Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:22]([O:23][CH3:24])=[N:21][C:20]([O:25][CH3:26])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[H-].[Na+]>CN(C=O)C.O>[CH2:27]([N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[C:13]1[C:22]([O:23][CH3:24])=[N:21][C:20]([O:25][CH3:26])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1cc(OC)nc(OC)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)nc(OC)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
The product of Example 30 (0.444 g, 1.16 mmol) was dissolved in DMF (4 mL) and cooled to 0° C. Benzyl bromide (0.186 mL, 1.6 mmol) followed by NaH (56 mg, 1.39 mmol, 60% dispersion in mineral oil) were added and the reaction was allowed to warm to room temperature. After 1 h, the reaction was diluted with water and extracted 4× Et2O. The organics were combined, washed with brine, dried over MgSO4, concentrated in vacuo to provide 0.545 g (100%) of pure methyl 3-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-2,6-dimethoxy-isonicotinate as an oil. Electrospray Mass Spec: 472.9 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][S:10]/[C:9]/2=[N:13]\[H])=[CH:4][CH:3]=1.[C:15](N1C=CN=C1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16]>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][S:10]/[C:9]/2=[N:13]\[C:15]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[O:16])=[CH:4][CH:3]=1
Reactant: [H]/N=C1\SCCN1c1ccc(Cl)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(/N=C1\SCCN1c1ccc(Cl)cc1)n1ccnc1

Procedure:
(2Z)-3-(4-Chlorophenyl)-1,3-thiazolidin-2-imine (233 mg, 1.095 mmol, Example 24A) and carbonyldiimidazole (195 mg, 1.205 mmol) in dry tetrahydrofuran were heated at 65° C. After 14 hours the reaction mixture cooled down, diluted with 75 mL of dichloromethane, and washed successively with sodium bicarbonate (50 mL) water and brine (50 mL), dried over magnesium sulfate and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])[CH2:17][CH2:18]2)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(Nc1ccc(CC2CCNCC2)cc1)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CC2CCN(S(=O)(=O)c3ccccc3)CC2)cc1)C(F)(F)F
Reaction time: 2 h
Yield: 57.6 %

Procedure:
A mixture of 2,2,2-trifluoro-N-[4-(piperidin-4-ylmethyl)-phenyl]acetamide (0.5 g, 1.75 mmol) and triethylamine (0.23 g, 2.1 mmol) in dichloromethane (10 mL) was cooled in an ice bath under nitrogen atmosphere. A solution of benzenesulfonyl chloride (0.37 g, 2.1 mmoL) in dichloromethane (1 mL) was added under to the mixture while stirring. After 2 hours, the reaction mixture was quenched with water. The separated organic layer was washed with cold water and brine, dried, and solvents removed in vacuo. The residue was crystallized from ethyl acetate/hexanes to give 2,2,2-trifluoro-N-[4-(1-benzenesulfonyl-piperidin-4-ylmethyl)-phenyl]acetamide (0.43 g, 57%), m.p. 194–195° C.; Analysis for C20H21N2O3SF3: Calc.: C, 56.32; H, 4.96; N, 6.57; Found: C, 56.54; H, 4.99; N, 6.68.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][S:34]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)(=[O:36])=[O:35])[C:28]=2[F:42])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[C:28]([F:42])=[C:29]([NH:33][S:34]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)(=[O:35])=[O:36])[CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(N)n3)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(N)n3)s2)CCNCC1
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl 4-(5-(2-amino-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-4-methyl-1-piperidinecarboxylate (64 mg, 0.104 mmol) in dichloromethane (DCM) (2 mL) was added TFA (500 μl, 6.49 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to the title compound (37 mg). MS (ESI): 515.2 [M+1]+.
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[NH:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>O>[NH2:1][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: NOS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1nccn1N
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 6.6 %

