Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[C:3](=O)[C:4]#[C:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:13][N:14]=2)[N:11]=1.[NH2:26]OS(O)(=O)=O.C(=O)(O)[O-].[Na+].[SH-:37].[Na+]>O.O1CCOCC1>[CH:2]([C:3]1[CH:4]=[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:13][N:14]=3)[N:11]=2)[S:37][N:26]=1)([CH3:25])[CH3:1]
Reactant: NOS(=O)(=O)O
Reactant: [SH-]
Reactant: CC(C)C(=O)C#Cc1ccc2nnc(CNC(=O)OC(C)(C)C)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1cc(-c2ccc3nnc(CNC(=O)OC(C)(C)C)n3n2)sn1
Temperature: 0 °C
Yield: 22.5 %

Procedure:
An aqueous mixture of tert-butyl (6-(4-methyl-3-oxopent-1-ynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.800 g, 2.33 mmol) and hydroxylamine-O-sulfonic acid (0.263 g, 2.33 mol) in water (8.0 mL) and 1,4-dioxane (8.0 mL) was stirred at 0° C. until complete consumption of the organic starting material was observed. The mixture was then carefully treated with solid sodium bicarbonate (0.196 g, 2.33 mmol), followed by treatment with 1.4 M aqueous sodium hydrosulfide (1.83 ml, 2.56 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and extracted with DCM (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The concentrated crude material was dissolved in minimal DCM and was purified via MPLC (eluting with 0-10% MeOH/NH4OH in DCM) to yield tert-butyl (6-(3-isopropylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.196 g, 22.5% yield) with 82% purity. MS (ESI pos. ion) m/z: 433.0 (M+H). Calc'd Exact Mass for C21H20N8OS: 432.51.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][C:24](O)=[C:23]([F:28])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:24]2[CH:25]=[CH:26][C:21]([Br:20])=[CH:22][C:23]=2[F:28])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: Oc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Br)cc2F)cs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.9 %

Procedure:
2-{[4-(2-hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (3.0 g) synthesized in Example 4 and 4-bromo-2-fluorophenol (1.91 g) were dissolved in tetrahydrofuran (20 mL), triphenylphosphine (2.62 g) and diethyl diazodicarboxylate (1.74 g) were added under ice-cooling, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=6:1) to give the title compound (3.2 g) as a colorless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[OH:28])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.O>[CH2:35]([O:28][C:19]1[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:18]=1[C:14]1[N:15]=[CH:16][N:17]=[C:12]([O:11][C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][CH:2]=[N:1]3)=[CH:6][CH:7]=2)[CH:13]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenol, (Example 191), (50 mg, 0.13 mmol) and K2CO3 (54 mg, 0.39 mmol) in DMF (2.0 mL) was added benzyl bromide (17 μL, 0.14 mmol, Aldrich) and the reaction mixture was stirred at room temperature for 4 h. The resulting mixture was diluted with water and extracted with CH2Cl2. The combined extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (gradient: 0% to 3.0% MeOH/CH2Cl2) provided the title compound as a light-yellow amorphous solid. MS (ESI, pos. ion) m/z: 474 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[CH:5]2.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[C:16]1[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH:15]=1
Reactant: Clc1cc2cc[nH]c2cc1Cl
Reactant: CN1CCC(=O)CC1
Product: CN1CC=C(c2c[nH]c3cc(Cl)c(Cl)cc23)CC1
Yield: 60.6 %

