Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:15]([C:16](=O)/[CH:17]=[CH:18]/N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:32]1([NH:37][C:38]([NH2:40])=[NH:39])[CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:40]=[C:38]([NH:37][CH:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[N:39]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N=C(N)NC1CCCC1
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2C(=O)/C=C/N(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of (2E)-1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (5.97 g, 14.7 mmol) in dimethylformamide (80 mL) was added N-cyclopentyl guanidine hydrochloride (4.33 g, 26.5 mmol; Prepared by modification of a procedure from Bannard, R. A. B. et al., Can. J. Chem. 1958, 36, 1541–1549), followed by potassium carbonate (2.03 g, 14.7 mmol). The resulting solution was heated at reflux for 6 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (4:6 ethyl acetate:hexane) to give N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-a]pyridin-7-amine (5.02 g, 73%) as a yellow solid. 1H NMR (CDCl3): δ 7.95 (d, 1H), 7.72 (d, 1H), 7.54 (dd, 2H), 7.25 (t, 1H), 6.94 (dd, 2H), 6.28 (d, 1H), 6.00–5.97 (m, 2H), 5.03 (d, 1H), 4.33–4.31 (m, 1H), 3.96 (m, 1H), 3.83 (s, 3H), 2.10–2.01 (m, 4H), 1.77–1.50 (m, 12H); MS m/z 469 (M+1); Anal. Calcd for C28H32N6O: C, 71.77; H, 6.88; N17.93. Found: C, 71.41; H, 7.02; N, 17.89.
Reaction SMILES: [C:1]([CH:3]([OH:18])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)#[N:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[C:1]([CH:3]([O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:10]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(O)C#N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CC(C#N)OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of tert-butyl 4-(2-cyano-2-hydroxyethyl)piperidine-1-carboxylate (67.0 g) and triethylamine (35.0 g) in dichloromethane (500 mL) was slowly added a solution of methanesulfonyl chloride (36.3 g) in dichloromethane (200 mL). The reaction system was stirred at room temperature for 2 hr, and added to ice water (300 mL). The organic layer was dried over anhydrous sodium sulfate, insoluble material was removed by filtration, and the filtrate was concentrated to give the title compound (80.0 g).
Reaction SMILES: [CH3:1][C:2]1O[C:6]2[CH2:8][CH2:9][O:10][CH2:11][C:5]=2[C:4](=[O:12])[CH:3]=1.[NH3:13]>>[CH3:1][C:2]1[NH:13][C:6]2[CH2:8][CH2:9][O:10][CH2:11][C:5]=2[C:4](=[O:12])[CH:3]=1
Reactant: Cc1cc(=O)c2c(o1)CCOC2
Reactant: N
Product: Cc1cc(=O)c2c([nH]1)CCOC2

Procedure:
Compound C1 (1.0 g) and aqueous ammonia solution (density, 0.91 g/ml; 15 ml) were heated at 120° C. in a sealed tube for 10 hours. Volatile material was removed by evaporation and the residue azeotroped with toluene (2×20 ml). The residue was recrystallised from a mixture of methanol and ethyl acetate to give 2-methyl-1,5,7,8-tetrahydropyrano[4,3-b]-pyridin-4-one (B1) (0.70 g), as an off-white solid, m.p. >285° C.; NMR (d6 -DMSO): 2.2(s,3H), 2.45-2.6(m,2H), 3.8(t,2H), 4.3(t,2H), 5.8(s,1H) 11.1(br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[CH2:35]([S:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])=[O:38])[CH3:36]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:43]3[CH2:42][CH2:41][N:40]([S:37]([CH2:35][CH3:36])(=[O:38])=[O:39])[CH2:45][CH2:44]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Product: CCS(=O)(=O)N1CCN(C(=O)N2C(c3ccc(OC)cc3OC(C)C)=N[C@@H](c3ccc(Cl)cc3)[C@H]2c2ccc(Cl)cc2)CC1

