Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:9][C:10]1[O:11][C@H:12]([C:35]([F:38])([F:37])[F:36])[CH2:13][C@:14]([C:17]2[CH:18]=[C:19]([NH:24][C:25](=[O:34])[C:26]3[C:31]([CH3:32])=[CH:30][C:29]([Cl:33])=[CH:28][N:27]=3)[CH:20]=[CH:21][C:22]=2[F:23])([CH3:16])[N:15]=1)(=O)C1C=CC=CC=1.N>>[NH2:9][C:10]1[O:11][CH:12]([C:35]([F:38])([F:37])[F:36])[CH2:13][C:14]([C:17]2[CH:18]=[C:19]([NH:24][C:25]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([Cl:33])=[CH:28][N:27]=3)=[O:34])[CH:20]=[CH:21][C:22]=2[F:23])([CH3:16])[N:15]=1
Reactant: Cc1cc(Cl)cnc1C(=O)Nc1ccc(F)c([C@]2(C)C[C@@H](C(F)(F)F)OC(NC(=O)c3ccccc3)=N2)c1
Agent: N
Product: Cc1cc(Cl)cnc1C(=O)Nc1ccc(F)c(C2(C)CC(C(F)(F)F)OC(N)=N2)c1
Temperature: 80 °C
Yield: 25.3 %

Procedure:
A sealable vial was charged with N-(3-((4S,6S)-2-benzamido-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide (rac 4n, 0.050 g, 0.091 mmol) and ammonia (2.0M solution in methanol; 3.0 ml, 6.00 mmol). The reaction mixture was heated to 80° C. for 17 hs. The reaction mixture was concentrated an the residue was diluted with a minimal amount of CH2Cl2. Purification by silica gel chromatography (gradient 0.0 to 5.0% 2 M ammonia in MeOH/CH2Cl2) afforded the title compound (0.0104 g, 0.023 mmol, 51.3% yield) as a white solid. MS m/z=445.0 [M+H]+. Calculated for C19H17ClF4N4O2: 444.098.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][C:17]=2[O:30]CC2C=CC=CC=2)[CH2:12][CH2:11]1)=[O:9].CO>C(OCC)(=O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=2[OH:30])[CH2:12][CH2:11]1)=[O:9]
Reactant: O=C(Nc1ccccn1)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1ccccn1)N1CCC(c2ccc(O)cc2O)CC1
Reaction time: 18 h
Yield: 39 %

Procedure:
20 mg of 4-(2,4-Bis(benzyloxy)phenyl)piperidine-1-carboxylic acid pyridin-2-ylamide are dissolved in 20 ml of ethyl acetate and then 1 ml of methanol is added. 10 mg of palladium-on-charcoal at 10% are added, and then the reaction mixture is stirred for 18 hours under a hydrogen atmosphere. The mixture is filtered and the residue is then crystallized from an ethyl acetate/heptane mixture. 5 mg of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid pyridin-2-ylamide. Yield: 39%
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH:19]([C:20]2[NH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=3)=[CH:23][N:24]=2)[CH2:18][C:13]2(OCC[O:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].O.CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:12][C:13](=[O:14])[CH2:18][CH:19]1[C:20]1[NH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([Br:31])=[CH:29][CH:30]=2)=[CH:23][N:24]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CC2(CC1c1ncc(-c3ccc(Br)cc3)[nH]1)OCCO2)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)NC(C(=O)N1CC(=O)CC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 60 °C
Reaction time: 72 h
Yield: 44.6 %

