Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][C@@H:38]4[CH3:43])[C:25]4[CH2:31][CH2:30][N:29]([CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:28][C:26]=4[N:27]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl.C(OC1N=C(NC2C=CC(C3N=C(N4CCOC[C@@H]4C)C4CCNCC=4N=3)=CC=2)C=CC=1)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.S(OCC(F)(F)F)(C(F)(F)F)(=O)=O>C(#N)C.C(OCC)(=O)C>[CH3:43][C@@H:38]1[N:37]([C:24]2[C:25]3[CH2:31][CH2:30][N:29]([CH2:32][C:33]([F:35])([F:34])[F:36])[CH2:28][C:26]=3[N:27]=[C:22]([C:19]3[CH:20]=[CH:21][C:16]([NH:15][C:13]4[NH:14][C:9](=[O:8])[CH:10]=[CH:11][CH:12]=4)=[CH:17][CH:18]=3)[N:23]=2)[CH2:42][CH2:41][O:40][CH2:39]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(OCc4ccccc4)n3)cc2)nc2c1CCN(CC(F)(F)F)C2
Agent: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(OCc4ccccc4)n3)cc2)nc2c1CCNC2
Agent: Cl
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(=O)[nH]3)cc2)nc2c1CCN(CC(F)(F)F)C2
Yield: 110 %

Procedure:
Step 1—Synthesis of (S)-6-(benzyloxy)-N-(4-(4-(3-methylmorpholino)-7-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)pyridin-2-amine (pk). To a solution of (S)-6-(benzyloxy)-N-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)pyridin-2-amine hydrochloride salt (ms) (51 mg, 0.094 mmol) in Acetonitrile (1.0 mL) and N,N-Diisopropylethylamine (0.10 mL, 0.57 mmol) was added trifluoroethanol triflate (0.020 mL, 0.14 mmol) at room temperature, and the reaction mixture was microwaved at 140° C. for 30 minutes, followed by the addition of a second portion of Trifluoroethanol triflate (0.030 mL, 0.21 mmol). The resultant reaction mixture was microwaved at 140° C. for 20 minutes. The reaction mixture was diluted with Ethyl acetate, and washed by NaHCO3, water, and brine till pH 7. The orange organic solution was evaporated after dried over Magnesium sulfate. The residue was purified on a silica gel column to give the desired product (pk) (61 mg, 110% yield) as yellow powder: 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J=8.4 Hz, 2H), 7.46 (m, 5H), 7.39 (t, J=7.5 Hz, 2H), 7.32 (t, J=7.2 Hz, 1H), 6.55 (s, 1H), 6.45 (d, J=7.8 Hz, 1H), 6.31 (d, J=7.9 Hz, 1H), 5.38 (s, 2H), 4.11 (m, 1H), 4.06-3.80 (m, 4H), 3.80-3.47 (m, 4H), 3.20 (q, J=9.4 Hz, 2H), 3.05-2.95 (m, 1H), 2.86 (m, 1H), 2.82-2.68 (m, 2H), 1.33 (d, J=6.6 Hz, 3H); LC-MS m/z=591 (M+H).
