Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[O:21][C:20]([C:23](=[O:25])[NH2:24])=[C:19]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:18]=3[CH:17]=[C:16]([CH3:33])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:36]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:22]3[O:21][C:20]([C:23](=[O:25])[NH:24][CH3:36])=[C:19]([CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:18]=3[CH:17]=[C:16]([CH3:33])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2oc(C(N)=O)c(Cc3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1oc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cc(C)cc2c1Cc1ccccc1

Procedure:
4-(3-Benzyl-2-carbamoyl-5-methyl-benzofuran-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.25 gm, 0.556 mmol) was dissolved in 5 ml DMF and sodium hydride (60% in oil, 0.033 gm, 0.83 mmol) was added, resulting in formation of a precipitate. Methyl iodide (0.052 ml, 0.83 mmol) was added and the solid dissolved to give a clear solution. After one hour the mixture was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography (3/97 methanol/dichloromethane). One band was again purified (40/60, tetrahydrofuran/hexane) to give 4-(3-Benzyl-5-methyl-2-methylcarbamoyl-benzofuran-7-yl)-piperazine-1-carboxylic acid tert-butyl ester. A second band was recrystallized from acetonitrile to give 4-(3-Benzyl-2-dimethylcarbamoyl-5-methyl-benzofuran-7-yl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(N2CCC(CO)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCC(CO)CC2)cc1
Temperature: 25 °C

Procedure:
Into a Round bottom flask, [A] [1-(4-Nitro-phenyl)-piperidin-4-yl]-methanol (5.021 g, 0.02125 mol), Ethanol (150 mL, 2.6 mol) and 10% Pd/C (10:90, Palladium:carbon black, 2.3 g, 0.0021 mol). The mixture was evacuated and charged with hydrogen via a balloon (3×). The reaction was stirred at RT under an atmosphere of Hydrogen over night. The solid was filtered and washed with Ethanol. The solvent was removed under vacuum to give [1-(4-Amino-phenyl)-piperidin-4-yl]-methanol a brown solid. The solid was triturated with Et2O to give a pink solid. NMR 1H (DSMO-d6)-6.68 (d, 2H, J=8.72 Hz), 6.47 (d, 2H J=8.68 Hz), 4.51 (bs, 2H), 4.43 (t, 1H, J=4.25 Hz), 3.22-3.40 (m, 4H), 2.43 (dt, 2H, JJ=2.24, 9.61 Hz) 1.70 (bd, 2H, J=11.15 Hz), 1.25-1.47 (m, 3H)
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:30])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24]OS(C)(=O)=O)[N:22]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[SH:37]>>[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][S:37][C:33]3[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=3)[N:22]=2)=[O:30])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cn1ccnc1S
Reactant: Cc1ccc(NC(=O)Nc2nc(CCOS(C)(=O)=O)cs2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2nc(CCSc3nccn3C)cs2)c(C(=O)C2CCCC2)c1
Yield: 43.6 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-{4-[2-(1-methyl-1H-imidazol-2-ylsulfanyl)-ethyl]-thiazol-2-yl}-urea (45 mg, 43%) was prepared from methanesulfonic acid 2-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-ethyl ester (0.10 g, 0.22 mmol) and 1-methyl-1H-immidazole-2-thiol (0.04 g, 0.33 mmol) following the general procedure Z.
Reaction SMILES: CI.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:13]=2)=[CH:6][C:5]=1[NH:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:28]=1.[C:39](=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH:13]=2)=[CH:6][C:5]=1[NH:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([S:34]([CH3:37])(=[O:35])=[O:36])[CH3:39])[CH:28]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(NS(C)(=O)=O)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(N(C)S(C)(=O)=O)c1
Temperature: 50 °C
Yield: 57.2 %

