Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][CH3:26])=[N:23][N:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.Cl.N[C@@H](CCN1CC(OC2C=CC([F:47])=CC=2)C1)CO>>[F:47][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][CH3:26])=[N:23][N:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: N[C@H](CO)CCN1CC(Oc2ccc(F)cc2)C1
Reactant: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)s1
Agent: Cl
Product: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(F)cc3)C2)s1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-urea in Example 99 except using (S)-2-amino-4-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][CH:10](OS([O-])(=O)=O)[CH2:11][CH:12]([CH3:14])[CH3:13])CC.[Na+].[OH2:21]>>[CH2:1]([OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14]
Reactant: O
Reactant: CCCCC(CC)CCC(CC(C)C)OS(=O)(=O)[O-]
Agent: [Na+]
Product: CC(C)CCCCCCCCCCCCCCCO
Temperature: 65 °C
Yield: 21.9 %

Procedure:
The reaction mixture was emulsified as follows: 300 g polycarbodiimide solution as prepared above was heated to 65° C. and added to a hot aqueous solution of Ethoquad™ C-12 (2% on solids), Tergitol 15S30 (3% on solids) and Tergitol™ TMN-6 (5.4% solids). 199 g water was added. The mixture was emulsified with 2 stage lab Manton-Gaulin at 220/20 bar (2 passes). The solvent was stripped off with a Büchi evaporator, using water jet vacuum. A stable, milky dispersion of 21.9% solids was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].Cl.Cl.[CH3:19][N:20]([CH3:28])[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].C(N(CC)CC)C.C>CCOC(C)=O>[CH3:19][N:20]([CH3:28])[C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:25]=[CH:26][CH:27]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: CN(C)c1cccc(N)c1
Agent: C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)c1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1

Procedure:
Prepared from 5.00 g of 4-chloro-6-nitroquinoline-3-carbonitrile, 5.38 g of 3-dimethylaminoaniline dihydrochloride and 5.17 g of triethylamine in the same manner as Example 377. The crude product was taken up in EtOAc, treated with Darco, filtered through Celite, evaporated and dried in vacuo (50° C.). The yield of 4-(3-dimethylaminophenylamino)-6-nitroquinoline-3-carbonitrile was 5.62 g as brick red crystals: mass spectrum (electrospray, m/e): M+H 334.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]2[O:18][CH2:17]2)=[N+:13]([O-:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]([OH:18])[CH2:17][NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[N+:13]([O-:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cc(OCc2ccccc2)ccc1C1CO1
Reactant: CC(C)(C)N
Solvent: CO
Product: CC(C)(C)NCC(O)c1ccc(OCc2ccccc2)c[n+]1[O-]

Procedure:
To 0.50 g. (0.0042 mole) of [5-benzyloxy-2-(1,2-epoxyethyl)pyridine N-oxide] in 20 ml. of methanol was added 0.5 ml. tert-butylamine and the resulting mixture heated to the reflux temperature for 4 hours. Solvent and excess tert-butylamine were removed in vacuo to give 280 mg. (43%) of the desired product after recrystallization from ether/ethyl acetate; m.p. 148°-150° (dec.). Mass spec (70 eV) m/e 300 (M-16), m/e 243 [MH2NC(CH3)3); NMR (DMSO d6)delta 7.90 (d, 1H, H6), 7.30 (m, 6H, benzyl C6H5 and H4), 7.00 (m, 1H, H3), ##STR14## and 1.13 [s, 9H, C(CH3 ]; ir (KBr) 1171 (N+ -O-).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:20])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH2:17][O:18][CH3:19])([CH3:16])[CH:8]=[CH:7]2)([O-:3])=[O:2].[H][H]>C(O)C.[C].[Pd]>[N+:1]([C:4]1[C:5]([CH3:20])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH2:17][O:18][CH3:19])([CH3:16])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: COCC1(C)C=Cc2c(C)c([N+](=O)[O-])c(C)c(C)c2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCC1(C)CCc2c(C)c([N+](=O)[O-])c(C)c(C)c2O1
Reaction time: 24 h
Yield: 100.3 %

