Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[O:20]=[S:21]1(=[O:40])[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([NH2:39])[C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:31][CH:32]=2)[CH2:23][CH2:22]1.Cl.O1CCOCC1>CN1C(=O)CCC1>[O:40]=[S:21]1(=[O:20])[CH2:22][CH2:23][N:24]([C:27]2[CH:28]=[C:29]([NH:39][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[N:5]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[C:3]=3[CH3:19])[C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:31][CH:32]=2)[CH2:25][CH2:26]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: Nc1cc(N2CCS(=O)(=O)CC2)cnc1N1CCOCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCS(=O)(=O)CC2)cnc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (61 mg, 0.22 mmol), 5-(1,1-dioxidothiomorpholin-4-yl)-2-morpholin-4-ylpyridin-3-amine (70 mg, 0.22 mmol) and a 4.0M solution of HCl in dioxane (0.05 mL, 0.22 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(5-(1,1-dioxido-4-thiomorpholinyl)-2-(4-morpholinyl)-3-pyridinyl)-7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, dd, J=3.5, 1.2 Hz), 7.87-7.99 (2H, m), 7.75-7.85 (2H, m), 7.61 (1H, d, J=2.7 Hz), 7.41 (1H, d, J=1.6 Hz), 7.32 (1H, s), 6.76 (1H, s), 6.22 (1H, d, J=2.7 Hz), 3.94 (4H, t, J=4.7 Hz), 3.53-3.67 (4H, m), 3.25 (4H, br. s.), 2.90-3.11 (4H, m), 2.37 (3H, s). Mass Spectrum (ESI) m/e=549.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12](C(OC(C)(C)C)=O)=[CH:11][C:10]=2NCCCCCC)=[CH:4][C:3]=1[N:29]([CH3:37])[C:30](=O)OC(C)(C)C.[O:38]=[C:39]1[NH:43][C:42](=[O:44])[CH:41]([CH2:45][C:46]2[CH:56]=[CH:55][C:49]([O:50][CH2:51]C(O)=O)=[CH:48][CH:47]=2)[S:40]1.C([N:59]([CH2:62][CH3:63])CC)C>O1CCCC1>[CH2:62]([NH:59][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:37]([CH2:51][O:50][C:49]4[CH:48]=[CH:47][C:46]([CH2:45][CH:41]5[S:40][C:39](=[O:38])[NH:43][C:42]5=[O:44])=[CH:56][CH:55]=4)[N:29]([CH3:30])[C:3]=3[CH:4]=2)=[CH:14][CH:13]=1)[CH2:63][CH2:7][CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCNc1cc(C(=O)OC(C)(C)C)ccc1Oc1ccc(N)c(N(C)C(=O)OC(C)(C)C)c1
Reactant: CCN(CC)CC
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Solvent: C1CCOC1
Product: CCCCCCNc1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 129.6 %

Procedure:
A mixture of t-butyl N-[2-amino-5-(4-t-butoxycarbonyl-n-hexylaminophenoxy)phenyl]-N-methylcarbamate (4.10 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (2.81 g), diethyl cyanophsphonate (1.63 g), triethylamine (1.01 g) and anhydrous tetrahydrofuran (100 ml) was stirred at ambient temperature for 28 hours. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. A mixture of the residue and 4N hydrogen chloride/dioxane (50 ml) was stirred at ambient temperature for 66 hours. Water was added to the reaction mixture and the mixture was neutralized with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate was dried over anhydrous sodium sulfate and evaporated. The residue was purified by chromatography on a silica gel column using n-hexane/ethyl acetate=2/3 as the eluant to give the title compound (2.89 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:11][C:10]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([N:33]2[C:37]3=[N:38][CH:39]=[N:40][C:41]([NH2:42])=[C:36]3[CH:35]=[N:34]2)[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.CO>C1COCC1>[C:21]1([C:10]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:27]4[CH2:32][CH2:31][CH:30]([N:33]5[C:37]6=[N:38][CH:39]=[N:40][C:41]([NH2:42])=[C:36]6[CH:35]=[N:34]5)[CH2:29][CH2:28]4)=[CH:8][CH:7]=3)=[N:14][CH:13]=[C:12]([C:15]3[N:16]=[CH:17][CH:18]=[CH:19][N:20]=3)[CH:11]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ncnc2c1cnn2C1CCNCC1
Reactant: BrCc1ccc(-c2ncc(-c3ncccn3)cc2-c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2c1cnn2C1CCN(Cc2ccc(-c3ncc(-c4ncccn4)cc3-c3ccccc3)cc2)CC1

