Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].Cl.[CH2:8]([O:10][C:11]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][C:14]1=[O:26])=[O:12])[CH3:9].IC.[NH4+].[Cl-]>C1COCC1>[CH2:8]([O:10][C:11]([C:13]1([CH3:1])[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:15][C:14]1=[O:26])=[O:12])[CH3:9]
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCN(Cc2ccccc2)CC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
A milky solution of 7.75 g (69.02 mmol) of potassium tert-butylate in 125 ml of THF was cooled (0° C.) and treated portion wise with 10.44 g (34.00 mmol) of ethyl-N-benzyl-3-oxo-4-piperidin-carboxylate hydrochloride so the temperature did not rise over 5° C. After 1 h at RT, the reaction was cooled (0° C.) and ad treated slowly with 5.07 ml (35.70 mmol) of iodomethane in 4 ml of THF. After 4.5 h at RT, the reaction was cooled (0° C.) and neutralized with 40 ml of aqueous saturated NH4Cl solution. The aqueous phase was extracted with Et2O (3×). The organic phases were washed with aqueous saturated NaCl, dried over Na2SO4 and evaporated to give 4.97 g (53%) of the titled compound as orange oil. MS: 276.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[S:48][C:47]([CH2:49][NH2:50])=[CH:46][CH:45]=1.C(N(C(C)C)CC)(C)C>CN(C)C(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:50][CH2:49][C:47]2[S:48][C:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=3)=[CH:45][CH:46]=2)=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: NCc1ccc(-c2ccccn2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C(=O)NCc2ccc(-c3ccccn3)s2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of Example 104A (32.5 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL) was added, followed by the addition of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (50.4 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). Then, commercially available [5-(2-pyridinyl)-2-thienyl]methylamine (36.2 mg, 0.19 mmol) dissolved in N,N-dimethylacetamide (0.6 mL) was added followed by the addition of diisopropyl ethyl amine (57.9 uL, 0.31 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). The mixture was shaken at room temperature overnight. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate) to give the titled compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.08-1.28 (m, 3H) 1.29-1.37 (m, 2H) 4.25-4.53 (m, 2H) 4.54-4.69 (m, 2H) 6.95-7.06 (m, 1H) 7.09-7.12 (m, 1H) 7.16-7.32 (m, 1H) 7.49-7.64 (m, 1H) 7.68-7.91 (m, 2H) 8.31-8.52 (m, 1H); MS (ESI) positive ion 380 (M+H).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][NH:5][C:4]2[CH:8]=[CH:9][C:10]([OH:12])=[CH:11][C:3]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:12][C:10]1[CH:9]=[CH:8][C:4]2[NH:5][CH2:6][CH2:7][O:2][C:3]=2[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc2nccc(Cl)c2cc1OCc1ccccc1
Reactant: Oc1ccc2c(c1)OCCN2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc4c(c3)OCCN4)c2cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 83.5 %

