Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[C:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@@H:3]([CH2:2][NH:1][C:24](=[O:25])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:4]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CNC(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(S)-tert-Butyl 3-(aminomethyl)piperidine-1-carboxylate (1.00 g, 4.67 mmol) was dissolved in 14 mL anhydrous CH2Cl2 under an N2 atmosphere and cooled to 0° C. Triethylamine (1.30 mL, 945 mg, 9.34 mmol) was added followed by the dropwise addition of benzyl chloroformate (0.99 mL, 1.20 g, 7.00 mmol). After 16 h, the reaction mixture was partitioned between H2O and CH2Cl2, and separated, and the aqueous layer was extracted twice with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to a light yellow oil. Purification via silica gel chromatography using 97% CH2Cl2/3% MeOH gave benzyl ((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate as a clear, colorless oil (895 mg, 55%). LC/MS: m/z 349.5 (M+H)+ at 3.21 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:8]=1[S:14]([CH2:17][C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([O:28][CH3:29])[C:21]([C:30]2[CH:34]=[CH:33][O:32][CH:31]=2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].Br[C:38]1C(OC)=C(C(CS(C2C=CC=CC=2/C=C\CN2CCCCC2)(=O)=O)=CC=1)C(OC)=O>>[O:32]1[CH:33]=[CH:34][C:30]([C:21]2[C:22]([O:28][CH3:29])=[C:23]([C:18]([CH2:17][S:14]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3/[CH:6]=[CH:5]\[CH2:4][N:3]3[CH2:35][CH2:36][CH2:38][CH2:2][CH2:1]3)(=[O:16])=[O:15])=[CH:19][CH:20]=2)[C:24]([O:26][CH3:27])=[O:25])=[CH:31]1
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2/C=C\CN2CCCCC2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2/C=C\CN2CCCCC2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 160, starting from (Z)-methyl 3-bromo-2-methoxy-6-((2-(3-(piperidin-1-yl)prop-1-enyl)benzenesulfonyl)methyl)benzoate (Intermediate 199).
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[N:19]=2)=[C:9]1[CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:20]2[N:19]=[C:18]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=4)[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:9]=3[CH3:38])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21]2(=[O:28])=[O:29])=[CH:32][CH:33]=1
Reactant: Cc1c(C2=NN(Cc3ccc(F)cc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(Cc3ccc(F)cc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
{3-[2-(4-Fluoro-benzyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.15 (d, 1H), 7.93 (t, 1H), 7.84 (t, 1H), 7.47 (m, 3H), 7.38 (dd, 1H), 7.21 (m, 2H), 6.89 (dt, 1H), 6.57 (dd, 1H), 5.09 (bs, 2H), 4.51 (s, 2H), 2.09 (s, 3H) ppm. MS calculated for C25H19F2N3O4S—H: 494, observed: 494.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:29][CH3:30])[CH:9]([C:17]1[NH:18][C:19](=[O:28])[C:20]([OH:27])=[C:21]([C:23]([O:25]C)=O)[N:22]=1)[CH2:10][CH2:11][C@H:12]([O:15][CH3:16])[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1.C(N(CC)CC)C>CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:29]([N:8]([CH:9]([C:17]1[NH:18][C:19](=[O:28])[C:20]([OH:27])=[C:21]([C:23]([NH:37][CH2:36][C:35]2[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=2)=[O:25])[N:22]=1)[CH2:10][CH2:11][C@H:12]([O:15][CH3:16])[CH2:13][OH:14])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH3:30]
Reactant: NCc1ccc(F)cc1
Reactant: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](CO)OC)c1nc(C(=O)OC)c(O)c(=O)[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](CO)OC)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)[nH]1
Temperature: 80 °C

Procedure:
To a solution of methyl 2-{(4S)-1-[(tert-butoxycarbonyl)(ethyl)amino]-5-hydroxy-4-methoxypentyl}-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (48 g, 112 mmol) in MeOH (1118 mL) was added 4-fluoro-benzylamine (28 g, 224 mmol) and triethylamine (31.2 mL, 224 mmol). The resulting mixture was sealed and heated at 80° C. overnight. The reaction mixture was cooled to ambient temperature, diluted with 10% citric acid (˜100 mL), and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was dissolved in acetonitrile and concentrated under reduced pressure (3×) to remove MeOH. The residue was dried under high vacuum for 2 days and used in the next reaction without purification. LC-MS: 523.5 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.[OH:22][CH2:23][C@@H:24]1[O:28][C:27]([C:29]2[NH:33][C:32]([C:34]3[CH:35]=[C:36]([OH:46])[CH:37]=[C:38]([O:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH:39]=3)=[CH:31][CH:30]=2)=[N:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:22][CH2:23][C@@H:24]1[O:28][C:27]([C:29]2[NH:33][C:32]([C:34]3[CH:35]=[C:36]([CH:37]=[C:38]([O:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH:39]=3)[O:46][C:2]3[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=3)=[CH:31][CH:30]=2)=[N:26][CH2:25]1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Reactant: COc1ccc(CN(C)S(=O)(=O)c2ccc(Cl)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)Cc3ccc(OC)cc3)nc2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