Procedure:
9.4 g of 6-nitro-2-methoxymethyl-2,5,7,8-tetramethyl (2H) chromene was dissolved in 100 ml of ethanol and 1.0 g of a 10% palladium carbon catalyst was added and, after sealing hydrogen, the catalytic hydrogenation reaction was carried out at room temperature under normal pressure for 24 hours. After the completion of the reaction, the reaction solution was filtered and then concentrated under reduced pressure to obtain 9.5 g of the objective oily compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[S:5][CH:6]=1.[NH2:24][C:25]1[N:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:23][C:9]1[N:8]=[C:7]([C:4]2[S:5][CH:6]=[C:2]([C:28]3[CH:27]=[N:26][C:25]([NH2:24])=[N:30][CH:29]=3)[N:3]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(Br)cs2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3cnc(N)nc3)cs2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-thiazol-2-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.80) (0.20 g, 0.50 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.133 g, 0.60 mmol) according to the general procedure VI. Obtained as a white solid (0.100 g, 48%/o). MS (ISP) 414.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[CH2:15]([OH:17])[CH3:16]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:17][CH2:15][CH3:16])=[O:12]
Reactant: COC(=O)/C=C/[C@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: CCO
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)[C@@H]1[C@H](/C=C/C(=O)OC)C1(C)C

Procedure:
Using the procedure of Example 3, 1.51 g of (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in 10 ml of benzene and 0.465 ml of ethanol were reacted to obtain 0.837 g of ethyl (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-21°±1.5° (c=1% in chloroform).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[N:24]([S:27]([C:30]5[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=5)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=34)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[CH3:37][C@@H:38]1[CH2:43][NH:42][CH2:41][CH2:40][NH:39]1.C(N(CC)CC)C>C(O)CCCC.Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:42]4[CH2:41][CH2:40][NH:39][C@H:38]([CH3:37])[CH2:43]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=23)=[CH:12][CH:13]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(Cl)nn45)ccnc32)cc1
Agent: Cl
Solvent: CCCCCO
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(N6CCN[C@H](C)C6)nn45)ccnc32)cc1
Yield: 68.8 %

Procedure:
A mixture of 0.330 g (0.58 mmol) of 6-chloro-2(4-fluorophenyl)-3-{1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine, 0.116 g (1.16 mmol) of (2R)-2-methylpiperazine and 0.08 ml (0.6 mmol) of triethylamine in 5 ml of pentanol is heated under reflux for 24 hours. The reaction medium is diluted with 100 ml of an aqueous solution of hydrochloric acid and the solution is washed with ethyl acetate. The aqueous phase is then basified by addition of aqueous ammonia and the product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The chestnut brown solid obtained is then purified by chromatography on a silica gel column (35 g) by eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5) in order to give 0.232 g of 2-(4-fluorophenyl)-6-[(3R)-3-methylpiperazin-1-yl]-3-{1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine in the form of a yellow powder after drying.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[N:7]=[C:6]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])[CH:17]=2)[C:10]([OH:12])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution of ethyl(2RS,3RS)-3-(6-fluoropyridin-2-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate (5.5 g, 13.1 mmol, (2RS,3RS) form: (2RS,3SR) form=6:1) in methanol (25 ml) was added 2N aqueous sodium hydroxide solution (13.1 ml, 26.2 mmol), and the mixture was stirred at room temperature for 2 hrs. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave (2RS,3RS)-3-(6-fluoropyridin-2-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionic acid (3.82 g, 74%).
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[CH2:20][CH2:19][CH2:18]2.[F-].C([N+:43](CCCC)(CCCC)CCCC)CCC>C1COCC1.CO.C(Cl)Cl.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]>[NH2:43][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[CH2:20][CH2:19][CH2:18]2
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCc3cc(Br)ccc32)CC1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3cc(N)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.6 %