Reaction SMILES: [Na].[CH3:2][C@@H:3]1[C@@H:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:6]2[C:7](Cl)=[N:8][C:9]3[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=[CH:11][C:10]=3[C:5]2=[N:4]1.[O-:28][CH2:29][CH2:30][CH3:31].[Na+].[Cl-]>C(O)CC>[CH3:2][C@@H:3]1[C@@H:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:6]2[C:7]([O:28][CH2:29][CH2:30][CH3:31])=[N:8][C:9]3[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=[CH:11][C:10]=3[C:5]2=[N:4]1
Reactant: CCC[O-]
Reactant: C[C@H]1N=C2c3cnn(-c4ccccc4)c3N=C(Cl)N2[C@@H]1c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CCCO
Product: CCCOC1=Nc2c(cnn2-c2ccccc2)C2=N[C@H](C)[C@@H](c3ccccc3)N12

Procedure:
51 mg sodium was dissolved in 5 ml n-propanol. 670 mg of the above product (2R-trans)-2,7-dihydro-2-methyl-3,7-diphenyl-5-chloro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine dissolved in 15 ml n-propanol was added to the propoxide solution with stirring. After 1 hour the reaction was poured into 200 ml saturated NaCl and the extracts were dried over MgSO4, filtered and concentrated to yield an oil which was purified by radial chromatography (30-50-70-90% ethanol/ hexane, 2 mm plate) to yield 600 mg of (2R-trans)-2,7-dihydro-2-methyl-3,7-diphenyl-5-propoxy-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][C:4]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:5]=1[NH2:6].[N:14]([O-])=O.[Na+].O>C(O)(=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[C:4]2[C:5](=[CH:7][CH:8]=[C:9]([Br:11])[CH:10]=2)[NH:6][N:14]=1
Reactant: Nc1ccc(Br)cc1CC(F)(F)F
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1n[nH]c2ccc(Br)cc12
Temperature: 15 °C

Procedure:
18 parts of 2-(2,2,2-trifluoro-ethyl)-4-bromo-aniline are dissolved in 490 parts by volume of glacial acetic acid. To this solution, well stirred at 15° C., is added all at once a solution of 4.9 parts of sodium nitrite in 11.9 parts of water. At the end of 3 days, the acetic acid is evaporated and the residue is taken up in 40 parts of water, the solid filtered off, washed and dried. 18 parts of 3-trifluoromethyl-5-bromo-indazole are thus obtained.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].C[CH2:19][N:20](CC)CC.CN>CO>[CH3:14][O:13][C:12]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:2][N:20]([CH3:19])[C:5]2=[O:6]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1CBr
Agent: CN
Solvent: CO
Product: COc1c([N+](=O)[O-])ccc2c1CN(C)C2=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
To a solution of methyl 2-(bromomethyl)-3-methoxy-4-nitrobenzoate (300 mg, 1.0 mmol) in MeOH (10 mL) was added Et3N (120 mg, 1.2 mmol) and CH3NH2 (1.0 mL, 4M in MeOH). The solution was stirred at 70° C. for 4 h. The solvent was evaporated in vacuo, and the residue was purified by silica gel-column (eluting with PE/EA=10:1) to afford 4-methoxy-2-methyl-5-nitroisoindolin-1-one as a yellow solid (110 mg, yield 50%). m/z (ES+APCI)+: [M+H]+223.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:16])[C:11]=1[O:12][CH2:13][C:14]#[CH:15])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:16])[C:11]=1[O:12][CH2:13][C:14]#[CH:15])[C:5]([OH:7])=[O:6]
Reactant: C#CCOc1c(F)cc(C(=O)OC)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#CCOc1c(F)cc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To 30 ml of ethanol were added 5.5 g of methyl 3,5-difluoro-4-(2-propynyloxy)benzoate and 10 ml of 15% aqueous sodium hydroxide solution and the mixture obtained was stirred at room temperature for 2 hours. Then, the reaction mixture was concentrated under reduced pressure. Hydrochloric acid was added to the residue for acidification and then, solid precipitated was collected by filtration to obtain 5.0 g of 3,5-difluoro-4-(2-propynyloxy)benzoic acid represented by the formula:
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[CH:6][CH:5]=[N:4][C:3]1=2.[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C=O)C>[N:12]([CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[CH:6][CH:5]=[N:4][C:3]1=2)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: BrC1CCCc2nccnc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC1CCCc2nccnc21
Temperature: 60 °C
Yield: 96.9 %

Procedure:
5-bromo-5,6,7,8-tetrahydroquinoxaline (2.75 g, 12.9 mmol) and sodium azide (1.68 g, 25.8 mmol) were dissolved in DMF (50 mL) under nitrogen atmosphere and the reaction mixture was warmed to 60° C. for 2 days. The mixture was cooled to room temperature and poured over water (500 mL), and was extracted with CH2Cl2 (3×300 mL). The organic extracts were washed with brine (2×200 mL), dried and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel using 1:1 EtOAc/hexanes to afford 2.19 g (97%) of 5-azido-5,6,7,8-tetrahydroquinoxaline as a yellow liquid: 1H NMR (CDCl3): δ 1.80-1.96 (m, 1H), 2.00-2.10 (m, 3H), 2.75-3.06 (m, 2H), 4.74 (t, 1H, J=6.5 Hz), 8.44 (d, 1H, J=3 Hz), 8.45 (d, 1H, J=3 Hz); 13C NMR (CDCl3): δ 18.6, 28.9, 31.7, 60.2, 142.6, 144.3, 150.3, 153.6.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH:17]=[O:18])[CH:14]=[N:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1.[CH3:19]N(C=O)C.[H-].[Na+]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=3)[N:8]2[CH3:19])=[CH:4][CH:3]=1
Reactant: O=Cc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cn1c(-c2cncc(C=O)c2)cc2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
A flask is charged with 5-(6-chloro-1H-indol-2-yl)-pyridine-3-carbaldehyde (Example 104, 7.8 g, 28.9 mmol), Mel (5.33 g, 37.5 mmol) and DMF (300 mL), and 60% NaH in mineral oil (1.386 g, 34.6 mmol) is added at 0° C. The mixture is stirred for 2 h. Water (100 mL) is added. The mixture is extracted with EtOAc twice and the combined organic phase is washed with water (2×200 mL) and brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography with a 0 to 2% methanol-DCM gradient to give 6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole. MS (ESI) m/z 271.0, 272.9 (M+H)+.
Reaction SMILES: C[O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[C:8]([NH2:23])=[N:9][C:10](=[O:22])[N:11]([CH:21]=1)[C@@H:12]1[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[C@H:13]1[OH:14])=O.N>C(Cl)Cl>[C@@H:12]1([N:11]2[CH:21]=[C:7]3[CH:6]=[CH:5][C:3](=[O:2])[N:23]=[C:8]3[NH:9][C:10]2=[O:22])[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[C@H:13]1[OH:14]
Reactant: COC(=O)/C=C/c1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)nc1N
Agent: N
Solvent: ClCCl
Product: O=c1ccc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c(=O)[nH]c-2n1
Yield: 65.5 %

Procedure:
44 mg of 2',3',5'-tri-O-acetyl-3-β-D-ribofuranosyl-2-oxo-7-chloropyrido[2,3-d]pyrimidine (c) was dissolved in 1 ml of methylene chloride and 10 ml of ammonia saturated methanol was added thereto. The mixture was made to undergo a reaction at room temperature for 12 hours. Thereafter, the reaction mixture was concentrated at reduced pressure and the residue was recrystallized in an ethanol-water system to give 26 mg of 3-β-D-ribofuranosyl-2-oxo-7-chloropyrido[2,3-d]pyrimidine (d). Its physical properties were as follows.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH2:23]O>>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH2:23][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(F)cc1F
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)cc2F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2,4-difluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.19 (2H, s), 5.74 (1H, d, J=2.0 Hz), 6.78-6.86 (2H, m), 7.33 (1H, dd, J=1.2 Hz, J=4.8 Hz), 7.39-7.45 (1H, m), 7.51 (1H, d, J=1.6 Hz), 7.94 (1H, s), 8.62 (1H, d, J=4.8 Hz). [M+H] Calc'd for C16H10F2N4O, 313; Found, 313.