Procedure:
[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-ethanesulfonyl-piperazin-1-yl)-methanone was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 6) and 1-ethanesulfonyl-piperazine (prepared from 1-tert-butyloxycarbonyl-piperazine and ethanesulfonyl chloride) in an analogous manner as described in example 8. LR-MS: 659.2 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([S:7]([N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=3)[CH2:30][CH2:29]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)s1)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of (5-bromo(2-thienyl))chlorosulfone (1.09 g, 4.16 mmol) in CH2Cl2 (30 mL) was added triethylamine (0.4 mL, 3.052 mmol), followed by (4-fluorophenyl)piperazine (500 mg, 2.77 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was treated with a saturated NaHCO3 solution (1 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with a saturated NaCl solution (10 mL), dried (MgSO4) and concentrated under reduced pressure to give a brown solid. The crude product was purified flash chromatography (10% EtOAc/hex) to give 5-bromo-2-{[4-(4-fluorophenyl)piperazinyl]sulfonyl}thiophene (1.12 g, 100%) as a white solid: mp 123-124° C.; TLC (EtOAc) Rf 0.44; HPLC ES-MS m/z 406 (MH+).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 2 from 8-benzylthio-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 188°-190° C.) and piperazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]([F:26])([F:25])[CH:16]1[C:21]2[CH:22]=[CH:23][S:24][C:20]=2[CH2:19][CH2:18][NH:17]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:17]3[CH2:18][CH2:19][C:20]4[S:24][CH:23]=[CH:22][C:21]=4[CH:16]3[C:15]([F:14])([F:26])[F:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: FC(F)(F)C1NCCc2sccc21
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2sccc2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-trifluoromethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:18]([CH2:33][CH2:34][CH2:35][CH3:36])=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:21][CH:22]=2)=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[Li+].[OH-]>O1CCCC1.CCOCC>[CH2:33]([C:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:37])=[O:3])=[CH:10][CH:11]=2)=[CH:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=2)[N:19]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1COc1ccc(OC(C)(C)C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1COc1ccc(OC(C)(C)C(=O)O)cc1
Yield: 91.9 %

Procedure:
297 mg (0.575 mmol) 2-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester and 2 ml 1N LiOH in 3 ml terahydrofurane were stirred over night at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. The crude product was suspended in AcOEt/heptane 1:19. The resulting crystals were filtered off providing 258 mg pure 2-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH2:13][OH:14])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:23](OC)([CH3:25])[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C:10]1([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:11][O:12][C:23]([CH3:25])([CH3:24])[O:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C)(C)OC
Reactant: OCC(CO)(COCc1ccccc1)C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)OCC(COCc2ccccc2)(C2CCCCC2)CO1

Procedure:
2-Benzyloxymethyl-2-cyclohexyl-propan-1,3-diol(3 g.),2,2-dimethoxypropane (8 ml), p-toluenesulphonic acid (150 mg.) and molecular sieves (type 4A) were heated in refluxing dry toluene (50 ml.) for four hours. The mixture was cooled and filtered. The filtrate was diluted with ether and the ethereal solution was extracted with aqueous sodium hydrogen carbonate solution. The ethereal solution was washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on silica, eluting with 1:5 ether:hexane. 5-Benzyloxymethyl-5-cyclohexyl-2,2-dimethyl-1,3-dioxane(3.0 g) was obtained as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[CH3:12][N:13]1[C:22]2[CH2:21][CH2:20][CH2:19][C:18](=O)[C:17]=2[CH:16]=[CH:15][C:14]1=[O:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][CH:18]2[CH2:19][CH2:20][CH2:21][C:22]3[N:13]([CH3:12])[C:14](=[O:24])[CH:15]=[CH:16][C:17]2=3)=[CH:5][CH:4]=1
Reactant: Cn1c2c(ccc1=O)C(=O)CCC2
Reactant: COc1ccc(CCN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CCNC2CCCc3c2ccc(=O)n3C)cc1
Temperature: 25 °C
Reaction time: 39 h
Yield: 80.4 %