Procedure:
A solution of 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol hydrochloride (0.626 g, 3.34 mmol), cesium carbonate (4.35 g, 13.3 mmol), and 6-(benzyloxy)-4-chloro-7-methoxyquinoline (1.00 g, 3.34 mmol) in DMF (10.0 mL) was stirred at 80° C. for 18 h. An additional 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol hydrochloride (0.626 g, 3.34 mmol) and cesium carbonate (4.35 g, 13.3 mmol) were added, and the mixture stirred at 80° C. for 3 days. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange-brown oil. This material was purified twice via column chromatography (RediSep 80 g column, gradient elution with 0-5% methanol-dichloromethane) to afford an orange oil. Trituration with methanol and filtering the resulting suspension afforded 7-(6-(benzyloxy)-7-methoxyquinolin-4-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.156 g, 83.6% yield) as an orange glass. MS (MH+) 415.1; Calculated 414 for C25H22N2O4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][CH2:30][NH2:31]>>[NH2:31][CH2:30][CH2:29][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[C:27]4[O:26][CH2:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:18]2)=[O:12])=[CH:7]1
Reactant: NCCCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2cccc3c2OCC3)CC1
Product: NCCn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-ethylamine gave the title compound.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH:3]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[C:21]([Cl:27])[CH:20]=1)/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=1.[F:30][C:31]([F:39])([F:38])[CH2:32][CH2:33][C:34]([NH:36][NH2:37])=[O:35].CN1CCOCC1>ClCCCl.O>[F:1][C:2]([F:29])([F:28])[CH:3]([C:19]1[CH:20]=[C:21]([Cl:27])[C:22]([Cl:26])=[C:23]([Cl:25])[CH:24]=1)/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:37][NH:36][C:34](=[O:35])[CH2:33][CH2:32][C:31]([F:39])([F:38])[F:30])=[O:11])=[C:8]([C:15]([F:16])([F:18])[F:17])[CH:7]=1
Reactant: O=C(Cl)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Reactant: NNC(=O)CCC(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: O
Product: O=C(CCC(F)(F)F)NNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a stirred solution of (E)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoyl chloride (143 mg, 0.288 mmol) in DCE (3 mL) were added 4,4,4-trifluorobutanehydrazide (45 mg, 0.29 mmol), and 4-methylmorpholine (63.4 μL, 0.577 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined EtOAc layers were washed with aqueous 1M HCl (−1×30 mL), saturated aqueous NaHCO3 (1×30 mL), and brine. The resulting organic solution was dried over Na2SO4 and concentrated under reduced pressure. Purification by automated flash column chromatography (SiO2, hexanes and EtOAc) afforded the title compound as a beige solid (78 mg, 42%): 1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 9.85 (s, 1H), 7.70-7.62 (m, 1H), 7.55 (dd, J=8.0, 1.6 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.41 (s, 2H), 6.59 (d, J=15.9 Hz, 1H), 6.44 (dd, J=15.9, 7.8 Hz, 1H), 4.19-4.05 (m, 1H), 2.51 (dd, J=9.0, 6.6 Hz, 2H), 2.37-2.18 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −59.46, −67.07, −68.59; ESIMS m/z 615 ([M−H]−).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=N>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: N=C(NO)c1ccccn1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3ccccn3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-pyridine-2-carboxamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.60 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)=[N:6][CH:7]=1.C([OH:24])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)=[N+:6]([O-:24])[CH:7]=1
Reactant: CC1(C)CC(c2ccc(Cl)cn2)c2cc(C#N)ccc2O1
Reactant: CCO
Product: CC1(C)CC(c2ccc(Cl)c[n+]2[O-])c2cc(C#N)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 39, from 4-(5-chloro-2-pyridyl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile there was obtained 5-chloro-2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 159°-161° C. (from ethanol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:21]([N:26]=[N+]=[N-])(=[O:25])[O:22][CH2:23][CH3:24]>CCOCC>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:8](=[N:26][C:21](=[O:25])[O:22][CH2:23][CH3:24])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)N=[N+]=[N-]
Reactant: Cc1ccccc1P(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)N=P(c1ccccc1)(c1ccccc1)c1ccccc1C
Reaction time: 48 h

Procedure:
A solution of 1.0 g of (2-methylphenyl)diphenylphosphine in 30 ml of ether was treated with 4 ml of 1M ethyl carbonazidate in ether. The mixture was allowed to stand 48 hours, then repeatedly concentrated and finally treated with fresh ether and refrigerated, giving 930 mg of the desired compound, mp 113°-114° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].Cl[S:29]([C:32]1[CH:33]=[CH:34][C:35]([O:53][CH3:54])=[C:36]([CH:52]=1)[C:37]([O:39][CH2:40][CH2:41][S:42]([C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=1)(=[O:44])=[O:43])=[O:38])(=[O:31])=[O:30].O>C(Cl)Cl>[C:48]1([CH3:51])[CH:49]=[CH:50][C:45]([S:42]([CH2:41][CH2:40][O:39][C:37](=[O:38])[C:36]2[CH:52]=[C:32]([S:29]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:31])=[O:30])[CH:33]=[CH:34][C:35]=2[O:53][CH3:54])(=[O:44])=[O:43])=[CH:46][CH:47]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(=O)OCCS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(S(=O)(=O)n2c(S(=O)Cc3nccc(OCC(F)(F)F)c3C)nc3ccccc32)cc1C(=O)OCCS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.3 %