5-Chloro-N-(4-methoxybenzyl)-N-methylpyridine-2-sulfonamide (427 mg, 1.31 mmol) synthesized in Example (121b) and 3-{5-[(5R)-5-(hydroxylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (568 mg, 1.64 mmol) synthesized in Example (125g) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (361 mg, 2.61 mmol) was added, followed by stirring at 100° C. for 2 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (40 mL) was added, and extraction was carried out twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-3.5%) to afford the desired compound (228 mg, yield 27%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1B(O)O>>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Reactant: OB(O)c1ccc(F)cc1F
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(-c3ccc(F)cc3F)c2cc1OC

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2,4-difluoro-phenylboronic acid to give [1-(2,4-difluoro-phenyl)-6,7-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 397(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21](OC)=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][O:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][NH:42][CH3:43])=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.C[Al](C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:25])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([N:42]([CH2:41][C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:31]4[CH2:32][CH2:33][CH:28]([O:27][CH3:26])[CH2:29][CH2:30]4)=[CH:40][CH:39]=3)[CH3:43])=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Reactant: CNCc1ccc(CN2CCC(OC)CC2)cc1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)Cc3ccc(CN4CCC(OC)CC4)cc3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.08 mmol), 1-{4-[(4-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine (35 mg, 0.14 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). The crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3. A portion of the fraction collected was further purified using prep method D to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:15](=[O:16])[CH2:14][C:13](=[O:17])[NH:12][C:11]3[C:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=4[CH:24]=[CH:25][C:10]2=3)[CH:6]=[CH:7][CH:8]=1)#[N:2].C([Sn]([N:39]=[N+:40]=[N-:41])(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH:39]1[C:1]([C:3]2[CH:4]=[C:5]([N:9]3[C:15](=[O:16])[CH2:14][C:13](=[O:17])[NH:12][C:11]4[C:18]5[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=5[CH:24]=[CH:25][C:10]3=4)[CH:6]=[CH:7][CH:8]=2)=[N:2][N:41]=[N:40]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1cccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC(=O)N(c2cccc(-c3nnn[nH]3)c2)c2ccc3c(c2N1)CCCC3
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To an anhydrous DMF (5 mL) solution of 5-(3-cyanophenyl)-8,9,10,11-tetrahydronaphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione (302 mg, 0.91 mmol) was added tri-n-butyltin azide (499 μL, 1.82 mmol). The mixture was stirred at 110° C. for 24 hours. The reaction mixture was cooled on standing, poured into saturated aqueous sodium hydrogen carbonate solution, and washed with ethyl acetate. After neutralization of the aqueous layer by addition of 1M hydrochloric acid, the layer was extracted with ethyl acetate, washed with purified water, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by chromatography (chloroform/methanol=95/5) to give the titled compound as slightly yellow powder (242 mg, yield 71%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[CH:2]1.Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:11]>>[C:10](=[O:11])([O:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1
Reactant: OCCc1ccsc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(OCCc1ccsc1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Using the method of Example 7a, 3-thiopheneethanol was treated with 4-nitrophenyl chloroformate to afford, after purification by flash chromatography (EtOAc:hexane (1:9)), the title product (56%); TLC, Rf= 0.25, EtOAc:hexane (1:9).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Reactant: Cc1ccnc(Br)c1
Product: Cc1ccnc(-c2cc(C)c(Br)c(C)c2)c1