Procedure:
A mixture of 2-(4-methoxyphenyl)ethylamine (5.6 g), 5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (5.5 g), and a catalytic amount of para-toluenesulfonic acid was heated in refluxing toluene (90 ml), with azeotropic removal of water, for 39 hrs. The solution was cooled and concentrated in vacuo. Sodium borohydride (1.2 g) was added to a solution of the residue in ethyl alcohol (90 ml), and the mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo, the residue was quenched with water, and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was washed with diethyl ether to afford 7.8 g (81%) of product. Recrystallization from ethyl acetate/hexanes provided with the analytical sample, mp 97°-99° C.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:24][CH2:23][C:16]3[N:17]=[CH:18][N:19]=[C:20](OC)[C:15]=3[CH2:14]2)=[N:11][CH:12]=1.C1(OC)C=CC=CC=1.[OH-].[K+]>C(#N)C>[Br:3][C:20]1[C:15]2[CH2:14][N:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][N:11]=3)[CH2:24][CH2:23][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: COc1ncnc2c1CN(c1ccc(Cl)cn1)CC2
Reactant: O=P(Br)(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: COc1ccccc1
Product: Clc1ccc(N2CCc3ncnc(Br)c3C2)nc1
Temperature: 0 °C
Yield: 37.6 %

Procedure:
Phosphorus oxybromide (14 g, 49 mmol) was added portionwise over 2 min to a stirred suspension of 6-(5-chloropyridin-2-yl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (3.36 g, 12.1 mmol), anisole (50 mL), and acetonitrile (50 mL) in a 250 mL flask. The stirred mixture clarified briefly and was then heated at reflux. The mixture was removed from the heat after 4.5 h. The cooled mixture was diluted with CH2Cl2 (100 mL), and poured onto a mixture of crushed ice (250 g) and 50% aqueous KOH (20 mL; 0.18 mol). The pH of the mixture was then adjusted to 12 with 2M aq. KOH, and extracted with CH2Cl2 (300 mL). The aqueous phase was diluted with brine (200 mL) and extracted with CH2Cl2 (2×100 mL). The combined CH2Cl2 layers were washed with saturated NaHCO3 (200 mL), dried (Na2SO4), filtered and concentrated to a brown oil which was purified by silica gel column (0-50% ethyl acetate/hexane) to give a yellow solid (1.48 g).
Reaction SMILES: [F-].[K+].[Br:3][C:4]1[N:8]2[N:9]=[C:10](Cl)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[CH:22]1[CH2:26][CH2:25][CH2:24][NH:23]1>CS(C)=O>[Br:3][C:4]1[N:8]2[N:9]=[C:10]([N:23]3[CH2:24][CH2:25][CH2:26][CH:22]3[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[CH3:14])[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: Cc1ccc(C)c(C2CCCN2)c1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(C)c(C2CCCN2c2ccc3ncc(Br)n3n2)c1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
In step 4-1, potassium fluoride (58 mg, 1.0 mmol), and (3-bromo-6-chloroimidazo[1,2-b]pyridazine (12-1) (100 mg, 0.43 mmol) was added to a solution of 2-(2,5-dimethylphenyl)pyrrolidine (100 mg, 0.57 mmol) in 3 mL of DMSO. The reaction mixture was heated to 130° C. and stirred for 6 hours at 130° C. The reaction mixture was cooled to room temperature and purified using normal phase flash chromatography with ethyl acetate and hexanes (1:1) as a mobile phase to yield 3-bromo-6-(2-(2,5-dimethylphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (4-1) as its racemic mixture. 1H NMR (400 MHz, D3 acetonitrile) δ ppm 7.50 (app d, J=9.5 Hz, 1H), 7.40 (br s, 1H), 7.08 (d, J=6.5 Hz, 1H), 6.92 (d, J=6.6 Hz, 1H), 6.82 (br s, 1H), 6.58 (br d, J=9.5 Hz, 1H), 5.28 (br d, J=5.0 Hz, 1H), 4.08-3.95 (m, 1H), 3.62 (app q, J=6.4 Hz, 1H), 3.30 (s, 1H), 2.51-2.42 (m, 1H), 2.24 (br s, 6H), 2.17-2.04 (m, 2H). LCMS observed m/z 371.1, 373.1 major ion.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)Cl>[F:1][C:2]1[C:3]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=c1[nH]c2cc(F)ccc2o1