Procedure:
Beginning with 0.136 gm (0.88 mMol) 5,6-dichloro-1H-indole and 0.216 mL (1.75 mMol) 1-methyl-4-piperidone, 0.150 gm (61%) of the title compound were recovered as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]23[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]4)[CH2:11]2)[CH2:17]3)[N:3]=1.[NH2:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>C(O)CCC>[C:10]12([NH:9][C:4]3[N:3]=[C:2]([NH:20][C:21]45[CH2:22][CH:23]6[CH2:29][CH:27]([CH2:26][CH:25]([CH2:24]6)[CH2:30]4)[CH2:28]5)[CH:7]=[C:6]([Cl:8])[N:5]=3)[CH2:17][CH:16]3[CH2:18][CH:12]([CH2:13][CH:14]([CH2:15]3)[CH2:19]1)[CH2:11]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: Clc1cc(Cl)nc(NC23CC4CC(CC(C4)C2)C3)n1
Solvent: CCCCO
Product: Clc1cc(NC23CC4CC(CC(C4)C2)C3)nc(NC23CC4CC(CC(C4)C2)C3)n1

Procedure:
A solution of 26.0 g (87.25 mmoles) of 4,6-dichloro-2-(1-adamantylamino)pyrimidine and 39.5 g (261.6 mmoles) of 1-aminoadamantane in 200 ml of n-butanol, the reaction mixture is boiled under reflux for 24 hours, and evaporated. The residue is suspended in 400 ml of ether and filtered off. After drying, the filtered-off residue is purified by chromatography on a silica gel column and eluted with chloroform. After recrystallization from ether, the title compound is obtained in a yield of 23.94 g (66.44%), m.p.: 232°-236° C.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]2[C:5](=[C:6]([O:17][CH3:18])[CH:7]=[CH:8][C:9]=2[O:15][CH3:16])[C:4]=1[O:19][CH3:20])=[O:2].[Cl-].[NH4+]>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]2[C:5](=[C:6]([O:17][CH3:18])[CH:7]=[CH:8][C:9]=2[O:15][CH3:16])[C:4]=1[O:19][CH3:20])[CH2:1][CH2:3][CH2:4][CH3:5]
Reactant: COc1ccc(OC)c2c(OC)c(C=O)cc(OC)c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC(O)c1cc(OC)c2c(OC)ccc(OC)c2c1OC
Reaction time: 1 h
Yield: 169 %

Procedure:
0.8 g (33 mmole) of magnesium and 4.47 g (33 mmole) of 1-bromobutane were added to 30 ml of dry tetrahydrofuran and the mixture was stirred for 2 hours to obtain a Grignard reagent. A solution of 3 g (10.9 mmole) of 2-formyl-1,4,5,8-tetramethoxynaphthalene dissolved in 30 ml of dry tetrahydrofuran was added dropwise to the Grignard reagent over 20 minutes through a dropping funnel. The reaction mixture was stirred at normal temperature for further one hour and then 80 ml of 10% aqueous ammonium chloride solution was added thereto. The mixture was extracted twice with dichloromethane solvent, dried over anhydrous magnesium sulfate and filtered through a filter paper. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 4.0×20 cm) using the solvent condition which increases the amount of ethylacetate so that the n-hexane/ethylacetate ratio can vary from 10:1 to 1:1, to obtain 3.08 g of the title compound as a yellow precipitate.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5][CH:4]=1)=[O:2].[CH:15]([Mg]Cl)([CH3:17])[CH3:16]>C1COCC1>[CH:13]([C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([CH:1]([OH:2])[CH:15]([CH3:17])[CH3:16])=[CH:4][CH:5]=1)=[O:14]
Reactant: CC(C)[Mg]Cl
Reactant: O=Cc1ccc(C=O)c2ccccc12
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc(C=O)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 14 %

