Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4][C:5]1[CH:14]=[CH:13][C:12](Cl)=[C:11]2[C:6]=1[CH:7]=[C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)[N:9]=[CH:10]2.[CH3:34][O:35]C1C=C2C(C=C(OS(C(F)(F)F)(=O)=O)N=C2)=CC=1>>[ClH:4].[ClH:1].[ClH:4].[CH3:34][O:35][C:13]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:16]3[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]4[CH:23]=[N:24][N:25]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:26]=4)[CH:21]=3)[N:9]=[CH:10]2)=[CH:5][CH:14]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Reactant: COc1ccc2cc(OS(=O)(=O)C(F)(F)F)ncc2c1
Agent: Cl
Product: COc1ccc2cc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)ncc2c1

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 7-methoxyisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester. This afforded the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.32-2.44 (m, 4H), 3.23-3.31 (m, 2H), 3.58-3.67 (m, 2H), 4.08 (s, 3H), 4.61-4.72 (m, 1H), 7.67-7.74 (m, 2H), 8.08 (s, 1H), 8.16 (d, J=8.8 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.40 (s, 1H), 8.65 (s, 1H), 8.79 (d, J=2.0 Hz, 1H), 9.51 (s, 1H). MS (ES+): m/z=401.14 [MH+]. HPLC: tR=1.88 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].[CH2:20]([O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35]O)=[CH:31][CH:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:20]([O:27][C:28](=[O:37])[C:29]1[CH:30]=[CH:31][C:32]([CH2:35][N:8]2[CH2:9][C:10](=[O:11])[N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[S:7]2(=[O:13])=[O:12])=[CH:33][CH:34]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Reactant: O=C(OCc1ccccc1)c1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)OCc4ccccc4)cc3)S2(=O)=O)c(OC)c1
Temperature: 0 °C

Procedure:
To a solution of the title B compound in Example 9, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2.0 g, 7.0 mmol) and 4-hydroxymethyl-benzoic acid benzyl ester (2.54 g, 10.5 mmol) in THF (50 mL) is added triphenylphosphine (3.67 g, 14 mmol) and the mixture is stirred until dissolved. The reaction is cooled to 0° C. and diethyl azodicarboxylate (2.20 mL, 14 mmol) dissolved in THF (20 mL) is added dropwise. The reaction is stirred for 16 h, while allowing to warm to RT, then concentrated. The residue is taken up in CH2Cl2, and chromatographed in two portions on a 110 g silica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 0:100 (EtOAc:hexane) to 5:95 over 10 min. Fractions containing product are combined and concentrated to yield 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid benzyl ester as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([S:8][CH3:9])=[N:4]1.[C:10]([OH:13])(=S)C.[C:14]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:10][O:13][C@:3]1([CH2:2][O:1][CH3:14])[CH2:7][S:6][C:5]([S:8][CH3:9])=[N:4]1
Reactant: CSC1=N[C@H](CO)CS1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(O)=S
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: COC[C@@]1(OC)CSC(SC)=N1
Reaction time: 1 h
Yield: 65 %

Procedure:
There were added 119 mg of 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine (6) and two molar equivalents of thioacetic acid, while cooled with ice, to 10 ml of tetrahydrofuran solution containing two molar equivalents of triphenylphosphine and two molar equivalents of diethylazodicarboxylate, and the resultant solution was stirred for one hour at the same temperature, and for further one hour at a room temperature. The solvent of the reaction liquid was evaporated in a vacuum, and the obtained residue was subjected to silica gel column chromatography (eluent: chloroform-ethanol), and, thus, there was obtained 107 mg (yield: 65%) of 3-acetylthio-1-(1,3-thiazolin-2-yl)azetidine (7).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1(C)[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].[C:20]1(C)C=CC=CC=1>>[CH3:20][C:9]1[CH:10]=[CH:5][C:6]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]2[NH:14][N:3]=[N:2][N:1]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccccc1
Reactant: Cc1ccccc1-c1ccccc1C#N
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 100 °C
Reaction time: 44 h

Procedure:
A 20 ml flask is dried under argon and then charged with 7 ml of diisobutylaluminium fluoride (1 molar in hexane) followed by 5 ml of toluene and 455 mg of NaN3 (7 mmol). After stirring the suspension for 4 hours at room temperature 966 mg of solid ortho-tolylbenzonitrile (OTBN) is added at 0° C. in one portion. The suspension is warmed up to 130° C. (ext. temp.) with an internal temperature of 100° C. After 44 h at 130° C. (ext. temp.) the conversion is >93%. The reaction mixture was quenched in hydrochloric acid (6 molar). After addition of 10 ml of toluene the layers are separated, the organic layer is washed twice with 20 ml of water, dried over sodium sulfate and evaporated to give a crystalline residue of the product.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10].[NH2:15][C:16]1[N:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=1.CO.ClCCl.CCOCC>ClCCl>[C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O-:12])(=[O:11])=[O:10].[NH2:13][N+:17]1[C:18]([CH3:23])=[CH:19][C:20]([CH3:22])=[N:21][C:16]=1[NH2:15]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Cc1cc(C)nc(N)n1
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C)[n+](N)c(N)n1
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1

