tert-butyl-1H-pyrazole-5-carboxylic acid in xylenes (3 mL) was added triethyl orthoformate (0.16 mL, 0.96 mmol) and a catalytic amount of PPTS. The reaction mixture was heated at 140° C. for 4 hours. The solvent was evaporated and the residue was treated with methylene chloride with stirring for 1 hour. The resulting solid was filtered and washed with methylene chloride to obtain 1-(benzo[d]oxazol-5-yl)-3-isopropyl-1H-pyrazole-5-carboxylic acid (0.1 g, 45% yield: for three steps). MS (ESI) m/z: 272.0 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH:37][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:33][CH:32]=2)[CH2:29][CH2:30]1
Reactant: Nc1ccc(N2CCN(c3ncccn3)CC2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(N2CCN(c3ncccn3)CC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (100 mg, 0.39 mmol) in methylene chloride (15 mL) was added 6-(4-pyrimidin-2-yl-piperazin-1-yl)-pyridin-3-ylamine (100 mg, 0.39 mmol) and diisopropylethylamine (0.35 mL, 1.90 mmol). To this solution was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBrOP) in one portion (280 mg, 0.59 mmol). The mixture was stirred at room temperature overnight. The residue was purified by HPLC to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-pyrimidin-2-yl-piperazin-1-yl)-pyridin-3-yl]-amide as a light yellow powder. The NMR spectrum obtained on the sample is compatible with its structure. LCMS calcd for C24H20F3N7O2 (m/e) 495, obsd 496 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]([NH:6][C:7]([O:9]C1C=CC([N+]([O-])=O)=CC=1)=O)=[O:5].[F:24][C:25]([F:34])([F:33])[C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1>>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]([NH:6][C:7]([NH:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([F:33])([F:24])[F:34])=[CH:31][N:30]=1)=[O:9])=[O:5]
Reactant: O=C(NC(=O)c1c(F)cccc1Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(C(F)(F)F)cn1
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(C(F)(F)F)cn1

Procedure:
A solution is made in an inert organic solvent of 2-chloro-6-fluorobenzamidocarboxylic acid, 4-nitrophenyl ester, and 5-trifluoromethyl-2-aminopyridine. The temperature of the reaction mixture is raised, and the mixture is stirred for a period of time. The mixture is then evaporated under vacuum, and the product named in the heading above, identical to the product of Example 4, is isolated and purified by recrystallization.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10](O)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH3:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[N:1]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[NH:8][C:7]=12
Reactant: Cc1ccnc(N)c1N
Reactant: CCCCCCCCCC(=O)O
Product: CCCCCCCCCc1nc2nccc(C)c2[nH]1

Procedure:
The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2 mmol) and decanoic acid (0.35 g, 2 mmol) according to the procedure described in Step 1 of Example 9. The crude product was purified by flash chromatography on silica-gel using EtOAc-MeOH (20:1) to give the pure product (0.38g, 72%) as a tan colored solid. 1H NMR (300 MHz, CDCl3): 8.16 (d, 1H, J=5 Hz), 7.05 (d, 1H, J=5 Hz), 3.03 (t, 2H, J=7.8 Hz), 2.69 (s, 3H), 1.25-2.0 (m, 14H), 0.90 (t, 3H, J=7.5 Hz).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.[C:11](=[O:14])([O-])[O-:12].[K+].[K+]>C1COCC1.O>[CH3:10][O:9][C:7]([C@@H:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:11](=[O:14])[O:12][C:4]([CH3:7])([CH3:5])[CH3:3])[CH2:3]1)=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H]1CC[C@H](N)C1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 24 h
Yield: 172.7 %

Procedure:
Boc-anhydride (2.90 ml, 13.1 mmol) was added to a solution of (1R,3S)-methyl 3-aminocyclopentanecarboxylate (1.70 g, 11.9 mmol) and potassium carbonate (3.29 g, 23.8 mmol) in THF (10 ml), water (20 ml) and stirred for 24 h. The reaction mixture was extracted with DCM (2×50 ml). The combined organic layer was washed with water (20 ml), brine solution (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under vacuo to afford 2.5 g (87%) of tert-butyl (1S,3R)-3-(methoxycarbonyl)cyclopentylcarbamate as a colorless liquid.
Reaction SMILES: Cl[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:5]=2[NH:4][C:3]1=[O:15].[N-:16]=[N+:17]=[N-:18].[Na+]>CS(C)=O>[N:16]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:5]=2[NH:4][C:3]1=[O:15])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)NC(=O)C(Cl)CC2
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)NC(=O)C(N=[N+]=[N-])CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (12.5 g) and sodium azide (4.3 g) in dimethylsulfoxide (150 ml) was maintained at 80° under an atmosphere of nitrogen for 3 hours. The reaction mixture was poured into ice/water (300 ml) and the suspension was stirred for 30 minutes. The solid was filtered off, washed with water (50 ml) and dried to give 3-azido-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one, m.p. 136°-138°.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]1([CH2:30][NH:31][C:32]2[N:37]=[CH:36][N:35]=[C:34]([C:38]3[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=3)[CH:33]=2)[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:43][CH2:42][C:41]1[CH:40]=[CH:39][C:38]([C:34]2[CH:33]=[C:32]([NH:31][CH2:30][CH:27]3[CH2:29][CH2:28]3)[N:37]=[CH:36][N:35]=2)=[CH:45][CH:44]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(-c2cc(NCC3CC3)ncn2)cc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(-c4cc(NCC5CC5)ncn4)cc3)c2CC1)C(F)(F)F
Yield: 78.6 %