Reaction SMILES: O1CCCCC1O[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:15].O1CCN(C2CCCC=2)CC1.[C:27]1(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28]1.C(OCC)C>C1C=CC=CC=1>[OH:32][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:8][CH2:9][C:10]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]=1
Reactant: O=C1CCCC1
Reactant: O=CCCCCCCOC1CCCCO1
Agent: C1=C(N2CCOCC2)CCC1
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C1CCC=C1CCCCCCCO
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(2-tetrahydropyranyloxy)heptanal (22 g.) and 1-morpholinocyclopentene, i.e. the morpholine enamine of cyclopentanone, (21.4 g.) in benzene (25 ml.) was heated under reflux for 12 hours under nitrogen, and the water liberated was continuously removed with a Dean and Stark head. Benzene (10 ml.) and then, dropwise, 18% hydrochloric acid (28 ml.) were added and the mixture was stirred for 2 hours. The organic layer was separated and evaporated. Concentrated hydrochloric acid (72 ml.) and butanol (300 ml.) were added to the residue. The mixture was heated at 100° C. for 1 hour, and then the solution was concentrated to give an oil. Diethyl ether was added, and the ether solution was washed with aqueous sodium bicarbonate and then water, and dried over sodium sulphate. The solvent was evaporated and the residue was distilled under reduced pressure to give 2-(7-hydroxyheptyl)cyclopent-2-en-1-one (11.7 g.), b.p. 125°-170° C./0.15 mm.Hg, nD25 1.490, λmax 228 mμ (ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:31]=[C:30]([CH2:32][O:33]C(=O)C)[O:29][N:28]=3)=[CH:23][CH:22]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:31]=[C:30]([CH2:32][OH:33])[O:29][N:28]=3)=[CH:23][CH:22]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(=O)OCc1nc(-c2ccc(CN(C3CCCCNC3=O)S(=O)(=O)c3ccc(Cl)cc3)cc2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1NCCCCC1N(Cc1ccc(-c2noc(CO)n2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 81.5 %

Procedure:
A solution of 0.03 g (0.05 mmol) acetic acid 3-(4-{[(4-chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-phenyl)-[1,2,4]oxadiazol-5-ylmethyl ester in 1 ml tetrahydrofuran was stirred with 0.2 ml (0.2 mmol) 1 molar aqueous sodium hydroxide for 3 hours at room temperature. Water and aqueous hydrochloric acid was added to reach pH 1. Extraction with ethylacetate, drying with sodium sulfate, filtration and removal of the solvent by distillation yielded 0.02 g (98%) 4-chloro-N-[4-(5-hydroxymethyl-[1,2,4]oxadiazol-3-yl)-benzyl]-N-(2-oxo-azepan-3-yl)-benzenesulfonamide as white solid, MS: m/e (%)=491.0 (MH+, 100).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:3]=1.[Li]C(C)(C)C.CCCCC.[C:28]([O:32][C:33]([N:35]1[CH:40]2[CH2:41][CH2:42][CH:36]1[CH2:37][C:38](=[O:43])[CH2:39]2)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])(O)=O.[Na+]>C1COCC1>[C:28]([O:32][C:33]([N:35]1[CH:40]2[CH2:41][CH2:42][CH:36]1[CH2:37][C:38]([C:2]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:3]=1)([OH:43])[CH2:39]2)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: CC(C)(C)[Si](C)(C)n1cc(Br)c2ccccc21
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1cn([Si](C)(C)C(C)(C)C)c3ccccc13)C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To 4.8 g (15.5 mmol) 3-bromo-1-(tert-butyl-dimethyl-silanyl)-1H-indole in 60 mL THF at −78° C. is added 19.1 mL (32.5 mmol) of a 1.7M solution of t-BuLi/pentane in drops over 10 min. After stirring at −78° C. for 30 min, 3.48 g (15.5 mmol) 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in 20 mL THF is added via a cannula over 5 min. After stirring at 23° C. for 3 h, the reaction mixture is poured into sat. aqueous NaHCO3, and extracted with 2×50 mL EtOAc. The combined organics are washed with 1×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered and evaporated to an orange oil. Flash chromatography on SiO2 gel, eluting with CH2Cl2/EtOAc (80/1 to 20/1), gives 3.74 g (8.2 mmol, a 53% yield) of the title compound as an off-white wax. MS (ES) m/z 457 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:29])([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C:9]([N:11]2[CH2:22][CH2:21][CH2:20][C@H:12]2[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:29])([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C:9]([N:11]2[CH2:22][CH2:21][CH2:20][C@H:12]2[C:13]([OH:15])=[O:14])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)C(O)(c1cccnc1)c1cccc(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCN1C(=O)C(O)(c1cccnc1)c1cccc(Cl)c1
Yield: 101 %

Procedure:
The polar isomer of tert-butyl 1-[(3-chlorophenyl)(hydroxy)pyridin-3-ylacetyl]-L-prolinate (0.059 g, 0.14 mmol) was dissolved in THF (1 mL) and 6N hydrochloric acid (2 mL) and stirred for 24 hours at room temperature. The mixture was then evaporated in vacuo and vacuum dried to yield the polar isomer of 1-[(3-chlorophenyl)(hydroxy)pyridin-3-ylacetyl]-L-proline (0.051 g, HPLC RT=2.399 min, Method A; LCMS m/z=361).