Procedure:
O-(Mesitylenesulfonyl)hydroxylamine containing ca. 18% water (3.03 g, 2.56 g dry wt., ca. 11.9 mmole) was dissolved in dichloromethane (15 mL) and dried over Na2SO4 and filtered. This was added dropwise to a solution of 2-amino-4,6-dimethylpyrimidine (1 g, 8.12 mmole) in 1:6 methanol-dichloromethane (10.5 mL) in an ice bath with stirring. Stirring was continued at 4 C overnight. Ether (20 mL) was added and the mixture was stirred at 4 C for 3 hr. The crude product was filtered out and dried (2.50 g). This was dissolved in a minimum amount of methanol, filtered and reduced in volume to 10 mL under reduced pressure. The solution was diluted with dichloromethane (15 mL) and then with ether (15 mL). After stirring at room temp. for 2 hr, the title compound was collected as crystal flakes and dried (2.26 g, mp 242–243 C).
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.Cl.[NH2:14][C:15]1[C:20]([C:21]([OH:23])=[O:22])=[C:19]([O:24][CH3:25])[C:18]([O:26][CH3:27])=[CH:17][CH:16]=1>O>[CH3:25][O:24][C:19]1[C:20]2[C:21](=[O:23])[O:22][C:1](=[O:2])[NH:14][C:15]=2[CH:16]=[CH:17][C:18]=1[O:26][CH3:27]
Reactant: COc1ccc(N)c(C(=O)O)c1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: O
Product: COc1ccc2[nH]c(=O)oc(=O)c2c1OC
Temperature: 25 °C
Yield: 125 %

Procedure:
Bis(trichloromethyl) carbonate (24.89 g, 84 mmol) was added into a solution of 6-amino-2,3-dimethoxybenzoic acid, Hydrochloride (28 g, 120 mmol) in Water (1.1 L). The mixture was stirred at r.t. over the weekend. The reaction mixture was filtered, the solid was collected and dried to afford 5,6-dimethoxy-1H-benzo[d][1,3]oxazine-2,4-dione (24 g, 105 mmol, 88% yield) as a light yellow solid. LCMS: (M+H)+: 223.9.
Reaction SMILES: N[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]2([CH3:24])[CH2:17][CH2:16][C:15]3[C:10](=[C:11]([CH3:23])[C:12]([CH3:22])=[C:13]([O:19][CH2:20][CH3:21])[C:14]=3[CH3:18])[O:9]2)=[CH:4][CH:3]=1.[ClH:27].N([O-])=O.[Na+].[C:32]([O:36][CH2:37][CH3:38])(=[O:35])[CH:33]=[CH2:34]>CC(C)=O>[Cl:27][CH:33]([CH2:34][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]2([CH3:24])[CH2:17][CH2:16][C:15]3[C:10](=[C:11]([CH3:23])[C:12]([CH3:22])=[C:13]([O:19][CH2:20][CH3:21])[C:14]=3[CH3:18])[O:9]2)=[CH:4][CH:3]=1)[C:32]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: Cl
Reactant: CCOc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(N)cc1)O2
Reactant: C=CC(=O)OCC
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(OCC)c(C)c(C)c3O2)cc1

Procedure:
The procedure described in Preparation 64 was repeated, except that 9.5 g of 2-(4-aminophenoxymethyl)-6-ethoxy-2,5,7,8-tetramethylchroman (prepared as described in Preparation 63), 10 ml of concentrated hydrochloric acid, 2.4 g of sodium nitrite, 26.8 g of ethyl acrylate, 0.4 g of cuprous oxide and 100 ml of acetone were used as the starting materials, to give the title compound.
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[NH:8][Si](C)(C)C.[C:15]([C:17]1[CH:37]=[CH:36][C:20]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1)#[N:16].Cl>C1COCC1>[C:15]([C:17]1[CH:37]=[CH:36][C:20]([C:21]([N:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:28]2)=[O:22])=[CH:19][CH:18]=1)(=[NH:8])[NH2:16]
Reactant: CCOC(=O)CCN1CCN(C(=O)c2ccc(C#N)cc2)CC1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CCN1CCN(C(=O)c2ccc(C(=N)N)cc2)CC1