Procedure:
Use a method similar to the General Procedure 1-3, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (260 mg, 0.6 mmol) and 4-[6-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzylamine (300 mg, 1.18 mmol), to give 7-chloro-6-{4-[6-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an off-white foam (250 mg, 78%). MS (ES+) m/z: 530 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:20])([CH3:19])[CH2:9][NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:22].[K+].[K+].OO>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:20])([CH3:19])[CH2:9][NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[O:22])=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(CNc1ccc(C#N)cn1)c1ccc(F)cc1
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(CNc1ccc(C(N)=O)cn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a cooled (0° C.) suspension of 6-(2-(4-fluorophenyl)-2-methylpropylamino)nicotinonitrile (75 mg, 0.28 mmol, 1.0 equiv) and K2CO3 (50 mg, 0.36 mmol, 1.3 equiv) in DMSO (1 mL) was added aq. H2O2 (250 uL, 30% by wt., 2.6 mmol, 9 equiv) by syringe. The reaction was allowed to warm to RT and stirred for 30 minutes. The resulting mixture was diluted with EtOAc and washed three times with satd. aq. LiCl and once with brine. The resulting solution was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (2%-10% MeOH/DCM) provided the title compound as an off-white foam (54 mg, 77%), (m/z [M+H]=288.1).
Reaction SMILES: C(OC([C:6]1[O:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:22]4[CH:23]=[CH:24][C:25]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)=[CH:26][C:21]4=[N:20][CH:19]=3)[CH:13]=2)=[N:9][N:10]=1)=O)C.[OH-].[Na+].Cl>O1CCOCC1.CCOCC>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[CH:24]=[CH:23][N:22]3[C:18]([C:14]4[CH:13]=[C:12]([NH:11][C:8]5[O:7][CH:6]=[N:10][N:9]=5)[CH:17]=[CH:16][CH:15]=4)=[CH:19][N:20]=[C:21]3[CH:26]=2)=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1nnc(Nc2cccc(-c3cnc4cc(-c5ccc(F)cc5)ccn34)c2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: Fc1ccc(-c2ccn3c(-c4cccc(Nc5nnco5)c4)cnc3c2)cc1
Temperature: 100 °C
Yield: 12 %

Procedure:
5-{3-[7-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenylamino}-[1,3,4]oxadiazole-2-carboxylic acid ethyl ester (120 mg, 0.27 mmol) and 5N NaOH (0.5 ml, 2.5 mmol) in dioxane (2 ml) was stirred and heated at 100° C. for 1 hour. After cooling to RT, 5N HCl (0.5 ml) was added. The mixture was diluted with Et2O and the liquid was decanted off. The residue was treated with EtOH and the solid was collected by filtration. This solid was suspended in EtOH (3 ml) and heated at reflux for 15 minutes. The volatiles were removed in vacuo and the residue was purified by preparative HPLC to give the title compound (12 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6C(=O)C(NC(OC(C)(C)C)=O)C6C=CC=CC=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH2:65]([N:67]([CH:72]([C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)[C:73]([OH:75])=O)[C:68]([O:70][CH3:71])=[O:69])[CH3:66]>>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:73](=[O:75])[CH:72]([N:67]([CH2:65][CH3:66])[C:68]([O:70][CH3:71])=[O:69])[C:76]6[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: CCN(C(=O)OC)C(C(=O)O)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Product: CCN(C(=O)OC)C(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Yield: 52 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using (Ethyl-methoxycarbonyl-amino)-phenyl-acetic acid (0.097 g, 0.410 mmol) to provide {1-[2-(5-{6-[4-(2-{1-[2-(Ethyl-methoxycarbonyl-amino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (0.120 g, 52%) as a white solid. LCMS-ESI+: calc'd for C49H54N8O6: 840.38 (M+); Found: 851.91 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=[O:5].[C-:11]#[N:12].[K+].OS([O-])=O.[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]([OH:5])[C:11]#[N:12]
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC(O)c1cc(Cl)ccc1F
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To 2-fluoro-5-chloro-benzaldehyde (12.7 g, 17 mmol) in ethyl acetate (50 mL) was added a solution of KCN (3.3 g) and NaHSO3 (5.3 g) dissolved in H2O (25 mL). It was left stirring overnight before extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 121A (3.1 g, 99% yield) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH2:9][C:10]#[N:11])=[CH:7][O:8][C:4]=2[CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH2:9][CH2:10][NH2:11])=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: N#CCc1coc2cc(Br)ccc12
Solvent: C1CCOC1
Product: NCCc1coc2cc(Br)ccc12
Reaction time: 8 h

