Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[Br:14][C:15]1[C:20](F)=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:17][C:16]=1[F:25]>C1COCC1.O>[Br:14][C:15]1[C:16]([F:25])=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Nc1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(Br)c1Nc1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
Potassium tert-butoxide (2.82 g, 25.2 mmol) was added to a solution of 2-aminopyridine (1.25 g, 13.2 mmol) in THF (40 mL) at 0° C. and the reaction mixture stirred at 0° C. for 30 min. 2-Bromo-1,3-difluoro-4-nitrobenzene (3 g, 12.6 mmol) was added as a solution in THF (10 mL) and the reaction mixture stirred at 0° C. for 2 h. The reaction mixture was diluted with water and the product extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a yellow solid (2.38 g, 60%). 1H NMR 400 MHz δ (CDCl3): 8.16 (1H, ddd, J=5.1, 2.0, 1.0 Hz), 8.08 (1H, dd, J=9.3, 5.6 Hz), 7.82 (1H, br s), 7.62 (1H, ddd, J=8.1, 7.3, 1.8 Hz), 6.99 (1H, dd, J=9.2, 7.1 Hz), 6.91 (1H, ddd, J=7.3, 5.0, 1 Hz), 6.82 (1H, dt, J=8.3, 1.0 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.Cl.[F:23][C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.[F-].[K+].C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1.CCOC(C)=O>[F:23][C@@H:24]1[CH2:28][CH2:27][N:26]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)=[CH:9][N:10]=3)[N:7]=2)[CH2:25]1
Reactant: F[C@@H]1CCNC1
Reactant: Clc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: F[C@@H]1CCN(c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)C1
Temperature: 170 °C
Reaction time: 4 h

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline (Example 14, 100 mg, 0.339 mmol), (R)-(−)-3-fluoropyrrolidine hydrochloride (220 mg, 1.696 mmol) and KF (99 mg, 1.696 mmol) were suspended in NMP (1.5 mL). N-Ethyldiisopropylamine (296 μL, 1.696 mmol) was then added and the RM was stirred at 170° C. for 4 h. The mixture was diluted with EtOAc and extracted with 1 M HCl (3×). The aqueous layer was washed with TBME (2×) and then adjusted to pH 10 with 2 M NaOH. The solution was extracted with DCM (3×). The organic layer was washed with water (2×), dried over sodium, filtered and concentrated. The residue was purified by flash chromatography (Flashmaster) and triturated in DCM to afford the title compound as a yellow foam (tR 4.14 min (conditions 4), MH+=348.5, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.29 (m, 1H); 7.93 (m, 2H); 7.81 (d, 1H); 7.76 (m, 1H); 7.49 (dd, 1H); 7.43 (s, 1H); 6.81 (d, 1H); 5.46 (m, 1H); 4.38 (s, 2H); 3.62 (m, 4H); 2.20 (m, 2H)).
Reaction SMILES: [C:1]1([CH:7]2[S:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][C:9]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[C:1]1([CH:7]2[S:16](=[O:31])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][C:9]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(C2CC3(CC(c4ccccc4)S2)OCCO3)cc1
Solvent: ClCCl
Product: O=S1C(c2ccccc2)CC2(CC1c1ccccc1)OCCO2
Reaction time: 16 h