Procedure:
Methyl iodide (0.023 ml) was added to a mixture of N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-methanesulphonylaminobenzamide (0.17 g), caesium carbonate (0.121 g) and DMF (10 ml) and the resultant mixture was stirred and heated to 50° C. for 72 hours. The reaction mixture was poured into water (200 ml). The precipitate was isolated, washed in turn with water and diethyl ether and dried under vacuum at 60° C. There was thus obtained the title compound (0.1 g); m.p. 208-209° C.; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 3.0 (s, 3H), 3.18 (t, 4H), 3.75 (t, 4H), 7.13 (m, 1H), 7.23 (d, 1H), 7.36 (m, 2H), 7.45 (d, 1H), 7.59 (m, 3H), 7.81 (d, 1H), 7.91 (d, 1H), 7.99 (d, 1H), 9.98 (s, 1H), 10.12 (s, 1H); Mass Spectrum: M+H+523.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][C@H:29]1[O:34][C@@H:33]([CH3:35])[CH2:32][NH:31][CH2:30]1>CN(C)C=O.C(OCC)(=O)C>[CH3:35][CH:33]1[CH2:32][N:31]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:30][CH:29]([CH3:28])[O:34]1
Reactant: COC(=O)c1ccc(-c2ccc(OCCCBr)cc2)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(OCCCN3CC(C)OC(C)C3)cc2)cc1
Yield: 45.8 %

Procedure:
A solution of methyl 4-[4′-(3-bromopropyoxy)phenyl]benzoate (1.5 g), potassium carbonate (1.2 g) and cis-2,6-dimethylmorpholine (990.6 mg) in N,N-dimethyformamide was stirred for 15 hours at room temperature, then diluted with ethyl acetate and washed with water (5x), dried over magnesium sulfate, evaporated, then purified by silica gel chromatography (20:1 dichloromethane-ethanol elution) to give methyl 4-[4′-[3-(2,6-dimethylmorpholino)propoxy]phenyl]benzoate (755 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.I[C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][N:43]=1>>[NH:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42]([C:5]2[N:4]=[C:3]3[C:8]([N:9]=[C:10]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]4)[N:2]3[CH3:1])=[C:7]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:6]=2)=[N:43]1
Reactant: Ic1n[nH]c2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3n[nH]c4ccccc34)nc21

Procedure:
2-(1-((9-Methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.5 g) was reacted with 3-iodo-1H-indazole via General Procedure G to give 68.3 mg of 162 as a white solid following reverse phase purification. MS (Q1) 491.2 (M)+
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.I[CH:12]([CH3:14])[CH3:13].C(N(CC)CC)C>CO>[CH:12]([NH:6][C:5]1[CH:7]=[CH:8][C:9]2[O:10][CH2:1][O:2][C:3]=2[CH:4]=1)([CH3:14])[CH3:13]
Reactant: CC(C)I
Reactant: Nc1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)Nc1ccc2c(c1)OCO2
Yield: 85 %

Procedure:
To a solution of 3,4-(methylenedioxy)aniline (9.0 g), and 2-iodopropane (5.9 ml) in methanol (100 mL) was added triethylamine (8.2 mL). The mixture was refluxed for 50 h, and then concentrated in vacuo. The residue was taken with 1:1 hexane/EtOA (180 mL), washed with water and brine, dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by chromatography (3:1 hexane/EtOAc) to yield the title compound as an oil (10.1 g, 85%). 1H NMR (CDCl3): 6.64 (d, J=8.3, 1H), 6.23 (d, J=2.2, 1H), 6.03 (dd, J=2.2, 8.3, 1H), 5.85 (s, 2H), 3.51 (m, 1H), 3.19 (br s, 1H), 1.18 (d, J=6.1, 6H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C@@H:8]2[C@H:13]3[CH2:14][C@H:10]([CH2:11][CH2:12]3)[C@@H:9]2[C:15](OC)=[O:16])=[CH:4][CH:3]=1.[CH3:21][S:22]([NH:25][C:26]1[CH:41]=[CH:40][C:29]2[NH:30][C:31]([CH2:36][C:37](O)=[O:38])=[N:32][S:33](=[O:35])(=[O:34])[C:28]=2[CH:27]=1)(=[O:24])=[O:23].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:37](=[O:38])[C:36]([C:31]3[NH:30][C:29]4[CH:40]=[CH:41][C:26]([NH:25][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:27][C:28]=4[S:33](=[O:35])(=[O:34])[N:32]=3)=[C:15]([OH:16])[C@@H:9]3[C@H:8]2[C@H:13]2[CH2:14][C@@H:10]3[CH2:11][CH2:12]2)=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H]1[C@H]2CC[C@H](C2)[C@H]1NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@H]3[C@H]4CC[C@H](C4)[C@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Yield: 46.3 %

