Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[O:11][CH2:12][CH2:13]2)=[N:8][C:7]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=O)=O.CC[O-].[Na+].CCO>C1COCC1>[OH:5][C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[O:11][CH2:12][CH2:13]2)=[N:8][C:7]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OS(C)(=O)=O)CCOC21CCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCOC21CCCC1
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a stirred suspension of ethyl 3′-(methylsulfonyloxy)-4′-oxo-6′,7′-dihydro-4′H-spiro[cyclopentane-1,9′-pyrimido[2,1-c][1,4]oxazine]-2′-carboxylate (0.6861 g, 1.84 mmol) in THF (50 mL) was added 1M EtONa/EtOH (10 mL). After 1 h, the resulting yellow solution was concentrated, acidified with 1 M aq. HCl (20 mL), extracted with CH2Cl2 (3×35 mL). The combined organic layers dried (Na2SO4), filtered and concentrated to give the title compound as a brown solid (0.4668 g, 86%). 1H NMR (500 MHz, CDCl3) δ: 10.49 (1H, s), 4.44 (2H, q, J=7.0 Hz), 4.03-3.97 (4H, m), 2.28-2.22 (2H, m), 2.06-2.01 (2H, m), 1.93-1.81 (4H, m), 1.42 (3H, t, J=7.0 Hz). HRMS (M+H) calcd for C14H19N2O5: 295.1294; found: 295.1293.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][CH3:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]([CH3:34])[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:25])[F:23])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1ccccc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccccc1F

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), (2-fluoro-phenyl)-methyl-amine (45 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 μL, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (2-fluoro-phenyl)-methyl-amide: MS m/z: (M+H) 522.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][NH:7]1.Br[CH2:29][C:30](Br)=[O:31].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:29][C:30]([NH:38][CH2:37][C:36]1[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=1[O:34][CH3:33])=[O:31]
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1OC)NCC2
Reactant: COc1ccccc1CN
Reactant: O=C(Br)CBr
Product: COc1ccccc1CNC(=O)CN1CCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1OC

Procedure:
prepared by reaction of 1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methoxy-benzyl-amine
Reaction SMILES: CS([O-])(=O)=O.[C:6]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:17]=[NH+:18][CH:19]=[CH:20][CH:21]=1)=[O:15])(=[O:8])[CH3:7].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[C:6]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)SCCCCC(=O)c1ccc[nH+]c1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)SCCCCC(=O)c1cccnc1
Yield: 86.3 %

Procedure:
A slurry of 3-(5-acetylmercaptopentanoyl)pyridinium methanesulphonate (7.0 g) in ethyl acetate (50 ml) is stirred with a solution of sodium bicarbonate (5 g) in water (50 ml). The ethyl acetate phase is then washed 3 times with water until its pH is 5, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give S-(4-nicotinoylbutyl) thioacetate (4.3 g) in the form of a dark oil which solidifies upon standing (m.p. 43° C.).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[C:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:19]2[CH2:20][CH2:21][N:16]([C:13](=[O:15])[CH3:14])[CH2:17][CH2:18]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(C)=O)CC2)ccc1[N+](=O)[O-]

Procedure:
The compound obtained in Step 1 above (300 mg), N-acetylpiperazine (300 mg), and potassium carbonate (500 mg) were dissolved in dimethylformamide (3 mL) and reacted at 80° C. overnight. The dimethylformamide of the reaction mixture was removed under reduced pressure, and added with water to form a solid. The solid was filtered to obtain a target compound as a yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2([OH:12])[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27].[Cl-].[NH4+]>O1CCCC1>[CH2:33]([Sn:28]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:29][CH2:30][CH2:31][CH3:32])[C:2]1[N:7]=[C:6]([C:8]2([OH:12])[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1)[CH2:34][CH2:35][CH3:36]
Reactant: OC1(c2cccc(Br)n2)CCC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(C2(O)CCC2)n1
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (10 mL) solution of 293.1 mg of 1-(6-bromo-2-pyridinyl)cyclobutanol obtained in Example 69-1 was cooled to −78° C. in an acetone/dry ice bath in a nitrogen atmosphere, and 1.8 mL of 1.58 M n-butyllithium/hexane solution was gradually added thereto, and stirred for 30 minutes. Subsequently, tetrahydrofuran (2.0 mL) solution of 0.36 mL of tri-n-butyltin chloride was added thereto at −78° C., and the reaction solution was stirred for 30 minutes. This was processed with aqueous saturated ammonium chloride solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline water, and purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 48.7 mg of the entitled compound as a pale yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:34]1[S:35][C:36]([CH2:39][N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:37][N:38]=1>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:18]=[CH:19][C:20]([C:34]2[S:35][C:36]([CH2:39][N:40]3[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]3)=[CH:37][N:38]=2)=[CH:21][CH:22]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Clc1ncc(CN2CCCCC2)s1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(CN3CCCCC3)s2)cc1
Yield: 110 %