Procedure:
23.4 g of 7,9-diphenyl-1,4-dioxa-8-thiaspiro[4.5]- decane are dissolved in 50 ml of methylene chloride and the solution is cooled to -10°. A solution of 16.0 g of m-chloroperbenzoic acid in 200 ml of methylene chloride is added dropwise in the course of about 7 hours, it being ensured that the temperature does not exceed -5°. The reaction mixture is then stirred at 0° for 16 hours and filtered and the residue is washed with 100 ml of methylene chloride. The combined methylene chloride solutions are washed three times with 150 ml of water each time, dried over sodium sulfate and evaporated. The colourless residue is stirred with 100 ml of 2N sodium hydroxide solution for 1 hour, filtered off, washed neutral, dried and crystallized from toluene. 7,9-Di-phenyl-1,4-dioxa-8-thiaspiro[4,5]-decane 8-oxide is obtained as colourless crystals of melting point 230°-32°.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH3:11][O:12][CH2:13]Br.O>CN(C=O)C>[CH3:11][O:12][CH2:13][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Br:3]
Reactant: Oc1ccccc1Br
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccccc1Br
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
To a stirring suspension of sodium hydride (1.2 g, 52.1 mmol, 60% dispersion in mineral oil) in DMF (75 mL) at 0° C. was added 2-bromophenol (6.0 g, 34.7 mmol) dropwise. After stirring for 20 min, bromomethyl methyl ether (4.3 g, 34.7 mmol) was added. After stirring for 16 h at room temperature, the mixture was poured into water (250 mL) and extracted with hexane. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, hexane) to yield the title compound as a colorless oil (4.0 g, 53%). 1HNMR (400 MHz, CDCl3) δ7.55 (d, 1H), 7.28 (t, 1H), 7.16 (d, 1H), 6.91 (t, 1H), 5.25 (s, 2H), 3.54 (s, 3H).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10])([CH3:6])([CH3:5])[CH3:4].[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C1(C)C=CC=CC=1>[C:3]([N:7]([C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[Br:17])[NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)NNC(=O)c1ccccn1
Reactant: O=C(Cl)c1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccn1)C(=O)c1ccccc1Br
Temperature: 23 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
An aqueous solution of sodium hydroxide (1.24 g of 50% NaOH diluted with 5 ml of water) was added to a solution of N'-t-butyl-N-(2-pyridinecarbonyl)hydrazine (1.0 g, 0.00518 mol) in 20 ml of toluene at 23° C. The mixture was cooled and treated with 2-bromobenzoyl chloride (1.137 g, 0.00518 mol). The mixture was then stirred at 23° C. overnight. The solids were removed by filtration, washed with water and dried to afford 0.96 g of N'-t-butyl-N-(2-pyridinecarbonyl)-N'-(2-bromobenzoyl)hydrazine as a white solid: m.p. 179°-180° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:19]1([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][C:29](B4OC(C)(C)C(C)(C)C4)=[CH:30][CH:31]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[C:3]2[C:10]([C:29]3[CH:28]=[C:27]4[C:32]([CH:33]=[CH:34][C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:26]4)=[CH:31][CH:30]=3)=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](C(N)=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@@H](C(N)=O)C1
Temperature: 80 °C

Procedure:
A mixture of cis-3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylic acid amide (131 mg, 0.367 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (146 mg, 0.441 mmol), Na2CO3 (97.2 mg, 0.917 mmol), Pd(PPh3)4 (25.5 mg, 0.0221 mmol), DMF (5 mL), and water (1 mL) was purged with nitrogen for 30 min and heated to 80° C. for 18 h. To the cooled reaction solution was added water (15 mL), the mixture was extracted with EtOAc (3×20 mL), the combined organic layers were washed with water (2×15 mL) and brine, dried over MgSO4, filtered, and concentrated. The residue was triturated with MeOH to give the title compound as yellow solid. 1H NMR (CDCl3, 400 MHz): δ=2.60-2.70 (m, 4H), 2.84-2.90 (m, 1H), 5.14-5.23 (quintet, 1H, J=8.7 Hz), 6.31 (brs, 2H), 6.92 (s, 1H), 7.40 (s, 1H), 7.50-7.62 (m, 3H), 7.78-7.82 (m, 2H), 8.08-8.10 (d, 1H, J=8.4 Hz), 8.15-8.23 (m, 3H), 8.30-8.37 (m, 2H), 8.49-8.51 (d, 1H, J=8.4 Hz). MS (ES+): 435.0 [MH+]. HPLC: tR=2.4 min (polar—5 min).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.C(N(CC)CC)C.[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36])([O-:28])=[O:27].O>C(Cl)Cl>[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([O:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:9])([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1)(=[O:37])=[O:36])([O-:28])=[O:27]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COS(=O)(=O)c2ccccc2[N+](=O)[O-])OC(C)(C)O1
Reaction time: 24 h
Yield: 122.9 %

Procedure:
To a stirring 20°-25° C. solution of the (4R cis)-1,1-dimethylethyl 6-hydroxymethyl-2,2-dimethyl -1,3-dioxane-4-acetate (European Patent Application 0319,847) (10 g, 0.038 mol) in methylene chloride (250 mL) containing triethylamine (7 mL, 0.05 mol) is added 2-nitrobenzenesulfonyl chloride (9.8 g, 0.043 mol). Stirring is continued at 20°-25° C. for 24 hours, a further portion of 2-nitrobenzenesulfonyl chloride (2.0 g, 0.009 mol) is added and the solution stirred for a further 4 hours. The solution is then poured onto 200 mL of water and the layers separated. The upper aqueous layer is extracted with 250 mL of methylene chloride and the combined organic layers are washed with 100 mL each of saturated sodium bicarbonate solution to ensure complete removal of 2-nitrobenzenesulfonyl chloride and then saturated sodium chloride. Drying the solution with magnesium sulfate and concentration in vacuo gives 20.8 g of the product as a green oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C@@:14]1([CH3:41])[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C@@H:17]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:16]([C@@H:34]([CH2:38][CH3:39])[CH:35]([OH:37])[CH3:36])[C:15]1=[O:40])[CH:12]=[CH2:13].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([C@@:14]1([CH3:41])[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C@@H:17]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[N:16]([C@@H:34]([CH2:38][CH3:39])[C:35](=[O:37])[CH3:36])[C:15]1=[O:40])[CH:12]=[CH2:13]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)O)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)=O)C1=O
Reaction time: 0.03 h

