Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][C:6]1=[O:15].[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]1=[O:15]
Reactant: COCCn1ccc(C(=O)OC)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCn1ccc(C(=O)O)cc1=O
Temperature: 80 °C
Yield: 68.6 %

Procedure:
Methyl 1-(2-methoxyethyl)-2-oxo-pyridine-4-carboxylate (1.56 g, 7.39 mmol), dioxane (16 mL) and NaOH (20 mL of 1M, 20 mmol) were combined and the mixture was heated at 80° C. for 50 min. The solvent was evaporated under reduced pressure and the residue was dissolved in water before it was washed with EtOAc (3×). The aqueous layer was acidified with 1N HCl and was washed with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to yield 1-(2-methoxyethyl)-2-oxo-pyridine-4-carboxylic acid (1.0 g, 69%) as a white solid. ESI-MS m/z calc. 197.2. found 198.3 (M+1)+; Retention time: 0.29 minutes (3 min run); NMR (400 MHz, DMSO) δ 13.59 (s, 1H), 7.72 (d, J=7.0 Hz, 1H), 6.84 (d, J=1.6 Hz, 1H), 6.53 (dd, J=7.0, 1.6 Hz, 1H), 4.08 (t, J=5.2 Hz, 2H), 3.58 (t, J=5.2 Hz, 2H), 3.23 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[N:12]=1)[CH2:2][CH3:3].Br[CH2:14][C:15]1[CH:34]=[CH:33][C:18]2/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:20]2=[C:21]([CH:24]=1)[O:22][CH2:23][C:17]1[CH:16]=[C:15]([CH2:14][N:5]3[C:6]4[CH:11]=[CH:10][N:9]=[CH:8][C:7]=4[N:12]=[C:4]3[CH2:1][CH2:2][CH3:3])[CH:34]=[CH:33][C:18]=1/[C:19]/2=[C:29](/[CH3:32])\[C:30]#[N:31]
Reactant: CCCc1nc2cnccc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: CCCc1nc2cnccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 13.6 %

Procedure:
Using 2-propyl-1H-imidazo[4,5-c]pyridine (135 mg, 0.838 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (300 mg, 0.838 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (50 mg, 14%) was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[N:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=O)[O:31]C2C=CC([N+]([O-])=O)=CC=2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:30]([NH:29][C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)=[O:31])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: O=C(Nc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)Nc3ccncc3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.9 %

Procedure:
To a solution of (S)-4-amino-5-(piperidin-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (Example 15a, 346 mg, 1.0 mmol) and 4-nitrophenyl pyridin-4-ylcarbamate (Example 28a, 518 mg, 2.0 mmol) in DMF (10 mL) was added potassium carbonate (414 mg, 3.0 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The compound was purified via preparative RP HPLC (10 to 90% acetonitrile in water to provide the desired product (120 mg, 28%). 1H NMR (DMSO-d6, 400 MHz): 1.47 (m, 1H), 1.65 (m, 4H), 1.80 (m, 1H), 3.12 (t, 1H, J=12.0 Hz), 4.03 (m, 1H), 4.17 (m, 1H), 4.61 (t, 1H, J=10.4 Hz), 4.93 (br s, 1H), 6.61 (d, 1H, J=8.4), 6.89 (d, 1H, J=8.4), 7.48 (m, 3H), 7.99 (br s, 1H), 8.30 (d, 2H, J=5.6 Hz), 8.35 (br s, 1H), 8.92 (s, 1H), 10.94 (s, 1H). M+H=431.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH3:26])[N:21]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>ClCCl>[CH3:26][CH:22]1[CH2:23][CH2:24][CH2:25][CH:20]([CH3:19])[N:21]1[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:16](=[O:18])[C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)=[CH:32][CH:33]=1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC1CCCC(C)N1Cc1ccc(N)cc1
Solvent: ClCCl
Product: CC1CCCC(C)N1Cc1ccc(NC(=O)C#Cc2ccc(-c3ccc(Cl)cc3)cc2)cc1

