Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5](=[O:13])[N:6]([CH2:9][CH2:10][CH2:11][CH3:12])[C:7]=1[NH2:8].[N:23]1[CH:28]=[CH:27][C:26]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=O)=[CH:35][CH:34]=2)(=[O:32])=[O:31])=[CH:25][CH:24]=1>>[CH2:9]([N:6]1[C:7]2[N:8]=[C:40]([CH2:39][C:36]3[CH:35]=[CH:34][C:33]([S:30]([NH:29][C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)(=[O:31])=[O:32])=[CH:38][CH:37]=3)[NH:1][C:2]=2[C:3](=[O:22])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5]1=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCn1c(N)c(N)c(=O)n(Cc2ccccc2F)c1=O
Reactant: O=C(O)Cc1ccc(S(=O)(=O)Nc2ccncc2)cc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(S(=O)(=O)Nc4ccncc4)cc3)nc21

Procedure:
Prepared from 5,6-diamino-1-butyl-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione (30.6 mg, 0.1 mmol) and [4-(pyridin-4-ylsulfamoyl)-phenyl]-acetic acid. 4-[3-Butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-N-pyridin-4-yl-benzenesulfonamide was obtained as a colorless solid; 1H NMR (DMSO-d6, 300 MHz) δH 13.50 (s, 1H), 12.65 (broad s, 1H), 8.00–7.80 (m, 2H), 7.75–7.60 (m, 2H), 7.55–7.35 (m, 2H), 7.30–6.80 (m, 6H), 5.08 (s, 2H), 4.11 (s, 2H), 3.93 (t, J=7.3 Hz, 2H), 1.70–1.50 (m, 2H), 1.35–1.15 (m, 2H), 0.83 (t, J=7.1 Hz, 3H); FAB-HRMS m/e calculated for C28H27FN6O4S (M+H)+ 563.1877, found 563.1858.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:3].[BH3-]C#[N:25].[Na+]>CO>[CH3:1][N:2]([CH:4]=[N:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH2:25])=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:3]
Reactant: [BH3-]C#N
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(C=O)cc1
Agent: [Na+]
Solvent: CO
Product: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.5 g of 4′-formyl-biphenyl-2-sulfonic acid dimethylaminomethyleneamide prepared according to H. Jendralla et al. (Liebigs Ann. 1995, 1253-7) in 15 ml MeOH were treated with 208.6 mg NaCNBH3 and the reaction was stirred for 4 hours at RT. The pH was adjusted to 4.0, the reaction was filtered, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel eluting with a gradient of 10-20% MeOH in DCM.
Reaction SMILES: [Si]([C:5]1[N:6]=NN[CH:9]=1)(C)(C)C.[N:10]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12](Cl)=[O:13]>S1(CCCC1)(=O)=O.[Cl-].[Na+].O>[CH2:21]([O:20][C:18]([N:10]1[CH2:17][CH2:16][CH2:15][CH:11]1[C:12]1[O:13][CH:9]=[CH:5][N:6]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[Si](C)(C)c1c[nH]nn1
Reactant: O=C(Cl)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: O=C(OCc1ccccc1)N1CCCC1c1ncco1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of TMS-triazole (14.17 g, 100.3 mmol, 1 equiv.) in sulfolane (290 mL) at rt under nitrogen, is added dropwise Z-L-Pro-Cl (26.85 g, 100.3 mmol, 1 equiv.) in sulfolane (70 mL). The resulting mixture is stirred at rt for 30 minutes, then the temperature is elevated to 140° C. for 3 hours. After the reaction mixture is cooled to rt, poured into excess brine and extracted with diethyl ether. The diethyl ether extracts are washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue is purified by flash chromatography (DCM:acetone=9:1) to give the title compound as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:33])([F:32])[F:31])[O:17][N:16]=[C:15]([C:18]3[N:19]4[C:23]([C:24]([C:27]([OH:29])=O)=[CH:25][CH:26]=3)=[CH:22][CH:21]=[CH:20]4)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:66][CH2:67][C:68]([NH:70][CH2:71][C:72]([F:75])([F:74])[F:73])=[O:69]>CN(C=O)C.C(Cl)Cl.O.CC(=O)OCC>[F:73][C:72]([F:75])([F:74])[CH2:71][NH:70][C:68]([CH2:67][NH:66][C:27]([C:24]1[C:23]2[N:19]([CH:20]=[CH:21][CH:22]=2)[C:18]([C:15]2[CH2:14][C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:4]=3)([C:30]([F:33])([F:32])[F:31])[O:17][N:16]=2)=[CH:26][CH:25]=1)=[O:29])=[O:69]