Procedure:
To a solution of oxalyl dichloride (78 μL, 0.87 mmol) in DCM (1.5 mL) at −60° C. was added a solution of DMSO (93 μL, 1.30 mmol) in DCM (1.5 mL) under N2. After being stirred for 2 min, a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one prepared in example 151, Step C (200 mg, 0.434 mmol) in DCM (1.5 mL) was added and the resulting solution was stirred for 15 min. at −60° C. Then, triethylamine (305 μL, 2.17 mmol) was added to the reaction solution. After being stirred at rt for 20 min, the reaction was quenched (water), extracted (2×EtOAc), and washed (2×sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by combi flash (SiO2, 24 g, 20% and 30% EtOAc/Hexanes) provided the title compound as a colorless foam.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11]NC(=O)CCC(N)=O>CC#N>[Br:11][C:5]1[CH:6]=[CH:7][C:8]([NH2:10])=[N:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: NC(=O)CCC(=O)NBr
Reactant: Nc1cccc([N+](=O)[O-])n1
Solvent: CC#N
Product: Nc1ccc(Br)c([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 153.3 %

Procedure:
To a stirred solution of 6-nitro-pyridin-2-ylamine (1.0 g, 7.18 mmol) in CH3CN (100 mL), protected from light and under nitrogen atmosphere, N-bromosuccinamide (636 mg, 3.59 mmol) was added at 0° C. After 1 hour, another portion of N-bromosuccinamide (636 mg, 3.59 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was then quenched by the addition of saturated aqueous Na2S2O3 and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water, brine, dried over MgSO4 (anhydrous) and concentrated in vacuo. The crude product was purified by Biotage using 10% ethyl acetate in hexane to afford 1.2 g of 5-bromo-6-nitro-pyridin-2-ylamine (10).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)=[CH:24][CH:23]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][N:38]1[CH2:39][CH2:40][CH:35]([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)=[CH:30][CH:31]=2)[CH2:36][CH2:37]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCBr)Nc1ccccc1Cc1ccccc1
Reactant: Fc1ccc(Cc2ccc(C3CCNCC3)cc2)cc1
Product: O=C(CCCN1CCC(c2ccc(Cc3ccc(F)cc3)cc2)CC1)Nc1ccccc1Cc1ccccc1

Procedure:
The compound (11) synthesized in Reference Example 11 and the compound (7) synthesized in Reference Example 7 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1)(=[O:4])=[O:3].[NH2:15][C@@H:16]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=1)[C@H:17]([OH:29])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:28])[CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:37][C:35]1[CH:36]=[C:31]([CH:32]=[C:33]([F:38])[CH:34]=1)[CH2:30][C@H:16]([NH:15][C:12]([CH:9]1[CH2:8][CH2:7][CH:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH2:11][CH2:10]1)=[O:14])[C@H:17]([OH:29])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:28])[CH:22]=1
Reactant: CS(=O)(=O)CC1CCC(C(=O)O)CC1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)C2CCC(CS(C)(=O)=O)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.4 %

Procedure:
To a stirred solution of acid from step 6 (100 mg, 0.5 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (190 mg, 0.5 mmol), and HATU (175 mg, 0.5 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (280 μL, 1.6 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, gradient 95:5 to 92:8 methylene chloride/methanol) provided the title compound (60 mg): mp 45-50° C.; ESI MS m/z 537 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[I:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:2]2[C:7]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[N:9]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:19][CH:18]=1
Reactant: CNc1nccc(-c2cccnc2Cl)n1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1nccc(-c2cccnc2Oc2ccc(I)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(2-Chloropyridin-3-yl)-N-methylpyrimidin-2-amine (3.30 g, 15.0 mmol), 4-iodophenol (3.96 g, 18.0 mmol), cesium carbonate (10.6 g, 30.0 mmol), and 15 mL of DMSO were added into a 50-mL round bottom flask. The flask was sealed with a septum and placed in a preheated oil bath at 130° C. After 3 h, the reaction was completed according to TLC and LC-MS analysis. The reaction was cooled to room temperature. Water was added into the reaction mixture until all product precipitated out of the solution. The solid was filtered, ground, and washed with water. The product was collected and dried in a vacuum oven overnight. The product, 4-(2-(4-iodophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine was obtained as a light brown solid. 1H NMR (Varian, 300 MHz, CDCl3): 8.40 (br s, 1H), 8.34 (d, J=4.1 Hz, 1H), 8.19 (dd, J=4.8, 2.2 Hz, 1H), 7.73 (m, 2H), 7.30 (dd, J=7.4, 4.8 Hz, 1H), 7.19 (m, 2H), 7.00 (m, 2H), 2.84 (d, J=4.8 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:15][S:16][CH:17]=[C:3]12.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1>CN(C)C=O.O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:15][S:16][CH:17]=[C:3]12
Reactant: NC(=O)c1ccc2nc3cscc3c(=O)n2c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2nc3cscc3c(=O)n2c1
Temperature: 95 °C