Procedure:
To a stirred solution of hydroxylamine-o-sulfonic acid (26.64 g, 235.8 mmol, 3.0 eq) in H2O (17 mL) at 0° C., ethyl 1H-imidazole-2-carboxylate (11.0 g, 78.6 mmol, 1.0 eq) was added and the resulting mixture was stirred at 90° C. for 30 min. The mixture was cooled to RT and K2CO3 (3.6 g, 26.2 mmol, 1.0 eq) was added in portions. The resulting mixture was stirred at RT overnight, filtered and rinsed with H2O (10 mL×3). The filtrate was extracted with ethyl acetate (50 mL×5). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (1% MeOH in DCM) to afford ethyl 1-amino-1H-imidazole-2-carboxylate (800 mg, 6.5% yield). ESI-MS m/z: 156.1 [M+H]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[S:14](Cl)([CH3:17])(=[O:16])=[O:15]>C(Cl)Cl>[CH3:17][S:14]([O:6][C@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:16])=[O:15]
Reactant: OC1CCOC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
A solution of tetrahydrofuran-3-ol (25.0 g, 283 mmol) in 150 ml of DCM was cooled to 0° C., to this was added triethylamine (59 ml, 425 mmol) and mesylchloride (26.0 ml, 340 mmol), stirred the reaction mixture for 4 h at room temperature. TLC indicated reaction completion, it was diluted with DCM (100 ml), washed with water and brine solution, dried over anhydrous sodium sulfate, organic layer was evaporated to yields (44.0 g) of title product which was used as such for the next step.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.O.[CH3:13][N:14]1CCCC1=O>>[NH:9]1[CH2:8][CH2:7][O:6][C:5]2[N:10]=[CH:11][C:2]([C:13]#[N:14])=[CH:3][C:4]1=2
Reactant: Brc1cnc2c(c1)NCCO2
Reactant: CN1CCCC1=O
Solvent: O
Product: N#Cc1cnc2c(c1)NCCO2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a 5 ml flask, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (24 mg, 0.111 mmol) was dissolved in N-methylpyrrolidone (NMP) (20.3 ml), and cuprous cyanide (CuCN) (16 mg, 0.178 mmol) was added thereto and then stirred in microwave at 180□ for 10 minutes using microwave (100 W) apparatus. The reaction mixture was cooled to room temperature and water (10 ml) was added thereto, and extracted with ethyl acetate (10 ml*2). The combined organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=20:1. The fractions containing the product were collected and evaporated to obtain pale-yellow solid (17 mg, quantitative yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:21][OH:22])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[CH3:30][S:31](O)(=[O:33])=[O:32].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[CH2:21][OH:22])[C:3]([CH2:2][NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Reactant: CS(=O)(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
A round bottom flask was charged with (R)-2-(3-(aminomethyl)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Example 8; 0.20 g, 0.50 mmol), methanesulfonic acid loaded TFP resin (0.9 mmol/g loading, 0.50 mmol), DIEA (0.13 g, 1.00 mmol), DMAP (0.067 g, 0.067 mmol), and THF (10 ml). The resulting solution was shaken vigorously at 60° C. for 8 hrs. The reaction was filtered and the resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.075 g, 31%). 1H NMR (400 MHz, CD3OD) δ 7.50-7.41 (m, 2H), 7.15 (d, J=9.1 Hz, 1H), 7.04-7.00 (m, 2H), 6.09 (br s, 1H), 5.22-5.03 (m, 1H), 4.20-4.07 (m, 2H), 3.86-3.74 (m, 2H), 2.98 (s, 3H), 1.89-1.85 (m, 1H), 1.04-0.92 (m, 2H), 0.78-0.66 (m, 2H). MS: Calcd.: 478. Found: [M+H]+ 479.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[CH3:18][O:19][C:20]1[CH:27]=[C:26]([CH2:28][CH:29]=O)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23].C([BH3-])#N.[Na+]>CO>[C:22]([C:21]1[CH:24]=[CH:25][C:26]([CH2:28][CH2:29][N:8]2[CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4][CH:3]2[C:2]([F:1])([F:16])[F:17])=[CH:27][C:20]=1[O:19][CH3:18])#[N:23]
Reactant: COc1cc(CC=O)ccc1C#N
Reactant: CC(C)(C)OC(=O)N1CCNC(C(F)(F)F)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCN2CCN(C(=O)OC(C)(C)C)CC2C(F)(F)F)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate (72 mg, 0.28 mmol) and 2-methoxy-4-(2-oxoethyl)benzonitrile (50 mg, 0.28 mmol) in methanol (2.5 mL) at 0° C. was added sodium cyanoborohydride (25 mg, 0.40 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by column chromatography (4->30% ethyl acetate:hexanes) to provide tert-butyl 4-[2-(4-cyano-3-methoxyphenyl)ethyl]-3-(trifluoromethyl)piperazine-1-carboxylate. LC-MS (IE, m/z): 414.4 [M+1]+.
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[C:21](=[O:25])[CH2:22][CH2:23][CH3:24]>CCO>[CH2:23]([CH:22]([C:21](=[O:25])[C:14]1[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[CH3:12])[C:3](=[O:5])[C:2]([O:9][CH2:10][CH3:11])=[O:8])[CH3:24]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCC(=O)c1c(C)cc(C)cc1C
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)C(CC)C(=O)c1c(C)cc(C)cc1C
Temperature: 50 °C
Yield: 53.2 %

