Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:31])[N:5]([C:28](=[O:30])[CH3:29])[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1.[C:32]1([C@@H:38]([CH3:42])[C:39]([O-:41])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cs+].[I-].[Na+].O>C(#N)C>[C:28]([N:5]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1)[C:4]([O:3][CH2:2][O:41][C:39](=[O:40])[C@@H:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:42])=[O:31])(=[O:30])[CH3:29]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCCl
Reactant: C[C@@H](C(=O)[O-])c1ccccc1
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@H](C)c1ccccc1
Temperature: 25 °C
Yield: 81 %

Procedure:
(R)-acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid chloromethyl ester (10) (0.40 g, 0.84 mmol), cesium 2(R)-phenyl-propionate (0.37 g, 1.31 mmol) and sodium iodide (0.13 g, 0.86 mmol) in acetonitrile (25 mL) are heated to reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-5% MeOH over 1 hour and 20 minutes) to afford the title compound. Isolated yield: 81%. 1H NMR (400 MHz, DMSO-d6): δ 7.43-7.38 (m, 1H), 7.33 (t, 1H), 7.27-7.15 (m, 6H), 5.78-5.72 (m, 2H), 4.63-4.57 (m, 1H), 4.04-3.95 (m, 2H), 3.84 (q, 1H), 3.76-3.69 (m, 2H), 3.36-3.26 (m, partially obscured by water, 2H), 3.17-3.12 (m, 1H), 3.07-3.04 (m, 2H), 2.31 (d, 3H), 2.11 (q, 2H), 2.01-1.97 (m, 2H), 1.35 (d, 3H); MS-APCI (m/z+): 341, 385, 517, 591.
Reaction SMILES: C(Cl)Cl.[O:4]=[CH:5][C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7].[CH2:16]([B:20]([O-:22])[O-:21])[CH2:17][CH2:18][CH3:19]>O>[O:4]=[CH:5][C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7].[C:16]1([B:20]([O-:22])[O-:21])[CH:6]=[CH:5][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCB([O-])[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: ClCCl
Product: [O-]B([O-])c1ccccc1
Reaction time: 0 h

Procedure:
A solution of 100 mg/dL of glucose his phenylboronate and dry methylene chloride was prepared and applied to CLINISTIX® glucose test strip pad. No color development was observed. The pads were then wetted with water and in 2 or 3 minutes color development was observed. Glucose his butylboronate was similarly applied to CLINISTIX® strips. Again no color was observed upon application. After wetting with water strong color development was observed in 10 to 15 seconds.
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].[CH2:5]([C:7]([OH:14])([CH2:10][CH2:11][CH:12]=C)[CH2:8][OH:9])[CH3:6].C(=O)=[O:16].O=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CC(C)=O>[CH2-:1][C:2]([CH3:4])=[O:3].[CH2:5]([C:7]([OH:14])([CH2:8][OH:9])[CH2:10][CH2:11][CH:12]=[O:16])[CH3:6]
Reactant: C=CCCC(O)(CC)CO
Reactant: O=C=O
Agent: O=[O+][O-]
Agent: [CH2-]C(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCC(O)(CO)CCC=O
Temperature: 25 °C
Yield: 76 %

Procedure:
A solution of 2S 2-ethyl-2-hydroxyhex-5-enol acetonide (1.2 g, 6.52 mmol) in dichloromethane (25 mL) was brought to -78° C. (dry ice, acetone) and ozone was bubbled through until the reaction mixture turned a pale blue (approx 15 min.) The reaction mixture was then flushed with nitrogen for 1 h, triphenylphophine (850 mg, 3.26 mmole) was added and the mixture was allowed to slowly warm to room temperature. The solvent was removed under reduced pressure and the residue was taken up in hexane, filtered and again concentrated. Flash chromatography on 50 g of silica gel, eluting with 3:2 hexane/ether, gave 0.92 g (76%) of the title aldehyde. TLC Rf 0.39 (silica gel, 3:2 hexane-ether).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:20]([O-:22])=[O:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:28]O>>[CH3:28][O:8][C:7](=[O:9])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([N+:20]([O-:22])=[O:21])[CH:10]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
30 g of 3,5-dinitro-4-phenoxy-benzoic acid in 200 ml of methanol are combined with 3 ml of concentrated sulphuric acid and the whole is boiled for 3 hours under reflux. After evaporation of the solvent, the residue is dissolved in ethyl acetate, and traces of unreacted acid are destroyed with dilute sodium bicarbonate solution. After drying of the ethyl acetate solution, the solvent is eliminated by evaporation, the residue is recrystallised from ethyl acetate/methanol. The desired ester melting at 171°-173 ° C. is obtained with a very good yield.
Reaction SMILES: [C:1]([C:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>CN(C=O)C.CCN(CC)CC>[OH:8][C:3]1([C:1]#[C:2][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:20]/[C:21]2[NH:22][CH:23]=[CH:24][C:25]=2[O:26][CH3:27])/[C:13](=[O:19])[NH:14]3)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C#CC1(O)CCCC1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC3(O)CCCC3)c21