Procedure:
A solution of Li--N(Si(CH3)3)2 in 20 ml of THF, freshly prepared from C4H9Li and 1.13 g of hexamethyldisilazane, is added dropwise at -78°, with stirring, to a solution of 3.15 g of ethyl 3-(4-(4-cyanobenzoyl)piperazin-1-yl)propionate (FAB 316; obtainable by reacting 4-cyanobenzoyl chloride with ethyl piperazin-1-ylpropionate) in 50 ml of THF. The mixture is left to warm up to 20°, with stirring, aqueous hydrochloric acid is added, the mixture is washed with ethyl acetate, sodium hydroxide solution is added to pH 7.5 and the mixture is worked up in conventional manner and evaporated to give ethyl 3-(4-(4-amidinobenzoyl)piperazin-1-yl)propionate, FAB 333.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:5][CH:4]=1.Br.C1(C)C=CC=CC=1>[Br-].C([P+](CCCC)(CCCC)CCCCCCCCCCCCCCCC)CCC.O>[CH2:9]([C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCc1ccc(OC)cc1
Agent: Br
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCc1ccc(O)cc1
Temperature: 135 °C
Reaction time: 5 h

Procedure:
The alkyl anisole of Example 1 (40 g) was transferred to a dry 3-neck 1-litre flask under nitrogen. To this was added tributylhexadecylphosphonium bromide (12.69 g) and HBr (48% aq., 71.4 ml). The resulting thick suspension was warmed to 135° C. and stirred for five hours. Toluene was added and the reaction was transferred to a separating funnel. The organic layer was shaken with water and then the aqueous extract shaken with fresh toluene. The organic extracts were combined and dried with MgSO4. The solvent was removed in vacuo to give the title compound as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O-:8])=[CH:4][CH:3]=1.[K+].Cl[CH2:11][C:12]([C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17]([OH:23])=[C:16]([CH:24]([CH3:26])[CH3:25])[CH:15]=1)=[O:13].Cl>CN(C)C=O>[OH:23][C:17]1[C:18]([CH:20]([CH3:22])[CH3:21])=[CH:19][C:14]([C:12](=[O:13])[CH2:11][O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:15][C:16]=1[CH:24]([CH3:26])[CH3:25]
Reactant: Cc1ccc([O-])cc1
Reactant: CC(C)c1cc(C(=O)CCl)cc(C(C)C)c1O
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCC(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To a solution of 4.47 g (30.6 mmol) of potassium 4-methylphenolate in 150 ml of dimethyl-formamide a solution of 3.90 g (15.3 mmol) of 2-chloro-1-(4-hydroxy-3,5-di-isopropylphenyl)-ethanone in 70 ml dimethylformamide is added at room temperature within a period of 100 minutes. After additional 2 hours of stirring at room temperature the pH is adjusted to 6-7 with 1 N HCl and the mixture is extracted with ethyl acetate. The collected organic phases are washed with water, dried and evaporated. Crystallization of the crude product from ethyl acetate/hexane gives 1.8 g of compound 105, m.p. 124-125° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[C:17]12[CH2:24][CH2:23][C:20]([C:25]#[N:26])([CH2:21][CH2:22]1)[CH2:19][CH2:18]2.NO.[F:29][C:30]([F:38])([F:37])[CH2:31][CH2:32][CH2:33][C:34](O)=[O:35].C(N1C=CN=C1)([N:41]1C=CN=C1)=O>C(O)C.C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:14])([F:16])[F:15])=[N:5][N:4]=[C:3]1[C:17]12[CH2:22][CH2:21][C:20]([C:25]3[N:41]=[C:34]([CH2:33][CH2:32][CH2:31][C:30]([F:38])([F:37])[F:29])[O:35][N:26]=3)([CH2:23][CH2:24]1)[CH2:19][CH2:18]2
Reactant: O=C(O)CCCC(F)(F)F
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C#N)(CC1)CC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: NO
Solvent: CCO
Solvent: ClCCl
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(c3noc(CCCC(F)(F)F)n3)(CC1)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of nitrile 1-F (0.56 g, 1.6 mmol) and hydroxylamine (50% aqueous, 4 ml) in ethanol (40 ml) was heated at 80° C. for 18 h. The resulting mixture was cooled to room temperature and concentrated in vacuo. The solid was stripped from toluene and dried under reduced pressure. A portion of the resulting white powder (0.050 g, 0.13 mmol) was added to a pre-stirred solution of 5,5,5-trifluoropentanoic acid (0.058 g, 0.37 mmol) and 1,1′-carbonyldiimidazole (0.050 g, 0.31 mmol) in methylene chloride (1 ml). The resulting mixture was stirred at room temperature for 24 h, then concentrated. The solid was resuspended in DMF and heated to 10° C. under a nitrogen atmosphere for 2 h. The crude product was purified by Gilson reverse phase chromatography eluting with a 10-90% CH3CN (0.1% TFA)/water (0.1% TFA) gradient. Solvent was removed in vacuo and the product free based from methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4 and the solvent removed to yield 1-G as a white powder. MS (ESI+)=514.34 (M+1); 1H NMR (500 MHz, CDCl3): δ 7.86-7.83 (m, 1 H), 7.73-7.69 (m, 2 H), 7.56 (s, 1 H), 3.51 (s, 3 H), 2.99 (t, 2 H), 2.30-2.22 (m, 8 H), 2.17-2.09 (m, 8 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][CH2:24][C@@:11]2([O:15][C:14](=[O:16])[N:13]([C:17]3[CH:18]=[N:19][C:20]([NH2:23])=[CH:21][CH:22]=3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]([CH3:46])[C:29]([C:31]1[N:40]([CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[C:34]2[N:35]=[C:36](Cl)[N:37]=[CH:38][C:33]=2[CH:32]=1)=[O:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][CH2:24][C@@:11]2([O:15][C:14](=[O:16])[N:13]([C:17]3[CH:18]=[N:19][C:20]([NH:23][C:36]4[N:37]=[CH:38][C:33]5[CH:32]=[C:31]([C:29](=[O:30])[N:28]([CH3:27])[CH3:46])[N:40]([CH:41]6[CH2:45][CH2:44][CH2:43][CH2:42]6)[C:34]=5[N:35]=4)=[CH:21][CH:22]=3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]2(CC1)CN(c1ccc(N)nc1)C(=O)O2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@]5(CCCN(C(=O)OC(C)(C)C)CC5)OC4=O)cn3)nc2n1C1CCCC1
Yield: 66 %