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-4-methyl-pyridine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=0.90 min; Mass spectrum (ESI+): m/z=276/278 (Br) [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH2:17])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1CNC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
A slurry of 3-(2-aminomethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (0.36 g, 1.43 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath and treated with triethyl amine (0.40 mL, 0.28 mmol) then dropwise with benzoyl chloride (0.18 mL, 1.55 mmol). The resulting solution was stirred 30 min, and the cooling bath was removed. After 30 min, the solution was concentrated, and the residue was partitioned between EtOAc (50 mL) and 1N HCl (10 mL). The organic layer was washed with brine (10 mL), dried (Na2SO4), and concentrated to a solid. The crude mixture was purified by radial chromatography (hexanes:EtOAc 3:1 to 2:1) to give the title compound as a white solid (325 mg, 64%): 1H NMR (400 MHz, CDCl3) 1.26 (s, 9H), 2.54 (t, J=7.1 Hz, 2H), 2.81 (t, J=6.8 Hz, 2H), 4.55 (d, J=2H), 6.68 (dd, J=8.3, 2.4 Hz, 1H), 6.86 (d, J=2.9 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 7.25-7.29 (m, 2H), 7.34-7.37 (m, 1H), 7.49 (br s, 1H), 7.16-7.79 (m, 2H); MS (ES) m/z 356.2 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][N:53]=1>C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:35](=[O:36])[CH:34]([C:38]2[CH:39]=[CH:40][C:41]([S:44]([C:47]([F:49])([F:50])[F:48])(=[O:46])=[O:45])=[CH:42][CH:43]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:53][CH:54]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cn1)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
A solution of triphenylphosphine (206 mg, 0.785 mmol) in methylene chloride (4 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (140 mg, 0.785 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (250 mg, 0.710 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-bromopyridine (271 mg, 1.57 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 hexanes/ethyl acetate) afforded the pure N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide (226 mg, 63%) as a yellow foam: mp 130–132° C.; EI-HRMS m/e calcd for C20H20BrF3N2O3S (M+) 504.0330, found 504.0325.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11]I)[C:6]=2[CH:13]=1.[CH3:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][N:28]3[CH2:29][CH2:30][N:25]([C:23]4[CH:24]=[C:15]([CH3:14])[CH:16]=[C:17]5[C:22]=4[N:21]=[CH:20][CH:19]=[CH:18]5)[CH2:26][CH2:27]3)[C:6]=2[CH:13]=1
Reactant: Clc1ccc2occ(CCI)c2c1
Reactant: Cc1cc(N2CCNCC2)c2ncccc2c1
Product: Cc1cc(N2CCN(CCc3coc4ccc(Cl)cc34)CC2)c2ncccc2c1

Procedure:
8-{4-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methyl-quinoline was prepared by generally following the procedure outlined in example 12, step 6, starting from the 2-(5-chloro-1-benzofuran-3-yl)ethyl iodide (306 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227 mg, 1 mmol). The product was purified by silica-gel column chromatography by initially eluting it with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown oil. Yield: 140 mg (34%); (M+H): 406; 1HNMR (400 MHz, CDCl3): δ□8.82˜8.80 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H), 8.03˜7.80 (dd, J1=1.7 Hz, J2=1.7 Hz 1H), 7.60˜6.70 (m, 7H), 3.48˜2.81 (m, 12H), 2.5 (s, 3H).
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:15]3[N:23]4[C:18]([CH:19]=[N:20][C:21](O)=[N:22]4)=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][OH:40])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[N:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:15]3[N:23]4[C:18]([CH:19]=[N:20][C:21]([NH:25][C:26]5[CH:31]=[CH:30][C:29]([CH:32]6[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][OH:40])[CH2:34][CH2:33]6)=[CH:28][CH:27]=5)=[N:22]4)=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(C2CCN(CCO)CC2)cc1
Reactant: O=S(=O)(c1cccc(-c2ccc3cnc(O)nn23)c1)N1CCCC1
Product: O=S(=O)(c1cccc(-c2ccc3cnc(Nc4ccc(C5CCN(CCO)CC5)cc4)nn23)c1)N1CCCC1
Yield: 25 %

Procedure:
The compound was prepared in an analogous fashion to Example 522 using 7-[3-(pyrrolidine-1-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 2-[4-(4-amino-phenyl)-piperidin-1-yl]-ethanol to provide 2-[4-(4-{7-[3-(pyrrolidine-1-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}phenyl)-piperidin-1-yl]ethanol as a brown lyophilate (49.2 mg, 25% yield). LCMS (E/I+) 547 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.22 (broad s, 1H), 9.04 (s, 1H), 8.53 (s, 1H), 8.42 (d, 1H, J=7.6 Hz), 7.82 (m, 2H), 7.70 (d, 2H, J=8.5 Hz), 7.29 (d, 1H, J=4.7 Hz), 7.22 (d, 2H, J=8.4 Hz), 7.00 (d, 1H, J=4.7 Hz), 3.77 (t, 2H, J=5 Hz), 3.42 (d, 2H, J=11.9 Hz), 3.37 (m, 1H), 3.18 (m, 6H), 3.09 (m, 2H), 2.75 (m, 1H), 1.95 (m, 3H), 1.65 (m, 4H).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1>>[CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:4]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CNC1CCNC1