Procedure:
(1-{8-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-1,4-dioxa-7-aza-spiro[4.4]nonane-7-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (230.0 mg, 0.453 mmol) was dissolved in acetone (10 mL) and water (0.2 mL) and p-TsOH∘H2O (53 mg, 0.278 mmol) were added. The reaction was heated at 60° C. for 20 hours, after which additional p-TsOH∘H2O (53 mg, 0.278 mmol) was added heating at 60° C. was continued. After three days, all volatiles were removed in vacuo. The crude material was taken into EtOAc and was washed with aqueous sodium bicarbonate solution and dried over sodium sulfate. Filtration and evaporation of solvents in vacuo gives the crude product. The crude material was purified via silica gel chromatography (eluent: EtOAc containing 10% MeOH/hexanes) to yield the product (93.9 mg, 0.202 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:13](=[O:14])[N:12]([CH3:11])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Product: CC(=O)c1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from 4′-hydroxyacetophenone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (78%, colourless oil). HPLC-MS: m/z=270.1 (M+1); Rt: 3.62 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.[CH:17]1([CH2:20]Br)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>COCCOC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH2:20][CH:17]1[CH2:19][CH2:18]1
Reactant: BrCC1CC1
Reactant: Brc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: Brc1ccc2[nH]cc(C[C@H]3CCCN3CC3CC3)c2c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
5-Bromo-3-(pyrrolidin-2(R)-ylmethyl)-1H-indole (1.84 g, 6.3 mmol) (see Preparation 55), cyclopropylmethyl bromide (0.67 ml, 6.9 mmol), sodium carbonate (0.73 g, 6.9 mmol) and sodium iodide (1.0 g, 6.7 mmol) in 1,2-dimethoxyethane (10 ml) was refluxed under nitrogen for 14 hours. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate and aqueous sodium carbonate. The organic phase was washed with more aqueous sodium carbonate, dried (Na2SO4) and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane/methanol/ammonium hydroxide (90:10:0.05) to yield the title compound as a foam (2.09 g). Found: C,61.22; H,6.40; N,8.39. C17H21BrN2 requires: C,61.26; H,6.35; N,8.41%.
Reaction SMILES: [Cl:1][C:2]1C=CC=C[C:3]=1C(O[Si](C)(C)C)C#N.Cl.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([OH:29])[C:26](=[NH:28])[OH:27]>>[ClH:1].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([OH:29])[C:26](=[NH:28])[O:27][CH2:2][CH3:3]
Reactant: C[Si](C)(C)OC(C#N)c1ccccc1Cl
Reactant: N=C(O)C(O)c1ccccc1Cl
Agent: Cl
Product: CCOC(=N)C(O)c1ccccc1Cl

Procedure:
By the procedure of Example 2, 2-(2-chlorophenyl)-2-trimethylsiloxyethanenitrile (15 g.) in 375 l. of saturated ethanolic hydrogen chloride was converted to ethyl 1-(2-chlorophenyl-1-hydroxymethanecarboximidate hydrochloride [13.4 g., 85%; m.p. 127°-129° C. (dec); ir (KBr) 3125, 3003, 2899, 1653, 1531 cm-1 ].
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>>[CH2:14]([O:13][C:11]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O

Procedure:
The amino group of L-aspartic acid was protected as in Example 2 using benzyl chloroformate, to form N-benzyloxycarbonyl-L-aspartic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Cl[Si](C)(C)C.[C:37]1([CH2:43][CH2:44][S:45][CH:46]([C:50](O)=[O:51])[C:47](O)=[O:48])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[K+].[Br-]>>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[O:20][C:47](=[O:48])[C:46]([S:45][CH2:44][CH2:43][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[C:50]([OH:51])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: COC(=O)c1ccc(COc2ccc(C(C)=O)cc2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Product: COC(=O)c1ccc(COc2ccc(-c3cc(O)c(SCCc4ccccc4)c(=O)o3)cc2)cc1