Solvent: ClCCl
Product: O=c1[nH]c2cc(F)c(S(=O)(=O)Cl)cc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
According to Scheme 11, a mixture of commercially-available 5-fluoro-1,3-benzoxazol-2(3H)-one (11-1, 1.02 g, 6.66 mmol) in DCM (66.6 ml) at RT was added chlorosulfonic acid (4.46 ml, 66.6 mmol). The suspension gradually became a solution and was stirred for 18 h at RT. Following this duration, LCMS showed complete consumption of starting material. The solution was cooled to 0° C. and carefully quenched with ice chips and then partitioned between water (100 mL) and EtOAc (100 mL). The layers were separated and the aqueous layer was back-extracted with 3×20 mL DCM and 2×20 mL EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3 (30 mL), dried over sodium sulfate and filtered. Concentration in vacuo to yield 11-2 (5-Fluoro-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonyl chloride) as a tan solid, which was used without purification.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[CH2:9][CH2:8]2)=[O:4].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:25])[C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH2:8][CH2:9][C:10]1=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(c1O)CCC(=O)N2Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c1N(Cc1ccccc1)C(=O)CC2
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (102 mg, 0.30 mmol), glycine (3.02 g, 40 mmol) and NaOMe solution (61 mL, 30 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 2 with 4M HCl and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 80 mg of the title compound as an off-white solid. MS: (+) m/z 381.13 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:17][CH3:18])[C:9]3[C:14]([OH:15])=[CH:13][N:12]=[CH:11][C:10]=3[N:16]=2)=[N:4][O:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38]I)[CH2:34][CH2:33]1)=O)(C)(C)C.O>CC(C)=O>[CH2:17]([N:8]1[C:9]2[C:14]([O:15][CH2:38][CH:35]3[CH2:36][CH2:37][NH:32][CH2:33][CH2:34]3)=[CH:13][N:12]=[CH:11][C:10]=2[N:16]=[C:7]1[C:3]1[C:2]([NH2:1])=[N:6][O:5][N:4]=1)[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Reactant: CCn1c(-c2nonc2N)nc2cncc(O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCn1c(-c2nonc2N)nc2cncc(OCC3CCNCC3)c21
Reaction time: 6 h
Yield: 39 %

Procedure:
A mixture of the product from Example 283 (0.1 g, 0.406 mmol) and K2CO3 (0.112 g, 0.812 mmol) in acetone (3 ml) at −78° C. was treated with 4-iodomethylpiperidine-1-carboxylic acid tert-butyl ester (Villalobos, A; et al, J. Med. Chem., 1994, 37(17), 2721) (0.145 g, 0.447 mmol) and heated at reflux for 18 hours. A further portion of 4-iodomethylpiperidine-1-carboxylic acid tert-butyl ester (0.145 g, 0.447 mmol) was then added and the heating continued for a further 6 hours. The reaction was then cooled, poured into water, extracted with dichloromethane, dried with NaSO4 and reduced. The residue was chromatographed on silica gel eluting with ethyl acetate to afford the title compound, (0.071 g, 39%); MS (ES+) m/e 444 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH-:10].[Na+]>>[CH2:2]([O:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCBr
Reactant: [OH-]
Agent: [Na+]
Product: CCCCCCCCOCCCCCCCC
Yield: 75 %