Procedure:
Following general N—C coupling procedure 1, (R)-3-(6-Amino-pyridin-3-yl)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylic acid tert-butyl ester was combined with 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide which gave (R)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylic acid tert-butyl ester as a white solid (0.175 g, 0.272 mmol) in 66% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 9H) 1.61-1.78 (m, 3H) 1.79-1.96 (m, 3H) 1.96-2.14 (m, 7H) 2.38-2.48 (m, 2H) 3.06 (d, J=10.54 Hz, 6H) 3.20-3.33 (m, 2H) 3.36-3.63 (m, 2H) 3.82-3.97 (m, 2H) 4.75 (quin, J=8.78 Hz, 1H) 6.63 (s, 1H) 7.98 (d, J=9.03 Hz, 1H) 8.34 (d, J=9.54 Hz, 1H) 8.44 (s, 1H) 8.81 (s, 1H) 9.78 (s, 1H). MS m/z 619.5 (M+H)+.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2]C.[NH2:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)([OH:12])[CH3:11].[CH2:21]1CCN2C(=NCCC2)CC1>C1COCC1>[OH:12][C:10]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)([CH3:11])[CH2:9][NH:8][S:4]([CH:1]([CH3:2])[CH3:21])(=[O:5])=[O:6]
Reactant: CCCS(=O)(=O)Cl
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1ccc(C(C)(O)CN)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(C)(O)CNS(=O)(=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
In a 500 mL-3n flask fitted with a stirrer and thermometer, 2.53 g. of propanesulfonyl chloride was added dropwise to 3.00 g. of 1-amino-2-(4-methoxyphenyl)propan-2-ol and 2.70 g. of DBU in THF (200 mL) while stirring at 0° C. under a nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred overnight at this temperature. In the morning, reaction was concentrated under reduced vacuum. The resulting oil was taken into ethyl acetate and the organic layer was washed two times with H2O, dried over Na2SO4, and concentrated under reduced vacuum to yield 3.61 g. as a solid. This material was purified via silica gel chromatography employing the Water's prep. 2000 and eluting with a solvent of hexane/ethyl acetate 9:1 to yield intermediate title compound (2.71 g, 57%) as a white solid. Ion spray M.S. 286.2 (M*−1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][CH:13]=[C:12]([C:15]#[N:16])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:17][OH:18]>>[Si:1]([O:8][CH2:9][C:10]1[S:14][CH:13]=[C:12]([C:15](=[N:17][OH:18])[NH2:16])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C#N)cs1
Reactant: NO
Product: CC(C)(C)[Si](C)(C)OCc1cc(C(N)=NO)cs1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1d) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)thiophene-3-carbonitrile (4.3 g, 17 mmol) that was obtained in Example 3 (3a) and a 40% aqueous solution of hydroxylamine (2.2 ml). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:10 to 2:5) as the eluent to afford the title compound (4.7 g) in a yield of 97% as a white crystalline solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([OH:38])=O)[C:31]2=[O:39])=[CH:26][CH:25]=1.[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1.C(N(CC)CC)C>CN(C=O)C>[C:44]1([CH3:47])[CH:45]=[CH:46][C:41]([NH:40][C:36]([C:32]2[C:31](=[O:39])[N:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=3)[CH:35]=[CH:34][CH:33]=2)=[O:38])=[CH:42][CH:43]=1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Cc1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccn(-c3ccc(F)cc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 273.6 %