Procedure:
Using Method D above, 1-ethynyl-cyclopentanol (86.3 mg, 0.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.1 g, 0.31 mmol) (Starting Material 1 above) using DPPFPdCl2 (12.6 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 2 days to yield (Z)-1,3-dihydro-4-[(1-hydroxycyclopentyl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 43 mg, 40%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH2:7][CH3:8])[CH2:4][NH2:5].Br[CH2:10][CH:11]1[O:15][CH2:14][CH2:13][O:12]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([O:6][CH2:7][CH3:8])[CH2:4][NH:5][CH2:10][CH:11]1[O:15][CH2:14][CH2:13][O:12]1
Reactant: CCOC(CN)OC
Reactant: BrCC1OCCO1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(CNCC1OCCO1)OC
Temperature: 25 °C

Procedure:
2-Methoxy-2-ethoxyethylamine (0.11 mole), 2-bromomethyl-1,3-dioxolane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2-methoxy-2-ethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)amine.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=O)C.[NH2:15][NH2:16]>C(O)C.C(O)(=O)C>[CH:8]1([C:6]2[CH2:5][C:4](=[O:3])[NH:16][N:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NN
Reactant: CCOC(=O)CC(=O)C1CCCCC1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1CC(C2CCCCC2)=NN1
Reaction time: 18 h

Procedure:
3-Cyclohexyl-3-oxo-propionic acid ethyl ester (0.5 g, 2.52 mmol) was stirred in ethanol and acetic acid (10:1, 2:0.2 mL), and treated with hydrazine (0.095 mL, 3.03 mmol). After 18 hrs, the resulting solid was filtered off and washed with a minimum amount of ethanol to yield 3-cyclohexyl-1H-pyrazol-5(4H)-one. Then, the 3-cyclohexyl-1H-pyrazol-5(4H)-one (0.2 g, 1.23 mmol) and 4-chloroquinoline N-oxide (1.23 mmol) were stirred in acetic anhydride (20 mL) at ambient temperature for 60-90 minutes. The reaction mixture was concentrated and the resulting solid filtered off and washed with a minimum amount of ether. (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-cyclohexyl-1H-pyrazol-5(4H)-one (0.05 g, 0.13 mmol) was dissolved in ethanol (1.5 mL) and 4-acetamidothiophenol (0.023 g, 0.13 mmol) was added. The reaction mixture was heated to 180° C. using a microwave reactor for 5-10 minutes. The solid was filtered and washed with ethanol to yield Example 48. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88-1.00 (m, 2H) 1.26-1.38 (m, 2H) 1.58 (d, J=10.61 Hz, 6H) 2.10 (s, 3H) 2.33 (t, J=9.47 Hz, 1H) 6.87 (s, 1H) 7.62-7.72 (m, 3H) 7.89 (t, J=7.83 Hz, 4H) 8.17 (d, J=8.34 Hz, 1H) 10.37 (s, 1H); ESI-MS: m/z calc'd for C26H26N4O2S 458.58. found 459.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][N:46]([CH3:51])[CH2:47][C:48](O)=[O:49]>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH:15][C:48](=[O:49])[CH2:47][N:46]([CH3:51])[CH3:45])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19]
Reactant: CN(C)CC(=O)O
Reactant: CN(C)c1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(N(C)C)c3)cc2s1
Temperature: 60 °C
Yield: 33.5 %