Procedure:
Methyl (1S,2S,3R,4R)-3-[(4-fluorobenzyl)amino]bicyclo[2.2.1]heptane-2-carboxylate (0.087 g, 0.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (2.8 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 0.1 g, 0.3 mmol) was added followed by N-methylmorpholine (0.07 mL, 0.63 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.061 g, 0.315 mmol) was added and the mixture was stirred at 25° C. for 4 h. Triethylamine (0.126 mL, 0.9 mmol) was added and the mixture was stirred at 50° C. for 16 h. Upon cooling to 25° C., the solution was diluted with ethyl acetate (25 mL) and washed with 1.0 M aqueous hydrochloric acid solution (2×25 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The oil was dissolved in methanol (4 mL) and the product was precipitated by the addition of 1.0 M aqueous hydrochloric acid solution (4 mL) while stirring. The solid was collected by vacuum filtration and further dried in vacuo to afford the desired product, N-{3-[(1R,2R,7S,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.0781 g, 0.139 mmol, 46%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.23-1.48 (6H, m), 2.67-2.68 (2H, m), 3.06 (3H, s), 3.24 (1H, d, J=15.0 Hz), 3.72 (1H, d, J=11.9 Hz), 4.07 (1H, d, J=15.6 Hz), 5.12 (1H, d, J=15.7 Hz), 7.14 (2H, t, J=8.4 Hz), 7.39 (2H, dd, J1=8.2 Hz, J2=5.8 Hz), 7.51 (1H, dd, J1=8.4 Hz, J2=2.3 Hz), 7.57-7.60 (2H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C25H25FN4O6S2 560.12, found 561.3 [M+H+]. ee=99% [HPLC-analysis: Chiralpak AS-RH 4.6×250 mm, 5 micron at r.t., Solvent A-Solvent B (see table for gradient), 0.8 mL/min, 310 nm, t1=7.58 min, t2=10.08 min (major)].
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[N:18]=[N:19][NH:20][CH:21]=3)=[C:9]([O:22]CC3C=CC=CC=3)[C:8]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N2C=CC(CCCC3N=NNC=3)=C(O)C2=O)C=CC=CC=1>C1COCC1>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[N:18]=[N:19][NH:20][CH:21]=3)=[C:9]([OH:22])[C:8]2=[O:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c(OCc2ccccc2)c(CCCCc2c[nH]nn2)ccn1-c1ccccc1
Agent: O=c1c(O)c(CCCc2c[nH]nn2)ccn1-c1ccccc1
Solvent: C1CCOC1
Product: O=c1c(O)c(CCCCc2c[nH]nn2)ccn1-c1ccccc1
Yield: 62.4 %

Procedure:
Reaction of 158c (0.25 g, 0.62 mmol) in anhydrous THF as described for synthesis of 159b gave 159c (0.12 g, 63%) of pure product. 1H NMR (400 MHz, CDCl3) δ 7.79 (m, 3H), 7.41 (t, J=7.6 Hz, 2H), 7.32 (t, J=7.4 Hz, 1H), 6.76 (m, 3H), 6.13 (t, J=7.2 Hz, 1H), 4.45 (t, J=6.8 Hz, 2H), 4.02 (t, J=7.1 Hz, 2H), 1.99 (m, 2H), 1.82 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 158.47, 147.63, 146.62, 130.41, 128.69, 127.99, 126.60, 125.53, 119.80, 114.15, 107.10, 49.38, 48.57, 27.02, 26.01. HRMS (EI) calcd for C17H18N4O2 [M]+ 310.1430. found 310.1425.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][S:19](O)(=[O:21])=[O:20]>C(Cl)Cl>[C:15]([NH:14][CH2:13][C:7]1([C:1]2[CH:6]=[CH:5][C:4]([S:19]([Cl:18])(=[O:21])=[O:20])=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)(=[O:17])[CH3:16]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)NCC1(c2ccccc2)CCCCC1
Solvent: ClCCl
Product: CC(=O)NCC1(c2ccc(S(=O)(=O)Cl)cc2)CCCCC1
Temperature: 50 °C
Reaction time: 10 h