Procedure:
Prepared analogously to Example 3.8. from (4′-chlorobiphenyl-4-yl)propynoic acid and 4-(2,6-dimethylpiperidin-1-ylmethyl)phenylamine. Yield: 100 mg (22% of theory); melting point: 158° C.-163° C.; C29H29ClN2O (M=457.01); calc.: molecular ion peak (M+H)+: 458/460 (Cl); found: molecular ion peak (M+H)+: 458/460 (Cl); Rf value: 0.50 (silica gel, dichloromethane/methanolic ammonia (90:10:0.1)).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@H:14](C4C=C(Br)C=CC=4S([O-])(=O)=O)[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[NH2:30][C@@H:31]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:32]([NH2:34])=[O:33]>C(#N)C>[F:28][C:2]([F:29])([F:1])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH:30][C@H:31]([C:32]([NH2:34])=[O:33])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)([O-])c1ccc(Br)cc1[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reactant: CC(C)C[C@H](N)C(N)=O
Solvent: CC#N
Product: CC(C)C[C@H](N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21)C(N)=O
Temperature: 85 °C

Procedure:
The title compound was prepared by combining (3aR,4R,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-yl-4-bromobenzenesulfonate from Step 4 (150 mg, 0.305 mmol) and (S)-2-amino-4-methylpentanamide (119 mg, 0.916 mmol) in acetonitrile (0.2 mL). The reaction mixture was heated at 85° C. for 3 days, and the acetonitrile was evaporated. This material was purified using a 12 g silica gel cartridge eluted with a gradient of 0-3% methanol (2 N ammonia)/dichloromethane over 20 minutes to give crude product. It was further purified on 2×0.25 mm thin-layer chromatography plate eluted with 45% methanol (2 N ammonia)/dichloromethane to give N2-{(3aR,4S,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.25 (s, 1H), 7.99 (s, 1H), 7.52 (t, J=7.9, 1H), 6.98 (d, J=7.2, 1H), 6.49 (d, J=8.6, 1H), 3.60 (dd, J=10.6, 9.0, 1H), 3.55-3.40 (m, 3H), 3.24 (dd, J=10.8, 3.7, 1H), 3.17 (dd, J=10.2, 5.7, 1H), 2.83-2.71 (m, 1H), 2.64-2.55 (m, 1H), 2.30-2.10 (bs, 1H) 2.08-1.93 (m, 3H), 1.76 (ddd, J=13.5, 8.1, 5.5, 1H), 1.71-1.64 (m, 1H), 1.58 (dd, J=12.7, 5.8, 1H), 1.31 (dd, J=12.7, 5.9, 1H), 0.96 (d, J=6.6, 3H), 0.93 (d, J=6.6, 3H); MS (ESI+) m/z 385 (M+H)+.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[NH:37][N:36]=1.[CH:50]1([CH:53]([NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[CH2:54]O)[CH2:52][CH2:51]1>C1COCC1.CCOC(C)=O>[CH2:43]([O:42][C:40]([C:39]1[C:35]([I:34])=[N:36][N:37]([CH2:54][CH:53]([NH:56][C:57]([O:58][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:63])[CH:50]2[CH2:51][CH2:52]2)[C:38]=1[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[O:41])[CH3:44]
Reactant: CCOC(=O)c1[nH]nc(I)c1C(=O)OCC
Reactant: CC(C)(C)OC(=O)NC(CO)C1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(I)nn(CC(NC(=O)OC(C)(C)C)C2CC2)c1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of PPh3 (15.52 g, 59.2 mmol) in THF (40.0 mL) cooled to −10° C. was added DIAD (11.50 mL, 59.2 mmol) and the resulting solution stirred at 0° C. for 0.5 h. Intermediate 104C (10 g, 29.6 mmol) was added as a solution in THF (10 mL) at 0° C. and stirred at RT for 45 min. A solution of Intermediate 348A (7.74 g, 38.5 mmol) in THF (10 mL) at was added at 0° C. and the reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with EtOAc (50 mL) washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (120 g REDISEP® column, eluting with 15% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 348B along with impurities arising from the coupling reagents (8.01 g, 84%); the crude material was taken to the next step without further purification. MS(ES): m/z=522 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:16])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH:11]([CH3:15])[CH2:12]3)=[CH:8][C:6]=2[N:7]=1.[N:17]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CCN(CC)CC>COCCOC>[CH3:15][CH:11]1[CH2:10][C:9]2[C:13](=[CH:14][C:5]3[N+:4]([O-:16])=[N:3][C:2]([NH:26][CH2:25][CH2:24][CH2:23][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[N:7][C:6]=3[CH:8]=2)[CH2:12]1
Reactant: NCCCN1CCOCC1
Reactant: CC1Cc2cc3nc(Cl)n[n+]([O-])c3cc2C1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CC1Cc2cc3nc(NCCCN4CCOCC4)n[n+]([O-])c3cc2C1
Yield: 95.5 %

