Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[NH:24]1[C:33]2[C:28](=[CH:29][C:30]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:11]
Reactant: CCOC(=O)CCc1ccc2c(c1)CCCN2
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc2c(c1)CCCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A stirred solution of 3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetic acid (0.232 g, prepared as described in Example 52B of International Patent Application Publication No. WO 96/22966) in anhydrous tetrahydrofuran (5 ml), under an atmosphere of argon and at 20° C., was treated with powdered molecular sieves 4 Å (2 g), ethyl 3-(1,2,3,4-tetrahydro-6-quinolinyl)propanoate (0.115 g, Reference Example 2), triethylamine (0.275 ml), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.223 g) and 4-dimethylaminopyridine (6 mg). After stirring at 20° C. for 1 hour the reaction mixture was filtered through a pad of celite. The filtrate was evaporated under reduced pressure (2.7 kPa) at 40° C. and the residue was treated with ethyl acetate (25 ml). The solution obtained was washed twice with saturated aqueous ammonium chloride solution (5 ml), then with water (5 ml), then dried over magnesium sulfate, and then evaporated under reduced pressure (2.7 kPa) at 40° C. The resulting white foamy solid (0.457 g) was subjected to flash chromatography on silica (0,040-0,063 mm) eluting with a mixture of cyclohexane and ethyl acetate (250 ml, 9:1, then 500 ml, 7:3, then 1000 ml, 4:6; v/v) to give the title compound (0.244 g) as a white foamy solid.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([O:18]C)=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:20].CCOC(C)=O>CO>[C:1]1([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([NH2:20])=[O:18])[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2oc(-c3ccccc3)nc12
Reactant: N
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2oc(-c3ccccc3)nc12
Temperature: 40 °C

Procedure:
To a solution of methyl 2-phenylbenzoxazole-4-carboxylate (0.02 g; 0.0905 mmol) in methanol (3 ml) was added aqueous ammonia (3 ml). This was warmed to 40° C. and left to stir, whilst the reaction was monitored by TLC (1:4 EtOAc:petrol). Once all the starting material had reacted a white precipitate was formed. The solvent was removed to yield a white solid, which was recrystallised from ethyl acetate and petrol (70%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][C:13]=2[N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[N+:36]([O-])=O)[C:27]2=[O:39])=[N:2]1.[Sn].Cl>C(O)C>[NH2:36][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:33]=1[C:34](=[O:35])[N:26]([C:13]1[CH:14]=[C:15]([C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[O:19])[CH:16]=[CH:17][C:12]=1/[CH:11]=[CH:10]/[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=1)[C:27]2=[O:39]
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)c(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)c1)N1CCOCC1
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: Nc1cccc2c1C(=O)N(c1cc(C(=O)N3CCOCC3)ccc1/C=C/c1n[nH]c3ccccc13)C2=O
Yield: 16.4 %

Procedure:
In a similar manner to Example 2, (E)-2-{2-[2-(1H-indazol-3-yl)vinyl]-5-(morpholin-4-ylcarbonyl)phenyl}-4-nitroisoindole-1,3-dione (0.30 g, 0.57 mmol) obtained in Step 2 was dissolved in ethanol (30 mL) and was reacted with tin (0.2 g, 1.7 mmol) and concentrated hydrochloric acid (7.0 mL) at room temperature to obtain Compound 288 (46 mg, 53%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nccc(C(F)(F)F)n2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-4-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 460 [M+1]+.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[N:21]=[C:20]([C:22]3[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[C:24]([F:35])[CH:23]=3)[C:19]([N:36](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:18][CH:17]=2)[CH2:12][C:11]1([F:52])[F:51])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:36][C:19]1[C:20]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([OH:28])=[O:27])=[C:24]([F:35])[CH:23]=2)=[N:21][C:16]([CH:13]2[CH2:14][CH2:15][CH:10]([O:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]([F:51])([F:52])[CH2:12]2)=[CH:17][N:18]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCC(OC(=O)c4ccccc4)C(F)(F)C3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(C2CCC(OC(=O)c3ccccc3)C(F)(F)C2)nc1-c1ccc(C(=O)O)c(F)c1
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-(6-(4-(benzoyloxy)-3,3-difluorocyclohexyl)-3-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)-2-fluorobenzoate (670 mg, 0.921 mmol) in DCM (12 mL) at RT was added TFA (4.96 mL, 64.4 mmol). The resultant mixture was stirred at RT for 2 hours. The mixture was concentrated, diluted with EtOAc, neutralized with NaHCO3 twice, then brine, the organic layer was separated, dried and concentrated to afford the crude product, which was used at the next step directly. (434 mg, 0.921 mmol, 100% yield). LC-MS (m/z): (MH+) 472.1, at 0.942 min. 1H NMR (400 MHz, DMSO) 6 ppm: 1.07 (t, J=7.04 Hz, 2H) 1.83 (t, J=10.17 Hz, 2H) 2.16 (d, J=5.09 Hz, 1H) 2.29-2.45 (m, 2H) 3.02 (br. s., 1H) 3.16-3.44 (m, 9H) 5.22-5.52 (m, 1H) 5.73 (s, 1H) 6.24 (s, 2H) 7.44-7.75 (m, 5H) 7.89 (t, J=7.83 Hz, 1H) 7.94-8.07 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH2:24]([N:26]([CH2:38][CH3:39])[CH2:27][C:28]#[C:29][CH2:30][NH:31][C:32]1[CH2:36][S:35][C:34](=[O:37])[N:33]=1)[CH3:25].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:36]2/[C:32]([NH:31][CH2:30][C:29]#[C:28][CH2:27][N:26]([CH2:24][CH3:25])[CH2:38][CH3:39])=[N:33][C:34](=[O:37])[S:35]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CCN(CC)CC#CCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CCN(CC)CC#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (780 mg) in 2-propanol (5 mL) were added 4-{[4-(diethylamino)but-2-yn-1-yl]amino}-1,3-thiazol-2(5H)-one (550 mg) and piperidinium acetate (334 mg) at room temperature. The reaction mixture was stirred at 60° C. for 3 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (640 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([O:37][C:38]3([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:41][CH2:40][CH2:39]3)[C:34]3[C:29](=[CH:30][C:31]([CH3:47])=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].C(Cl)Cl>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([O:37][C:38]3([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:39][CH2:40][CH2:41]3)[C:34]3[C:29](=[CH:30][C:31]([CH3:47])=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)c3ccc(C)cc3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)c3ccc(C)cc3n2)CC1