Procedure:
The title compound was prepared by Method A using 4-[[(4-acetyl) phenoxy]methyl]benzoic acid methyl ester (2.0 g, 7.04 mmol), lithium hexamethyldisilazide (2.36 g, 14.08 mmol), chlorotrimethylsilane (2.38 g, 14.08 mmol) and diethyl ester of [(2-phenylethyl) thio]propanedioic acid (1.0 g, 3.05 mmol). m.p. 157-158° C.; 1H NMR (400 MHz, DMSO-d6) δ2.78 (t, 2 H), 2.97 (t, 2 H), 3.86 (s, 2 H), 5.31 (s, 2 H), 6.67 (s, 1 H), 7.17 (q, 4 H), 7.25 (m, 3 H), 7.61 (d, 2 H), 7.78 (d, 2H), 8.0 (d, 2H); IR (KBr) 3023, 2936, 2581, 1632, 1510, 1404, 1258, 1184, 1098, 1009, 818, 718 cm-1 ; MS (CI) m/e 517 (M+29, 7), 489 (M+H, 55), 384 (19), 149 (40), 105 (100).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:26]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2cc(OCCCCCCSc3ccccc3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCCCCS(=O)c3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-(6-phenylmercapto-hexoxy)-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([F:13])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C)C(=O)C>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:8]([F:13])[CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(F)c(F)c1
Reactant: C1CNCCN1
Solvent: CC(=O)N(C)C
Product: CCS(=O)(=O)c1ccc(N2CCNCC2)c(F)c1
Temperature: 80 °C

Procedure:
To 2.0 mmol 4-ethanesulfonyl-1,2-difluoro-benzene in 5 ml N,N-dimethylacetamide was added 5.6 mmol piperazine and the mixture was heated at 80° C. for 45 min. The mixture was then concentrated in vacuo to afford the title compound. MS (m/e): 273.0 (M+H+, 100%)
Reaction SMILES: O=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[CH2:28]([N:30]=C=S)[CH3:29].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>>[CH2:28]([NH:30][C:2]1[N:3]([CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[CH:8][N:7]=[C:6]([C:11]1[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=13)[N:5]=2)[CH3:29]
Reactant: CCN=C=S
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1nc2cnc(-c3cnn4ccc(C#N)cc34)nc2n1C1CCOCC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a suspension of the compound obtained in example 1 section d (100 mg, 0.30 mmol) in CH2C2 (2 mL), ethyl isothiocyanate (0.042 mL, 0.48 mmol), EDC.HCl (171 mg, 0.89 mmol) and DIPEA (0.25 mL, 1.49 mmol) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 80° C. and 150 W for 30 min. Then, it was evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using MeOH/EtOAc mixtures of increasing polarity as eluent, to afford 42 mg of the desired compound (36% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:24])[CH:9]=[C:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(N)ncnn23)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Temperature: -20 °C
Reaction time: 1 h
Yield: 119.9 %

Procedure:
To a cooled (−20° C.) solution of tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (660 mg, 2.08 mmol) in tetrahydrofuran (10 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (297 mg, 1.04 mmol) in 3 portions over 10 min. The mixture was allowed to stir (−20° C.) for 1 h. The reaction was quenched with the addition saturated aqueous Na2SO3 (10 mL) and was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×20 mL). The combined organics were washed with brine (25 mL), dried (Na2SO4) and evaporated. The crude material was purified by ISCO® chromatography using a gradient of 75 to 100% ethyl acetate in hexanes to afford 494 mg (60%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.83 (s, 1H), 6.64 (s, 1H), 4.10-3.96 (m, 2H), 3.29-3.19 (m, 1H), 1.90 (d, 2H), 1.55-1.42 (m, 2H), 1.41 (s, 9H); ES-MS m/z 396.1 [M+H]+, HPLC RT (min) 2.79.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([F:11])[C:5]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C(Cl)(=O)[C:21](Cl)=[O:22]>C(Cl)CCl>[Cl:1][C:2]1[C:7]([C:8]([N:10]=[C:21]=[O:22])=[O:9])=[C:6]([F:11])[C:5]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(N)=O)c1F
Solvent: ClCCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Temperature: 65 °C
Yield: 307.5 %