Procedure:
A mixture of crude 2-{6-[4-(bromomethyl)phenyl]-5-phenylpyridin-3-yl}pyrimidine (0.050 g, 0.124 mmol), 1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.030 g, 0.137 mmol), and DIEA (0.065 mL, 0.373 mmol) in 1:1 MeOH:THF (1 mL) was stirred for 1 hr. Reaction concentrated and the residue was purified by reverse phase HPLC (5% CH3CN: 95% H2O: 0.01% TFA to 95% CH3CN: 5% H2O: 0.01% TFA) to give the title compound. 1H-NMR (500 MHz, d6 DMSO) δ 9.77 (bs, 1H), 9.60 (d, 1H, J=2.0 Hz), 9.00 (d, 2H, J=4.9 Hz), 8.70 (bs, 1H), 8.68 (d, 2H, J=2.0 Hz), 8.45 (bs, 1H), 8.37 (s, 1H), 8.30 (s, 1H), 7.58 (t, 1H, J=4.9 Hz), 7.54-7.37 (m, 9H), 5.05-4.93 (m, 1H), 4.35 (s, 2H), 3.49 (d, 2H, J=11.23 Hz), 3.37-3.21 (m, 2H), 2.47-2.33 (m, 2H), 2.15 (d, 2H, J=11.7 Hz) HRMS m/z (M+H) Calcd: 540.2619, found: 540.2616.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[O:15][C:14]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=3[NH:19][C:18]3=[C:29]([C:32](O)=[O:33])[NH:30][CH:31]=[C:17]23)=[CH:13][CH:12]=1.C[N:36](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[O:15][C:14]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][C:22]([CH3:27])([CH3:28])[CH2:21][C:20]=3[NH:19][C:18]3=[C:29]([C:32]([NH2:36])=[O:33])[NH:30][CH:31]=[C:17]23)=[CH:13][CH:12]=1
Reactant: CC1(C)CC(=O)C2=C(C1)Nc1c(c[nH]c1C(=O)O)C2c1ccc(Sc2nc3ccccc3[nH]2)o1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(=O)C2=C(C1)Nc1c(c[nH]c1C(N)=O)C2c1ccc(Sc2nc3ccccc3[nH]2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
To a solution of 60 mg (0.126 mmol) of 9-[5-(1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-6.6 dimethyl-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid in 2 ml dimethylformamide was added successively 72 mg (0.189 mmol) of HBTU, 14 mg (0.253 mmol) of ammonium chloride, 74 mg (0.574 mmol) of N,N-diisopropylethylamine in a round bottom flask. The reaction mixture was stirred overnight at room temperature. Water was then added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by preparative LCMS (method C) giving 8.9 mg of 9-[5-(1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-6,6-dimethyl-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxamide (12% yield). Analytical LC/MS method B: [M+H]+=474.5; retention time: 2.90 min; 70% UV (DAD) purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][S:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:63]1[CH2:68][CH2:67][S:66][CH2:65][CH2:64]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: C1CSCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCSCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and thiomorpholine in DMSO at ambient temperature.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br.N.CO.C(Cl)Cl>CC(O)=O>[CH:1]1([N:6]2[C:10]3[C:11]([Br:16])=[C:12]([NH2:15])[CH:13]=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2ncn(C3CCCC3)c2c1
Reactant: BrBr
Agent: N
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc2ncn(C3CCCC3)c2c1Br
Yield: 50 %

Procedure:
To a solution of 3-cyclopentyl-5-aminobenzimidazole (1.0 g, 5.0 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 0.70 g (2.5 mmol, 50%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[C:13]([NH:26][CH2:27][CH:28]([OH:30])[CH3:29])=[N:14][C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:16][C:11]=2[NH:10][N:9]=1.C(N(CC)C(C)C)(C)C.NN>O1CCOCC1.CCO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[C:13]([NH:26][CH2:27][C@@H:28]([OH:30])[CH3:29])=[N:14][C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:16][C:11]=2[NH:10][N:9]=1
Reactant: CC(O)CNc1nc(Oc2ccc(F)cc2F)cc2[nH]nc(-c3ccccc3Cl)c12
Agent: NN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H](O)CNc1nc(Oc2ccc(F)cc2F)cc2[nH]nc(-c3ccccc3Cl)c12
Temperature: 90 °C
Yield: 35.7 %