Procedure:
A solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-4-(1-(ethoxycarbonyl)cyclobut-1-oxy)quinoline (75 mg, 0.09 mmol) in 50% trifluoroacetic acid-methylene chloride (2 ml) was stirred at ambient temperature for 1 hour. The solvent was evaporated in vacuo and the resulting residue was purified by preparative HPLC to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-(1-(ethoxycarbonyl)cyclobut-1-oxy)quinoline as a white solid (60 mg, 93%, trifluoroacetic acid salt); NMR (DMSO-d6) 1.03 (t, 3), 1.16 (t, 3), 1.82 (m, 1), 2.00 (m, 3), 2.26 (m, 2), 2.55 (s, 3), 2.59 (m, 2), 2.77 (m, 2), 3.38 (m, 6), 3.60 (m, 2), 4.02 (q, 2), 4.12 (q, 2), 4.98 (m, 1), 6.92 (s, 1), 7.52 (d, 1), 7.88 (s, 1), 8.14 (d, 1), 8.85 (d, 1) ppm.
Reaction SMILES: Cl.Cl.[CH2:3]1[C@H:8]2[CH2:9][NH:10][CH2:11][CH2:12][N:7]2[CH2:6][CH2:5][O:4]1.[CH3:13][C:14]([O:17][C:18]([N:20]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:21]([C:29]1[C:34]([F:35])=[C:33](Cl)[N:32]=[C:31]([Cl:37])[N:30]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOCC>[CH3:16][C:14]([O:17][C:18]([N:20]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:21]([C:29]1[C:34]([F:35])=[C:33]([N:10]2[CH2:11][CH2:12][N:7]3[C@@H:8]([CH2:3][O:4][CH2:5][CH2:6]3)[CH2:9]2)[N:32]=[C:31]([Cl:37])[N:30]=1)[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[O:19])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: C1CN2CCOC[C@H]2CN1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(N2CCN3CCOC[C@H]3C2)c1F
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of crude (9aR)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (1.7185 g, 7.99 mmol) in DMF (40 mL) was added tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (3.97 g, 7.98 mmol) and N,N-diisopropylethylamine (4.60 mL, 26.41 mmol). The solution was stirred overnight and then diluted with Et2O (200 mL). The mixture was washed with water (2×100 mL), and the combined aqueous phase was extracted with a fresh portion of Et2O (100 mL). The combined organic phase was washed with a fresh portion of water (50 mL), and then dried over anhydrous Na2SO4. The mixture was filtered, concentrated in vacuo, and the residue was dissolved in DCM (200 mL) and dried over anhydrous Na2SO4. The mixture was filtered, and the solution was concentrated in vacuo. The residue was purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N) to afford tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (4.34 g, 90%) as a white foam. LCMS: (M+H)+: 603.3.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f1) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16]CBr)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-:20].[K+].[K+]>CS(C)=O.O>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16][OH:20])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCc1nc(=O)c2cc(CCBr)ccc2[nH]1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(=O)c2cc(CO)ccc2[nH]1
Temperature: 25 °C
Yield: 44.6 %