Procedure:
A solution of 11-6 (10.9 g, 0.0462 mol) in THF (100 mL) was cooled to 0° C. and treated dropwise with BH3 /THF solution (1Molar, 110.8 mL, 0.11 mol). The cold bath was removed and the reaction stirred overnight. MeOH was carefully added (20 mL) and the solvent removed under vacuum. The residue was dissolved in 50 mL MeOH and 400 mL MeOH saturated with HCl and heated to reflux for 3 hours. The volatile components were removed under vacuum and the residue was suspended in Et2O. A bright yellow solid percipitated and was collected and washed five times with Et2O, then dried under vacuum to give 11-7 as a tan solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[NH2:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([Cl:20])[N:14]=1.[OH-].[Na+]>O.CC(C)=O>[Cl:20][C:15]1[CH:16]=[C:17]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)[N:18]=[C:13]([NH2:12])[N:14]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Nc1nc(Cl)cc(Oc2ccc3ncccc3c2)n1

Procedure:
To a mixture containing 7.25 g (0.05 mol) 6-hydroxy-quinoline, 8.25 g (0.05 mol) 2-amino-4,6-dichloropyrimidine in 300 mL of water/acetone 1:1 are added 2.0 g (0.05 mol) sodium hydroxide. On heating a clear solution is first obtained from which a thick precipitate separates. Stirring under reflux is continued for a total of 6 h. The mixture is cooled, filtered and the solid washed with acetone/water 1.1 and dried. The title compound is obtained as a solid: map. 248-250° C.; MS: [M+1]+=273; HPLC: CtRet=1.30; TLC (dichloromethane/methanol 95:5): Rf=0.46.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([F:14])=[C:4](Cl)[N:3]=1.[CH:16]([O:19][C:20]1[NH:24][N:23]=[C:22]([NH2:25])[CH:21]=1)([CH3:18])[CH3:17].CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([F:14])=[C:4]([NH:25][C:22]2[CH:21]=[C:20]([O:19][CH:16]([CH3:18])[CH3:17])[NH:24][N:23]=2)[N:3]=1
Reactant: CN(c1nc(Cl)nc(Cl)c1F)S(C)(=O)=O
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)Oc1cc(Nc2nc(Cl)nc(N(C)S(C)(=O)=O)c2F)n[nH]1
Temperature: 70 °C
Yield: 46.2 %

Procedure:
To a solution of N-(2,6-dichloro-5-fluoro-pyrimidin-4-yl)-N-methyl-methanesulfonamide (Method 21, 440 mg, 1.6 mmol) in n-BuOH (3 ml) was added 5-isopropoxy-1H-pyrazol-3-ylamine (227 mg, 1.6 mmol) and DIPEA (207 mg). The mixture was heated at 70° C. overnight. LC/MS showed the completion of the reaction. The solvent was evaporated and the residue was dissolved in DCM, which was then washed by aqueous NaHCO3, dried and concentrated. Flash chromatography was performed with EtOAc/Hex (50%) as eluent. A colourless solid (280 mg) was obtained, yield 46%. 1H-NMR (300 MHz, CD3OD) 5.84 (s, 0.8H), 4.61 (m, 1H), 3.32 (s, 3H), 3.27 (s, 3H), 1.36 (d, J=6.0; 6H). MS (ES+) m/z 378.86, 380.86 [MH+]. MS (ES−) m/z 376.88, 378.87 [M−].
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:8][C:9]1C=CC=C[CH:10]=1.C=O>>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH:10]=[CH:9][NH:8]1
Reactant: Nc1ccccc1
Reactant: Oc1ccccc1
Agent: C=O
Product: C1=Cc2ccccc2ON1
Yield: 73.7 %