Procedure:
1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[4,3-c]pyridin-4-ylamino]-propan-2-ol (690 mg, 1.6 mmol) was taken up in a mixture of 15 mL dioxane and 2 mL EtOH. N,N-diisopropylethylamine (0.3 mL) and anhydrous hydrazine (0.15 mL) were added, and the reaction mixture was slowly heated to 90° C. with stirring. The reaction mixture was stirred for six hours at 90° C., then was cooled to room temperature and quenched by addition of water and partitioned with ethyl acetate, followed by back extraction of the aqueous phase with additional ethyl acetate. The combined organic phases were were washed with saturated brine and water, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by preparative scale TLC (3.5% MeOH in methylene chloride), then recrystallized from methylene chloride/hexanes to give 246 mg of (S)-1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[4,3-c]pyridin-4-ylamino]-propan-2-ol. Mass spec., M+1=432. Mp=171.2-172° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]2=[O:13].[F:16][C:17]([F:21])([F:20])[CH2:18][NH2:19]>C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(=O)OCC>[F:16][C:17]([F:21])([F:20])[CH2:18][N:19]1[C:6](=[O:13])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:15])[F:14])[CH:4]=2)[C:8]1=[O:12]
Reactant: O=C1OC(=O)c2cc(C(F)(F)F)ccc21
Reactant: NCC(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: O=C1c2ccc(C(F)(F)F)cc2C(=O)N1CC(F)(F)F
Reaction time: 16 h
Yield: 80 %

Procedure:
5.0 g of 5-trifluoromethyl-isobenzofuran-1,3-dione were dissolved using 50 ml of toluene(anhydrous) and 4.6 g of 2,2,2-trifluoro-ethylamine added. The mixture was left at ambient temperature for 16 h. 50 mg of toluene-4-sulfonic acid were then added and the mixture was refluxed for 5 h. 200 ml of EA were added and the mixture was washed twice using 50 ml of a 10% aqueous Na2CO3-solution. The organic layer was dried over MgSO4 and the solvent was removed in vacuo to yield 5.5 g of a viscous oil (Rf(DIP)=0.57; MS (EI): 298 (M+1)+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])=[O:4].[NH2:17][C:18]1[N:23]=[C:22]([CH:24]2[CH2:26][CH2:25]2)[N:21]=[C:20]([O:27][CH3:28])[N:19]=1>C(Cl)Cl>[CH:24]1([C:22]2[N:21]=[C:20]([O:27][CH3:28])[N:19]=[C:18]([NH:17][C:15]([NH:14][S:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:3]([O:2][CH3:1])=[O:4])(=[O:12])=[O:13])=[O:16])[N:23]=2)[CH2:26][CH2:25]1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1nc(N)nc(C2CC2)n1
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(C2CC2)n1
Temperature: 25 °C

Procedure:
2.1 g of 2-methoxycarbonylbenzenesulfonylisocyanate are added with stirring, under a nitrogen atmosphere, to a solution of 1.3 g of 2-amino-4-cyclopropyl-6-methoxy-1,3,5-triazine in 10 ml of CH2Cl2. A slight exothermic reaction occurs, which soon however subsides. Stirring is maintained for 14 hours at room temperature, and the solution is then caused to crystallise by the addition of ether. The precipitate is filtered off and dried. The yield is 2.3 g of the above urea, which melts at 166°-168° C.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]([CH:20]=1)[C:17](Cl)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:29]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][N:29]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:17](=[O:18])[C:16]1[CH:20]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=[CH:14][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:35]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: CCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)Cl)c1
Product: CCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Yield: 82 %