Procedure:
To a suspension of 2.0 g of impure 2-butyl-6-(bromethyl)-4(1H)-quinazolinone (from Example 3) in 35 ml of dimethylsulfoxide and 20 ml of water is added 1.0 g of potassium carbonate. The reaction mixture is heated at reflux for 6 hours, resulting in a complete solution. Upon cooling slowly to room temperature a white precipitate forms and is collected by filtration. The filter cake is purified by flash chromatography on silica gel, eluting with 9:1 chloroform-methanol to give 0.67 g of the desired product as a white solid. CI MASS SPEC 233(MH+).
Reaction SMILES: Cl.[F:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][NH:6][CH2:5]1.Br[CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][N:6]([CH2:10][CH2:11][OH:12])[CH2:5]1
Reactant: OCCBr
Reactant: FC[C@@H]1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCN1CC[C@@H](CF)C1
Temperature: 80 °C
Yield: 64.4 %

Procedure:
A mixture of (R)-3-(fluoromethyl)pyrrolidine hydrochloride (Intermediate 8, 4.26 g, 30.6 mmol), 2-bromoethanol (4.35 mL, 61.3 mmol), and potassium carbonate (12.7 g, 92 mmol) in acetonitrile (120 mL) was heated at 80° C. overnight. After cooling, solids were filtered off and washed with acetonitrile. The filtrate was concentrated on a rotary evaporator to give a residue that was purified by silica gel chromatography eluting with 10:7 ethyl acetate/hexanes to 10:7:2:1 ethyl acetate/hexane/methanol/triethylamine to afford 2.9 g of (R)-2-(3-(fluoromethyl)pyrrolidin-1-yl)ethanol as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 4.44 (t, 1H), 4.34 (dd, 1H), 4.22 (dd, 1H), 3.44 (q, 2H), 2.58-2.51 (m, 1H), 2.48-2.38 (m, 5H), 2.32-2.28 (m, 1H), 1.85-1.74 (m, 1H), 1.39-1.31 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]C)[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1[Cl:27]>Cl>[ClH:27].[ClH:27].[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1[Cl:27]
Reactant: COc1nc(N)c(Cl)cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: Nc1[nH]c(=O)c(C(=O)NCC2CCNCC2)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 262.1 %

Procedure:
A suspension of 1,1-dimethylethyl 4-[({[6-amino-5-chloro-2-(methyloxy)-3-pyridinyl]carbonyl}amino)methyl]-1-piperidinecarboxylate (step 1, 350 mg, 0.88 mmol) in aqueous 2 N hydrochloric acid (20 ml) was refluxed with stirring for 12 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was crystallized from methanol/diisopropyl ether to give 275 mg (88%) of the title compound as a gray powder.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:18]([NH:21][C:22]1[CH:31]=[CH:30][C:25]([S:26](Cl)(=[O:28])=[O:27])=[CH:24][CH:23]=1)(=[O:20])[CH3:19]>O1CCOCC1.C(N(CC)CC)C>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:26]([C:25]4[CH:24]=[CH:23][C:22]([NH:21][C:18](=[O:20])[CH3:19])=[CH:31][CH:30]=4)(=[O:28])=[O:27])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(N2CCC3(CC2)OCCO3)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC4(CC3)OCCO4)cc2)cc1
Reaction time: 18 h
Yield: 38.6 %

Procedure:
To a stirred solution of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine (which was obtained in Example 214) (2.8 g, 11.9mol) in 1.4-dioxane (150 mL) and triethylamine (7 mL) was added a solution of N-acetylsulfanilyl chloride (3.5 g, 15 mmol) in 75 mL of 1,4-dioxane at room temperature. The reaction was stirred for 18 hours. The reaction mixture was concentrated. The residue was dissolved in methylene chloride and washed with diluted hydrochloric acid. The white solid in water layer was collected and dried to give the title compound as a white solid (2.5 g, 43%); 1H NMR (300 MHz, DMSO-d6) δ 1.92 (brs, 4H), 2.06 (s, 3H), 3.68 (brs, 4H), 3.93 (s, 4H), 7.06 (d, J=8.4 Hz, 2H), 7.33 (brs, 2H), 7.68 (d, J=9.0 Hz, 2H), 7.71 (d, J=9.0Hz, 2H), 10.24 (brs, 1H), 10.38 (s, 1H); MS (ES) m/z: 432.3 (MH+); HRMS Calcd. for C21H25N3O5S(M+): 431.1515. Found: 431.1530.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@:34]4([CH3:39])[CH2:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH3:40][C:41]([CH3:43])=O>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@:34]4([CH3:39])[CH2:38][CH2:37][CH2:36][N:35]4[CH:41]([CH3:43])[CH3:40])=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@]4(C)CCCN4)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@]4(C)CCCN4C(C)C)ncn3)cccc2s1