Procedure:
TBTU (276 mg, 0.851 mmol) was added to the mixture of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (147 mg, 0.567 mmol), p-toluidine (73.7 mg, 0.681 mmol), and triethylamine (120 μl, 0.851 mmol) in DMF (3 ml) at rt. The combined mixture was stirred at rt for 16 h. After that time, the solvent was removed to give a black solid (500 mg). It was purified by chromatography on silica gel (15 g) eluting with 40% (100 ml), 50% (100 ml), 60% (100 ml) and 70% (100 ml) EtOAc/hexane to give the title compound as a light-brown solid. 1H NMR (400 MHz, CDCl3): δ=2.31 (s, 3H), 6.58 (dd, J=6.8 & 7.2 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.23-7.29 (m, 2H), 7.38-7.42 (m, 2H), 7.56-7.63 (m, 3H), 8.74 (dd, J=2.0 & 6.8 Hz, 1H), 11.69 (brs, 1H). MS (ES+): m/z 323.09 [MH+]. HPLC: tR=3.69 min (polar—5 min, ZQ3).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21](CC(O)(C)C)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.I[CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33].C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33])[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(O)CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: FC(F)(F)CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(CCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-cyclopropyl-N-[1-(2-hydroxy-2-methyl-propyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide (80 mg), 1-iodo-3,3,3-trifluoropropane (108 mg), and K2CO3 (63 mg) in N-methyl-2-pyrrolidone (2 mL) is stirred at room temperature for 4 h and then at 60° C. over night. Since conversion of starting material is still incomplete, K2CO3 (63 mg) and two portions of 1-iodo-3,3,3-trifluoropropane (54 mg each) are added while stirring the reaction mixture for two more days at 80° C. Water is added to the reaction mixture and the aqueous phase is extracted with ethyl acetate. The combined extracts are washed with brine dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 75:25→50:50). The crude product is triturated with diethyl ether, filtered off, and dried to give the title compound. LC (method 3): tR=1.08 min; Mass spectrum (ESI+): m/z=408 [M+H]+.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(NC(C)C)(C)C.[C:21]([O:25][C:26](=[O:56])[NH:27][C:28]1([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[C:47](=[O:48])[C:46]4[C:41](=[C:42](Br)[CH:43]=[CH:44][CH:45]=4)[O:40][C:39]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:34][CH:33]=2)[CH2:31][CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22].[CH3:57][Si:58]([C:61]#[CH:62])([CH3:60])[CH3:59]>C1(C)C=CC=CC=1.[Cu]I.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[C:21]([O:25][C:26](=[O:56])[NH:27][C:28]1([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[C:47](=[O:48])[C:46]4[C:41](=[C:42]([C:62]#[C:61][Si:58]([CH3:60])([CH3:59])[CH3:57])[CH:43]=[CH:44][CH:45]=4)[O:40][C:39]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:34][CH:33]=2)[CH2:31][CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(C#C[Si](C)(C)C)cccc4c3=O)cc2)CCC1
Yield: 99.4 %

Procedure:
Copper(I) iodide (1 mg, 0.005 mmol) and bis(benzonitrile)dichloro palladium(II) (2 mg, 0.005 mmol) were dissolved in toluene (1 mL) with stirring. Tri-tert-butylphosphine (2 mg, 0.01 mmol), diisopropylamine (0.017 ml, 0.118 mmol), {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (50 mg, 0.091 mmol) and (trimethylsilyl)acetylene (0.015 mL, 0.109 mmol) were added, the vial was sealed, and reaction mixture was stirred at RT under an atmosphere of argon for 3 h. The mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, gradient 0 to 10% ethyl acetate in DCM) to afford the title compound as a white solid (51 mg, 100%). LCMS (Method G): RT=5.30 min, [M+H]+=564.