Procedure:
Using an analogous procedure to that described in Method 44, N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13, 219 mg, 0.5 mmol) was reacted with 1-[(2-chloro-1,3-thiazol-5-yl)methyl]piperidine (108 mg, 0.5 mmol) to give the title compound (271 mg, >100%) which was carried through the next step; Mass Spectrum: M+H+ 493.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1[O:21][CH3:22].[C:23]([O-])([O-])=O.[K+].[K+].CO.[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CCOCC>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[CH:23])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1[O:21][CH3:22]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1nc(-c2ccc(C=O)cc2)c(F)c(N)c1OC
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: C#Cc1ccc(-c2nc(C(=O)OC)c(OC)c(N)c2F)cc1
Reaction time: 4 h
Yield: 73.4 %

Procedure:
To a 20 mL reaction vial were added methyl 4-amino-5-fluoro-6-(4-formylphenyl)-3-methoxypicolinate (0.41 g, 1.347 mmol), K2CO3 (0.372 g, 2.69 mmol), and CH3OH (20 mL). Dimethyl 1-diazo-2-oxopropylphosphonate (0.311 g, 1.617 mmol) was added in one portion. After stirring for 4 h, the reaction mixture was diluted with Et2O (50 mL) and washed with 5% NaHCO3 (25 mL). The organic layer was dried over MgSO4 (5 g), filtered, and concentrated on a rotary evaporator. The resulting residue was purified using a Teledyne ISCO purification system with a gradient eluent system of CH2Cl2 and EtOAc to yield the title compound as an off-white solid (297 mg, 73%): 1H NMR (400 MHz, CDCl3) δ 7.93-7.85 (m, 2H), 7.62-7.53 (m, 2H), 4.57 (s, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 3.15 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −139.97; ESIMS m/z 301 ([M+H]+), 299 ([M−H]−).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][C:25]([O-:27])=[O:26])=[C:17]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:16]=2)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][C:25]([OH:27])=[O:26])=[C:17]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:16]=2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2nc(N3CCOCC3)c3ncn(CC(=O)[O-])c3n2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CC(=O)O)c3n2)cn1
Yield: 73.5 %

Procedure:
Crude 2-(2-(2-(bis(tert-butoxycarbonyl)amino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)acetate (240 mg) was reacted with 3 eq of lithium hydroxide in 1:1 THF/water solution. After completion, the THF was concentrated in vacuo and the water solution was acidified to pH 2 using a concentrated HCl solution. The product precipitated as a fine white solid and was filtered to yield 2-(2-(2-(tert butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)acetic acid (145 mg), of which 40 mg was subjected to General Procedure E and purified via reverse phase HPLC to give 19.5 mg 125 as a white solid. MS (Q1) 357.2 (M)+
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[NH2:7][C:8]1[S:12][N:11]=[C:10](/[C:13](=[N:17]/[O:18][C:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH3:21])[CH3:20])/[C:14](O)=[O:15])[N:9]=1.C(OC(C)C)(C)C>C(Cl)Cl>[ClH:2].[NH2:7][C:8]1[S:12][N:11]=[C:10](/[C:13](=[N:17]/[O:18][C:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH3:21])[CH3:20])/[C:14]([Cl:2])=[O:15])[N:9]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)O)c1nsc(N)n1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)Cl)c1nsc(N)n1
Product: Cl
Yield: 144 %

Procedure:
To a solution of phosphorus pentachloride (11.11 g) in methylene chloride (167.8 ml) was added (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetic acid (16.78 g) at -20° C. The resultant mixture was stirred at -20° to -10° C. for 1.5 hours, and to the mixture was added dropwise diisopropyl ether (671.2 ml) at -20° to -10° C. The mixture was stirred under ice-cooling for 1 hour and the resultant precipitate was collected by filtration to give (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetyl chloride hydrochloride (14.8 g).
Reaction SMILES: C1(N2C(C(F)(F)F)=C(C3ON=C4C5C(CCC=34)=CC(C=C)=CC=5)C=N2)C=CC=CC=1.[CH:31]([C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)/[C:39](=[N:43]/[OH:44])/[CH2:38][CH2:37][CH2:36]2)=[CH2:32].[CH:45]1([C:51]2[CH:60]=[CH:59][C:54]([C:55](OC)=O)=[CH:53][C:52]=2[C:61]([F:64])([F:63])[F:62])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>>[CH:45]1([C:51]2[CH:60]=[CH:59][C:54]([C:55]3[O:44][N:43]=[C:39]4[C:40]5[C:35]([CH2:36][CH2:37][C:38]=34)=[CH:34][C:33]([CH:31]=[CH2:32])=[CH:42][CH:41]=5)=[CH:53][C:52]=2[C:61]([F:62])([F:63])[F:64])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]1
Reactant: COC(=O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Agent: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(C2CCCCC2)c(C(F)(F)F)c1