Procedure:
4.5 g of N-(1-Phenyl-cyclohexylmethyl)-acetamide were dissolved in 80 ml of methylenechloride and 3.8 ml of chlorosulfonic acid were added. The reaction mixture was stirred at 50° C. for 10 hours and was poured on ice water. The organic layer was separated, washed twice with 50 ml brine and then dried over MgSO4. The solvent was removed in vacuo to obtain 1.5 g of a light yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][O:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2.[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH:4]=[C:5]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][CH2:9][O:8][C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]2=3)[CH2:28][CH2:27]1)=[O:25])[CH3:22]
Reactant: CCOC(=O)C1CCNCC1
Reactant: BrCCC=C1c2ccccc2OCOc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCC=C2c3ccccc3OCOc3ccccc32)CC1
Temperature: 65 °C
Yield: 47 %

Procedure:
A mixture of 12-(3-bromo-1-propylidene)-12H-dibenzo[d,g][1,3]dioxocine (4.0 g, 12 mmol, prepared as described in example 1, 4-piperidinecarboxylic acid ethyl ester (1.9 g, 12 mmol), anhydrous potassium carbonate (5.0 g) and sodium iodide (0.2 g) in N,N-dimethylformamide (40 ml) was heated at 60-70° C. for 5 h. After cooling, the inorganic salts were filtered off and washed with benzene (40 ml), and the filtrate was diluted with additional benzene (120 ml). The benzene solution was washed with water (3×50 ml), dried over MgSO4 and evaporated in vacuo. The oily residue (4.8 g) was purified by chromatography on silica gel using a mixture of benzene and ethyl acetate as eluent to give 1-(3-(12H-dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-4-piperidinecarboxylic acid ethyl ester as an oil (2.3 g, 47%).
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C@@H:3]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14][C@H:2]12.[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C>[O:7]=[C:5]1[CH2:6][O:1][C@H:2]2[CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C@H:3]2[N:4]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CBr
Reactant: O=C1CO[C@H]2Cc3ccccc3[C@H]2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)CO[C@H]2Cc3ccccc3[C@H]21
Reaction time: 0.17 h

Procedure:
To a solution of (4aR,9aS)-4,4a,9,9a-tetrahydroindeno[2,1-b][1,4]oxazin-3(2H)-one from Step B (600 mg, 3.17 mmol) in DMF (15 mL) at 0° C. was added NaH (228 mg of a 60% dispersion in oil, 5.71 mmol) and the resulting mixture was stirred for 10 min. Ethyl bromoacetate (0.288 mL, 3.5 mmol) was added and the reaction mixture was stirred for 18 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL) and then extracted with EtOAc (2×40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc 80:20 to 0:100, to give the title compound. MS: m/z=276 (M+1)
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:37])=[N:14][C:15]2[N:16]([N:29]=[C:30]([C:32]([O:34]CC)=[O:33])[CH:31]=2)[C:17]=1[C:18]1[CH:27]=[CH:26][C:21]2[O:22][CH2:23][CH2:24][NH:25][C:20]=2[C:19]=1[Cl:28])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:37])=[N:14][C:15]2[N:16]([N:29]=[C:30]([C:32]([OH:34])=[O:33])[CH:31]=2)[C:17]=1[C:18]1[CH:27]=[CH:26][C:21]2[O:22][CH2:23][CH2:24][NH:25][C:20]=2[C:19]=1[Cl:28])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(-c3ccc4c(c3Cl)NCCO4)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1-c1ccc2c(c1Cl)NCCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
To a solution of ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (315 mg, 0.593 mmol) in EtOH (6 mL) was added 1N NaOH (0.712 mL, 0.712 mmol) and the resulting mixture was stirred at room temp for 4 h. A this point LCMS indicated completion of reaction. Then, the reaction mixture was concentrated and the residue diluted with water (3 mL), acidified with 1N HCl, extracted with ethyl acetate (25 mL), washed with brine (10 mL), dried (Na2SO4), filtered and concentrated to afford 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (230 mg, 0.457 mmol, 77% yield) as off-white solid (approx 2:1 mixture of mono and di-acid) which was used as is in the next step without further purification. LCMS (M+H)=503.3.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.Cl.[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[I:1][C:2]1[C:7]([C:8]([NH:21][NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1
Reactant: COc1nccc(I)c1C(=O)O
Reactant: NNc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1nccc(I)c1C(=O)NNc1ccccc1
Yield: 53.4 %