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)n2cccc12
Reactant: NCC(=O)NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(CNC(=O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)n2cccc12)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
5-[5-(3,5-Bistrifluoromethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-indolizine-8-carboxylic acid (50 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC.HCl, 22.5 mg), 1-hydroxybenzotriazole monohydrate (HOBt.H2O, 20 mg) and N-methylmorpholine (22 μL) were stirred in a mixture of DMF-DCM (½, 1 mL) for 20 minutes at room temperature prior to adding 2-amino-N-(2,2,2-trifluoroethyl)acetamide (50 mg, Ukrorgsynthesis Ltd. Kiev, UKRAINE). The reaction mixture was stirred overnight at room temperature. The mixture was diluted with water and EA. The organic layer was collected, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, DCM/MeOH) to afford the title compound as an orange-reddish solid (11.1 mg, 17%). MS (ES): M/Z [M+H]=649. 1H NMR (400 MHz, CHLOROFORM-d): 3.88-4.04 (m, 3H), 4.33 (d, J=5.3 Hz, 2H), 4.39 (d, J=16.6 Hz, 1H), 6.84 (d, J=7.4 Hz, 1H), 7.05-7.08 (m, 1H), 7.08-7.21 (m, 3H), 7.33 (t, J=4.9 Hz, 1H), 8.01 (s, 1H), 8.13 (s, 2H), 8.72 (d, J=1.8 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −80.0 (s, 3F), −72.9 (t, J=9.2 Hz, 3F), −63.3 (s, 6F).
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH2:16][CH3:17])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:14])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C(N(CC)CC)C.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH2:15]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=3)(=[O:33])=[O:32])[CH:11]=2)[CH2:6]1)[CH2:16][CH3:17]
Reactant: CCCN(CCC)C1Cc2ccc(O)cc2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC)C1Cc2ccc(OS(=O)(=O)c3ccc(C)cc3)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
2-Dipropylamino-indan-5-ol (Preparation 9, 140 mg, 0.47 mmol) was dissolved in dichloromethane (25 mL) and cooled to 0 C. Thereafter was added triethylamine (99 mg, 0.98 mmol) and toluene-4-sulfonyl chloride (101 mg, 0.54 mmol). The reaction mixture was allowed to reach room temperature and was then stirred at ambient temperature for 2 h. Aqueous Na2CO3 solution (25 mL, 10%) was added and the mixture was stirred for an additional 5 min. The layers were separated and the organic layer was washed, dried (Na2SO4) and the solvent evaporated. The crude product was chromatograped using dichloromethane-methanol (19:1) as eluant. The pure fractions were pooled, and the solvent removed in vacuo yielding 135 mg (78%) of toluene-4-sulfonic acid 2-dipropylamino-indan-5-yl ester as an oil. The amine was converted to its hydrochloride salt (hydroscopic).; 1H NMR (300 MHz, CDCl3) δ 0.85 (t, 6H), 1.45 (m, 4H), 2.4-2.5 (m, 7H), 2.75-2.85 (m, 2H), 2.90-3.00 (m, 2H), 3.60-3.70 (m, 1H), 6.65 (dd, J=2.5, 8.3 Hz, 1H), 6.85 (d, J=2.5 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H); 13C NMR (75.4 MHz, CDCl3) δ 11.99, 20.24, 21.73, 36.11, 36.70, 53.37, 63.44, 118.57, 120.14, 125.03, 128.51, 129.67, 132.60, 140.96, 143.74, 145.16, 148.27; MS m/e 387 (3, M+), 358 (100), 232 (49), 91 (15), 155 (13).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[C:24]([CH3:33])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:22]3[CH2:21][CH2:20][CH2:25][C:24]([CH3:33])([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: CC1(c2ccccc2)CCCC(Br)C1=O