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 89A employing 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1) and methyl 4-cyclohexyl-3-(trifluoromethyl)benzoate (Preparation 118C) as starting materials. The compound had an HPLC retention time=4.83 min. (condition C); LC/MS M+1=424.3.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[ClH:24]>C(O)C>[ClH:24].[CH:16](=[C:11]1[C:12](=[O:15])[C:13](=[CH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][N:9]([CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CN(CCc2ccccc2)CC1=Cc1ccccc1
Reaction time: 16 h

Procedure:
Twenty-five grams of 1-(2-phenylethyl)-4-piperidone and 38 g of benzaldehyde are reacted in 180 ml of ethanol in the presence of 40 ml of concentrated hydrochloric acid at reflux temperature for about 5 hours and left at room temperature for about 16 hours yielding 25.5 g of material, melting point 217°-220° C, dec. Crystallization from 50 ml of hot dimethylformamide and 100 ml of acetonitrile yields 22 g of the title compound, melting point 225°-227° C, dec.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)([C:13](Cl)=[O:14])=O.C[CH2:18][N:19](CC)CC.O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:19]([O:14][CH3:13])[CH3:18])=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)c1cncc(Br)c1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 5-bromo-nicotinic acid (100 g, 0.5 mol) in THF (2 L) at 0° C., (COCl)2 (95 g, 0.74 mol) was added. After stirring for 0.5 h, Et3N (152 g, 1.5 mol) and O, N-dimethyl hydroxylamine. HCl (140 g, 1.5 mol) were added. The reaction mixture was stirred at room temperature for 2.5 hours and then water (200 mL) and EtOAc (500 mL) were added. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to afford 5—the title compound as a brown oil in 82% yield, 100%.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O-:25])(=[O:3])=[O:2].[CH2:18]([N+:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccncc1
Reactant: OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: c1ccc(C[n+]2ccccc2)cc1
Temperature: 5 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
19.07 g (0.1 mol) of tosyl chloride and 15.82 g (0.2 mol) of pyridine were dissolved in 60 g of acetone, and, after cooling to 5° C., there was added 10.81 g (0.1 mol) of benzyl alcohol. While suppressing excessive elevation of the temperature, reaction was allowed for 5 hours. After the completion of the reaction, the mixture was concentrated and the precipitated white solid was washed with ether and dried to give N-benzylpyridinium tosylate. Yield: 80%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:21]=[CH:22][C:23]([OH:30])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26])#[CH:19]>C(N(CC)CC)C.O1CCCC1.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.[Cu]I>[OH:30][C:23]1[CH:22]=[CH:21][C:20]([C:18]#[C:19][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: O=S(=O)(Nc1ccccn1)c1ccc(I)cc1
Reactant: C#Cc1ccc(O)c(C(=O)OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Temperature: 60 °C