Procedure:
A mixture of 6-(6-chloro-5-(dimethylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (70 mg, 230 μmol), HATU (210 mg, 552 μmol), and 2-(dimethylamino)acetic acid (45 mg, 436 μmol) in DMF (2.5 mL) was heated to 60° C. for 2 h. The solution was diluted with H2O (20 mL) until it became cloudy and cooled to rt. The mixture was filtered, washed with H2O (10 mL), Na2HCO3 (saturated, 5 mL), and H2O (5 mL). The filter was dissolved in MeOH (10%) in DCM and dried over MgSO4. The organic was filtered, concentrated to a yellow solid. This was further purified on silica using MeOH in EtOAc (0-5%) to give a light yellow solid. A second purification with 1:1 hexane-acetone removed the less polar impurity (NAc) effectively, affording a white solid (30 mg). MS (ESI, POS. ION) M/Z: calc'd for C18H20ClN5OS: 389.1. found: 390.1. 1H NMR (400 MHz, chloroform-d) δ ppm 2.43 (s, 3H) 2.93 (s, 3H) 3.25 (s, 2H) 7.52 (d, J=2.15 Hz, 1H) 7.63 (dd, J=8.41, 1.76 Hz, 1H) 7.87 (d, J=8.41 Hz, 1H) 7.99 (d, J=1.56 Hz, 1H) 8.27 (d, J=2.15 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16]S(C)(=O)=O)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[F:21][C:22]([F:32])([F:31])[O:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1>>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:22]([F:21])([F:31])[F:32])[CH:25]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: COC(=O)c1cc(F)cnc1N1CC(OS(C)(=O)=O)C1
Product: O=C(O)c1cc(F)cnc1N1CC(Oc2cccc(OC(F)(F)F)c2)C1
Yield: 22.1 %

Procedure:
The title compound (D134) (27 mg) was prepared according to the experimental procedure described in Description 133 starting from Methyl 5-fluoro-2-(3-((methylsulfonyl)oxy)azetidin-1-yl)nicotinate (D71) (100 mg, 0.328 mmol) and 3-(trifluoromethoxy)phenol (0.042 ml, 0.328 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].[CH:20]1([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][C:24]=2I)[CH2:22][CH2:21]1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.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]>[CH:20]1([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][C:24]=2[C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[CH:11]=[C:10]([C:12]4[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=4)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=23)[CH2:22][CH2:21]1
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Reactant: Ic1cnn(-c2ccccc2)c1C1CC1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3cnn(-c4ccccc4)c3C3CC3)c12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (40 mg, 0.160 mmol), 5-cyclopropyl-4-iodo-1-phenyl-1H-pyrazole (62 mg, 0.20 mmol), copper (I) iodide (9.1 mg, 0.048 mmol), and tetrakis(triphenylphosphine)palladium (0) (18.3 mg, 0.016 mmol) in N,N-dimethylformamide (2 ml), was added triethylamine (0.044 ml, 0.32 mmol). The mixture was sparged with argon for 3 minutes and heated to 70° C. After 1 h, reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 3-[(5-cyclopropyl-1-phenyl-1H-pyrazol-4-yl)ethynyl]-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine.
Reaction SMILES: [N:1]1([C:7](=[O:26])[CH2:8][O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[O:17][C:18]4[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH:35]1[CH2:37][CH2:36]1>CN(C=O)C.C(OCC)(=O)C>[CH:35]1([CH2:34][O:25][C:23]2[CH:22]=[CH:21][C:19]3[N:20]=[C:16]([N:13]4[CH2:12][CH2:11][CH:10]([O:9][CH2:8][C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[O:26])[CH2:15][CH2:14]4)[O:17][C:18]=3[CH:24]=2)[CH2:37][CH2:36]1
Reactant: O=C(COC1CCN(c2nc3ccc(O)cc3o2)CC1)N1CCOCC1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)N1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{4-[2-(morpholin-4-yl)-2-oxoethoxy]piperidin-1-yl}-1,3-benzoxazol-6-ol (2.81 g) in DMF (26 mL) were added potassium carbonate (3.22 g) and (bromomethyl)cyclopropane (1.51 mL), and the mixture was stirred at 80° C. overnight. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate. The diluted solution was washed with distilled water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (NH, hexane/ethyl acetate) to give the title compound (2.10 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:36])[CH2:33][C:34]#[N:35])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:42][CH2:41][CH2:40][CH2:39]C1.C1(C=O)CC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([C:33](=[CH:39][CH:40]4[CH2:42][CH2:41]4)[C:34]#[N:35])=[O:36])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4c(F)cccc4F)cc3)c3c(N)ncnc32)C1
Reactant: C1CCNCC1
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4c(F)cccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.4 %