Product: COc1cc(Nc2nc3c(s2)CCCC3(C)c2ccccc2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (0.45 g, 1.72 mmol) and 6-bromo-2-methyl-2-phenyl-cyclohexanone (0.69 g, 2.6 mmol) using in analogous manner the procedure described in example 1b). Obtained as an off-white solid (0.29 g, 39%). MS ISP (m/e): 431.4 [(M+H)+]. mp 123-126° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][NH:10]1.F[C:21](F)(F)S(OC)(=O)=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]1[CH3:21]
Reactant: CCOC(=O)c1c[nH]n(-c2ccc(F)cc2F)c1=O
Reactant: COS(=O)(=O)C(F)(F)F
Product: CCOC(=O)c1cn(C)n(-c2ccc(F)cc2F)c1=O
Yield: 65 %

Procedure:
In the same manner as in Reference Example 64 and using ethyl 2-(2,4-difluorophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (3.6 g, 13 mmol) and methyl trifluoromethanesulfonate (3 mL) as starting materials, the title compound (2.4 g, 65%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1(CC(N)=O)[C:14](=O)[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=[C:4]2[CH2:3]1.[OH-].[Na+].CC1([NH2:32])CC2C(=CC=CC=2)C1>C(O)(=O)C.OS(O)(=O)=O.[Pd]>[CH3:1][C:2]1([NH2:32])[CH2:14][C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=[C:4]2[CH2:3]1
Reactant: CC1(N)Cc2ccccc2C1
Reactant: CC1(CC(N)=O)Cc2cc3c(cc2C1=O)CCCC3
Agent: [Pd]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(N)Cc2cc3c(cc2C1)CCCC3

Procedure:
A 4:1 mixture of geometrical isomers, containing predominantly 2,2,2-trifluoro-.N.-(2-methyl-1-oxo-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-yl)-acetamide, is hydrogenated over Pd/C in acetic acid/H2SO4 and the products are saponified with NaOH according to the procedures described for the preparation of 2-methyl-indan-2-ylamine. The resulting product mixture is recrystallised repeatedly from hexane to give the title compound, a single isomer.
Reaction SMILES: C1(B(O)O)C=CC=CC=1.[CH3:10][N:11]([CH3:35])[C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][C:15]([C:24]2[N:25]=[C:26](O)[C:27]3[CH:28]=[CH:29][CH:30]=[N:31][C:32]=3[CH:33]=2)=[CH:14][CH:13]=1.[NH2:36][CH2:37][CH2:38][CH2:39][NH2:40]>>[NH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:26]1[N:25]=[C:24]([C:15]2[CH:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]([N:11]([CH3:35])[CH3:10])=[CH:13][CH:14]=2)[CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][CH:30]=[N:31]2
Reactant: NCCCN
Reactant: CN(C)c1ccc(-c2cc3ncccc3c(O)n2)cc1-c1ccccc1
Agent: OB(O)c1ccccc1
Product: CN(C)c1ccc(-c2cc3ncccc3c(NCCCN)n2)cc1-c1ccccc1

Procedure:
Treatment of the above intermediate with 2-methylnicotinic acid according to Method A (Example 1) provided the corresponding [1,6]napthyridin-5-ol. Treatment of this with phenylboronic acid using the procedure described in Example 5 provided 7-(6-dimethylamino-biphenyl-3-yl)-[1,6]naphthyridin-5-ol. Conversion to the 5-chloro intermediate using Method B, followed by treatment of this with 1,3-diaminopropane by the procedure described in Method C (Example 3) provided the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.82 (dd, 1H), 8.16 (d, 1H), 8.04 (dd, 1H), 8.00 (d, 1H), 7.63 (dd, 2H), 7.52 (s, 1H), 7.41 (t, 2H), 7.29 (t, 1H), 7.19 (dd, 1H), 7.08 (d, 1H), 3.84 (t, 2H), 3.00 (t, 2H), 2.58 (s, 6H), 1.99 (t, 1H), MS (m/e) calculated for C25H27N5 397, found 398.3 (M+H).
