Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6]Br.C(=O)([O-])[O-].[Na+].[Na+].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24].O>C(O)C>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:24][CH2:6][CH2:5][O:4][C:3]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=1[Cl:1]
Reactant: NCc1cccc(Cl)c1
Reactant: Clc1ccc(OCCBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1cccc(CNCCOc2ccc(Cl)cc2Cl)c1

Procedure:
2.70 Grams (10.0 mmol) of 2-(2,4-dichlorophenoxy)ethyl bromide was dissolved in 30 ml of ethanol, followed by the addition of 1.06 g (10.0 mmol) of anhydrous sodium carbonate and 4.25 g (30.0 mmol) of 3-chlorobenzylamine. The mixture was refluxed for 6 hours on an oil bath. After cooling, the reaction mixture was poured into 100 ml of water and was extracted with chloroform (20 ml×3).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([OH:21])=[O:20])[C:3]=1[O:22][CH3:23].C([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CS(C)=O.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:20])[C:3]=1[O:22][CH3:23]
Reactant: COc1c(C(=O)O)nc(-c2ccc(Cl)c(OC)c2F)c(F)c1N
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1c(C(=O)OCc2ccccc2)nc(-c2ccc(Cl)c(OC)c2F)c(F)c1N
Temperature: 100 °C
Yield: 70.8 %

Procedure:
To a solution of 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-3-methoxypicolinic acid (140 mg, 0.406 mmol) in DMSO (1.354 mL) were added K2CO3 (67.4 mg, 0.487 mmol) and (bromomethyl)benzene (76 mg, 0.447 mmol). The reaction mixture was heated at 100° C. for 5 min in a Biotage microwave. The reaction mixture was then diluted with H2O and extracted with CH2Cl2. The organic extracts were separated from the aqueous layer in a Biotage phase separator. The organic layer was then concentrated, and the residue was purified by flash chromatography (eluting with 0-50% acetone in hexanes) to afford a white solid (125 mg, 69%): mp 119° C.; 1H NMR (400 MHz, acetone-d6) δ 7.56-7.49 (m, 2H), 7.43-7.27 (m, 5H), 5.98 (s, 2H), 5.40 (s, 2H), 3.97 (d, J=1.1 Hz, 3H), 3.85 (s, 3H), ESIMS m/z 436 ([M+H]+), 434 ([M−H]−).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[S:4][C:5]([C:12](O)=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl.CN(C)C=O>[F:1][C:2]([F:16])([F:15])[C:3]1[S:4][C:5]([C:12]([Cl:19])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1sc(C(F)(F)F)nc1C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1sc(C(F)(F)F)nc1C(F)(F)F
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a 500 mL 1-neck RBF under N2 was added 2,4-bis-trifluoromethylthiazole-5-carboxylic acid (31.5 g, 1.0 equiv., 0.119 moles) in 25 mL chloroform and 1 mL dimethylformamide (DMF). To this solution was added thionyl chloride (28.3 g, 2.0 equiv., 0.24 moles). The reaction was then heated at reflux for 6 hours. The reaction was cooled to room temperature and concentrated by rotary evaporation at 30° C. to remove solvent. Chloroform was added, 3×25 mL portions, concentrating by rotary evaporation each time, to give 29.8 g (88.4% yield) product as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)[CH2:6][CH2:7][CH2:8][CH3:9].[CH3:21][C:22]1([CH3:31])[CH2:27]C(O)[CH2:25][C:24]([CH3:30])([CH3:29])[NH:23]1.[NH2-].[Li+].CO>CCCCCCCC>[CH3:21][C:22]1([CH3:31])[CH2:27][CH:1]([O:2][C:3](=[O:20])[CH2:4][N:5]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:25][C:24]([CH3:30])([CH3:29])[NH:23]1
Reactant: CCCCN(CC(=O)OC)C1CC(C)(C)NC(C)(C)C1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: [Li+]
Agent: [NH2-]
Solvent: CO
Solvent: CCCCCCCC
Product: CCCCN(CC(=O)OC1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Yield: 80.8 %

Procedure:
To the same flask as used in Example 1 were added 28.4 g (0.1 mole) of N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-n-butylglycine methyl ester, 17.3 g (0.11 mole) of 2,2,6,6-tetramethyl-4-piperidinol, 0.23 g (0.01 mole) of lithium amide and 100 g of n-octane. The temperature was raised with stirring, and reaction was carried out at 128° to 130° C. for 5 hours, during which methanol was removed from the reaction system by means of the Deanstark trap. After completion of the reaction, water was added to the reaction solution to dissolve the product in the n-octane. The n-octane layer was separated, and n-octane in the layer was removed by distillation to obtain 33.1 g of N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-n-butylglycine(2,2,6,6-tetramethyl-4-piperidinyl)ester as a brown oily product. Yield, 81% based on N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-n-butylglycine methyl ester.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]([CH:11]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:10].Br[CH2:32][C:33](=[O:44])/[CH:34]=[CH:35]/[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=1.BrCC(OCC)=O>C1(C)C=CC=CC=1>[CH3:43][O:42][C:38]1[CH:37]=[C:36](/[CH:35]=[CH:34]/[C:33](=[O:44])/[CH:32]=[CH:11]/[C:9]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:10])[CH:41]=[CH:40][CH:39]=1
Reactant: COCCOCCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(/C=C/C(=O)CBr)c1
Agent: CCOC(=O)CBr
Solvent: Cc1ccccc1
Product: COCCOCCOC(=O)/C=C/C(=O)/C=C/c1cccc(OC)c1

Procedure:
A solution of 14.9 g (35.2 mmol) of [[[2-(2-methoxyethoxy)ethoxy]carbonyl]methylene]triphenylphosphorane (preparation see paragraph (c)) in 100 ml of toluene was treated with 4.48 g (17.6 mmol) of (E)-1-bromo-4-(3-methoxyphenyl)-3-buten-2-one (preparation see paragraph d)). The reaction mixture was stirred at reflux for 2 hours and then filtered. After the addition of 1.63 ml (17.6 mmol) of ethyl bromoacetate, the filtrate was again stirred at reflux for 2 hours. The separated solid was filtered off. The filtrate was concentrated and purified by flash chromatography on 500 g of silica gel (elution agent ether/hexane 10:1). Crystallization of the purified product from methylene chloride/ether/hexane yielded 2-(2-methoxyethoxy)ethyl (E,E)-6-(3-methoxyphenyl)-4-oxo-2,5-hexadienoate of melting point 59°-60°.
Reaction SMILES: C(O)C.[OH-].[K+].[CH2:6]([C:10]1[N:11]([CH2:18][C:19]2[CH:27]=[CH:26][C:25]3[C:21](=[CH:22][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([O:36]CC)=[O:35])[N:24]=3)[CH:20]=2)[C:12]([CH:16]=[O:17])=[C:13]([Cl:15])[N:14]=1)[CH2:7][CH2:8][CH3:9]>O>[CH2:6]([C:10]1[N:11]([CH2:18][C:19]2[CH:27]=[CH:26][C:25]3[C:21](=[CH:22][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([OH:36])=[O:35])[N:24]=3)[CH:20]=2)[C:12]([CH:16]=[O:17])=[C:13]([Cl:15])[N:14]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nn(-c3ccccc3C(=O)OCC)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nn(-c3ccccc3C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
Ethanol (0.8 ml), ion-exchanged water (0.2 ml), and potassium hydroxide (28 mg) were added to 2-butyl-4-chloro-1-[2-(2-ethoxycarbonylphenyl)-2H-indazol-5-yl]methyl-1H-imidazole-5-carbaldehyde (61 mg, 0.13 mmol) as obtained in Example 1, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in an evaporator, and partitioned by ion-exchanged water (2.5 ml) and diethyl ether (5 ml). The water layer was separated and conc. hydrochloric acid was dropwise added thereto to adjust its pH to 1. The resultant solid was filtered off and washed three times with ion-exchanged water (1 ml). It was then dried in vacuo overnight at 37° C. to give 36 mg of 2-butyl-4-chloro-1-[2-(2-carboxyphenyl)-2H-indazol-5-yl]methyl-1H-imidazole-5-carbaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>ClCCl>[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=3)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:3]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 29 %

