Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:35])[C@H:23]([CH2:32][CH2:33]O)[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(Br)(Br)(Br)[Br:37]>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:35])[CH:23]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:32][CH2:33][Br:37]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)[C@H](CCO)NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(CCBr)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.2 %

Procedure:
A solution of triphenylphosphine (2.20 g, 8.39 mmol) in dry CH2Cl2 (20 mL) was added dropwise via syringe to a solution of N-Boc homoserine methyl ester 18 (8.39 mmol) and carbon tetrabromide (4.18 g, 12.60 mmol) in dry CH2Cl2 (20 mL). The resulting dark solution was stirred at room temperature for 16 h. Hexanes was added and precipitates were removed by suction filtration. The filtrate was concentrated under reduced pressure and subject to flash silica gel column chromatography using ethyl acetate/hexanes (1:10, v/v then 1:6, v/v) to give the desired product 19 as a yellow oil (501 mg, 20% overall yield from homoserine). 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 2.12-2.48 (m, 2H), 3.39-3.47 (m, 2H), 3.78 (s, 3H), 4.33-4.48 (m, 1H), 5.10-5.22 (m, 1H). m/z (ESI) 296 [C10H18BrNO4+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][O:17][N:16]([CH3:15])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=1
Reactant: CNOC
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(Trifluoromethyl)-benzoyl chloride (5 mL, 332 mmol), N,O-dimethyl-hydroxylamine hydrochloride (42 g, 431 mmol) and methylene chloride were combined under argon, then cooled in an ice bath. Triethylamine (108 mL, 775 mmol) was added dropwise with stirring over 0.5 h. The contents of the reaction flask were then warmed to room temperature slowly. After 18 h, the reaction suspension was washed successively with 5% potassium bisulfate, sat. sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate then concentrated in vacuo to give Compound 1 as an oil: 82 g, (332 mmol, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16](=[S:18])[NH2:17])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].Br[CH2:25][C:26]([C:28]1[N:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=[CH:30][CH:29]=1)=O.O>C(O)C>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2[S:18][CH:25]=[C:26]([C:28]3[N:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=[CH:30][CH:29]=3)[N:17]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cccc(C(=O)CBr)n1
Reactant: COc1ccc(C(N)=S)c2c1oc1ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cccc(-c2csc(-c3ccc(OC)c4oc5ccccc5c34)n2)n1
Reaction time: 20 h
Yield: 28 %

Procedure:
To a stirred solution of 4-methoxydibenzo[b,d]furan-1-carbothioamide (140 mg, 0.544 mmol) in ethanol (5 mL) was added sodium bicarbonate (60 mg, 0.714 mmol) and ethyl 6-(2-bromoacetyl)picolinate (150 mg, 0.551 mmol). The stirring was continued at room temperature for 20 hours. The reaction mixture was poured into the water (25 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated at reduced pressure to give the product, which was purified by column chromatography by using a gradient of ethyl acetate in hexane (0-6%). Yield—28%; Rf 0.5 (Ethyl acetate:Hexane (3:7); HPLC (purity): 98.1%; 1H-NMR (CDCl3) δ: 1.48-1.57 (m, 3H), 4.14 (s, 3H), 4.50-4.55 (m, 2H), 7.07 (d, 1H), 7.49-7.53 (m, 1H), 7.65-7.69 (m, 2H), 7.94-7.98 (m, 1H), 8.09 (d, 1H), 8.42 (s, 1H), 8.47 (d, 1H), 8.73 (d, 1H); MS m/z: 431.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([CH:8]=O)=[CH:5][CH:4]=[CH:3]1.[CH2:10]([O:12][C:13]([C:15]1[NH:16][CH:17]=[CH:18][C:19]=1[NH2:20])=[O:14])[CH3:11].CC(O)=O.[BH3-]C#N.[Na+]>CCO>[CH2:10]([O:12][C:13]([C:15]1[NH:16][CH:17]=[CH:18][C:19]=1[NH:20][CH2:8][C:6]1[NH:7][C:2](=[O:1])[CH:3]=[CH:4][CH:5]=1)=[O:14])[CH3:11]
Reactant: O=Cc1cccc(=O)[nH]1
Reactant: CCOC(=O)c1[nH]ccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]ccc1NCc1cccc(=O)[nH]1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 84.8 %