Reaction SMILES: [PH4+].[C:2]([OH:5])(=O)[CH3:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:2]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:5])[CH3:3]
Reactant: Nc1ccccc1
Reactant: CC(=O)O
Agent: [PH4+]
Product: CC(=O)Nc1ccccc1
Yield: 90 %

Procedure:
To the same reaction mixture containing the phosphonium salt as in Example 1 was added a mixture of 3.0 g. (0.05 mole) of acetic acid and 5.2 g. (0.056 mole) of aniline, and the resulting mixture was reacted under reflux for 2 hours. Thereafter, the same aftertreatment as in Example 1 was effected to obtain acetanilide, yield 90% based on acetic acid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@@H:5]1[NH:28][C:26](=[O:27])[C@@H:25]([CH:29]([CH3:31])[CH3:30])[O:24][C:22](=[O:23])[C@H:21]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:20]([CH3:39])[C:18](=[O:19])[C@@H:17]([CH:40]([CH3:42])[CH3:41])[O:16][C:14](=[O:15])[C@H:13]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:12]([CH3:50])[C:10](=[O:11])[C@@H:9]([CH:51]([CH3:53])[CH3:52])[O:8][C:6]1=[O:7])[CH3:3].[C:54]1(CN)[C:55]([CH2:60][NH2:61])=[CH:56][CH:57]=[CH:58][CH:59]=1>C(Cl)Cl>[CH3:3][CH:2]([CH2:4][C@@H:5]1[NH:28][C:26](=[O:27])[C@@H:25]([CH:29]([CH3:30])[CH3:31])[O:24][C:22](=[O:23])[C@H:21]([CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:20]([CH3:39])[C:18](=[O:19])[C@@H:17]([CH:40]([CH3:41])[CH3:42])[O:16][C:14](=[O:15])[C@H:13]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:12]([CH3:50])[C:10](=[O:11])[C@@H:9]([CH:51]([CH3:53])[CH3:52])[O:8][C:6]1=[O:7])[CH3:1].[CH:59]1[CH:54]=[C:55]([CH2:60][NH2:61])[CH:56]=[C:57]([CH2:10][NH2:12])[CH:58]=1
Reactant: NCc1ccccc1CN
Agent: CC(C)C[C@@H]1NC(=O)[C@@H](C(C)C)OC(=O)[C@H](Cc2ccccc2)N(C)C(=O)[C@@H](C(C)C)OC(=O)[C@H](Cc2ccccc2)N(C)C(=O)[C@@H](C(C)C)OC1=O
Solvent: ClCCl
Product: NCc1cccc(CN)c1

Procedure:
By using 1-phenyl-1,2,3,4-tetrahydroquinoline-6-carboxyaldehyde-1',1'-diphenylhydrazone (C-2) as a charge-transfer substance, (PC-1) as a binder resin material and xylylenediamine (MXDA) as a crosslinking agent, a solution of (C-2):(PC-1):MXDA:methylene chloride=1:1:0.2:8 (weight ratio) was produced to use it as a coating fluid. On standing for one month, the coating fluid did not whiten nor set to gel.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([CH:24]([CH3:26])[CH3:25])=[N:16][CH:15]([NH:27]C(OCC3C=CC=CC=3)=O)[C:14]1=[O:38])=[O:11])[CH2:2]2.C([O-])=O>CO.[Pd]>[NH2:27][CH:15]1[N:16]=[C:17]([CH:24]([CH3:25])[CH3:26])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:13]([CH2:12][C:10]([N:3]2[CH2:2][CH:1]3[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]3)[CH2:4]2)=[O:11])[C:14]1=[O:38]
Reactant: CC(C)C1=NC(NC(=O)OCc2ccccc2)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Product: CC(C)C1=NC(N)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2ccccc21
Reaction time: 4 h
Yield: 73.4 %

Procedure:
Pd—C (5 wt %, 0.10 g) was added to a suspension of (3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (0.718 g) in methanol (20 ml) and then anmonium formate (0.351 g) at room temperature. The mixture was stirred at the same condition for 4 hours and filtered on Celite® to remove the catalyst. The filtrate was concentrated in vacuo and the residue was taken up with ethyl acetate (100 ml) and a saturated aqueous sodium hydrogen carbonate (50 ml). The organic layer was washed with a brine (50 ml) and dried over anhydrous sodium sulfate. Filtration and evaporation gave (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (0.39 g) which was used in a following reaction step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH2:37].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:37][CH2:36][C:35]5[CH:38]=[CH:39][CH:40]=[C:33]([Cl:32])[CH:34]=5)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4cccc(Br)n4)cnc23)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4cccc(NCc5cccc(Cl)c5)n4)cnc23)CC1