Procedure:
The 3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol from EX-528C (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (25 μL, 0.18 mmol) followed by 4-fluorobenzene-sulfonyl chloride were added. The solution was stirred at room temperature for 5 hours, at which time HPLC analysis indicated that no free amine starting material remained. The reaction was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 20.1 mg (29%) of the desired 4-fluoro-N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]benzenesulfonamide product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C24H21F8N2O4S: 585.1094 [M+H]+, found: 585.1083. 1H NMR (CDCl3) δ 3.6 (m, 2H), 3.8 (dd, 1H), 4.3 (m, 1H), 4.6 (s, 2H), 5.9 (tt, 1H), 6.4 (d, 1H), 6.5-6.6 (m, 3H), 6.9-7.4 (m, 7H), 7.6 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]1[CH:20]=[CH:19][C:12]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](ON1C(=O)CCC1=O)([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29].C([O-])(O)=O.[Na+].Cl>O1CCOCC1.O>[C:28]([NH:15][C@H:14]([C:16]([OH:18])=[O:17])[CH2:13][C:12]1[CH:19]=[CH:20][C:9]([CH:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:10][CH:11]=1)([O:30][CH2:31][CH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:29]
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(C[C@H](N)C(=O)O)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 4-(di-tert-butoxycarbonyl-methyl)-L-phenylalanine (818 mg, 2.16 mmol), Fmoc-OSu (727 mg, 2.16 mmol) and NaHCO3 (906 mg, 10.8 mmol, 5 equivalents) in 48 ml of dioxane-water (1:1) was stirred at room temperature overnight. The reaction mixture was then cooled to 0° C. and acidified with 180 ml of 0.2 M HCl. The reaction product was extracted with ethyl acetate (30 ml×3), and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by silica gel chromatography (CDCl3-EtOAc-MeOH) to provide N-Fmoc-4-(di-tert-butoxycarbonyl-methyl)-L-phenylalanine as a white solid (650 mg, 50.7%). 1H NMR (DMSO) δ: 12.704 (1H, s, br), 7.786 (2H, d, J=7.32 Hz), 7.760 (1H, d, J=8.54 Hz), 7.658 (2H, t, J=7.81 Hz), 7.435˜7.200 (4H, m), 7.254 (4H, s), 4.586 (1H, s), 4.274˜4.081 (4H, m), 3.111˜3.040 (1H, dd, J=4.40, 13.67 Hz), 2.913˜2.815 (1H, dd, J=10.75, 13.92 Hz), 1.390 (1H, s), 1.380 (1H, s). FABMS (+Ve), m/z 602 [MH+], 546 [MH+−C4H8], 490 [MH+−2 C4H8]. Anal. calcd. for C20H29NO6: C, 66.90; H, 6.5; N, 2.3. Found: C, 69.40; H, 6.67; N, 2.24.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][C@H:2]12.CS(O[CH:16]1[CH2:19][N:18]([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17]1)(=O)=O.C(N(CC)CC)C>C(#N)C>[C:21]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]2[CH2:19][CH:16]([N:6]3[CH2:5][CH2:4][N:3]4[C:7](=[O:10])[CH2:8][CH2:9][C@@H:2]4[CH2:1]3)[CH2:17]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C1CC[C@@H]2CNCCN12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CC[C@@H]2CN(C3CN(C(c4ccccc4)c4ccccc4)C3)CCN12
Temperature: 150 °C
Yield: 53 %

Procedure:
(8aR)-Hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (see WO 03/066635; 0.17 g, 1.2 mmol), 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (see J. Org. Chem.; 56; 1991; 6729; 0.40 g, 1.3 mmol) and triethylamine (0.20 mL, 1.4 mmol) were dissolved in acetonitrile. The mixture was heated for 15 min at 150° C. using microwave single node heating and then the solvent was removed by evaporation. The residue was partitioned between ethyl acetate and aqueous NaHCO3 and the aqueous phase extracted further with ethyl acetate. The organic phase was dried and then the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol-methylene