Procedure:
A suspension of Pd2(dba)3 (29 mg, 0.032 mmol) in 2 mL anhydrous THF was treated with PtBu3 (400 μL of a 10% wt in hexanes solution, 0.13 mmol) and stirred at room temperature for 5 minutes. To this mixture was added tert-butyl 4-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)piperidine-1-carboxylate (250 mg, 0.63 mmol) followed by lithium hexamethyldisilizane (1.3 mL of a 1 M solution in THF, 1.3 mmol). The resulting dark brown suspension was heated at 95° C. for 3 hours. The mixture was cooled to room temperature and treated with 5 ml of a 1M tetrabutylammonium fluoride solution in THF then stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate (100 mL) and H2O (20 mL). After extraction, the organic layer was separated, dried over Na2SO4, filtered and concentrated to give a dark brown residue. This residue was subjected to flash chromatography on silica gel using 2.5% 2M NH3 in methanol/CH2Cl2 to give a viscous dark brown residue (160 mg, 76.6%). 1H-NMR (CDCl3) δ 6.56 (d, J=8.4 Hz, 1H), 6.48 (dd, J=2.7, 8.7 Hz, 1H), 6.43-6.42 (m, 1H), 4.25-4.21 (m, 2H), 3.69-3.59 (m, 1H), 3.24 (br s, 2H), 3.07 (t, J=5.4 Hz, 2H), 2.78-2.72 (m, 2H), 2.66 (t, J=6.6 Hz, 2H), 1.93-1.83 (m, 2H), 1.76-1.55 (m, 4H), 1.47 (s, 9H). MS (ESI): 332.2 (M+1, 100%).
Reaction SMILES: C(OC([N:8]([CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([C:27]#[N:28])=[CH:22][CH:23]=2)[CH2:18]1)[CH2:9][CH2:10][NH:11][CH2:12][C:13](OC)=[O:14])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:14]=[C:13]1[CH2:12][NH:11][CH2:10][CH2:9][N:8]1[CH:17]1[CH2:18][C:19]2[CH:20]=[C:21]([C:27]#[N:28])[CH:22]=[CH:23][C:24]=2[CH2:25][CH2:26]1
Reactant: COC(=O)CNCCN(C(=O)OC(C)(C)C)C1CCc2ccc(C#N)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CC(N1CCNCC1=O)CC2

Procedure:
A solution of Methyl ({2-[(tert-butoxycarbonyl)(7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)amino]ethyl}amino)acetate (145 mg, 0.37 mmol) in 15 mL of anhydrous DCM and 5 mL of TFA was stirred at room temperature for 2-3 hours. The reaction was concentrated. The residue was used directly in the next step. The residue was dissolved in 10 mL of EtOH, and was treated with TEA (5 mL). The mixture was heated to reflux overnight. The reaction was concentrated. The crude material was adsorbed onto silica gel and purified by MPLC (DCM:MeOH) to afford the title compound. MS m/z: 256 [M+1]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[N:10]([CH2:14][C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:16])[CH2:9][C@@H:8]3[CH2:25][O:26][CH2:27][CH2:28][N:7]3[C:6]=2[N:5]=1.CI.[CH3:31]COC(C)=O>CN(C=O)C>[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[N:10]([CH2:14][C:15]([N:17]([CH3:31])[CH2:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[O:16])[CH2:9][C@@H:8]3[CH2:25][O:26][CH2:27][CH2:28][N:7]3[C:6]=2[N:5]=1
Reactant: CCOC(C)=O
Reactant: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)NCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(CC1CCOCC1)C(=O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Yield: 70.4 %