Reaction SMILES: B.[Na].[Cl:3][C:4]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[CH:16](O)[CH2:17][CH2:18][CH3:19])[C:11]#[N:12].S(Cl)(Cl)=O.ClC1C=C(Cl)C=CC=1COC1C=C(C=CC=1C(Cl)CCC)C#N.[Na].[NH:54]1[CH:58]=[CH:57][N:56]=[CH:55]1>O1CCOCC1.CN(C)C=O.C(#N)C1C=CC=CC=1>[Cl:3][C:4]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[CH:16]([N:54]1[CH:58]=[CH:57][N:56]=[CH:55]1)[CH2:17][CH2:18][CH3:19])[C:11]#[N:12]
Reactant: c1c[nH]cn1
Reactant: CCCC(O)c1ccc(C#N)cc1OCc1ccc(Cl)cc1Cl
Agent: B
Agent: CCCC(Cl)c1ccc(C#N)cc1OCc1ccc(Cl)cc1Cl
Agent: [Na]
Solvent: N#Cc1ccccc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCCC(c1ccc(C#N)cc1OCc1ccc(Cl)cc1Cl)n1ccnc1

Procedure:
3-Bromo-1-butyryloxybenzene is obtained by esterification of 3-bromophenol with butyric acid chloride and further is reacted, by Fries reaction and etherification of the phenolic hydroxyl group, with 2,4-dichlorobenzyl chloride into the 3-(2,4-dichlorobenzyloxy)-4-butyryl-1-bromobenzene. The 3(2,4-dichlorobenzyloxy)-4-butyrylbenzonitrile with a melting point of 97°-98° C. is obtained by reaction of substituted bromobenzene with copper(I) cyanide in N-methyl pyrrolidone (3 hours at 180° C.). The aromatic keto group is reduced with sodium boron hydride in aqueous dioxane to 3-(2,4-dichlorobenzyloxy)-4-(1-hydroxybutyl)-benzonitrile, melting point of 101°-105° C. The 3-(2,4-dichlorobenzyloxy)-4-(1-chlorobutyl)benzonitrile thionyl chloride. The substituted benzyl chloride is reacted with the sodium salt of the imidazole in dimethylformamide to 3-(2,4-dichlorobenzyloxy)-4-(imidazolyl)-butyl]-benzonitrile (melting point of 105°-107° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1>>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:19]=[N:18]1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)nc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(-c2cc(Oc3ccc(N)cn3)ccn2)cn1
Yield: 64 %

Procedure:
Using a procedure analogous to Example A13, 6-(2-chloropyridin-4-yloxy)pyridin-3-amine (6.06 g, 27.3 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.53 g, 41.0 mmol) were combined to provide 6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-3-amine (4.67 g, 64% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.3 (m, 1H), 8.2 (s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.3 (s, 1H), 7.25-7.2 (m, 1H), 6.85-6.81 (m, 1H), 6.6-6.55 (m, 1H), 5.3 (s, 2H), 3.8 (s, 3H); MS (ESI) m/z: 268.1 (M+H+).
Reaction SMILES: C(OC(N1CCN(C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)CC1)=O)(C)(C)C.[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45][CH2:46][CH2:47]OS(C)(=O)=O)=[CH:41][C:40]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:39]2)[CH2:36][CH2:35]1.[NH:62]([CH2:66][CH2:67][OH:68])[CH2:63][CH2:64][OH:65]>>[OH:65][CH2:64][CH2:63][N:62]([CH2:47][CH2:46][CH2:45][C:42]1[C:43](=[O:44])[N:38]([CH2:37][CH:34]2[CH2:35][CH2:36]2)[N:39]=[C:40]([C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=2)[CH:41]=1)[CH2:66][CH2:67][OH:68]
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: OCCNCCO
Agent: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Product: COc1ccc(-c2cc(CCCN(CCO)CCO)c(=O)n(CC3CC3)n2)cc1F
Yield: 13.1 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and diethanolamine were reacted to yield the title compound as a yellow oil (yield: 13.1%).