Procedure:
At room temperature, phenol, aniline and paraformaldehyde were added according to the molar ratio of phenolic hydroxyl group:amine group:aldehyde group of 1:1:2. After being homogeneously stirred, the mixture was heated to a molten state, reacted for 4 h and placed in a cooling unit to obtain a yellowish, translucent viscous body. The viscous body was washed, purified and dried to obtain a benzoxazine intermediate having the following structural formula, wherein the yield is 73.7%.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I-:12].[Na+].C(Cl)(=O)C>CC#N>[I:12][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: Ic1ccc2ccccc2n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 61.8 %

Procedure:
2-Iodoquinoline was prepared according to the procedure of Kimber, et. al. (Tetrahedron 2000, 56, 3575). To a solution of 2-chloroquinoline (10.0 g, 61.5 mmol) in CH3CN (100 mL) was added sodium iodide (14 g, 92.3 mmol) and acetyl chloride (8.8 mL, 123 mmol). The reaction mixture was stirred at 100° C. for 5 hours, then cooled to room temperature and quenched with 10% aqueous K2CO3 (100 mL) and 5% aqueous NaHSO3 (50 mL). The aqueous layer was extracted twice with dichloromethane then the combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 20% EtOAc in hexanes) to provide 9.7 g (70%) of 2-iodoquinoline as a yellow solid.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C@:19]1([CH3:25])[CH2:23][O:22]C(=O)[NH:20]1)[CH:13]=[CH:12]2.C(O)C.O.[OH-].[Li+].O>>[NH2:20][C@@:19]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][C@@H:2]3[CH2:3][C@@H:4]4[CH2:7][C@H:1]3[CH2:6][CH2:5]4)[CH:10]=2)[CH:15]=1)([CH3:25])[CH2:23][OH:22]
Reactant: C[C@@]1(c2ccc3cc(O[C@@H]4C[C@H]5CC[C@@H]4C5)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2cc(O[C@@H]3C[C@H]4CC[C@@H]3C4)ccc2c1
Yield: 34.3 %

Procedure:
The compound was prepared in a manner similar as to that described (R)-4-(6-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-yloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (100 mg, 0.0003 mol), ethanol (2.2 g, 0.049 mol), 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol) to give 32 mg of the desired product as a white solid (32%). ESI-MS: 339 (M-16)+. 1H NMR (400 MHz, CDCl3) δ=7.94-7.61 (m, 3 H), 7.50 (d, J=8.5 Hz, 1 H), 7.23-7.05 (m, 2 H), 4.33-4.17 (m, 1 H), 3.84-3.51 (m, 2 H), 2.49-0.78 (m, 13 H).
Reaction SMILES: [CH:1]1([CH:4]=[C:5]2[CH2:9][C:8](=[O:10])[CH:7]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[C:6]2=[O:20])[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:4][CH:5]2[CH2:9][C:8](=[O:10])[CH:7]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[C:6]2=[O:20])[CH2:2][CH2:3]1
Reactant: Cc1cc(C)c(C2C(=O)CC(=CC3CC3)C2=O)c(C)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(C2C(=O)CC(CC3CC3)C2=O)c(C)c1
Reaction time: 1.5 h
Yield: 20.5 %

Procedure:
To 5% w/w Pd/C (5 mg) was added a solution of 4-[1-cyclopropyl-methylidene]-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (28 mg, 0.09 mmol) in MeOH (10 ml). The reaction was stirred under an atmosphere of H2 (1.5 bar) for 1.5 hours, filtered through a pad of celite and washed through with MeOH (20 ml). The solvent was removed under reduced pressure to give the crude product (20 mg) which was purified by mass-directed HPLC to give the desired product (5 mg).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>O1CCCC1>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1nccc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1nccc(C(F)(F)F)n1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
According to the procedure described in Example 113B, to a solution of 4-(trifluoromethyl)pyrimidin-2-amine (500 mg, 3.1 mmoles) in 20 mL of tetrahydrofuran was added potassium carbonate (533 mg, 4 mmoles) followed by phenyl chloroformate (626 mg, 4 mmoles). The mixture was stirred at room temperature overnight. After 24 hours, and additional portion of phenyl chloroformate was added and the reaction heated to 60° C. for 3 days. This solution was concentrated to dryness and purified by silica chromatography (eluted with a gradient of 0-5% ethyl acetate/dichloromethane) to afford phenyl 4-(trifluoromethyl)pyrimidin-2-ylcarbamate. 1H NMR (300 MHz, DMSO-d6) δ 11.50 (s, 1H), 9.05 (s, 1H), 7.69 (m, 1H), 7.46 (m, 2H), 7.25 (m, 3H).