Procedure:
Into a 10 mL sealed tube, was placed a solution of 3-[(3R)-3-[4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (150 mg, 0.31 mmol, 1.00 equiv) in methanol (5 mL), piperidine (78 mg, 0.92 mmol, 3.0 equiv), and cyclopropanecarbaldehyde (64 mg, 0.91 mmol, 3.0 equiv). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The residue was diluted with 10 mL of dichloromethane, ans the solution was washed with saturated aqueous ammonium chloride, water and brine. The organics were dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (20/1) to give 36 mg (21%) of 2-[[(3R)-3-[4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]carbonyl]-3-cyclopropylprop-2-enenitrile as a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Cl[CH:10]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18].O>C1(C)C=CC=CC=1>[C:1]1([O:7][CH:10]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Clc1ccc(C(Cl)c2cccnc2)c(Cl)c1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(C(Oc2ccccc2)c2cccnc2)c(Cl)c1

Procedure:
1 gm of phenol is added to 100 ml of toluene in a 250 Erlenmeyer flask equipped with a refluxing condensor. 0.26 gm sodium is added and the system is heated at reflux until the sodium has dissolved. The system is then allowed to come to room temperature. At this time, 2.50 gm of alpha-chloro-2,4-dichloro-alpha-(3-pyridyl)toluene in 30 ml of toluene is added over 1 hour. The system is then heated at reflux for 6 hours. The system is added to water and the product extracted in the organic phase. The toluene is removed by stripping to give the 3-pyridyl-2,4-dichlorophenylcarbinol phenylether.
Reaction SMILES: [F:1][C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:15]C([O-])(C)C.[K+].CI>CN(C)C(=O)C>[F:1][C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]2[N:6]([CH3:15])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: N#Cc1cc2c(cc1F)OCC(=O)N2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Product: CN1C(=O)COc2cc(F)c(C#N)cc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonitrile (CAS Reg. No. [151982-49-9], 4.71 g) in N,N-dimethylacetamide (108 ml) were added KOtBu (3.08 g) and methyl iodide (3.83 g). The mixture was stirred at room temperature for 3.5 h. Ice water was added. The suspension was filtered and the solid was washed with water and dried to give the title compound (4.07 g) as an off-white solid.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:17][CH2:18][C@@H:19]([OH:21])[CH3:20]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:17]([CH2:18][C@@H:19]([OH:21])[CH3:20])[C:5]=32)=[CH:10][CH:9]=1
Reactant: C[C@H](O)CN
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(ccn1C[C@H](C)O)C2
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-6-methoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.94 g of (S)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.5 g (63%) of (S)-1-(7-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a solid with m.p. 74°.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[CH:6]=[C:7]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[N:12]=[C:11]([CH3:13])[NH:10][C:9]=2[CH:14]=1)=[O:4].[H-].[Na+].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>CN(C)C=O>[CH3:23][N:2]([CH3:1])[C:3]([C:5]1[CH:6]=[C:7]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[N:12]=[C:11]([CH3:13])[N:10]([S:33]([C:30]3[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[C:9]=2[CH:14]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2c(OCc3ccccc3)cc(C(=O)N(C)C)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(C)nc3c(OCc4ccccc4)cc(C(=O)N(C)C)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a suspension of N,N,2-trimethyl-4-[(phenylmethyl)oxy]-1H-benzimidazole-6-carboxamide (928 mg, 3.0 mmol, STEP 5) in N,N-dimethylformamide (20 mL) was added sodium hydride (60% in mineral oil, 180 mg, 4.50 mmol) at 0° C. After stirring at room temperature for 30 minutes, the reaction mixture was cooled to 0° C. To the mixture was added 4-methylbenzenesulfonyl chloride (572 mg, 3.00 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography on silica gel (gradient elution from dichloromethane only to ethyl acetate only) to afford the title compound as a white solid (1.00 g, 72%).
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][C:23]2([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[C:9]#[C:10][CH3:11].C(N(CC)CC)C>C(Cl)Cl>[CH2:32]([O:31][C:29]([C:23]1([CH2:22][S:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:8][C:9]#[C:10][CH3:11])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[CH2:24][CH2:25][N:26]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:27][CH2:28]1)=[O:30])[CH3:33]
Reactant: CC(C)(C)N=C=O
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(C(=O)NC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a solution of tert-butylisocyanate (0.097 ml, 0.85 mmol) in 8.0 mL of CH2Cl2, was added 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid ethyl ester (prepared from example 36, step 2) (0.337 g, 0.81 mmol) and triethylamine (0.135 ml, 0.97 mmol) and stirred at room temperature for 2 h. The reaction was diluted with CH2Cl2 and washed with H2O, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with ether:hexanes (1:1) to provide 0.284 g (73%) of the desired product as a white solid. Electrospray Mass Spec: 479.2 (M+H)+.