Procedure:
Sodium (1.0 g, 42.1 mmol, spheres ) was cautiously added to 25 mL of absolute EtOH with stirring. After the sodium had dissolved, diethyl oxalate (6.0 g, 42.1 mmol) was added dropwise to the resulting solution at 0° C., followed by addition of a solution of 2',4',6'-trimethylbutyrophenone (8 g, 42.1 mmol) in 5 mL of absolute EtOH. The reaction mixture was slowly warmed to 50° C. and stirred overnight. The solvent was then evaporated. The resulting residue was washed with hexane, diluted with water, acidified with 1 N HCl, and then extracted with ether. The extracts were washed with brine, dried over Na2SO4 and concentrated to give 6.5 g of an oil which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13](=O)[C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[Zn][CH2:18][Zn]C[Zn]Br.C1OCCC1>O1CCCC1>[CH2:1]([N:8]1[CH2:14][C:13](=[CH2:18])[C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(Cc2ccccc2)CC12CC2
Reactant: Br[Zn]C[Zn]C[Zn]Br
Solvent: C1CCOC1
Product: C=C1CN(Cc2ccccc2)CC12CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5-benzyl-5-azaspiro[2.4]heptan-7-one (300 mg) was dissolved into anhydrous tetrahydrofuran (10 ml) and Nysted reagent (1.5 eq, 20% solution) was added to the reaction. The reaction was stirred at RT for two days and quenched with NH4Cl solution and extracted with EtOAc followed by washing with water, then brine and dried over Na2SO4 and purified with silica gel column to give the titled compound. Mass: (M+1), 200
Reaction SMILES: CC(C)(C)C(N[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[C:14]([N:16](C(C)C)C(C)C)=O)=O.Cl.C[OH:31]>>[C:10]1(=[O:31])[C:11]2[C:6](=[N:16][CH:14]=[C:13]3[C:12]=2[CH:26]=[CH:25][CH:24]=[CH:23]3)[CH:7]=[N:8][CH2:9]1
Reactant: CC(C)N(C(=O)c1ccccc1-c1ccncc1NC(=O)C(C)(C)C)C(C)C
Reactant: CO
Agent: Cl
Product: O=C1CN=Cc2ncc3ccccc3c21
Reaction time: 24 h

Procedure:
All of 2-[3-(2,2-dimethyl-propionylamino)-pyridin-4-yl]-N,N-diisopropylbenzamide from the previous step was carried on and dissolved in methanol (20 mL). Concentrated HCl (1 mL) was added, followed by 24 h of refluxing. A white solid which precipitated out of solution was filtered and dissolved in H2O. After 15 minutes of stirring, the free base crashed out of solution. The solid was filtered and dried, providing 150 mg (33% for two steps) of the desired final product as a white solid. Mp=303-309° C.; 1H NMR (DMSO-d6, 300 MHz) δ 8.70 (s, 1H), 8.60 (d, 1H), 8.41 (t, 2H), 8.31 (d, 1H), 7.95 (t, 1H), 7.80 (t, 1H); C12H8N2O.(0.3 H2O).(0.2 ClH). Anal: Calcd for: C, 68.99; H, 4.25; N, 13,41. Found: C, 68.83; H, 3.99; N, 13.26.
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[K+].[C:27](Cl)(Cl)=[S:28]>C(Cl)(Cl)Cl>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:27]=[S:28])[C:14]([N:15]3[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: S=C(Cl)Cl
Reactant: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2N)CC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Reaction time: 2 h