Procedure:
6-Oxo-1,6-dihydropyridine-2-carbaldehyde (WO 2002/006272) (0.31 g, 2.5 mmol) was dissolved in EtOH (10 mL). 3-Amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.19 g, 1.3 mmol) was added, followed by HOAc (0.14 mL, 2.5 mmol). The mixture was stirred for 75 minutes at r.t. and then NaCNBH3 (0.16 g, 2.5 mmol) was added. The reaction mixture was stirred at r.t. overnight. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (CH2Cl2/methanol gradient; 0 to 10% methanol), obtaining 0.288 g (85%) of the title product as an oil that crystallized upon standing.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)[N:3]=1
Reactant: Cc1cccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)n1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)n1
Yield: 20.7 %

Procedure:
To a mixture of the amidine of Step 1 (4.9 g, 16.95 mmol) and sodium bicarbonate (2.85 g, 33.9 mmol) in isopropanol (300 ml), 3-bromo-1,1,1-trifluoroacetone (2.65 ml, 25.4 mmol) was added. After heating at 80°-85° C. for 24 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude mixture (9 g) was chromatographed (silica gel, ethyl acetate/isopropanol/ammonium hydroxide 95/5/0.5) to give 2-methyl-6-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine (1.4 g, 21%) as a white solid: Anal. Calc'd. for C17H16N3SO3F3 : C, 51.12, H, 4.02, N, 10.52. Found: C, 51.43, H, 3.96, N, 10.06.
Reaction SMILES: CC(C)(OC(NC(C1C=CC=CC=1)CC(O)CNC(CC1C=CC=CC=1)C(O)C[NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)C>CO>[C:17](=[O:26])([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH2:16]
Reactant: CC(C)(C)OC(=O)NC(CC(O)CNC(Cc1ccccc1)C(O)CNC(=O)OCc1ccccc1)c1ccccc1
Solvent: CO
Product: NC(=O)OCc1ccccc1

Procedure:
Compound 186 was prepared as a colorless solid from a 1:1 mixture of 1b(i) and 1b(ii) by a procedure analogous to that used for the synthesis of Compound 185d. mp 90°-95° C.; [α]D =-4.0° (c 0.10, MeOH). MS: (M+H)+ @578+Analysis calc. for C33H43N3O6. 0.9 6H2O:
Reaction SMILES: [C:1]1([N:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]1([N:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]3([CH2:10][CH2:11][N:12]([C:21](=[O:24])[CH2:22][CH3:23])[CH2:13][CH2:14]3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(=O)Cl
Reactant: c1ccc(N2CC3(CCNCC3)c3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC(=O)N1CCC2(CC1)CN(c1ccccc1)c1ccccc12

Procedure:
A mixture of 1-phenylspiro[indoline-3,4'-piperidine] (Example 11), propionyl chloride and sodium bicarbonate in chloroform is stirred at reflux. The mixture is permitted to cool, filtered, and the filtrate concentrated, leaving 1-phenyl-1'-propionylspiro[indoline-3,4'-piperidine]. In a similar fashion, 1-phenylspiro[indoline-3,4'-piperidine] is treated with benzoylchloride to provide 1'-benzoyl-1-phenylspiro[indoline-3,4'-piperidine].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:13]([CH2:29][CH2:30][N:31]=3)[C:14]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)=[N:15][C:16]=2[C:17]=1[O:18][CH3:19].C(N(CC)C(C)C)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>CN(C)C=O>[CH3:19][O:18][C:17]1[C:16]2[N:15]=[C:14]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[N:13]3[CH2:29][CH2:30][N:31]=[C:12]3[C:11]=2[CH:10]=[CH:9][C:8]=1[O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:42]([CH3:41])(=[O:44])=[O:43]
Reactant: COc1c(OCCOCCN)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(OCCOCCNS(C)(=O)=O)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.4 %

