Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]([C:14]([OH:16])=O)[CH2:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[CH2:42][NH2:43].Cl.CN(C)CCCN=C=NCC>ClCCl>[Cl:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[CH2:42][NH:43][C:14](=[O:16])[C@@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCc1ccc(F)cc1Cl
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1Cl)[C@@H]1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
5-Oxo-1-(phenylmethyl)-proline (0.176 g, 0.80 mmol, prepared as described below) was dissolved in dichloromethane (3 ml) and to this was added 1-hydroxybenzotriazole (0.119 g, 0.88 mmol), triethylamine (0.113 ml, 0.81 mmol), [(2-chloro-4-fluorophenyl)methyl]amine (0.134 g, 0.84 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.169 g, 0.88 mmol) under an atmosphere of argon. The mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed sequentially with 2M aqueous hydrogen chloride and saturated aqueous sodium hydrogen carbonate. The organic layer was filtered through a phase separator and then evaporated to give the crude product. The crude material was purified by mass-directed automated HPLC to give pure N-[(2-chloro-4-fluorophenyl)methyl]-5-oxo-1-(phenylmethyl)-prolinamide (0.112 g) as a white solid. LC/MS [M+H]+=361.2, retention time=2.55 minutes.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:21]S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)([CH3:20])[CH2:9][O:10][C@@:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:14])=O)[C:5]([F:34])=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:20])[CH2:9][O:10][C@@:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:14])=[N:21]2)[C:5]([F:34])=[CH:4][CH:3]=1
Reactant: C[C@@](CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1nc(Br)ccc1F
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[C@@]1(c2nc(Br)ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 148.7 %

Procedure:
A suspension of (R)-2-[(R)-2-(6-bromo-3-fluoro-pyridin-2-yl)-2-(4-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide (8.43 g, 14.70 mmol) and triethylamine (5.12 ml, 36.8 mmol) in 85 ml DCM was cooled to 0-5° C. Trifluoroacetic anhydride (2.49 ml, 17.64 mmol) was added dropwise over 30 min. Additional triethylamine (1.54 ml, 11.07 mmol) and trifluoroacetic anhydride (0.75 ml, 5.29 mmol) were added to complete the reaction. The reaction mixture was quenched by addition of 14 ml aqueous ammonia (25%) and 14 ml water. The emulsion was stirred for 15 min, more water and DCM were added and the layers were separated. The organic layer was dried with MgSO4 H2O, filtered and evaporated. Purification by column chromatography on a silica gel (hexanes/10-25% EtOAc) gave 8.09 g of the title compound as a yellow resin.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][S:6][CH:7]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:23])[O:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:19]([NH:2][C:3]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][S:6][CH:7]=1)=[O:23])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1cscc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1cscc1C(=O)OC

Procedure:
A mixture of 50.0 g (0.258 mol) of methyl 4-aminothiophen-3-carboxylate-hydrochloride, 700 ml of toluene, 26 g (0.257 mol) of triethylamine and 27 ml (0.283 mol) of ethyl chlorocarbonate was refluxed for 5 hours. The insoluble matter was filtered off, the filtrate was evaporated down in vacuo and the residue was crystallised from petroleum ether. 59.0 g (99.8% of theory) of colourless crystals of melting point 52° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[CH2:11](Br)/[CH:12]=[C:13](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])\[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:14][C:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:12][CH2:11][O:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: Oc1ccc2c(c1)OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)=CCCC(C)=CCOc1ccc2c(c1)OCC2
Reaction time: 70 h