Procedure:
To a cooled mixture of 2.1 g of 6-amino-2-tert-butyl-5-(4-methylpiperidin-1-yl)benzothiazole and 2.8 g of potassium bicarbonate in 20 ml of chloroform is added dropwise 1.6 g of thiophosgene in 5 ml of chloroform under stirring. The stirring is continued for 2 hours maintaining the temperature at 0°-2° . The solid is filtered and the filtrate is evaporated. The solid thus obtained is dissolved in chloroform and filtered through a silica gel column. The filtrate is evaporated to give 2-tert-butyl-6-isothiocyanato-5-(4-methylpiperidin-1-yl)benzothiazole, melting at 54°-58°.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].F[C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[N:22][C:23]([NH2:27])=[N:24]2)=[CH:19][CH:18]=1>CN(C)C=O>[NH2:27][C:23]1[N:22]=[CH:21][C:20]2[C:25](=[CH:26][C:17]([N:4]3[C:5]4[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=4[C:2]([CH3:1])=[CH:3]3)=[CH:18][CH:19]=2)[N:24]=1
Reactant: Nc1ncc2ccc(F)cc2n1
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc3cnc(N)nc3c2)c2c1C(=O)CC(C)(C)C2
Yield: 81.4 %

Procedure:
3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.65 g, 3.68 mmol), sodium hydride (60% in oil, 0.177 g, 4.4 mmol), 7-fluoroquinazolin-2-amine (0.60 g, 3.68 mmol), and N,N-dimethylformamide are sealed in a microwave vessel and irradiated at 150 degrees Celsius for 1500 seconds. The mixture is purified by column chromatography and recrystallized from dichloromethane/hexane, affording 0.96 g of 1-(2-Amino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (81%). LC/MS m/z=321 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[C:32]([CH3:31])[CH:33]=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)c1
Yield: 45 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 3-methylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (45%).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][C:5]1[N:9]=[C:8]([CH2:10][C:11]([OH:13])=[O:12])[O:7][N:6]=1>C(OCC)C.O>[CH3:4][C:5]1[N:9]=[C:8]([CH2:10][C:11]([O:13][CH3:3])=[O:12])[O:7][N:6]=1
Reactant: C=[N+]=[N-]
Reactant: Cc1noc(CC(=O)O)n1
Solvent: O
Solvent: CCOCC
Product: COC(=O)Cc1nc(C)no1