Procedure:
4-Iodo-N-(2-pyridinyl)benzenesulfonamide (35 g, 97 mmol) was dissolved in a mixture of triethylamine and tetrahydrofuran (750+750 ml). The mixture was deaerated with nitrogen and dichlorobis(triphenylphosphine)palladium (1.2 g, 1.7 mmol) and copper(I) iodide (0.6 g, 3.4 mmol) were added. Finally methyl 5-ethynyl-2-hydroxybenzoate (23 g, 130 mmol) was added. The mixture was heated to 60° C. for 4 h, evaporated to dryness. The residue was dissolved in chloroform (1000 ml) and washed with water (3 x 200 ml) and dried with MgSO4. The solvent was evaporated in vacuo. Yield 31 g (77% ). The product can be purified by flash-chromatography on silica with chloroform as the eluent.
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCC[CH2:2]1.[C:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][Br:24])=[CH:21][CH:20]=1)([OH:18])=[O:17].C(O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][Br:24])=[CH:21][CH:20]=1)([O:18][CH2:1][CH3:2])=[O:17]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(CBr)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 16.09 g (78 mmol) of 1,3-dicyclohexylcarbodiimide (Aldrich) in 100 ml methylene chloride was added a suspension of 15.4 g (71 mmol) of 4-carboxybenzyl bromide in 100 ml methylene chloride and then 4.9 g (106.5 mmol) of absolute ethanol and 0.81 g (7.1 mmol) of 4-dimethylaminopyridine. A further 50 ml of methylene chloride was added to the reaction mixture and mixture heated at reflux for 2 hours. The mixture was allowed to cool to room temperature and the resultant white precipitate removed by filtration. The filtrate was washed with water, dried (MgSO4) and then concentrated in-vacuo to give the title compound as a colorless oil which crystallized on standing. PMR (CDCl3); δ 1.39 (3H, t, J~7.2 Hz), 4.38 (2H, q, J~7.2 Hz), 4.50 (2H, s), 7.45 (2H, d, J~7.7 Hz), 8.03 (2H, d, J~7.7 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([CH:21]=C)[N:12]2[CH:17]([CH3:18])[CH2:16][N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:29].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([CH:21]=[O:29])[N:12]2[CH:17]([CH3:18])[CH2:16][N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1c(C(=O)OCC)c(OCc2ccccc2)c2n1C(C)CN(C)C2=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C=O)C(C)CN(C)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 8-(benzyloxy)-2,4-dimethyl-1-oxo-6-vinyl-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (0.11 g, 0.29 mmol), osmium tetroxide (2.5% in t-butanol, 0.59 mL, 0.058 mmol), sodium periodate (0.19 g, 0.87 mmol) in aqueous THF (6 mL, 1:2 v/v) was stirred at room temperature for 4 hours. The reaction mixture was treated with 10% aqueous sodium sulfite and diluted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with a hexanes and ethyl acetate gradient to provide the titled product.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:2]=1.N1C2C(=NC=CC=2)N(CC2C=CC3N=C(S(C)(=O)=O)SC=3C=2)C=1.[NH2:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][CH2:49][C@H:48]1[CH2:53][OH:54].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:46][C@@H:47]4[CH2:52][CH2:51][CH2:50][CH2:49][C@H:48]4[CH2:53][OH:54])[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1CO
Agent: CS(=O)(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: OC[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 120 °C
Reaction time: 4.5 h

Procedure:
A 4:1 mixture of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole (120 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (2 mL), and then ((1R,2R)-2-aminocyclohexyl)methanol (180 mg, 1.40 mmol) from Step 1 of this Example and DIEA (188 mg, 1.46 mmol) were added. The reaction vessel was sealed and the mixture was heated with stirring at 120° C. for 4.5 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford ((1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol.
Reaction SMILES: C1(C2SC(C(N)C)=CC=2)C=CC=CC=1.Cl.O1CCOCC1.[C:22]1([C:28]2[S:32][C:31]([CH:33]([NH:35][S:36]([CH2:38][CH:39]([CH3:41])[CH3:40])=[O:37])C)=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[C:22]1([C:28]2[S:32][C:31]([CH:33]=[N:35][S:36]([CH2:38][CH:39]([CH3:41])[CH3:40])=[O:37])=[CH:30][CH:29]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)CS(=O)NC(C)c1ccc(-c2ccccc2)s1
Agent: CC(N)c1ccc(-c2ccccc2)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)CS(=O)N=Cc1ccc(-c2ccccc2)s1
Reaction time: 2 h
Yield: 53.5 %

Procedure:
1-(5-Phenyl-thiophen-2-yl)ethylamine (Isomer 2, Preparation 171) Add 4N hydrogen chloride in dioxane (1.112 mL, 4.449 mmol) to a stirred solution of N-[1-(5-phenylthiophen-2-yl)ethyl]-2-methylpropanesulfinamide (Isomer 2) (684 mg, 2.225 mmol) in methanol (10 mL) at room temperature. Stir for 2 h and remove the solvent in vacuo to obtain a solid that was washed with ethyl ether. Dissolve the solid in DCM and wash with saturated aqueous NaHCO3. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (347 mg, 77% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1cccc(CN2CCCCC2)c1
Solvent: CCO
Product: Nc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.8 %

Procedure:
In ethanol (100 ml) was dissolved 1-(3-nitrobenzyl)-piperidine (32.2 g), and to the mixture was added dried 10% palladium on carbon (1.61 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 24 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was recrystallized from diisopropylether-hexane to give 1-(3-aminobenzyl)piperidine (15.8 g) as colorless crystals.