Product: CNC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 110 °C

Procedure:
N-methylpyrrolidin-3-amine (0.788 g, 7.87 mmol) was added to 1-fluoro-4-nitrobenzene (1.11 g, 7.87 mmol) slowly (CAUTION: extreme exotherm!!!). The resulting mixture was heated at 110° C. for 10 min. After cooling down to room temperature, another portion of amine (0.156 g) was added to the reaction mixture. The resulting mixture was heated at 110° C. for 1 h. After cooling down to room temperature, the obtained black solid product (Example 43A) was used for next step without further purification. LCMS (ES): m/z 252.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:16][NH:17][C@H:18]([CH3:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([N:17]([CH3:16])[C@H:18]([CH3:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CN[C@H](C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](Cc1ccccc1)N(C)c1cc(Cl)nc(N)n1
Temperature: 140 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a suspension of 4,6-dichloro-2-pyrimidinamine (1.0 g, 6.10 mmol) and K2CO3 (1.69 g, 12.2 mmol) in CH3CN (6.0 mL) was added (2R)—N-methyl-1-phenyl-2-propanamine (1.09 g, 7.32 mmol), and the reaction mixture was heated at 140° C. under microwave conditions with stirring for 2 hours. The mixture was filtered and washed by EtOAc (50 mL). The solution was concentrated, and the resulting residue was purified by reversed phase chromatography using CH3CN in water from 45% to 55% (0.5% ammonium hydrogen carbonate in water) to afford the title compound (910 mg) as a white solid. LC-MS (ES) m/z=277 [M+H]+.
Reaction SMILES: CCN(CC)CC.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[C:26]3[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[NH:30][C:29]4[N:37]=[CH:38][CH:39]=[CH:40][C:28]=4[N:27]3[C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([C:48]3([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:51][CH2:50][CH2:49]3)=[CH:44][CH:43]=2)[CH:21]=[CH:22][CH:23]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[NH:14]([C:15]([NH:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[C:26]3[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[NH:30][C:29]4[N:37]=[CH:38][CH:39]=[CH:40][C:28]=4[N:27]3[C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([C:48]3([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:57])([CH3:56])[CH3:58])[CH2:49][CH2:50][CH2:51]3)=[CH:44][CH:43]=2)[CH:21]=[CH:22][CH:23]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4cccc(N)c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: O=C=Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4cccc(NC(=O)Nc5ccccc5)c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
Et3N (29.3 μL, 0.260 mmol) and phenyl isocyanate (8.0 μL, 0.0771 mmol) were added to a solution of tert-butyl (1-{4-[2-(3-aminophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (40.0 mg, 0.0701 mmol) in DCM (1 mL) at 0° C., and stirred at room temperature. After reaction was completed, the mixture was diluted with sat. NaHCO3 and extracted with CHCl3 (3×). The combined organic layers were dried over anhydrous Na2SO4, and concentrated. The residue was purified by PTLC (CHCl3/MeOH=9:1) to afford desired product (35.4 mg, 69.3%) as white solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.15 (dd, J=7.8, 1.4 Hz, 1H), 8.05 (dd, J=4.6, 1.8 Hz, 1H), 7.90-6.59 (m, 20H), 6.30 (s, 1H), 6.18-5.38 (m, 1H), 2.67-2.54 (m, 2H), 2.52-2.39 (m, 2H), 2.25-2.10 (m, 1H), 2.06-1.86 (m, 1H), 1.37 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:52][CH2:51][C:46]2([O:50][CH2:49][CH2:48][O:47]2)[CH2:45][CH2:44]1)=O>>[O:50]1[C:46]2([CH2:51][CH2:52][N:43]([CH2:41][CH2:40][O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]4[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=4[CH:17]4[CH2:26][CH2:25][C:24]5[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=5[CH2:18]4)=[CH:37][CH:38]=3)[CH2:44][CH2:45]2)[O:47][CH2:48][CH2:49]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Reactant: O=C(CCl)N1CCC2(CC1)OCCO2
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCC4(CC3)OCCO4)cc2)C(C)C)c1
Yield: 17.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-1-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethanone (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.2 mg) was obtained.