Procedure:
N-{8-[2-(2-Aminoethoxy)-ethoxy]-7-methoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl}-nicotinamide (Step 4, 75 mg, 0.18 mmol) was dissolved in dimethylformamide (2 mL). N,N-diisopropylethylamine (0.03 mL) was added, followed by methanesulfonyl chloride (0.01 mL, 0.14 mmol). The mixture was stirred at rt for 3 h, then was quenched by the addition of water. Saturated aqueous sodium bicarbonate was added, and the mixture was extracted several times with dichloromethane. The combined organic extracts were dried and concentrated to afford a residue, which was purified by preparative HPLC (gradient elution of 10-70% acetonitrile in water, 0.1% TFA). The product fractions were free based with saturated aqueous sodium bicarbonate, and the desired was isolated by extraction with dichloromethane. The organic layer was dried over sodium sulfate, and concentrated to give the title compound (8.7 mg, 12%). HPLC MS RT=1.79 min, MH+=503.2. 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.89 (3H, s), 3.11 (2H, t), 3.56 (2H, t), 3.85 (2H, m), 4.03 (3H, s), 4.26 (2H, m), 4.43 (2H, m), 4.57 (2H, m), 7.50 (1H, d), 7.86 (1H, m), 8.02 (1H, d), 8.83 (1H, m), 8.94 (1H, m), 9.47 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH3:10][N:11]=[C:12]=[O:13]>C(OC(C)C)(C)C>[CH3:10][NH:11][C:12]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)=[O:13]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CN=C=O
Solvent: CC(C)OC(C)C
Product: CNC(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 0 °C

Procedure:
A mixture of 27.4 g of 3,4-dichloroaniline in 140 ml of isopropyl ether was added slowly to 9 g of methyl isocyanate in 100 ml of isopropyl ether and the mixture was refluxed for 2 hours and was then cooled to 0° C. The precipitate formed was recovered by vacuum filtration and was washed with isopropyl ether. The mother liquors were concentrated to obtain a second crop. The two combined crops weighing 19.5 g and melting at 156° C. were crystallized from ethyl acetate to obtain N-methyl-N'-(3,4-dichlorophenyl)-urea melting at 160° C., identical to the product described by Onley et al., J. Ass. Off. Anal. Chem., Vol. 52 (1969), p. 545.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:20]([CH3:22])[CH3:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:23]([O:27][CH3:28])(=[O:26])[C:24]#[CH:25]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([CH:20]([CH3:22])[CH3:21])[N:9](/[CH:25]=[CH:24]/[C:23]([O:27][CH3:28])=[O:26])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1
Reactant: C#CC(=O)OC
Product: COC(=O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Yield: 46.6 %

Procedure:
From 4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazole (2.00 g) and methyl propiolate (2.55 g) by the process as described for the preparation of Intermediate (7 a) to afford an orange solid which was purified by FCC eluting with System A (3:17) to afford the title compound (1.194 g) as a white solid. λmax (MeOH) 248.4 (22,180) and 300 (inf) nm (ε9410).
Reaction SMILES: [Br-].[CH2:2]([N:4]([C:7]1[O:8][C:9]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20]C=CC=3[P+](C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=[CH:12][C:10]=2[N:11]=1)C=O)[CH3:3].[CH2:36]([N:43]1[CH:47]=[CH:46][N:45]=C1C=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CC(C)([O-])C.[K+]>O1CCCC1>[CH2:36]([N:43]1[CH:47]=[CH:46][N:45]=[C:20]1[CH:21]=[CH:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([NH:4][CH2:2][CH3:3])[O:8][C:9]=2[CH:15]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=Cc1nccn1Cc1ccccc1
Reactant: CCN(C=O)c1nc2ccc(-c3ccccc3[P+](C)(c3ccccc3)c3ccccc3)cc2o1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCNc1nc2ccc(C=Cc3nccn3Cc3ccccc3)cc2o1
Yield: 63.3 %

Procedure:
A mixture of [2-(N-ethylformamido)benzoxazol-6-yl]-methyltriphenylphosphonium bromide (0.5 g), 1-benzyl-2-imidazolecarbaldehyde (0.2 g) and potassium tert-butoxide (0.1 g) in tetrahydrofuran (5.0 ml) was refluxed for 50 minutes. Evaporation of a solvent gave a residue, which was purified by a column chromatography on silica gel eluting with a mixture of chloroform and methanol (19:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 6-[2-(1-benzylimidazol-2-yl)vinyl]-2-ethylaminobenzoxazole (0.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[CH:5]=[O:6].Br[CH:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19]>>[CH2:23]([N:20]([CH2:21][CH3:22])[C:18](=[O:19])[CH:17]([N:13]1[CH2:14][CH2:15][N:10]([C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH2:11][CH2:12]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24]
Reactant: CCN(CC)C(=O)C(Br)c1ccccc1
Reactant: O=Cc1ccc(N2CCNCC2)c(F)c1
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(C=O)cc2F)CC1
Yield: 90.1 %