Procedure:
To a solution of 6-chloro-2-fluoro-3-(pivalamidomethyl)benzamide (0.300 g, 1.04 mmol) in EDC (10 mL) was added oxalyl chloride (0.11 mL, 1.25 mmol). The reaction mass was heated at 60-70° C. for 4-5 h. Excess of solvent was removed under vacuum to afford 1.0 g of desired product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.O1CCCC1.ON1C2C=CC=CC=2N=N1.[F:30][C:31]1[C:36]([C:37]2[C:41]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)=[CH:40][NH:39][N:38]=2)=[C:35]([F:48])[CH:34]=[CH:33][C:32]=1[NH2:49]>>[F:30][C:31]1[C:36]([C:37]2[C:41]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)=[CH:40][NH:39][N:38]=2)=[C:35]([F:48])[CH:34]=[CH:33][C:32]=1[NH:49][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:13])=[CH:8][CH:7]=1
Reactant: Nc1ccc(F)c(-c2n[nH]cc2-c2ccncc2)c1F
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(Cc1ccc(C(F)(F)F)cc1)Nc1ccc(F)c(-c2n[nH]cc2-c2ccncc2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (4-trifluoromethyl-phenyl)-acetic acid (49 mg, 0.24 mmol) in anhydrous tetrahydrofuran (3 mL) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (63 mg, 0.24 mmol) was added, after 10 minutes 1-hydroxybenzotriazole (38 mg, 0.28 mmol) and after 30 minutes 2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine (60 mg, 0.22 mmol) (prepared as described in Example 22) were added. The reaction was stirred under nitrogen atmosphere at room temperature overnight to yield a mixture of mono- and bis-amide (3:1 ratio at 254 nm). The reaction was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed successively with NaHCO3 saturated solution and the organic layer was dried over anhydrous sodium sulfate and filtered. The monoamide derivative was isolated by silica gel column chromatography eluting with ethanol 7% in methylene chloride.
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:12]=[C:11]([CH:36]2[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]2)[C:3]=1[C:4](OC(C)(C)C)=[O:5].COCCO[AlH2-]OCCOC.[Na+]>O1CCCC1>[NH2:1][C:2]1[C:3]([CH2:4][OH:5])=[C:11]([CH:36]2[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:47])([CH3:48])[CH3:46])=[O:43])[CH2:37]2)[CH:12]=[C:13]([C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:31][CH2:32][CH:33]2[CH2:34][CH2:35]2)[N:14]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(CO)c(N)n2)cc1
Reaction time: 1 h