Procedure:
To a solution of 1,4-diformylnaphthalene (490 mg, 2.66 mmol) in THF (12 mL) was added dropwise at 0° C. isopropyl magnesium chloride (1.3 mL of a 2 M solution in THF). The mixture was stirred at room temperature for 3 hr, diluted with satd. NH4Cl (10 mL), and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (silicagel, hexane:ethyl acetate, 5:1) provided the title compound (81 mg, 14%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]1[CH2:9][OH:10].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:31])=[C:22]([CH:30]=1)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Cl>CS(C)=O>[Cl:17][C:18]1[C:19]([O:10][CH2:9][CH:3]2[CH:4]([CH3:8])[CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])=[CH:20][C:21]([F:31])=[C:22]([CH:30]=1)[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24]
Reactant: CC1CCCC(C)C1CO
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC1CCCC(C)C1COc1cc(F)c(C(=O)OC(C)(C)C)cc1Cl
Temperature: 70 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
To a solution of (2,6-dimethylcyclohexyl)methanol (0.34 g, 2.40 mmol) in anhydrous dimethylsulfoxide (5 mL) were added cesium carbonate (1.56 g, 4.80 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (0.53 g, 2.16 mmol) and the reaction mixture was stirred at 70° C. for 16 hours. The reaction mixture was cooled down and acidified to pH=1 with 5% aqueous hydrochloric acid solution and extracted with ethyl acetate (2×15 mL), the combined organics were washed with brine (15 mL); dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (0 to 10% ethyl acetate in hexanes) afforded the title compound (0.43 g, 54%): MS (ES+) m/z 317.2, 315.2 (M−54); MS (ES−) m/z 315.1, 313.1, (M−56).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:6]2[O:28][CH:27]=[CH:26][C:7]=2[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[O:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1>>[CH3:4][C:5]1[C:6]2[O:28][CH:27]=[CH:26][C:7]=2[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:35]([CH:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)=[O:36])[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)=[N:9][CH:10]=1
Reactant: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c2ccoc12
Reactant: O=C(O)C1CCOCC1
Agent: Cl
Product: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](NC(=O)C4CCOCC4)CC3)CC2)c2ccoc12

Procedure:
The title compound, white solid (121 mg, 89%), MS (ISP) m/z=455.4 [(M+H)+], mp 228° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate F) (136 mg, 0.3 mmol) and tetrahydropyran-4-yl-carboxylic acid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Reactant: Cc1ccc(CBr)cc1
Product: Cc1ccc(CC2CCCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)cc1
Yield: 53 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-4-methylbenzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 53% yield: mp 110-113° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.37-7.22 (m, 5H), 7.12-6.99 (m, 4H), 6.09 (t, J=5.6 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H), 4.28-4.19 (m, 1H), 3.99-3.86 (m, 1H), 3.43-3.29 (m, 1H), 2.82-2.66 (m, 2H), 2.63 (s, 3H), 2.29 (s, 3H), 2.06-1.69 (m, 3H), 1.61-1.43 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 172.2, 162.7, 157.0, 152.1, 138.0, 136.1, 135.8, 129.2, 129.1, 128.8, 127.9, 127.6, 119.4, 48.1, 44.2, 44.0, 37.1, 24.8, 21.2, 21.1, 17.4; MS (ES+) m/z 434.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[C:4]([NH:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1)=[O:5].N1C=CC=CC=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[C:4]([NH:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][N:10]([S:35]([C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=3)(=[O:37])=[O:36])[C:9]=2[N:8]=1)=[O:5]
Reactant: O=C(Nc1ccc2c(n1)NCCC2)c1c(F)cccc1F
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc2c(n1)N(S(=O)(=O)c1ccc(F)cc1)CCC2)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2,6-Difluoro-N-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)benzamide (30 mg, 0.10 mmol) was dissolved in dichloromethane (0.3 mL) and pyridine (0.025 mL, 0.31 mmol). 4-Fluorobenzenesulfonyl chloride (23 mg, 0.12 mmol) was then added and the reaction mixture was stirred at room temperature for 12 hours. Next, the reaction mixture was washed with 1M HCl(aq), sat'd NaHCO3(aq), and brine. The resulting organic solution was concentrated, dissolved in DMSO, and purified by HPLC to give 2,6-difluoro-N-(8-(4-fluorobenzenesulfonyl)-5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl]benzamide. 1H NMR 250 MHz CDCl3 δ 8.13 (bs, 1H), 8.03 (dd, J=7.9, 4.3 Hz, 2H), 7.83 (d, J=7.9 Hz, 1H), 7.48 (p, J=6.5 Hz, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.15 (t, J=7.9 Hz, 2H), 7.06 (t, J=7.8 Hz, 2H), 4.07 (dd, J=5.8, 4.3 Hz, 2H), 2.76 (t, J=6.5 Hz, 2H), 2.06 (p, J=5.8 Hz, 2H). LCMS (ESI): calc. C21H16F3N3O3S=447; obs. M+H=448.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:22][C@@H:23]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[C:24]([NH2:26])=[O:25]>>[C:24]([C@@H:23]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:27][CH:28]1[CH2:30][CH2:29]1)(=[O:25])[NH2:26]
Reactant: O=C(O)c1ccc(N2CCC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)CC1CC1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(N2CCC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (Example 78 b) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=409.3 [M+H]+.
Reaction SMILES: I[CH2:2][CH:3]1[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH2:4]1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1.C(N(CC)CC)C>CN(C)C=O>[C:3]1([CH2:2][N:11]2[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=1
Reactant: ICC1Cc2ccccc21
Reactant: O=C(O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)C1CCN(CC2=Cc3ccccc32)CC1
Reaction time: 6 h