Procedure:
A mixture of 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide (3.8 g., 0.015 mol), p-toluenesulfonyl chloride (4.4 g., 0.023 mol) and pyridine (3.8 ml, 0.046 mol) in dimethylformamide (50 ml) is heated at 95° C. for 1 hour. The mixture is cooled, diluted with water (5 ml) and stirred. The precipitate is filtered, washed with water and dried. Recrystallization from 2-propanol gives golden crystals (2.5 g.) mp 233°-234° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[C@@H:13]([CH2:33][N:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[S:35]([CH3:38])(=[O:37])=[O:36])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH3:45]>CO>[NH2:45][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[C@@H:13]([CH2:33][N:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[S:35]([CH3:38])(=[O:37])=[O:36])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N(C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)c1ccccc1
Reactant: N
Solvent: CO
Product: CS(=O)(=O)N(C[C@H]1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)c1ccccc1
Temperature: 140 °C

Procedure:
A 5-mL microwave vial was charged with N-(((2R)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-phenylmethanesulfonamide (0.134 g, 0.194 mmol, step 1) and 2M NH3 in MeOH (2 mL). The reaction mixture was heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 3 h. Then the mixture was then heated at 130° C. (thermal) for 12 h. The solvent was removed and the crude product was purified by column chromatography (25 g of silica gel, 10 to 90% EtOAc in hexanes) to afford N-(((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-phenylmethanesulfonamide (0.0385 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(OCC)(=O)C>CCOCC>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][N:22]=[CH:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:19][CH:20]=1)([O-:14])=[O:13]
Reactant: O=CCCc1ccc(F)cc1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(NN=CCCc2ccc(F)cc2)cc1
Yield: 41.7 %

Procedure:
A solution of 3-(4-fluorophenyl)propanal (7.0 g) in ether (50 ml) was addedto a stirred suspension of 4-nitrophenylhydrazine (7.0 g) in ether (1 50 ml), followed by sufficient ethyl acetate to achieve a clear solution. Thesolution was filtered and evaporated and the residue was crystallised from ethyl acetate/hexane to give the title compound (5.48 g), m.p. 125°-127° C. Found: C,62.81; H,4.87; N,14.44. C15 H14FN3O2 requires: C,62.71; H,4.91; N,14.63%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[N+:17]([O-])[CH:16]=[CH:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)(O)[O-:24].[Na+]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([OH:24])=[N:17][CH:16]=[CH:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Nc1ccc2c[n+]([O-])ccc2c1)c1ccc(Cl)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=S(=O)(Nc1ccc2c(O)nccc2c1)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
In acetic anhydride (0.75 ml) was dissolved 50 mg of 6-(4-chlorobenzenesulfonylamino)isoquinoline-N-oxide (intermediate in Example 83), followed by heated under stirring at 80° C. for 16 hours and then for 2 hours. After standing to cool, an aqueous saturated sodium bicarbonate was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was dissolved in ethanol (2.0 ml) and water (0.5 ml), followed by heating under reflux for 0.5 hour. After evaporating the solvent, the residue was purified by silica gel column, to give the title compound (20 mg) as a pale red solid.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]1([N:9]2[C:17]3[C:12](=[C:13]([O:23][CH3:24])[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=3)[CH:11]=[CH:10]2)[CH2:8][CH2:7]1.CN([CH:28]=[O:29])C>CCOC(C)=O.[OH-].[Na+]>[CH:6]1([N:9]2[C:17]3[C:12](=[C:13]([O:23][CH3:24])[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=3)[C:11]([CH:28]=[O:29])=[CH:10]2)[CH2:7][CH2:8]1
Reactant: CCOC(=O)c1cc(OC)c2ccn(C3CC3)c2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OC)c2c(C=O)cn(C3CC3)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.28 ml of POCl3 was added dropwise to a solution of 3.24 g of ethyl 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylate in 30 ml of DMF and the mixture was stirred at 0° C. for 2 hrs. The mixture was diluted with EtOAc and 25 ml of 1N NaOH was added. Then the mixture was made basic using saturated NaHCO3aq. The mixture was extracted with EtOAc and the extract was washed with water and saturated brine, dried over Na2SO4, then concentrated. The residue was purified on SiO2 column chromatography (EtOAc-n-Hexane system) to give 2.4 g of ethyl 1-cyclopropyl-3-formyl-4-methoxy-1H-indole-6-carboxylate.