Procedure:
To a cooled solution of tert-butyl 2-amino-4-[1-(tert-butoxycarbonyl)-3-piperidinyl]-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}nicotinate (4.9 g, 7.426 mmol) in tetrahydrofuran (60 mL) was added dropwise Vitride® (10 mL) under an argon atmosphere. The stirring was continued at 0° C. for 1 hr. After quenched by saturated aqueous NH4Cl solution, saturated aqueous potassium sodium tartrate was added to the mixture, then the mixture was stirred vigorously. The mixture was extracted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give tert-butyl 3-[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-(hydroxymethyl)-4-pyridinyl]-1-piperidinecarboxylate, which was used for the next step without further purification (4.38 g, yield; quant.).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:17][CH:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:36]([CH3:38])[CH3:37])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])[C:22]2C=[CH:40][CH:41]=[CH:42][C:21]=2N(C2C=CC=CC=2)[C:19]1=O)=O)(C)(C)C.[H-].[Na+].CI.[CH3:54][N:55]([CH:57]=[O:58])[CH3:56]>>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:17][C:18]1([CH3:19])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:36]([CH3:38])[CH3:37])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:28])[C:22]2[CH:21]=[CH:42][CH:41]=[CH:40][C:54]=2[N:55]([C:56]2[CH:18]=[CH:17][CH:9]=[CH:10][CH:11]=2)[C:57]1=[O:58]
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2cc3ccccc3n2C(=O)OC(C)(C)C)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CC(C)N(C(=O)CN1C(=O)C(C)(Cc2cc3ccccc3[nH]2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 190 mg (0.28 mmol) of 2-[3-(N-tert-butoxycarbonyl-indol-2-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide, prepared as in Intermediate 37, in 4 mL of DMF at 0° C. is added 17 mg (0.43 mmol, 1.5 equiv) of sodium hydride (60% dispersion in mineral oil). The resulting solution is stirred 5 min, then 26 μL (0.43 mmol, 1.5 equiv) of methyl iodide is added. The reaction mixture is stirred 2 h at RT and then heated to 50° C. for 3 h, then quenched with 1 mL H2O. The reaction mixture is diluted with 40 mL EtOAc and washed with 40 mL H2O. The organic layer is dried (MgSO4) and the solvents removed in vacuo. The crude material is then dissolved in 3 mL of dichloromethane, 1 mL of TFA is added, and the reaction mixture is stirred 3 h at RT. The volatiles are removed in vacuo and the resulting crude oil purified via reverse phase MPLC using a C-18 column and 75% acetonitrile/25% H2O with 0.1% TFA as eluent followed by lyophilization afforded 15 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ9.22 (s, 0.33H), 7.68-7.00 (m, 17H), 6.84 (m, 1H), 6.28 (s, 0.33H), 6.16 (s, 0.66H), 5.26 (m, 0.66H), 5.10 (m, 0.33H), 4.72 (d, 0.66H, J=16.3), 4.45 (d, 0.33H, J=16.6), 4.02 (m, 0.33H), 3.82 (d, 0.66H, J=16.3), 3.70 (m, 0.33H), 3.45 (d, 0.33H), 3.15 (d, 0.66H, J=14.9), 2.62 (d, 0.66H, J=14.9), 1.42 (s, 2H), 1.26 (m, 7H); low resolution MS (FAB)m/e 571 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([F:22])=[C:12]([CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH:13]=2)[CH:5]=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([F:22])=[C:12]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-c2ccc(F)c(C(O)c3ccccc3)c2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Nc1nccc(-c2ccc(F)c(C(=O)c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A round-bottomed flask was charged with [5-(2-amino-4-pyrimidinyl)-2-fluorophenyl]-(phenyl)methanol and dissolved in methylene chloride (10 mL). The resulting solution was treated with Dess-Martin periodinane and stirred at room temperature for 30 min. The reaction was quenched with a saturated solution of sodium bicarbonate, then the organic layer was removed, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography to provide [5-(2-amino-4-pyrimidinyl)-2-fluorophenyl](phenyl)methanone (30 mg) as a white powder. H1 NMR (d6-dmso): 8.28-8.36 (m, 2H), 8.27 (dd, 1H), 7.79 (d, 2H), 7.70 (t, 1H), 7.56 (t, 2H), 7.50 (dd, 1H), 7.17 (d, 1H), 6.71 (br s, 2H). Mass (ES+)=294.1 (100%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH:26]([N:29]1[CH:33]=[N:32][N:31]=[C:30]1[C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)(C)C.O>[CH:26]([N:29]1[CH:33]=[N:32][N:31]=[C:30]1[C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH:36][C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)=[S:3])([CH3:28])[CH3:27]
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: CC(C)n1cnnc1-c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)n1cnnc1-c1ccccc1NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 20.7 %

Procedure:
3-(4-Isothiocyanatophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (WO 2011/017513) (0.088 g, 0.24 mmol), 2-(4-isopropyl-4H-1,2,4-triazol-3-yl)aniline (0.080 g, 0.40 mmol), and cesium carbonate (0.16 g, 0.50 mmol) in isopropyl alcohol (1.2 mL) was stirred at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated. The residue was loaded onto Celite® cartridge and purified by flash chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes as eluent to provide the title compound as a yellow solid (0.028 g, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[NH:15][CH:14]=[C:13]([CH2:17][O:18][CH3:19])[C:12]2=[O:20])=[O:5].Cl.Cl[CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN1CCCC1=O>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][O:18][CH3:19])=[C:12]2[O:20][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:5]
Reactant: ClCc1cccnc1
Reactant: COCc1c[nH]c2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN1CCCC1=O
Product: COCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1OCc1cccnc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 65.5 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-1,4-dihydro-3-methoxymethyl-4-oxoquinoline (209 mg) in N-methylpyrrolidone (4 ml) were added 3-chloromethylpyridine hydrochloride (109 mg), potassium carbonate (153 mg) and sodium iodide (20 mg), and the mixture was stirred for 4 hours at 80° C. The mixture was partitioned between ethyl acetate and water, and the separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-3-methoxymethyl-4-(pyridin-3-ylmethoxy)quinoline (170 mg) as white crystal.