chloride 5:95). There was obtained 0.23 g (54%) of (8aR)-2-[1-(diphenylmethyl)azetidin-3-yl]hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one as a pale yellow oil. 1H NMR (500 MHz, CDCl3): 1.5-1.6 (m, 2H), 1.7-1.8 (m, 1H), 2.1-2.2 (m, 1H), 2.3-2.4 (m, 2H), 2.6-2.7 (d, 1H), 2.8 (m, 1H), 2.8-2.9 (m, 3H), 3.0 (qn, 1H), 3.4 (t, 2H), 3.6 (m, 1H), 4.0 (d, 1H), 4.4 (s, 1H), 7.2 (m, 2H), 7.2-7.3 (m, 4H), 7.4 (m, 4H); LCMS: m/z 362 (M+1)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:20][C:11]1[N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=[C:17]([C:32]3[CH:31]=[CH:30][C:29]([CH2:28][N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)=[CH:34][CH:33]=3)[CH:18]=[C:13]2[CH:12]=1
Reactant: Cc1cc2cc(Br)cnc2n1S(=O)(=O)c1ccccc1
Reactant: CN1CCN(Cc2ccc(B(O)O)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc2cc(-c3ccc(CN4CCN(C)CC4)cc3)cnc2n1S(=O)(=O)c1ccccc1
Yield: 74.1 %

Procedure:
1-Benzenesulfonyl-5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (378 mg, 1.076 mmole) and 4-((4-methylpiperazin-1-yl)methyl)phenylboronic acid (303 mg, 1.29 mmole) are dissolved in acetonitrile (10 mL) and treated with 10 mL 1 M sodium carbonate solution. To this is added 40 mg of PdCl2(PPh3)2 catalyst, and the mixture is irradiated for 5 minutes at 150 degrees in a Biotage microwave reactor. After cooling, the reaction mixture is diluted with water and extracted with ethyl acetate, dried, and concentrated. MPLC silica gel chromotagraphy 5-20% MeOH in dichloromethane gradient elution, provided 367 mg of the title compound as a solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]>>[F:10][C:11]1[CH:16]=[C:15]([N+:1]([O-:4])=[O:2])[CH:14]=[CH:13][C:12]=1[F:17]
Reactant: O=[N+]([O-])O
Reactant: Fc1ccccc1F
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(F)c(F)c1
Temperature: -12 °C
Reaction time: 0.75 h

Procedure:
This material is prepared as described by R. W. Taft, G. B. Klingensmith, and S. Ehrenson, (J. Am. Chem. Soc., 87, 3620 (1965)). To a stirred mixture of 5.0 ml of concentrated nitric acid and 13.9 ml of concentrated sulfuric acid cooled to -12° C. is added 9.7 g (0.085 mole) of 1,2-difluorobenzene. A slight exotherm is observed and the mixture is cooled to -20° C. whereupon it solidifies. The mixture is stirred for 45 minutes at -5° to 0° and is then allowed to warm slowly to room temperature. After 1 hour the mixture is poured onto ice, and the mixture extracted with diethyl ether (3×75 ml). The combined ether extracts are washed with water, 10% aqueous Na2CO3, and water again. The ether solution is dried (MgSO4) and concentrated in vacuo without external heating to give the crude product (11.9 g), which is distilled (kugelrohr apparatus) to give 10.2 g of colorless liquid. The nmr spectrum of this material is consistent with the structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.97 g, 9.2 mmol) was dissolved in 150 mL dry diethyl ether under Ar, cooled in an ice water bath, added dry pyridine (3.7 mL, 45.8 mmol) followed by the dropwise addition of oxalyl chloride (2 mL, 22.9 mmol). A precipitate forms immediately. The reaction was stirred vigorously at 0° C. for 2 hours, then at ambient temperature for one hour. Added 100 mL diethyl ether, filtered off solids washing with diethyl ether. Concentrated the filtrates to an off-white oil. Redissolved oil in 100 mL dry DCM under Ar, cooled to 0° C., added 3 mL pyridine followed by 2-amino-5-bromopyridine (1.32 g, 7.6 mmol). The reaction was allowed to warm to ambient temperature, stirred for 3 hours then concentrated. Redissolved in 250 mL EtOAc, washed with 10% HCl (3×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated to yield title compound as a yellow sticky solid. (2.74 g, 97%) APCI (AP−): 368.0, 370.0 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([CH3:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[CH:34]=[C:33]([NH2:35])[CH:32]=[N:31]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:35][C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: Cc1cnc(Cl)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 150 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