Procedure:
The reaction of 5-(decyloxy)-2-(phenylmethoxy)benzoic acid chloride with diethyl iminodiacetate under conditions described in Example 80 gave N-(2-ethoxy-2-oxoethyl)-N-[5-(decyloxy)-2-(phenylmethoxy)benzoyl]glycine ethyl ester (82% yield, mp 37°-38°).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][NH:5][S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1Cl)(=[O:8])=[O:7].[H-].[Na+].[OH2:23]>>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][NH:5][S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1[OH:23])(=[O:8])=[O:7]
Reactant: CN(C)CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O

Procedure:
Following the general hydrolysis procedure outlined in example 15, crude N-[2-(dimethylamino)ethyl]-2,6-dichloro-3-nitrobenzenesulfonamide (480 mg), 60% NaH (168 mg, 4.2 mmol) and water (25 μL, 1.4 mmol) were reacted. The crude product (80 mg) was carried on to the next step without purification. EI-MS (m/z) 321.98, 323.96 (M−).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:26]2[CH2:27][CH2:28][CH2:29][C@@H:25]2[CH3:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
(R)-3-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (52 g, 0.15 mol, 1.0 eq) prepared in accordance of the procedures set forth in Intermediate (i), (2S)-2-methyl pyrrolidine (25.2 g, 0.3 mol, 2.0 eq), anhydrous CH3CN (500 ml), and dry K2CO3 powder (50 g, 36 mmol, 2.4 eq) were added to a 2 L round-bottom flask equipped with a mechanical stirrer and a reflux condenser. The resulting suspension was stirred at 75° C. for 2 h. The heating block was set at 88° C. LC/MS showed a trivial amount of starting material at m/z 363. The reaction mixture was concentrated in vacuo. The residue was partitioned between 200 ml of water and 400 ml of DCM. The aqueous layer was washed with 50 ml of DCM twice. The organic extracts were combined and washed with 150 ml of saturated NaHCO3 solution, 150 ml of brine, and dried over K2CO3. The crude was purified by silica gel column, eluted with 5-10% MeOH in DCM. The product still had weak UV absorptions at 254 nm and 280 nm. A pale yellow oil was obtained, yield: 24.5 g (64%).
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[N:8]([CH:16]=[CH:17][CH:18]=3)[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:26]([N:2]1[CH2:3][CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]3[CH:16]=[CH:17][CH:18]=[C:7]3[CH:6]2[CH2:1]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc2c(c1)Cn1cccc1C1CNCCN21
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CCN2c3ccccc3Cn3cccc3C2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred solution of 1.3 g of 1,3,4,14b-tetrahydro-2H,10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine (Example 4) and 550 mg of triethylamine in 15 ml of tetrahydrofuran is added 765 mg of benzoyl chloride. After allowing the mixture to stir at room temperature overnight it is evaporated and the residue taken up in 100 ml of water. The mixture is extracted with diethyl ether, washed successively with water and brine, dried and evaporated, to yield 2-benzoyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine melting at 137°-139° after recrystallization from isopropanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].[C:11]([P:15](Cl)[C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])([CH3:13])[CH3:12].C1(C)C=CC=CC=1>O1CCCC1.[Cu](Cl)Cl.O>[C:11]([P:15]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: COc1ccccc1Br
Agent: Cl[Cu]Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1P(C(C)(C)C)C(C)(C)C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, a Grignard reagent solution previously prepared from 12.1 g (0.065 mol) of 2-bromoanisole and 2.1 g (0.085 mol) of metallic magnesium in 65 ml of tetrahydrofuran, and 0.13 g (0.0010 mol (corresponding to 2% by mol)) of copper(II) chloride were placed. To the contents of the flask, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride was dropwise added as it is without being dissolved in a solvent, over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at 50° C. for 3 hours. After the temperature of the reaction solution was returned to room temperature, gas chromatography analysis was carried out, and as a result, di-tert-butylphosphinous chloride was present in trace amounts. Thereafter, 65 ml of toluene and 50 ml of water were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent and a low-boiling component were distilled off under reduced pressure to obtain 11.9 g (purity: 95.0%) of the aimed di-tert-butyl(2-methoxyphenyl)phosphine was obtained. The yield was 89.7%.
Reaction SMILES: [NH2:1][C:2]1[N:29]=[CH:28][C:27]([Br:30])=[CH:26][C:3]=1[C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=1)=[O:5].Cl>O1CCOCC1>[N:12]1([C:10]2[N:11]=[C:6]([C:4]([C:3]3[C:2]([NH2:1])=[N:29][CH:28]=[C:27]([Br:30])[CH:26]=3)=[O:5])[CH:7]=[CH:8][CH:9]=2)[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(C(=O)c3cc(Br)cnc3N)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncc(Br)cc1C(=O)c1cccc(N2CCCNCC2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.9 %