Procedure:
3-Fluoro-4-piperazin-1-yl-benzaldehyde (0.65 g, 3.1 mmol) was treated with 2-bromo-N,N-diethyl-2-phenyl-acetamide (0.95 g) as described in previous examples to provide 1.11 g of the title compound. MS (ESI): mass calcd. for C21H29FN2O3, 376.47. m/z found, 377.5 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([C:11]([O:10][CH3:9])=[O:19])=[CH:17][CH:16]=2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine (300 mg, 2.0 mmol), 4-aminobenzoic acid methyl ester (302 mg, 2.05 mmol) in acetonitrile (3 mL), DIPEA (0.35 mL, 2.0 mmol) was added. After 30 minutes at room temperature, resulting solid was filtered and washed with acetonitrile and dried to give methyl 4-(4-chloro-1,3,5-triazin-2-ylamino)benzoate (Int-1). MS found for C11H9ClN4O2 as (M+H)+ 265.07. A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)H-imidazo[1,2-a]pyridine (139 mg, 0.57 mmol), Int-1 (150 mg, 0.57 mmol), 2.0M Sodium carbonate solution (0.6 mL, 1.25 mmol), PdCl2(dppf) (14 mg, 0.02 mmol), dioxane (2 mL) was heated in a microwave (Emry's Optimizer) at 125° C. for 15 minutes. The reaction mixture was then poured into water and the resulting solid was filtered and washed with ether and dried to give 5 methyl 4-(4-(H-imidazo[1,2-a]pyridin-3-yl)-1,3,5-triazin-2-ylamino)benzoate (Int-2) which was used without further purification. MS found for C18H14N6O2 as (M+H)+ 347.25. To solid Int-2 in MeOH (5 mL) was added 1N NaOH (5 mL) and stirred at 60° C. for 2 hours. The reaction mixture was concentrated, diluted with water and neutralized with 6N HCl (1.5 mL). The aqueous phase was then extracted with ethyl acetate and the combined organic layers were concentrated to give 4-(4-(H-imidazo[1,2-a]pyridin-3-yl)-1,3,5-triazin-2-ylamino)benzoic acid (Int-3). MS found for C17H12N6O2 as (M+H)+ 333.34. To Int-3 in DMF (6 mL), was added HATU (260 mg, 0.7 mmol), 1,2-phenylenediamine (123 mg, 1.1 mmol) and DIPEA (0.4 mL, 2.3 mmol) and stirred at room temperature for 3 hours. The reaction mixture was diluted with water and acetonitrile and directly purified by preparative HPLC affording the title compound, after lyophilization. MS found for C23H18N8O as (M+H)+ 423.09. 1H NMR (400 MHz, dmso-d6): δ 10.49 (s, 1H); 9.89 (brs, 1H); 9.56 (s, 1H); 8.78 (s, 1H); 8.57 (s, 1H); 7.99-7.77 (m, 6H); 7.54 (t, J=7.6 Hz, 1H); 7.23 (t, J=6.4 Hz, 1H); 7.14 (d, J=7.6 Hz, 1H); 6.94 (m, 1H); 6.75 (d, J=8.0 Hz, 1H); 6.57 (t, J=7.6 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([C@@H:24]([NH2:27])[CH2:25][CH3:26])=[CH:20][CH:19]=1>>[CH3:12][C:8]1([CH3:11])[CH2:7][O:6][C:5]2([CH2:13][CH2:14][C:2]([CH2:15][CH2:16][NH:27][C@H:24]([C:21]3[CH:20]=[CH:19][C:18]([CH3:28])=[CH:23][CH:22]=3)[CH2:25][CH3:26])([OH:1])[CH2:3][CH2:4]2)[O:10][CH2:9]1
Reactant: CC[C@H](N)c1ccc(C)cc1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: CC[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(C)cc1
Yield: 55 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-p-tolyl-propylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 55% of theory; LC (method 5): tR=1.10 min; Mass spectrum (ESI+): m/z=376 [M+H]+.
Reaction SMILES: N1CCCCC1.C1C2C(CO[C:22]([N:24](C)[C@@H:25]([CH2:29][S:30][S:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([OH:28])=[O:27])=O)C3C(=CC=CC=3)C=2C=CC=1>O1CCCC1>[C:32]([S:31][S:30][CH2:29][C@H:25]([NH:24][CH3:22])[C:26]([OH:28])=[O:27])([CH3:35])([CH3:34])[CH3:33]
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](CSSC(C)(C)C)C(=O)O
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CN[C@@H](CSSC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
Piperidine (1.8 ml, 18.2 mmol) was added to a solution of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(tert-butyldisulfanyl)propanoic acid (Compound 2c-B) (2.70 g, 6.06 mmol) in tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=100/0→60/40) to afford (R)-3-(tert-butyldisulfanyl)-2-(methylamino)propanoic acid (Compound 2f-G) (610 mg, 45%).
Reaction SMILES: [C:1]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:51])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:50])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:49])[N:34]([CH2:37][CH2:38][CH2:39][N:40](C(OC(C)(C)C)=O)[CH3:41])[O:35][CH3:36])=[CH:29][CH:28]=2)[CH3:19])[CH2:12][CH2:11]1.Cl.O1CCOCC1.C(=O)([O-])O.[Na+]>O1CCOCC1.CO>[C:1]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:51])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:50])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33](=[O:49])[N:34]([O:35][CH3:36])[CH2:37][CH2:38][CH2:39][NH:40][CH3:41])=[CH:31][CH:32]=2)[CH3:19])[CH2:12][CH2:11]1
Reactant: CON(CCCN(C)C(=O)OC(C)(C)C)C(=O)c1ccc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CNCCCN(OC)C(=O)c1ccc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.4 %