Procedure:
A mixture of 27.7 g. of 6-hydroxy-2,3-dihydrobenzofuran, 52.1 g. of geranyl bromide and 41.4 g. of anhydrous powdered potassium carbonate in 200 ml. of methyl ethyl ketone is heated under reflux with stirring for 70 hours. The cooled reaction mixture is filtered, the residual potassium carbonate washed with acetone and the filtrate evaporated. By chromatography on silica gel with hexane/diethyl ether (4:1 parts by volume) there is obtained pure 6-[(3,7-dimethyl-2,6-octadienyl)-oxy]-2,3-dihydrobenzofuran of boiling poiint 130° C./0.001 mmHg.; nD20 = 1.5414.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH:7]2[C:20](=[O:21])[N:11]3[C:12]4[C:17]([C:18]([CH3:19])=[C:10]3[CH2:9][CH2:8]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:3]=[CH:2]1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH3:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]2[C:20](=[O:21])[CH:7]([CH2:6][C:4]3[N:3]=[CH:2][N:1]([CH3:24])[CH:5]=3)[CH2:8][CH2:9][C:10]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)C(Cc1c[nH]cn1)CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c2n(c3ccccc13)C(=O)C(Cc1cn(C)cn1)CC2
Temperature: 5 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
To a solution of 8,9-dihydro-7-[(1H-imidazol-4-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (1.4 g) in N,N-dimethylformamide (14 ml) at 5° C. was added sodium hydride (60% in mineral oil) (220 mg). After stirring for 1 hour at 5° C., methyl iodide (852 mg) in dimethylformamide (5 ml) was added dropwise at 5° C. for 10 minutes. The mixture was stirred at 5° C. for 1 hour and at 20° C. for 2 hours. After evaporation of the solvent, the residue was diluted with 5% methanol-chloroform. The organic layer was washed twice with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The obtained residue contained two products which showed close Rf values (0.5 and 0.4 respectively) by TLC (20% methanol-chloroform). Separation with silica gel column chromatography (5% methanol-chloroform) gave two fractions. The first eluted fraction, containing a mixture of two products, was concentrated. The crystalline residue was recrystallized from ethyl acetate to give 8,9-dihydro-10-methyl-7-[(1-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (0.4 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([S:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][NH2:20]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][NH:20][C:2]1[C:11]2[C:6](=[C:7]([S:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: CSc1cccc2c(Cl)cc(C)nc12
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: CSc1cccc2c(NCc3ccc(Cl)c(Cl)c3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methyl-8-methylsulfanylquinoline and 3,4-dichlorobenzylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:25]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:29]2[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(F)cc3)c2c1O
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CCOC(=O)c1nc(-c2ccc(C#N)cc2)c2snc(-c3ccc(F)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-bromo-3-(4-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 4-cyanophenylboronic acid: MS (m/z) 420.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.F[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH2:34])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:30]4[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=4[C:32]([NH2:34])=[O:33])[CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:27][CH:28]=1
Reactant: NC(=O)c1ccccc1F
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2C(N)=O)cc1
Temperature: 90 °C
Yield: 71.7 %

Procedure:
To a solution of INTERMEDIate M (900 mg, 2.08 mmol) and 2-fluorobenzamide (293 mg, 2.08 mmol, Aldrich) in DMF (10 mL) was added cesium carbonate (1.01 g, 3.12 mmol). The reaction mixture was heated at 90° C. for 48 h. After completion, the reaction mixture was diluted with ethyl acetate (30 mL) and water (20 mL). The layers were separated and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude material which was purified by combi flash silica gel column chromatography (column size: 40 g, elution: 25% ethyl acetate in hexane) to provide 2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)benzamide (800 mg, 71.4%); LCMS (ESI) m/z; 537.12 (M+H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]([F:26])=[C:17]([CH:25]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].Cl>CS(C)=O>[CH2:1]([O:5][C:14]1[C:13]([Cl:12])=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[C:16]([F:26])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: CCCCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCCCOc1cc(F)c(C(=O)OC(C)(C)C)cc1Cl
Temperature: 70 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
To a solution of butanol (0.07 g, 0.99 mmol) in anhydrous dimethylsulfoxide (2 mL) were added cesium carbonate (0.59 g, 1.81 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (0.22 g, 0.90 mmol) and the reaction mixture was stirred at 70° C. for 16 hours. The reaction mixture was cooled down to room temperature and acidified to pH=1 with 5% aqueous hydrochloric acid solution and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine (15 mL); dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (0 to 10% ethyl acetate in hexanes) afforded the title compound (0.23 g, 72%); MS (ES+) m/z 303.2, 305.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C[C@@H](OC)[C@H](F)[C@H]1C(O)=O)=O)(C)(C)C.[Cl:37][C:38]1[C:39]([F:46])=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][NH2:42].CCCP(=O)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16](=[O:18])[NH:42][CH2:41][C:40]1[CH:43]=[CH:44][CH:45]=[C:38]([Cl:37])[C:39]=1[F:46])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CO[C@H]1[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C[C@@H]1F
Reactant: NCc1cccc(Cl)c1F
Agent: CCCP(=O)=O
Agent: CO[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)[C@H]1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CO[C@H]1[C@@H](C(=O)NCc2cccc(Cl)c2F)N(C(=O)OC(C)(C)C)C[C@@H]1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.55 g, 5.89 mmol) in CH2Cl2 (50 mL) were added 3-chloro-2-fluoro-benzylamine (1.03 g, 6.48 mmol), propylphosphonic anhydride (50% in EtOAc, 5.20 mL, 8.83 mmol) and DIPEA (3.08 mL, 17.7 mmol). The reaction mixture was stirred at RT for 2 h and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 7:3) to give (2S,3S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Rf, TLC (c-hexane/EtOAc 1:1)=0.35; MS (UPLC): 405.1/407.2 [M+H]+, 349.1/351.1 [MH−tBu]+, 449.2/451.2 [M+HCOO]−; tR (HPLC conditions f): 2.12 min and (2R,3R,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-3-fluoro-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Rf, TLC (c-hexane/EtOAc 1:1)=0.5; MS (UPLC): 405.1/407.2 [M+H]+, 349.0/351.1 [MH−tBu]+, 449.2/451.2 [M+HCOO]−; tR (HPLC conditions f): 2.20 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11]OS(C)(=O)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CCN2CCCCC2)c1
Yield: 44 %