Procedure:
To a suspension of tert-butyl 4-(6-(2-amino-5-bromonicotinoyl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (50 mg, 0.1 mmol) in 1,4-dioxane (2 ml) at 0° C. was added 4 M HCl in 1,4-dioxane (1 ml). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated to dryness to leave an orange solid which was further purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a yellow solid (13.5 mg, 36% yield).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)=[N:10][C:5]2=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].[SnH4]>O1CCCC1>[N:12]1([CH2:11][C:9]2[CH:8]=[CH:7][N:6]3[C:2]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:3][N:4]=[C:5]3[N:10]=2)[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1cnc2nc(Cn3cncn3)ccn12
Agent: CC(C)[Mg]Cl
Agent: [SnH4]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(Cn3cncn3)ccn12
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of 3-bromo-7-([1,2,4]triazol-1-ylmethyl)-imidazo[1,2-α]pyrimidine (0.42 g, 1.50 mmol) in tetrahydrofuran (15 ml) was added isopropylmagnesium chloride (0.82 ml of a 2M solution in tetrahydrofuran, 2.37 mmol). Mixture was allowed to warm to −45° C. and stirring at this temperature was continued for 0.5 h. Mixture was recooled to −78° C., tributyltin chloride (0.47 ml, 1.72 mmol) added in a dropwise fashion, stirred for 10 min at −78° C. and then allowed to warm to ambient temperature. This process of Grignard formation with subsequent transmetallation to the stannane intermediate was repeated to encourage completion of the reaction giving 7-([1,2,4]triazol-1-ylmethyl)-3-tributylstannylimidazo[1,2-α]pyrimidine as a solution in tetrahydrofuran (ca. 0.1M); m/z (ES+) 487, 489, 490 (M++H).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH:8]([C:26](C)(C)[O:27][SiH2]C(C)(C)C)[CH2:9][O:10][C:11]1[C:18]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:17][C:14]([CH:15]=[O:16])=[C:13]([O:24][CH3:25])[CH:12]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:6][CH2:7][CH:8]([CH2:26][OH:27])[CH2:9][O:10][C:11]1[C:18]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:17][C:14]([CH:15]=[O:16])=[C:13]([O:24][CH3:25])[CH:12]=1
Reactant: COc1cc(OCC(CO[Si](C)(C)C(C)(C)C)C(C)(C)O[SiH2]C(C)(C)C)c(-c2cccs2)cc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(OCC(CO)CO)c(-c2cccs2)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
Ex-50C: To a solution of 4-[3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propoxy]-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-50B, 0.78 g, 1.41 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 3.0 mL, 2.9 mmol) and the mixture was stirred at rt for 30 min. The reaction was diluted with ethyl acetate (50 mL) and washed with a 50% ammonium chloride solution (1×30 mL), water (2×30 mL), brine (1×30 mL), dried over sodium sulfate and concentrated to a crude yellow solid. Silica gel chromatography afforded 0.37 g (99%) of the expected 4-(3-hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-benzaldehyde as a pale yellow solid, 90% yield, mp 144–145° C. 1H-NMR (300 MHz, CDCl3) δ 10.33 (s, 1H), 8.10 (s, 1H), 7.38 (dd, 1H, J=3.6, 1.5 Hz), 7.30 (dd, 1H, J=5.1, 1.5 Hz), 7.07 (dd, 1H, J=5.1, 3.6 Hz), 6.59 (s, 1H), 4.35 (d, 2H, J=6.0 Hz), 4.02 (t, 4H, J=4.8 Hz), 3.96 (s, 3H), 2.33 (pentet, 1H, J=6.0 Hz), 1.89 (t, 2H, J=4.8 Hz). MS (ESI) m/z=323 ([M+H]+, 100%). Anal. Calcd. for C16H18O5S: C, 59.61; H, 5.63; S, 9.95. Found: C, 59.34; H, 5.75; S, 9.82.