Procedure:
The compound (130 mg, 0.165 mmol) obtained in Example 87b was dissolved in a mixed solvent of 1,4-dioxane (1.6 mL) and methanol (1.6 mL), a 4 N hydrochloric acid-dioxane solution (0.412 mL, 1.65 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, the mixture was extracted (×3) with methylene chloride, and the resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography to give the title compound (48 mg; yield, 42%) as a colorless oily substance.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][N:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN1CC=C(c2c[nH]c3ncccc23)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)n2cc(C3=CCN(C)CC3)c3cccnc32)cc1

Procedure:
(16.4 mg, 41%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole (24.8 mg, 0.12 mmol) and 4-methoxybenzoyl chloride (35 μL, 0.24 mmol); HRMS-FAB+ for C21H21N3O2: calculated MH+:348.17120; found:348.16994.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].F[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)=[N:11][CH:12]=[N:13]2>>[NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)=[N:11][CH:12]=[N:13]2
Reactant: Cc1cc(Nc2ncnc3cccc(F)c23)ccc1O
Reactant: CC(C)(N)CO
Product: Cc1cc(Nc2ncnc3cccc(OCC(C)(C)N)c23)ccc1O
Yield: 78 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using 2-amino-2-methylpropan-1-ol and 4-[(5-fluoroquinazolin-4-yl)amino]-2-methylphenol (obtained as described in Example 3, preparation of starting materials) to give 4-{[5-(2-amino-2-methylpropoxy)quinazolin-4-yl]amino}-2-methylphenol as a white solid in 78% yield; NMR spectrum (DMSO-d6) 1.34 (s, 6H), 4.23 (s, 2H), 6.97 (d, 1H), 7.18 (d, 1H), 7.35 (d, 1H), 7.52 (dd, 1H), 7.73 (t, 1H), 7.96 (d, 1H), 8.46 (s, 1H), 10.50 (s, 1H); Mass spectrum MH+ 360.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[N:11]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][C:12]=1[CH3:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:15]3[CH:16]=[N:11][C:12]([CH3:26])=[CH:13][CH:14]=3)=[N:3]2)=[N:7][CH:8]=1
Reactant: Brc1nn2c(I)cnc2s1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2nn3c(I)cnc3s2)cn1
Temperature: 110 °C

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (169 mg, 0.512 mmol, 1 eq), 2-picoline-5-boronic acid pinacol ester (137 mg, 0.614 mmol, 1.2 eq), PdCl2(PPh3)2 (73 mg, 0.102 mmol, 0.2 eq) and 2M aq Na2CO3 (1.5 mL) in dioxane (7 mL) was heated at 110° C. for 2 h. The solvent was removed under reduced pressure, redissolved in dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated. The residue (226. mg) was used in the next step of the synthesis without further purification. HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mUrnin, 50° C.): tR=3.79 min, [M+H]+ m/z 342.9.