Procedure:
To a clear solution of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (740 mg, 2.0 mmol) and NaH (60 mg, 2.5 mmol) in 10 mL of CH2Cl2 was added 2-(p-toluenesulfonyl)ethyl 5-chlorosulfonyl-2-methoxybenzoate (Intermediate 7, 1.0 g, 2.3 mmol). The resulting mixture was stirred at room temperature for 1.5 h. Thereafter water was added and the mixture was extracted with CH2Cl2. The dichloromethane layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give a thick oil. The oil was purified by column chromatography (silica gel, CH2Cl2 to 2% MeOH in CH2Cl2) to give 1.0 g (65%) of 2-methoxy-5-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}benzoic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 8).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]3[NH:14][N:15]=[CH:16][C:9]=23)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[CH:27]=[CH:26][C:25]2[C:24]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)=[N:23][CH:22]=[CH:21][C:20]=2[C:19]=1[NH2:39].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].N.CO>C1COCC1.CC(O)=O.CO>[NH:14]1[C:10]2=[N:11][CH:12]=[N:13][C:8]([C:7]3[C:2]([NH:39][C:19]4[C:20]5[CH:21]=[CH:22][N:23]=[C:24]([NH:28][C:29]6[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=6)[C:25]=5[CH:26]=[CH:27][C:18]=4[CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=3)=[C:9]2[CH:16]=[N:15]1
Reactant: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1N
Reactant: Fc1ncccc1-c1ncnc2[nH]ncc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1Nc1ncccc1-c1ncnc2[nH]ncc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(2-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (30 mg, 139 μmol) and 6-methyl-N1-(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine (49 mg, 153 μmol) in THF (3 mL) was treated with lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 627 μL, 627 μmol). The mixture was stirred at it for 3 h and then heated in a microwave at 100° C. for 20 min. The mixture was poured into MeOH (15 mL) and AcOH (0.5 mL) and then 2M NH3/MeOH (30 mL) was added. Solvent was removed in vacuo. The product was purified by flash chromatography eluting with MeOH/DCM (1-5%) to give N5-(3-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-6-methyl-N1-(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine. MS (ESI, pos. ion) m/z: 513.2 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[O:17][C:16](=O)[NH:15][C:14](=[O:20])[C:13]=3[CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[NH4+:22]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[NH:22][C:16](=[O:17])[NH:15][C:14](=[O:20])[C:13]=3[CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)c(F)c1)COC2
Reactant: [NH4+]
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)COCC2c1ccc(F)c(F)c1

Procedure:
8-(3,4-difluorophenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (Intermediate Y(3)) was reacted as described in Intermediate X(4) with ammonium hydroxide to give 8-(3,4-difluorophenyl)-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione (Intermediate Y(4)). LC-MS (M−H)+=279.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]2[O:35][CH2:34][CH2:33][NH:32][C:31]=2[CH:36]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCN(CC)CC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:4]2[C:5]([C:8]([N:32]3[C:31]4[CH:36]=[C:27]([Cl:26])[CH:28]=[CH:29][C:30]=4[O:35][CH2:34][CH2:33]3)=[O:10])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:14])=[O:13])=[CH:16][C:17]=1[C:22]([F:24])([F:25])[F:23]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Clc1ccc2c(c1)NCCO2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCOc2ccc(Cl)cc21

Procedure:
6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazine 5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid, T3P, and Et3N were reacted according to the procedure D to provide the title compound. HPLC purification provided 4-chloro-N-[5-chloro-2-(6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide. Reverse phase HPLC gradient acetonitrile 0.1% TFA 20-95% in 4 min: 3.180 min MS m/z: 567.1 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:11])([CH3:10])[CH2:8][OH:9])=[CH:3][CH:2]=1>C(O)(=O)C.[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:11])([CH3:10])[CH2:8][OH:9])[CH2:3][CH2:2]1
Reactant: CC(O)(CO)c1ccncc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(O)(CO)C1CCNCC1
Reaction time: 16 h
Yield: 101 %

Procedure:
A solution of 2-(4-pyridyl)propane-1,2-diol (2.0 g) in acetic acid (30 cm3) was hydrogenated over platinum oxide (0.10 g) at 60° and 60 p.s.i. pressure for 16 hours. The catalyst was removed by filtration through "Avicel" and volatile material was removed in vacuo to afford 2-(4-piperidyl)propan-1,2-diol (2.1 g). (Crude acetate salt, oil).
Reaction SMILES: [NH2:1][C:2]([CH2:11][OH:12])=[CH:3][C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:13][C:14]1[C:15]([NH:20]N)=[N:16][CH:17]=[CH:18][CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[Cl:13][C:14]1[C:15]([N:20]2[C:4]([OH:10])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][C:2]([CH2:11][OH:12])=[N:1]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(=O)C=C(N)CO
Reactant: NNc1ncccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1(O)CC(CO)=NN1c1ncccc1Cl

Procedure:
A mixture of ethyl 4-amino-5-hydroxy-2-oxopent-3-enoate (2.5 g, 14 mmol), 3-chloropyridin-2-ylhydrazine (2.07 g, 14 mmol) and p-toluenesulphonic acid monohydrate (2.5 g, 13 mmol) was stirred in 25 ml of acetonitrile at 25° C. for 5 hours. The precipitate was isolated by filtration and the filtrate was concentrated under reduced pressure. The product was purified by column chromatography on SiO2 (eluent: hexane/ethyl acetate). Oil. Yield 4.2 g (90%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:29])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:28][CH2:27][C@@H:16]3[N:17]4[C:26]5[C:25]([C@@H:15]3[CH2:14]2)=[CH:24][CH:23]=[CH:22][C:21]=5[NH:20][CH2:19][CH2:18]4)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:29])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:28][CH2:27][C@@H:16]3[N:17]4[C:26]5[C:25]([C@@H:15]3[CH2:14]2)=[CH:24][CH:23]=[CH:22][C:21]=5[NH:20][CH2:19][CH2:18]4)=[CH:5][CH:4]=1
Reactant: O=C(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCN3)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCN3)c1ccc(F)cc1
Yield: 94.8 %