Procedure:
0.028 mole of 1-(iodomethyl)benzocyclobutene (Process 1, stage G}, 0.028 mole of 4-piperidinecarboxylic acid and 0.028 mole of triethylamine are mixed in 95 ml of dimethylformamide. The mixture is brought to 60° C. for 6 hours. It is evaporated to dryness, the residue is taken up with ethyl acetate and water and settling is allowed to take place.
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: Clc1ccc2c(c1)NCCO2
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
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+]([CH:4](O)C1C=CC=CC=1)([O-])=O.C[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][P+:29]1([O-:41])[O:39][C:38]([CH3:40])=[C:37]2[C@H:32]([CH2:33][O:34][C:35]2=[O:36])[CH2:31][O:30]1>>[CH3:40][C:38]1[O:39][P+:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([CH3:13])[CH3:4])([O-:41])[O:30][CH2:31][C@H:32]2[CH2:33][O:34][C:35](=[O:36])[C:37]=12
Reactant: CCCCCCCCCCCCCCCCO[P+]1([O-])OC[C@H]2COC(=O)C2=C(C)O1
Reactant: O=[N+]([O-])C(O)c1ccccc1
Product: CC1=C2C(=O)OC[C@@H]2CO[P+]([O-])(OCCCCCCCCCCCCCC(C)C)O1

Procedure:
By high-resolution FAB mass spectrometry using a nitrobenzylalcohol matrix, the following molecular weight was found: 445.2721 amu, corresponding to (M+H)+ for cyclipostin P of C23H42O6P. From this, an empirical formula for cyclipostin P 2 of C23H41O6P resulted, molecular weight: 444. By electron spray mass spectrometry, in the positive ionization mode (ESI, positive) a peak at 445 amu, corresponding to (M+H)+ was found; moreover the characteristic peak at 221 amu, corresponding to C7H10O6P, was found. In the ESI negative mode, 443 amu (M−H)−, 321 amu (C16H34O4P) and 219 amu (C7H8O6P) were found.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)[N:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:18]=3)=[CH:13][C:12]2=[O:31])=[CH:6][C:5]=1[F:37].[CH3:38]I>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:32]2[CH:36]=[N:35][N:34]([CH3:38])[CH:33]=2)[N:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:18]=3)=[CH:13][C:12]2=[O:31])=[CH:6][C:5]=1[F:37]
Reactant: CI
Reactant: O=c1cc(-c2nc(NC3CCOCC3)ncc2F)ccn1C(c1cn[nH]c1)c1ccc(Cl)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C(c2ccc(Cl)c(F)c2)n2ccc(-c3nc(NC4CCOCC4)ncc3F)cc2=O)cn1
Reaction time: 0.25 h
Yield: 23 %