Procedure:
A solution of chloride 95 (367 mg, 1.6 mmol), 3-(4-morpholinyl)propylamine (0.34 mL, 2.3 mmol) and Et3N (0.33 mL, 2.3 mmol) in DME (50 mL) was stirred at reflux temperature for 8 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 98 (525 mg, 98%) as a yellow solid: mp (MeOH/DCM) 138-140° C.; 1H NMR δ 8.04 (s, 1H, H-9), 7.35 (s, 1H, H-5), 6.10 (br t, J=5.0 Hz, 1H, NH), 3.75 (br t, J=4.7 Hz, 4H, 2×CH2O), 3.56-3.61 (m, 2H, CH2N), 3.08-3.18 (m, 2H, CH2), 2.56-2.65 (m, 3H, CH, CH2), 2.44-2.52 (m, 6H, 3×CH2N), 1.83 (br p, J=6.5 Hz, 2H, CH2), 1.15 (d, J=6.1 Hz, 3H, CH3); 13C NMR δ 158.8, 154.2, 148.9, 142.8, 129.8, 120.7, 114.8, 67.0 (2), 57.3, 53.8 (2), 41.2, 40.8, 40.4, 34.9, 25.3, 20.4. Anal. calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 63.2; H, 7.2; N, 20.4%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Br)[CH3:17]>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:22])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1CC
Temperature: 60 °C
Yield: 81.9 %