Procedure:
A solution of 4-iodo-2-methoxynicotinic acid (1.5 g) obtained in Step C of Example 6, phenylhydrazine hydrochloride (0.933 g), DIEA (3.0 mL), EDCI hydrochloride (1.24 g) and HOBt (0.872 g) in DMF (100 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.06 g).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]([NH2:17])=[O:16])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]([NH2:17])=[O:16])[C:9]3[C:4](=[N:5][CH:6]=[CH:7][N:8]=3)[CH:3]=2)=[CH:22][CH:21]=1
Reactant: NC(=O)CCNc1nc(Cl)cc2nccnc12
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: CN(C)c1ccc(-c2cc3nccnc3c(NCCC(N)=O)n2)cc1

Procedure:
The title compound was prepared according to the procedure of Compound 1 (B) using 3-(7-chloropyrido[4,3-b]pyrazin-5-ylamino)propanamide prepared above and 4-(dimethylamino)phenylboronic acid. MS (m/z): 337 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][C:12]([NH2:18])=[C:11]3[C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.CO.N#N>CCOC(C)=O.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH2:13][CH:12]([NH2:18])[CH:11]3[C:19]([F:22])([F:20])[F:21])=[CH:6][CH:7]=1
Reactant: Nc1cnc2ccc(-c3ccc(F)cc3)cc2c1C(F)(F)F
Agent: [Pd+2]
Agent: N#N
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC1CNc2ccc(-c3ccc(F)cc3)cc2C1C(F)(F)F
Reaction time: 16 h
Yield: 15.4 %

Procedure:
To a solution of 147B (400 mg, 1.3 mmol) in EtOAc (5 mL)-MeOH (15 mL) was bubbled with N2 for 15 min, then palladium hydroxide (20 weight % palladium on carbon) (200 mg) was added. The resulting suspension was subjected to hydrogenation under 80 psi of pressure for 16 h., then filtered. The filtrate was concentrated. The residue was chromatographed (silica gel) eluting with 20% EtOAc in hexane (100 mL), 50% EtOAc in hexane (100 mL), 100% ETOAc (100 mL), 5% MeOH in EtOAc (150 mL) to give title compound (62 mg, 15% yield) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][C:24]([OH:26])=O.C(Cl)(=O)C([Cl:30])=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][C:24]([Cl:30])=[O:26]
Reactant: CC1=C(CC(=O)O)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC1=C(CC(=O)Cl)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1

Procedure:
(Z)-5-Fluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid (20 g, 53.70 mmol) was suspended in dichloromethane (400 mL). Oxalylchloride (2M in CH2Cl2; 35 mL; 70 mmol) was added at room temperature. The reaction mixture was refluxed (24 h), and was evaporated to yield the title compound, which was used as such in the next step.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:35]([NH:38][C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1[Cl:34]>>[Cl:34][C:33]1[CH:32]=[CH:31][C:30]([S:35](=[O:37])(=[O:36])[NH:38][C:39]([CH3:42])([CH3:43])[CH2:40][OH:41])=[CH:29][C:28]=1[NH:27][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:1])([F:26])[F:25])=[CH:4][C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=3)=[N:6][C:7]=12)=[O:13]
Reactant: CC(C)(CO)NS(=O)(=O)c1ccc(Cl)c(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1ccc(Cl)c(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-4-chloro-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.10) according to general procedure II. Yellow solid. MS (ISP) 634.0 [(M−H−]; mp 246° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][C@H:16]([O:18][CH3:19])[C@@H:15]([O:20][CH3:21])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH2:32])=[CH:27][CH:26]=2>>[CH3:21][O:20][C@@H:15]1[C@@H:16]([O:18][CH3:19])[CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:32][C:28]3[CH:29]=[C:30]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:22])=[CH:31]4)[CH:8]=2)=[O:12])[CH2:14]1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CO[C@H]1CN(C(=O)c2cc3nccc(Cl)c3s2)C[C@@H]1OC
Product: CO[C@H]1CN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)C[C@@H]1OC

Procedure:
The title compound was prepared from (3S,4S)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3,4-dimethoxy-pyrrolidin-1-yl)-methanone and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C MS: 437.4 (MH+); HPLC Rf: 4.432 min.; HPLC purity: 98%.