Procedure:
Sodium hydride (60% in oil) (12.57 mg, 0.314 mmol) was added to a suspension of (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (PREPARATION x26, 100 mg, 0.262 mmol) in DMF (1 mL) at 0° C. The resultant mixture was stirred at room temperature for 30 minutes. Methyl iodide (0.021 mL, 0.340 mmol) was added to the reaction mixture at room temperature, and the resultant mixture was stirred at room temperature for 15 minutes. After addition of EtOAc, the resultant mixture was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was washed with EtOAc to afford the title compound as a white solid (73 mg, 70.4%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.38 (m, 2 H), 1.48 (d, J=11.12 Hz, 2 H), 1.75-1.99 (m, 1 H), 2.80-3.01 (m, 4 H), 3.09-3.31 (m, 7 H), 3.40-3.64 (m, 2 H), 3.79-4.06 (m, 5 H), 4.17-4.27 (m, 1 H), 4.34-4.44 (m, 1 H), 7.12-7.29 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H26ClN5O3, 396.18; found 396.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN1C(=O)CCC1.Cl.O1CCOCC1>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22]([C:13]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]=3[CH3:11])=[CH:14][CH:15]=[N:16]2)=[CH:21][CH:20]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Cc1cc2cc(F)ccc2[nH]1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc(F)cc2c1-c1ccnc2cc(Cl)ccc12
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A solution of 5-fluoro-2-methylindole (149 mg) and 4,7-dichloroquinoline (198 mg) in NMP (2 ml) and 4M hydrogen chloride in dioxan (0.2 ml) was stirred at 140° C. overnight and then at 150° C. for 1 h. and evaporated. The residue was taken up in ethyl acetate, washed with brine (3×), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica chromatography using acetone/isohexane (2:8) as eluent to give the sub-title compound (250 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]2[C:23]3[C:18](=[N:19][C:20]([NH:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:21][CH:22]=3)[N:17](COCC[Si](C)(C)C)[N:16]=2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]2[C:23]3[C:18](=[N:19][C:20]([NH:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[N:21][CH:22]=3)[NH:17][N:16]=2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccccc3)n2)c2cnc(NCCN3CCOCC3)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CNc2cccc(-c3n[nH]c4nc(NCCN5CCOCC5)ncc34)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3-(6-benzylamino-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (95 mg, 0.17 mmol) in dichloromethane (2 mL) was added TFA (2 mL). The reaction mixture was stirred for 2 hours at room temperature. The mixture was adjusted to about pH 8 with saturated NaHCO3 solution. The resulting mixture was extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by prep-HPLC to give [3-(6-benzylamino-pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine. (Yield 18 mg, 25%).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:12]([C:13](OC)=O)=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH2:2][CH3:3].O.[C:18](OCC)(=[O:20])[CH3:19]>C1COCC1>[CH2:1]([C:4]1[NH:5][C:6]2[C:12]([CH2:13][CH:18]([OH:20])[CH3:19])=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH2:2][CH3:3]
Reactant: CCOC(C)=O
Reactant: CCCc1nc2cccc(C(=O)OC)c2[nH]1
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc2cccc(CC(C)O)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
[step 1] To a mixture of methyl 2-amino-5-bromobenzoate (2.3 g, 10.0 mmol) and propionic anhydride (14 mL) was added dropwise fuming nitric acid (2.1 mL, 50.0 mmol) under ice-cooling. After stirring at 70° C. for 15 min, water and ethyl acetate were added to the mixture, and the mixture was extracted. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30) to give methyl 3-amino-5-bromo-2-butylamidobenzoate (1.23 g, 36%). [step 2] Methyl 3-amino-5-bromo-2-butylamidobenzoate (1.22 g, 3.53 mmol) obtained in step 1 was dissolved in methanol (20 mL) and the mixture was stirred in the presence of 10% palladium carbon (240 mg) under a hydrogen atmosphere at room temperature for 7 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in acetic acid (1 mL), and the mixture was stirred at 100° C. for 1 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=90/10) to give methyl 2-propylbenzimidazole-4-carboxylate (0.299 g, 39%). [step 3] Methyl 2-propylbenzimidazole-4-carboxylate (0.295 g, 1.35 mmol) obtained in step 2 was dissolved in THF (10 mL), 3 mol/L methylmagnesium chloride THF solution (4.5 mL, 13 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the mixture were added water and ethyl acetate, and the mixture was extracted. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=90/10) to give the title compound (0.201 g, 68%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=2)O1.C[O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][N:28]=1)=[O:26]>O.C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([C:30]2[CH:31]=[CH:32][C:27]([C:25]([OH:26])=[O:24])=[N:28][CH:29]=2)=[CH:16][N:17]=1
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ncc(-c2ccc(C(=O)O)nc2)cn1
Temperature: 120 °C
Yield: 57.8 %