Procedure:
To a stirred solution of 2-ethylphenol (5ml, 42.4mmoles, 1eq) in dry DMF (120ml, 0.35M) was added potassium carbonate (6.45g, 46.6mmoles, 1.1eq) and ethylbromoacetate (4.7ml, 42.2mmoles, 1eq) and heated to 60° C. overnight. After cooling to room temperature the reaction mixture was partitioned between ethyl ether and 1N NaOH. The phases were separated and the organic portion washed twice with 1N NaOH, twice with H2O, brine, dried over Na2SO4, filtered and concentrated in vacuo to yield 7.2g (82%) of product.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:17])[CH2:9][C:10](=[O:16])[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH2:7][C@H:8]([CH3:17])[CH2:9][C:10]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:16]
Reactant: C[C@H](CC(=O)N1CCCC1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)CC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ((R)-1-methyl-3-oxo-3-pyrrolidin-1-yl-propyl)-carbamic acid tert-butyl ester (crude from step 1, 189 mg, 0.74 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (2.0 mL, 27.0 mmol). The reaction mixture was stirred at room temperature for 2 h then concentrated to give (R)-3-amino-1-pyrrolidin-1-yl-butan-1-one trifluoroacetate as a pale yellow oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:18]=[C:19]([C:23]4[N:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[N:24]=[CH:25][C:26]([CH2:29][N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)=[CH:27][N:28]=4)[CH:18]=3)[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=Cc1cnc(-c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)nc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(Cc2cnc(-c3cccc(Cn4nc(-c5cc(F)cc(F)c5)ccc4=O)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
7.2 A suspension of 472 mg (1.17 mmol) of 2-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carbaldehyde in 5 ml of dichloromethane is given successively with 166 μl of 1-methylpiperazine, 495 mg (2.34 mmol) of sodium triacetoxyborohydride and 67 μl of acetic acid, and the reaction mixture is stirred at room temperature for 42 hours. The reaction mixture is partitioned between dichloromethane and 1 N NaOH. The organic phase is separated off, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent: 6-(3,5-difluorophenyl)-2-{3-[5-(4-methylpiperazin-1-ylmethyl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one (“A14”) as colourless crystals; ESI 489;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([Cl:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 3-chlorophenylacetic acid (51 g) was added thionyl chloride (100 ml) and N,N-dimethylforraamide (50 μl). After stirring at room temperature for 18 hours, the thionyl chloride was evaporated at reduced pressure. The residue was dissolved in toluene (60 ml) and again evaporated at reduced pressure to give 3-chlorophenylacetylchloride.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[Na].[C:14](OCC)(=[O:23])[CH2:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=O>C(O)(=O)C>[CH2:21]([O:20][C:18]([C:16]1[CH:15]=[C:14]([OH:23])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=2)[N:10]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: NNc1ccc(C(F)(F)F)cc1
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(O)n(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
A solution of 6.83 g 4-(trifluoromethyl)phenylhydrazine and 9.05 g diethyl oxalacetate sodium salt in 120 ml acetic acid was stirred at 100° C. for 2 h. The product precipitated was filtered, codistilled twice with toluene and suspended with heptane/ethyl acetate 3:1. The suspension was filtered again and the cude product obtained dried in vacuo.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]([CH2:13][CH3:14])[CH:9]([C:11]#[N:12])[OH:10])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][OH:18]>CO.C[O-].[Na+]>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH:9]([OH:10])[C:11](=[NH:12])[NH:17][OH:18])[CH2:13][CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C#N
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)C(=N)NO
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 32.2 %

Procedure:
A solution of (2-cyano-1-ethyl-2-hydroxy-ethyl)-carbamic acid tert-butyl ester (9.53 g, 44 mmol) in methanol (80 ml) was cooled to 0° C. and treated successively with hydroxylamine hydrochloride (3.05 g, 44 mmol) in methanol (80 ml) and 25% sodium methoxide solution in methanol (10.2 ml). After stirring at 0° C. for 5 minutes the reaction mixture stirred at room temperature for 5 hours and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4) and then evaporated under reduced pressure. The residual yellow oil was subjected to mplc, eluting with a mixture of ethyl acetate and heptane to give {(S)-1-[hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic acid tert-butyl ester (3.5 g) as white solid. MS: M(H+) 248.
Reaction SMILES: Cl[CH2:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=1.[C:18]([O:22][C:23]([NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]2[N:33]([CH2:42][C:43]#[C:44][CH3:45])[C:34]3[C:39](=[O:40])[NH:38][N:37]=[CH:36][C:35]=3[N:41]=2)[CH2:27]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:18]([O:22][C:23]([NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]2[N:33]([CH2:42][C:43]#[C:44][CH3:45])[C:34]3[C:39](=[O:40])[N:38]([CH2:2][C:3]4[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[O:7][C:6]5[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=5[N:4]=4)[N:37]=[CH:36][C:35]=3[N:41]=2)[CH2:27]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2cn[nH]c(=O)c21
Reactant: ClCC1=Nc2ccccc2Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2cnn(CC3=Nc4ccccc4Oc4ccccc43)c(=O)c21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
317 mg 11-chloromethyl-dibenzo[b,f][1,4]oxazepin are added to 400 mg 2-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 276 mg potassium carbonate in 4 ml N,N-dimethylformamide. The reaction mixture is stirred for two hours at 80° C. For working up it is combined with water and the precipitate formed is suction filtered. The crude product is purified by chromatography over a silica gel column with methylene chloride/methanol (100:0 to 70:30) as eluant.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(C)cc(C)c1NS(=O)(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 1.00 g (2.86 mmol) of the product of Example 28 in 10 mL of DMF was added 0.14 g (3.57 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 min at room temperature and then 0.42 mL (3.57 mmol) of benzyl bromide was added. This reaction mixture was stirred overnight at room temperature, poured into water and then extracted with ether. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide a white solid which was recrystallized from ethyl acetate (EtOAc)/Hexanes to provide 1.084 g (85%) of the desired product as a white solid. Electrospray Mass Spec: m/z 428.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][F:18])=[CH:11][CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[S:20]([NH2:30])(=[O:29])([C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)=[O:21]>C(O)(C)C.C(O)(C(F)(F)F)=O>[NH2:30][S:20]([C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][F:18])=[CH:11][CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)=[CH:26][CH:27]=1)(=[O:21])=[O:29]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: FCCCc1ccc(Nc2nc(Cl)ncc2F)cc1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(Nc2ncc(F)c(Nc3ccc(CCCF)cc3)n2)cc1
Temperature: 100 °C