Procedure:
A solution of an excess of diazomethane in diethyl ether was added to a stirred, cold (about 2° C.) solution of 14 g of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid in 500 ml of diethyl ether. After the initially vigorous evolution of nitrogen was finished, the solution was concentrated on the steam bath to about 250 ml. The solution was washed three times with 100 ml of water and the wash waters were combined, adjusted to a pH of 9.0 and were extracted with diethyl ether to obtain the part of the product which dissolved in water during the washings. The combined ethereal extracts were filtered through a water repelling paper filter and then were evaporated in vacuo. After keeping the residue for 1 hour at 8 mm the residual oil weighed 14.8 g. The yellow oil was distilled at 0.4-0.5 mm and the collected fraction with a boiling point 70°-71° C. to obtain 12.3 g of methyl 3-methyl-1,2,4-oxadiazol-5-yl-acetate with a refractive index nD25 =1.4472.
Reaction SMILES: C([N:4](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:34][C:35]([C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][C:38]=1NCC1CC1)=[O:36]>CN(C)C=O.CO>[C:37]1([C:35]([NH2:34])=[O:36])[CH:45]=[CH:44][C:40]([C:41]([NH2:4])=[O:42])=[CH:39][CH:38]=1
Reactant: NC(=O)c1ccc(C(=O)O)cc1NCC1CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N,N-Diisopropylethylamine (101 uL, 0.66 mmol) was added to a mixture of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (53 mg, 0.14 mmol), and 4-(aminocarbonyl)-3-[(cyclopropylmethyl)amino]-benzoic acid (synthesized according to reagent preparation 39) (31 mg, 0.13 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 1-[6-(3-endo-amino-8-azabicyclo[3.2.1]oct-8-yl)pyridin-3-yl]-3-(1-methylpiperidin-4-yl)propan-1-one hydrochloride salt (51 mg, 0.13 mmol) in N,N-dimethylformamide (0.5 mL) was added and stirring was continued for 18 hours. The reaction mixture was diluted with methanol (1.5 mL), and purified by preparatory reverse phase HPLC (ammonium acetate buffered aqueous acetonitrile eluent) to give 2-[(cyclopropylmethyl)amino]-N4-(8-{5-[3-(1-methylpiperidin-4-yl)propanoyl]pyridin-2-yl}-8-azabicyclo[3.2.1]oct-3-endo-yl)benzene-1,4-dicarboxamide as the acetate salt, (54 mg, 66% yield). 1H NMR (400 MHz, d4-Methanol): 8.65 (d, 1H), 7.97 (dd, 1H), 7.54 (d, 1H), 6.96 (d, 1H), 6.82 (dd, 1H), 6.67 (d, 1H), 4.57, (Br, 2H), 3.89 (tr, 1H), 3.04 (m, 2H), 2.95 (d, 2H), 2.87 (tr, 2H), 2.44 (s, 3H), 2.37 (tr, 2H), 2.21-2.01 (m, 6H), 1.91 (br, 1H), 1.88 (br, 1H), 1.80 (s, 3H), 1.78 (m, 1H), 1.58 (q, 4H), 1.38 (br, 1H), 1.22 (m, 2H), 1.02 (m, 1H), 0.47 (m, 2H), 0.20 (m, 2H); MS (EI) for C33H44N6O3: 573 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:10])[NH2:9])=[CH:4][CH:3]=1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:10]=1
Reactant: N=C(N)c1ccc(F)cc1
Reactant: SC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(-c2nsc(Cl)n2)cc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
To a solution of 4-fluorobenzenecarboximidamide (1.38 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1.5 hours. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.82 g (84.7%) of the desired product as a solid.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[C:8]4[S:16][CH2:15][CH2:14][N:9]43)=[CH:4][C:3]=2[O:2]1.C(=O)([O-])[O-].[K+].[K+].[C:27]([O:33][CH2:34]Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:20])[C:7]([C:17]([O:19][CH2:34][O:33][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:18])=[C:8]4[S:16][CH2:15][CH2:14][N:9]43)=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)c1c2n(c3cc4c(cc3c1=O)OCO4)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)C(=O)OCOC(=O)c1c2n(c3cc4c(cc3c1=O)OCO4)CCS2
Temperature: 100 °C
Reaction time: 6 h
Yield: 71.8 %

Procedure:
7,8-Methylenedioxy-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)-quinoline-4-carboxylic acid (200 mg, 0.687 mmol) was dissolved in 5 ml of dimethyl formaide, then 152 mg of anhydrous potassium carbonate (1.1 mmol) and 328 mg (2.18 mmol) of pivaloyloxymethyl chloride were added thereto, the mixture was heated with stirring at 100° C. for six hours, the content was concentrated under reduced pressure, water was added to the residue, then insoluble matter was collected by filtration, washed with water, air dried and recrystallized from a mixture of chloroform and ether to give 200 mg of the title compound (71.9 percent yield). Melting point 229.0° to 229.5° C. Elementary analysis calculated as C19H19NO7S.1/4 H2O: C 55.67, H 4.79, N 3.42; Found: C 55.65, H 4.59, N 3.49.