Temperature: 110 °C

Procedure:
A mixture of {4-[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 40 supra) (0.487 g, 1.0 mmol), 3-chloro-benzylamine (0.283 g, 2.0 mmol), Pd2(dba)3 (60 mg), Davephos (80 mg), NaOtBu (200 mg, 0.2 mmol) in dioxane (25 mL) in a sealed tube was bubbled with N2 for several minutes and then heated under N2 at 110° C. for 15 hours. The solution was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The obtained crude product was purified by preparative-HPLC to give (4-{3-[6-(3-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 430 mg). LC-MS: [M+H]+ 548.
Reaction SMILES: [OH-].[CH2:2]([N+:4]([CH2:9][CH3:10])([CH2:7][CH3:8])[CH2:5][CH3:6])[CH3:3].C([O:13][Si:14]([O:21]CC)([O:18]CC)[O:15]CC)C>O>[Si:14]([O-:21])([O-:18])([O-:15])[O-:13].[CH2:2]([N+:4]([CH2:9][CH3:10])([CH2:7][CH3:8])[CH2:5][CH3:6])[CH3:3].[CH2:2]([N+:4]([CH2:9][CH3:10])([CH2:7][CH3:8])[CH2:5][CH3:6])[CH3:3].[CH2:2]([N+:4]([CH2:9][CH3:10])([CH2:7][CH3:8])[CH2:5][CH3:6])[CH3:3].[CH2:2]([N+:4]([CH2:9][CH3:10])([CH2:7][CH3:8])[CH2:5][CH3:6])[CH3:3]
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: CC[N+](CC)(CC)CC
Agent: [OH-]
Solvent: O
Product: [O-][Si]([O-])([O-])[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
About 412 g (400 ml) of 40 percent aqueous tetraethylammonium hydroxide solution (Fluka, D-710 Neu-Ulm) were diluted with 200 ml of water, and then 225 g (240.6 ml= 1.08 mol of Si) of tetraethoxysilane were slowly added. The mixture was then stirred at room temperature for 24 hours. It was then concentrated by distillation to 45.2 percent of the original weight and the solution was crystallized at 4° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:8][C:7]2=[O:18])(=[O:3])[CH3:2].[CH3:19][Mg]Br>O1CCCC1.C(OCC)C>[CH2:14]([C:9]1[NH:10][C:11]2[C:6]([C:7](=[O:18])[N:8]=1)=[CH:5][C:4]([C:1]([OH:3])([CH3:19])[CH3:2])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(C)(C)O)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.00 g 6-acetyl-2-butyl-4-(1H)-quinazolinone in 250 ml of dry tetrahydrofuran, cooled to 0° C., is added dropwise 16.4 ml of 3.0M methylmagnesium bromide in diethyl ether. The reaction is stirred at 0° C. for 0.5 hours and then allowed to warm to room temperature followed by quenching with 100 ml of saturated ammonium chloride solution. The mixture is diluted with 50 ml of water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 100:0.25 chloroform-methanol to give 2.75 g of the desired product as a white solid. CI MASS SPEC 261(MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]([CH2:23][CH3:24])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[CH:13]=3)=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1.C(OCC)(=O)C>[C:19]([C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=2)[N:11]([CH2:23][CH3:24])[C:10]=1[C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:3][CH:4]=1)#[N:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCn1c(C#Cc2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCn1c(C#Cc2ccc(NS(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (50 mg, 0.16 mmol), prepared as described by the method of Example 1H, is dissolved in pyridine (550 μL) at room temperature. Methanesulfonyl chloride (17 μL, 0.21 mmol) is added dropwise. This is stirred overnight at room temperature. The reaction mixture is then diluted in ethyl acetate and is washed with aqueous HCl, followed by brine. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2/EtOAc) yields N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-methanesulfonamide (58 mg, 92%) as an off-white solid.