Procedure:
NaH (3.05 mg, 0.0762 mmol; 60% oil dispersion) neat as a solid was added to a stirred solution of 1-((4-chloro-3-fluorophenyl)(1H-pyrazol-4-yl)methyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (38 mg, 0.0762 mmol) in DMF (1 mL) at room temperature under nitrogen. After 15 minutes, a red solution had formed. Methyl iodide (4.75 μL, 0.0762 mmol) was then added neat by syringe. After stirring overnight, the reaction was quenched by addition of saturated ammonium chloride solution (1 mL). The mixture was partitioned between ethyl acetate (15 mL) and saturated sodium bicarbonate (15 mL). The organics were isolated and washed with water (3×15 mL) and with brine (15 mL). TLC in 95/5 ethyl acetate/methanol showed complete consumption of starting material with two new major spots of higher rf. The organics were isolated, dried (MgSO4), filtered and concentrated. The crude product was loaded onto a 20 cm×20 cm×0.5 mm prep plate and eluted with 95/5 ethyl acetate/methanol. Three bands were scraped off the plate. Compound was freed from the silica gel by stirring for 15 minutes with ethyl acetate (50 mL) and filtration. The high rf material shows two methyl signals by 1H-NMR and is presumed to be dimethylated byproduct. The lower rf material was isolated as a clear oil, 1-((4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (9 mg, 23%) and appears to be the desired product by comparison to the non-fluoro analog (see Example 35). 1H NMR (400 MHz, CDCl3) δ 8.27 (d, 1H), 7.36 (m, 3H), 7.30 (br s, 1H), 7.23 (s, 1H), 7.01 (m, 2H), 6.80 (d, 1H), 5.09 (d, 1H), 4.00 (m, 3H), 3.91 (s, 3H), 3.54 (m, 2H), 2.04 (m, 2H), 1.57 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][OH:28])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][O:28][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1
Reactant: OCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Yield: 100 %

Procedure:
Stir a solution of 2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-ethanol (293 mg, 0.78 mmol) and methane sulfonyl chloride (68μL, 0.81 ml) in dried pyridine (5 mL) for 2 hours. Remove the pyridine in vacuo and recover the residue with chloroform. Wash the organic layer with saturated sodium bicarbonate and dry over sodium sulfate to give the desired subtitled intermediate as a white foam (425 mg, 100%). MS ES+ m/e 451.1 (M+1).
Reaction SMILES: C([CH:4]1[CH:9]2[NH:10][C:11]3[CH:12]=[N:13][C:14]4[C:19]([C:20]=3[C:8]2=[C:7]([CH3:22])[NH:6][CH2:5]1)=[CH:18][CH:17]=[C:16]([Cl:21])[CH:15]=4)(=O)C.Cl>>[Cl:21][C:16]1[CH:15]=[C:14]2[C:19]([C:20]3[C:8]4=[C:7]([CH3:22])[NH:6][CH2:5][CH2:4][CH:9]4[NH:10][C:11]=3[CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: CC(=O)C1CNC(C)=C2c3c(cnc4cc(Cl)ccc34)NC21
Agent: Cl
Product: CC1=C2c3c(cnc4cc(Cl)ccc34)NC2CCN1
Yield: 72.6 %

Procedure:
A mixture prepared from 17.5 g of 8-acetyl-3-chloro-11-methyl-7,8,9,10-tetrahydro-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline and 125 ml of concentrated hydrochloric acid was refluxed for one hour. The product precipitated as hydrochloride salt and it was recovered by filtration. The salt was suspended in water and the mixture was basified with 50% sodium hydroxide solution. The resultant solid was recovered by filtration and recrystallized from isopropanol to give 11 g of crystalline solid with a melting point of 209°-212° C.