Procedure:
2-Chloro-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-4-pyrimidineamine (100 mg) and sulfanilamide (100 mg) were suspended in isopropanol (1 mL) and TFA (5 drops). The solution was heated at 100° C. overnight. The solution was evaporated and purified by flash column chromatography (2.0 M NH3/MeOH in dichloromethane=1-3%) and recrystallized from ethyl acetate to give N2-(4-aminosulfonylphenyl)-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 1.89-2.02 (m, 2H), 2.67 (t, J=8.1 Hz, 2H), 4.38 (t, J=5.7 Hz, 1H), 4.53 (t, J=5.7 Hz, 1H), 7.11 (br, 2H), 7.19 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.65 (d, J=8.1 Hz, 2H), 7.80 (d, J=8.7 Hz, 2H), 8.12 (d, J=3.9 Hz, 1H), 9.38 (br, 1H), 9.57 (br, 1H); 19F NMR (282 MHz, DMSO-d6): δ-201.79; LCMS: purity: 91.96%; MS (m/e): 420.74 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Br:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:14])=[CH:15][CH:16]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cn2nccc2Br)cc1
Reactant: C1CCNC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(c1ccc(Cn2nccc2Br)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
4-((5-bromo-1H-pyrazol-1-yl)methyl)benzoic acid (200 mg, 0.71 mmol), pyrrolidine (61 mg, 0.85 mmol) and EDC-HOBt (452 mg, 2 mmol) were combined in CH2Cl2 and stirred for 4 h at room temperature. The mixture was evaporated in vacuuo and the residue dissolved in ethyl acetate and washed with water. The separated organic layer was dried and concentrated affording the product as an oil (231 mg, yield 99%), which was used in next step without further purification. LCMS (m/z): 334.2 [M+H]+
Reaction SMILES: CC([O-])=O.[Na+].C([O:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=2)=[CH:13][C:12]=1[C@H:27]1[C@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@H:30]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@@H:29]([CH2:57][O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[O:28]1)C=C>CC(O)=O.O.Cl[Pd]Cl>[Cl:17][C:15]1[C:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=2)=[CH:13][C:12]([C@H:27]2[C@H:32]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@@H:31]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:30]([O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C@@H:29]([CH2:57][O:58][CH2:59][C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[O:28]2)=[C:11]([CH2:10][OH:9])[CH:16]=1
Reactant: C=CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(CO)cc2Cl)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
PdCl2 (23.7 mg, 0.133 mmol, 2.2 eq) and NaOAc (76 mg, 0.285 mmol, 4 eq) were added to a solution of (2S,3S,4R,5R,6R)-2-(2-(allyloxymethyl)-4-chloro-5-(4-ethylbenzyl)phenyl)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran (intermediate O-1) (50 mg, 0.061 mmol) in HOAc:H2O (9:1) (1 mL), and the mixture was stirred at 70° C. for 1 h. Then the mixture was cooled to room temperature, extracted with ethyl acetate, and the combined organic layers were washed with water, dried over anhydrous Na2SO4, concentrated and purified by preparative TLC to obtain 30 mg of intermediate V-1.