Procedure:
(2S)-N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-2-methylpyrrolidine-2-carboxamide (Example 57) was reacted with acetone under the conditions of Example 3(d) to give the title compound as a white solid. MS (ESI, pos. ion.) m/z: 599 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH:29](=O)[CH:30]([CH3:32])[CH3:31]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][N:20]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1
Reactant: CC(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(CC(C)C)C3)cc1

Procedure:
Method as described for example 26 using (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 7) and iso-butyraldehyde as starting materials. Purified by prep HPLC (low pH).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+]([O-])(O)=O.[N+:18]([O:21][CH2:22][CH2:23][NH2:24])([O-:20])=[O:19]>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:24][CH2:23][CH2:22][O:21][N+:18]([O-:20])=[O:19])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: O=[N+]([O-])O
Product: CC(=O)Oc1ccc(C(=O)NCCO[N+](=O)[O-])cc1
Yield: 74.6 %

Procedure:
Starting from 0.113 mole of 4-acetoxybenzoic acid chloride and 0.110 mole of 2-nitrooxy-ethylamine nitrate, and operating substantially as described in the preceding Example, 22 g of the title compound were obtained. M.p. 95°-97° C. (ethyl ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][C@H:14]2[CH2:22][O:23][CH2:24][C:25]([OH:27])=O)(=[O:12])=[O:11])=[C:5]([CH3:28])[CH:4]=1.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH:61]1([N:64]2[CH2:69][CH2:68][N:67]([C:70]3([CH2:76][NH:77][C:78](=[O:85])[C:79]4[CH:84]=[CH:83][N:82]=[CH:81][CH:80]=4)[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]3)[CH2:66][CH2:65]2)[CH2:63][CH2:62]1>ClCCl.CN(C=O)C>[CH:61]1([N:64]2[CH2:69][CH2:68][N:67]([C:70]3([CH2:76][NH:77][C:78](=[O:85])[C:79]4[CH:80]=[CH:81][N:82]=[CH:83][CH:84]=4)[CH2:75][CH2:74][N:73]([C:25](=[O:27])[CH2:24][O:23][CH2:22][C@@H:14]4[CH2:15][C:16]5[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=5)[N:13]4[S:10]([C:6]4[C:5]([CH3:28])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:11])=[O:12])[CH2:72][CH2:71]3)[CH2:66][CH2:65]2)[CH2:62][CH2:63]1
Reactant: O=C(NCC1(N2CCN(C3CC3)CC2)CCNCC1)c1ccncc1
Reactant: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2COCC(=O)O)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2COCC(=O)N2CCC(CNC(=O)c3ccncc3)(N3CCN(C4CC4)CC3)CC2)c(C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a solution of (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)indolin-2-yl)methoxy)acetic acid AC10 (0.282 mmol) in dichloromethane (10 ml/mmol) was added diisopropyl ethylamine (4 equiv.) at 0° C. followed by the addition of HOBT (1.0 equiv.) and EDCI (1.5 equiv.). The resultant solution was stirred at 25° C. for 15 min. It was again cooled to 0° C. and a solution of N-((4-(4-cyclopropyl-piperazin-1-yl)piperidin-4-yl)methyl)isonicotinamide dihydrochloride AM12 (1.2 equiv.) in DMF (2 ml) was added. The reaction mixture was stirred for 16 h at 25° C. The mixture was diluted with dichloromethane, washed with saturated ammonium chloride solution, brine, saturated sodium bicarbonate and finally again with brine. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to yield the crude product which was purified by column chromatography. Yield: 58%. MS, Rt=3.2 min, m/z=731.5 [MH]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH:6]2[N:8]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH:3]1[CH2:4][C@H:5]2[C:19]([O:21][CH2:22][CH3:23])=[O:20].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][CH:6]2[N:8]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH:3]1[CH2:4][C@H:5]2[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)[C@@H]1CC2C(O)CC1N2C(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC2C(=O)CC1N2C(=O)OCc1ccccc1
Reaction time: 12 h
Yield: 90 %

Procedure:
A mixture of O7-benzyl O5-ethyl (5R)-2-hydroxy-7-azabicyclo[2.2.1]heptane-5,7-dicarboxylate (0.37 g, 1.1 mmol), Dess-martin reagent (1.38 g, 3.3 mmol) in DCM (50 mL) was stirred for 12 hours. After removal of solvent, the residue was purified by silica gel chromatography to give O7-benzyl O5-ethyl (5R)-2-oxo-7-azabicyclo[2.2.1]heptane-5,7-dicarboxylate 151e. Yield: 90%. MS: calc'd (MH +) 304, measured (MH +) 304.