Reaction SMILES: O1CCCC1.Cl.[C:7]([C:9]1([O:16][Si](C)(C)C)[CH2:14][CH:13]2[CH2:15][CH:10]1[CH2:11][CH2:12]2)#[N:8].C(=O)([O-])O.[K+]>O>[C:7]([C:9]1([OH:16])[CH2:14][CH:13]2[CH2:15][CH:10]1[CH2:11][CH2:12]2)#[N:8]
Reactant: C[Si](C)(C)OC1(C#N)CC2CCC1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1(O)CC2CCC1C2
Temperature: 25 °C

Procedure:
Into a 200 milliliter Erlenmeyer flask, 38.37 grams (183.3 millimoles) of 2-cyano-2-trimethylsiloxynorbornane obtained in A, a PTFE-coated stirrer bar, 30 milliliters of tetrahydrofuran, 10 milliliters of water, and 1 milliliter of 2N hydrochloric acid were placed. This mixture was vigorously stirred at room temperature. Three hours later, the disappearance of the starting norbornane compound was confirmed by thin-layer chromatography, and 1 milliliter of 2N aqueous potassium hydrogencarbonate solution was then added to the reaction mixture and the mixture was vigorously stirred for 5 minutes. The reaction mixture was poured into water and extracted three times with diethyl ether, and the extracts were combined, washed with brine, and dried with anhydrous sodium sulfate. The sodium sulfate was then filtered out. The solvent was subsequently removed in vacuo to thereby yield a crude product. Distillation of the crude product under reduced pressure gave 2-cyano-2-hydroxynorbornane (exo/endo mixture) as a colorless, clear liquid having a boiling point of 85.5°-86.0° C. (0.35 mmHg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](Cl)=[C:7]([S:10]([CH3:13])(=[O:12])=[O:11])[S:6](=[O:15])(=[O:14])[N:5]=1)[CH3:2].C[Si]([NH:20][Si](C)(C)C)(C)C.CO>C(#N)C>[CH2:1]([O:3][C:4]1[C:8]([NH2:20])=[C:7]([S:10]([CH3:13])(=[O:12])=[O:11])[S:6](=[O:15])(=[O:14])[N:5]=1)[CH3:2]
Reactant: CCOC1=NS(=O)(=O)C(S(C)(=O)=O)=C1Cl
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CO
Solvent: CC#N
Product: CCOC1=NS(=O)(=O)C(S(C)(=O)=O)=C1N
Temperature: 25 °C
Yield: 79.6 %

Procedure:
To a solution of 3-ethoxy-4-chloro-5-methylsulfonylisothiazole-1,1-dioxide (1.1 g, 4.0 mmol) in acetonitrile (15 ml) under a nitrogen atmosphere was added hexamethyldisilizane (0.85 ml, 4.0 mmol). After an immediate exothermic reaction, the solution was heated at gentle reflux for 1 hour. Upon cooling to room temperature, methanol (1.0 ml) was added and any solid removed by filtration. The organic solution was evaporated and the solid residue triturated with ethyl acetate/methanol to give crystalline title compound (0.81 g), mp 214°-217°.