Procedure:
1-(4-Fluoro-phenyl)-4-((6bR,10aS)-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one HCl salt (500 mg, 1.20 mmol) is suspended in 20 mL of methanol. NaBH4 (136 mg, 3.60 mmol) is added slowly into the suspension at room temperature. The suspension changed into a clear solution during the addition of NaBH4. After an hour, additional 90 mg of NaBH4 is added into the mixture to push the reaction to completion. The reaction mixture is quenched by adding 10 mL of water. After solvent is removed by rotary evaporation, the residue is treated with 10 mL of 1N NaOH aqueous solution, and then extracted with methylene chloride three times. The combined organic phase is washed with water, dried with anhydrous sodium sulfate, and then evaporated to dryness under vacuum to give 434 mg off-white foamy solids with 98% purity and 95% yield. MS (ESI) m/z 382.2 [M+H]+
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O>CS(C)=O>[I:1][C:2]1[C:7]2[C:8](=[O:10])[N:14]3[CH2:21][CH2:20][CH2:19][C@H:15]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(I)c2c(=O)o1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: O=C1Nc2cccc(I)c2C(=O)N2CCC[C@@H]12

Procedure:
14.6 g (0.050 mol) of 6-iodo-isatoic acid anhydride and 6.6 g (0.058 mol) of L-proline in 50 ml of dimethyl sulphoxide are heated to 70° for 30 minutes, the solvent is removed in a high vacuum and the oil obtained is heated to 170° for 15 minutes. The crude product is purified by chromatography on silica gel using methylene chloride and a mixture of methylene chloride and ethyl acetate for the elution. There is obtained (S)-1,2,3,11a-tetrahydro-6-iodo-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione which melts at 212°-215° after recrystallization from methanol.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[CH2:8][C:9]1[N:10]([CH3:35])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH2:33][CH3:34])[N:12]=2.[O:36]1[CH2:39][C:38](=O)[CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:33]([C:25]1[N:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([CH2:8][N:2]4[CH2:3][C@@H:4]5[CH2:7][C@H:1]4[CH2:6][N:5]5[CH:38]4[CH2:39][O:36][CH2:37]4)[N:10]3[CH3:35])=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34]
Reactant: O=C1COC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4C3COC3)n(C)c2n1
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A solution of 8-[(1S,4S)-1-(2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-2-(2-ethyl-benzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (250 mg, 0.53 mmol), oxetan-3-one (40 mg, 0.31 mmol) and molecular sieves (4 Å, powdered, 200 mg) in DCE (7 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (148 mg, 0.70 mmol) was added and the mixture stirred for 16 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH, gradient from 100:0 to 90:0) to afford 598 as a white solid (125 mg, 45%). LCMS (method I): RT=2.39 min, M+H+=530. 1H NMR (CDCl3, 400 MHz) δ 8.02 (m, 1 H), 7.76 (m, 1 H), 7.26 (m, 2 H), 4.72-4.65 (m, 4 H), 4.34 (m, 4 H), 4.01-3.86 (m, 10 H), 3.35 (m, 4 H), 2.99 (m, 1 H), 2.82 (m, 1 H), 2.76 (m, 2 H), 1.79 (m, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)[C:5]([NH2:13])=[C:4]([Cl:14])[N:3]=1.[C:15](OC(OCC)OCC)(=O)C>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([N:13]=[CH:15][N:8]2[CH:9]2[CH2:10][CH2:11][CH2:12]2)=[C:4]([Cl:14])[N:3]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: Nc1c(Cl)nc(Cl)nc1NC1CCC1
Solvent: CCOC(C)=O
Product: Clc1nc(Cl)c2ncn(C3CCC3)c2n1
Temperature: 80 °C
Yield: 53 %

Procedure:
2,6-Dichloro-N4-cyclobutylpyrimidine-4,5-diamine (crude, 5.65 mmol) in diethoxymethyl acetate (8 mL) was stirred and heated at 80° C. for 16 hr. The mixture was cooled to rt, diluted with EtOAc (80 mL) and washed with water (80 mL), sat. NaHCO3 (80 mL) and brine (80 mL). The organic layer was dried over Na2SO4 and concentrated. The crude product was purified via flash chromatography eluting with 20-50% EtOAc/heptanes to give the title compound as an off-white solid (727 mg, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (1 H, s) 5.07 (1 H, quin, J=8.56 Hz) 2.59-2.77 (2 H, m) 2.42-2.50 (2 H, m) 1.71-1.96 (2 H, m); m/z (APCI+) for C9H8Cl2N4 243.10 (M+H)+.