Reaction SMILES: [C:1]([N:9]([CH3:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>ClCCl>[C:1]([N:9]([CH3:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:18])=[O:25])=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(CN(C)C(=O)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(Cc1ccc(S(C)=O)cc1)C(=O)c1ccccc1
Yield: 56.9 %

Procedure:
To a solution of N-benzoyl-N-methyl-N-(4-methylthiobenzyl)amine (6.8 g) in dichloromethane (120 ml) is added gradually m-chloroperoxybenzoic acid (5.5 g) with stirring at a temperature below 5° C. and the mixture is stirred at the same temperature for 15 minutes. After the reaction, the reaction mixture is washed successively with 5% aqueous potassium carbonate solution and aqueous sodium chloride solution, and subsequently dried over magnesium sulfate. After dichloromethane is distilled off from the mixture, the residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=100:0-100:5) to give N-benzoyl-N-methyl-N-(4-methylsulfinylbenzyl)amine (4.1 g).
Reaction SMILES: COC1C=C(C)C(S(N2CCCCC2COCC(O)=O)(=O)=O)=C(C)C=1.CN1CCC(N2CCNCC2)CC1.C(=O)([O-])O.[Na+].[CH3:44][O:45][C:46]1[CH:51]=[C:50]([CH3:52])[C:49]([S:53]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH:57]2[CH2:62][O:63][CH2:64][C:65]([N:67]2[CH2:72][CH2:71][N:70]([CH:73]3[CH2:78][CH2:77][N:76]([CH3:79])[CH2:75][CH2:74]3)[CH2:69][CH2:68]2)=[O:66])(=[O:55])=[O:54])=[C:48]([CH3:80])[CH:47]=1.[Cl:81][Si](C)(C)C>ClCCl.C(C(C)=O)C.C(O)C.CC(C)=O.C(OCC)C>[ClH:81].[ClH:81].[CH3:44][O:45][C:46]1[CH:51]=[C:50]([CH3:52])[C:49]([S:53]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH:57]2[CH2:62][O:63][CH2:64][C:65]([N:67]2[CH2:72][CH2:71][N:70]([CH:73]3[CH2:78][CH2:77][N:76]([CH3:79])[CH2:75][CH2:74]3)[CH2:69][CH2:68]2)=[O:66])(=[O:55])=[O:54])=[C:48]([CH3:80])[CH:47]=1
Reactant: C[Si](C)(C)Cl
Agent: CN1CCC(N2CCNCC2)CC1
Agent: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCN(C3CCN(C)CC3)CC2)c(C)c1
Agent: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)O)c(C)c1
Solvent: CC(C)=O
Solvent: CCO
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (272 mg, 1.696 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (600 mg, 1.615 mmol) in dichloromethane (15 ml), and the mixture was stirred for 1 h at room temperature. A solution of 1-(1-methylpiperidin-4-yl)piperazine (293 mg, 1.615 mmol) in dichloromethane (5 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature. Saturated sodium hydrogen carbonate solution (20 ml) was then added to the reaction mixture, and then the aqueous phase was extracted with dichloromethane (2×20 ml). The combined organic phases were extracted with saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using dichloromethane/methanol (5:1). 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone (590 mg, 1.105 mmol) was dissolved in methyl ethyl ketone/ethanol (1:1) (20 ml) [plus a few drops of acetone], and chlorotrimethylsilane (168 μl, 1.326 mmol) was added slowly. Diethyl ether (20 ml) was then added, and the mixture was stirred for 1 h at 0° C. The resulting precipitate was filtered off, dried with the exclusion of air and washed with diethyl ether.