Procedure:
Sodium carbonate (0.636 g, 6.0 mmol) in water (2.0 mL) was added to a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.442 g, 2.0 mmol), 5-bromopyridine-2-carboxylic acid methyl ester (0.518 g, 2.4 mmol) and tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol) in ethanol (3.0 mL) and toluene (3.0 mL). The resulting mixture was heated at 120° C. for 3 h. The organic solvents were removed under reduced pressure. The residue was diluted with water, and adjusted with 1N HCl to pH=4. The precipitates were collected by filtration, washed with water and EtOAc, and dried to give the desired product (0.25 g, 58%). LCMS: (M+H)=217.0.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([C:16]2[C:24]3[N:23]=[CH:22][N:21]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])[C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH:10]=1)C1C=CC=CC=1.C(S)C.B(F)(F)F>C(Cl)Cl.CO>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:21]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([N:11]3[CH:12]=[CH:13][C:14](=[O:15])[C:9]([OH:8])=[CH:10]3)[C:24]=2[N:23]=[CH:22]1
Reactant: O=c1ccn(-c2cccc3c2ncn3Cc2ccccc2Cl)cc1OCc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCS
Solvent: CO
Product: O=c1ccn(-c2cccc3c2ncn3Cc2ccccc2Cl)cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.8 %

Procedure:
To a solution of 3-(benzyloxy)-1-[1-(2-chlorobenzyl)-1H-benzimidazol-4-yl]pyridin-4(1H)-one (2.6 g, 5.9 mmol) in DCM (40 mL) was added ethanethioi (4 mL) and BF3 Et20 (4 mL) and the mixture was stirred at r.t. for 4 h. The mixture was diluted with MeOH, stirred for 10 min, then concentrated. The residue obtained was purified by prep-HPLC to give 1.2 g (58%) of 1-[1-(2-chlorobenzyl)-1H-benzimidazol-4-yl]-3-hydroxypyridin-4(1H)-one. ′H-NMR (CD3OD, 400 MHz) δ 8.48-8.44 (m, 3H), 7.78 (d, J−7.6 Hz, 1H), 7.58-7.51 (m, 3H), 7.41-7.25 (m, 4H), 5.75 (s, 2H). MS (ESI) (M+H 352.1/354.1.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=1)[C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20].NN>C(O)C>[NH2:3][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1)N1CCCCC1
Agent: NN
Solvent: CCO
Product: NCCCOc1cccc(C(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a warm solution of 0.5 g. of 1-[3-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)propoxy]benzoyl]piperidine in 20 ml. of absolute ethanol is added 1 ml. of hydrazine. The mixture is stirred at room temperature for 1 hour and is filtered. The filtrate is allowed to stand at room temperature for 18 hours and again is filtered. The filtrate is evaporated in a rotary evaporator and the residue is partitioned between 50 ml. of ether and 50 ml. of water. The ether layer is dried over magnesium sulfate, is filtered and is evaporated to give 80 mg. of oil. The oil is purified by HPLC using 1-Silica Prep Pac (Waters) and a combination of methanol, ethyl acetate and 1% triethylamine to give the analytical sample.