Procedure:
The use of quaternary salt catalysts in the production of symmetrical ethers is also known. A. W. Herriott and D. Picker (Tet. Lett. 44, p. 4,521 (1972)) teach that the reaction of 1-bromooctane with 2N sodium hydroxide in the presence of a quaternary ammonium salt catalyst produces di-n-octyl ether in 75% yield. R. D. Gordon (U.S. Pat. No. 3,824,295) also teaches that the reaction of an alkyl halide, sulfate or sulfonate with aqueous caustic in the presence of a quaternary salt catalyst produces a symmetrical ether.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:16]=[CH:15][C:7]2[NH:8][C:9]([CH3:14])=[N:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1>>[OH:3][C:4]1[CH:16]=[CH:15][C:7]2[NH:8][C:9]([CH3:14])=[N:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)N=C(C)N2
Agent: Cl
Product: CC1=NS(=O)(=O)c2cc(O)ccc2N1
Temperature: 0 °C
Yield: 74.6 %

Procedure:
HCl (20 g) is heated to 210° C. and 5 g of 7-methoxy-3-methyl-4H-1,2,4-benzothiadiazine-1, 1-dioxide are added. This mixture was kept at about 210° C. for about 11/2 hours. The mixture was then cooled slightly and about 60 ml of ice cold water was added with stirring. This mixture was filtered and the solid washed with 25 ml. of cold water and dried yielding 3.5 g of 7-hydroxy-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide (A). An additional 0.63 g of A was recovered from the filtrate to allowing it to stand in the refrigerator for about one hour. Total yield of this product was 4.13 g (88%), m.p. 333°-336° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:21][CH2:20][N:19]3[C@H:14]([CH2:15][O:16][CH2:17][CH2:18]3)[CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[Sn](Cl)Cl.Cl>O1CCOCC1.C1COCC1>[CH2:15]1[C@@H:14]2[CH2:13][N:12]([C:5]3[CH:6]=[CH:7][C:8]([NH2:9])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:21][CH2:20][N:19]2[CH2:18][CH2:17][O:16]1
Reactant: COc1cc(N2CCN3CCOC[C@@H]3C2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1cc(N2CCN3CCOC[C@@H]3C2)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To (9aS)-8-[3-(methyloxy)-4-nitrophenyl]octahydropyrazino[2,1-c][1,4]oxazine (0.196 g, 0.660 mmol) in dioxane (8 mL) and THF (4 mL) cooled to 0° C. was added tin(II) chloride (0.544 g, 2.86 mmol) in HCl (2.20 mL, 37% in water, 24.6 mmol) dropwise. The reaction warmed to rt and stirred overnight. An additional amount of tin(II) chloride (1.00 g, 5.27 mmol) in HCl (4.40 mL, 37% in H2O, 49.1 mmol) was added to the reaction. When complete by TLC, the reaction was cooled to 0° C. and quenched with 6N NaOH (50 mL). The mixture was poured into H2O/EtOAc and separated. The organic layer was washed with brine and the resultant aqueous layer was back extracted with EtOAc. The combined organic layer was dried (MgSO4) and concentrated to provide the title compound of step B (0.170 g, 0.640 mmol, 98%). 1H NMR (400 MHz, DMSO-d6) b ppm 1.47 (dt, J=14.9, 6.5 Hz, 1H), 1.65-1.74 (m, 1H), 2.14-2.25 (m, 1H), 2.26-2.31 (m, 1H), 2.55-2.66 (m, 1H), 2.74 (d, J=10.8 Hz, 1H), 3.10 (t, J=10.4 Hz, 1H), 3.17 (d, J=11.5 Hz, 1H), 3.31 (d, J=11.7 Hz, 1H), 3.37 (q, J=6.2 Hz, 1H), 3.47 (td, J=11.3, 2.1 Hz, 1H), 3.60 (t, J=6.7 Hz, 1H), 3.63-3.74 (m, 4H), 4.41 (t, J=5.3 Hz, 1H), 4.46 (s, 1H), 6.23 (dd, J=8.3, 2.5 Hz, 1H), 6.42-6.50 (m, 2H).