To a suspension of tert-butyl 9-((2-chloro-5-methylpyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (332.2 mg, 0.84 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (252.2 mg, 1.89 mmol) in n-BuOH (8 mL) was added DIPEA (445.9 mg, 3.45 mmol). The reaction mixture was stirred at 150° C. in a sealed tube for 16 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the title compound as yellow oil (0.38 g, 99%).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:22])C=1.O>ClCCl>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCCCSc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: O=S(CCCCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5-Phenylthiopentyl chloride (1.84 g) was dissolved in dichloromethane (50 ml), and one equivalent of m-chloroperbenzoic acid was added thereto, which was followed by stirring at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.20 g of 5-phenylsulfinylpentyl chloride.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:9][OH:10].C(N(CC)CC)C.[Cl:18][C:19]1[S:23][C:22]([S:24](Cl)(=[O:26])=[O:25])=[CH:21][CH:20]=1>ClCCl>[Cl:18][C:19]1[S:23][C:22]([S:24]([NH:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]2[CH2:9][OH:10])(=[O:26])=[O:25])=[CH:21][CH:20]=1
Reactant: N[C@@H]1CCCC[C@H]1CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a suspension of trans-2-aminocyclohexylmethanol hydrochloride (214 mg, 1.30 mmol) and triethylamine (0.538 mL, 3.9 mmol) in 5 mL dichloromethane at 0° C. was added a solution of 5-chlorothiophene-2-sulfonyl chloride (0.267 mL, 1.23 mmol) in 1 mL dichloromethane. The reaction was stirred at 0° C. for 30 min and at room temperature for 30 min. The crude reaction mixture was purified by flash chromatography on silica gel using a gradient of 0 to 100% ethyl acetate in hexane to give 5-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)thiophene-2-sulfonamide (330 mg, 84%). 1H NMR (400 MHz, CDCl3) δ ppm 7.40 (d, J=4.03 Hz, 1H), 6.91 (d, J=4.03 Hz, 1H), 5.24 (d, J=7.30 Hz, 1H), 3.86 (d, J=11.33 Hz, 1H), 3.32-3.48 (m, 1H), 3.05 (d, J=6.55 Hz, 1H), 2.32 (br. s., 1H), 1.72-1.83 (m, 1H), 1.58-1.73 (m, 3H), 1.11-1.36 (m, 5H). MS [M+H]+=310; [M+Na]+=332.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([CH3:15])[C:5]=1[CH:6]=[O:7]>C(O)C.Cl.O>[CH3:15][C:8]1[CH:9]=[C:10]([CH:12]([CH3:13])[CH3:14])[CH:11]=[C:4]([CH3:3])[C:5]=1[CH2:6][OH:7]
Reactant: Cc1cc(C(C)C)cc(C)c1C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(C)C)cc(C)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
A solution of sodium borohydride (0.04 g, 1.04 mmol) in 90% ethanol (5 mL) was added dropwise to a solution of 2,6-dimethyl-4-isopropylbenzaldehyde (Example 1) (0.55 g, 3.1 mmol) in absolute ethanol (5 mL). The reaction mixture was allowed to stir at room temperature for 1 hour, then heated at 60° C. for 30 min. The solution was cooled to 0° C. and the unreacted sodium borohydride was decomposed by the addition of a few drops of 3N HCl. The solvent was removed under reduced pressure to give a red oil which was suspended in water (10 mL) and extracted with ether (2×20 mL). The ether was removed under reduced pressure to afford a red oil which was purified by flash chromatography using silica gel (eluted with hexane-EtOAc, 93:3) to give 0.48 g (87%) of the title compound as a white solid; mp 75-77° C.