Procedure:
Methanesulfonic acid 2-(3-nitro-phenyl)-ethyl ester was dissolved in piperidine (20 eq) and THF and stirred at 60° C. for one hour. The solvent was removed. The crude product was diluted with ethyl acetate, washed three times with water, dried with anhydrous sodium sulfate, filtered and concentrated. The product was clean enough to carry forward without purification. 44% yield. MH+=235.1.
Reaction SMILES: C([Sn]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(CCCC)CCCC)CCC.Cl[C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:20]1[CH:25]=[C:24]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[N:23]=[CH:22][N:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Clc1cc(Cl)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1csc(-c2cc(-c3cccs3)ncn2)c1
Yield: 72 %

Procedure:
A mixture of tri-n-butylstannylthiophene (10.52 g, 28.19 mmol), 4,6-dichloropyrimidine (2.00 g, 13.42 mmol), tetrakis(triphenylphosphine)palladium(0) (0.345 g, 0.30 mmol) and few crystals of 2,6-di-tert-butyl-4-methylphenolo in dry toluene (20 mL) was deareated twice with nitrogen. The reaction mixture was refluxed for 6 hours and, after cooling, a white precipitate was formed in the reaction flask. The solid was collected and the organic phase was diluted with ether (100 mL), poured onto a solution of NH4F (3 g, 100 ml) and separated. After drying over MgSO4, the solvent was evaporated affording a solid material. The two solid phase were combined and crystallized from toluene to give the pure product as a white crystals (2.36 g, 9.66 mmol, 72.0% yield). mp 146° C.; 1H NMR (CDCl3) δ 9.07 (1H, d, 2J=1.4), 7.86 (1H, d, 2J=3.7), 7.83 (1H, d), 7.57 (1H, d, 2J=5.1), 7.20 (1H, dd).
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([OH:13])=O.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>CN(C=O)C>[Cl:3][C:8]1[CH:9]=[CH:10][N:5]=[C:6]([C:11]([NH:18][CH2:17][CH2:16][N:15]([CH3:19])[CH3:14])=[O:13])[CH:7]=1
Reactant: O=C(O)c1ccccn1
Reactant: O=S(Cl)Cl
Reactant: CN(C)CCN
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1cc(Cl)ccn1
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 45.7 %

Procedure:
To a solution of thionyl chloride (7.4 mL, 101 mmol) in DMF was added pyridine-2-carboxylic acid (2.5 g, 20.3 mmol). The reaction mixture was heated at 95° C. for 12 h and then concentrated. The residue was redissolved in DMF (7 mL) and N,N-dimethylethane-1,2-diamine (11 mL, 101.5 mmol) was added. After stirring for 15 min, the mixture was concentrated and the residue was purified by column chromatography (0-10% methanol/dichloromethane) to yield 2.11 g of the title compound (46%). LCMS: (FA) ES+ 227.9 (M+1)
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(#N)C>[CH3:26][S:27]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[N:8]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 6-(hydroxymethyl)pyridin-2-ylcarbamate 78 (3.0 g, 13.4 mmol) and diisopropylethylamine (5.0 g, 40 mmol) in acetonitrile (30 mL) was added methanesulfonyl chloride (2.0 g, 17.4 mmol) over a period of 30 min at 0° C. and the mixture was stirred for 2 h at room temperature. The reaction was quenched by adding saturated aqueous NaHCO3 and extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford quantitative yield of crude 79.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)([CH3:3])=[CH2:2].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:11][CH2:10][C@H:7]1[CH2:8][CH2:9][C@@H:4]([C:1]([CH3:3])=[CH2:2])[CH2:5][CH2:6]1)(=[O:14])[CH3:13]
Reactant: C=C(C)[C@H]1CC[C@@H](CO)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@H]1CC[C@@H](COC(C)=O)CC1

Procedure:
3.9 g of cis-4-isopropenyl-cyclohexylmethanol, 50 ml of acetic anhydride and 20 ml of pyridine were kept overnight at room temperature. The reaction mixture was then poured onto crushed ice and extracted with ether. The organic layer was successively washed with a 2N solution of Na2CO3, HCl at 10% in water and finally with a saturated aqueous NaCl solution. After the usual treatments of drying and evaporation, the fractional distillation of the obtained residue yielded 3.2 g (65%) of cis-4-isopropenyl-cyclohexylmethyl acetate, bp 105° - 108°/10 Torr.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([NH2:22])[CH2:20][CH3:21].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]([NH:22][CH2:19][CH2:20][CH3:21])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Yield: 91.1 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (10 mg, 0.385 mmol) and propylamine (228 mg, 3.85 mmol) in methanol (50 ml) were heated at 120° C. for 10 hours in autoclave. The reaction mixture was condensed in vacuo and to the residue was added 5N aqueous sodium hydroxide, followed by extraction with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (99 mg, yield 91%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:12]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22]#[N:23])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[ClH:31].[NH2:32][OH:33].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[Cl:31][C:2]1[CH:3]=[C:4]([CH:12]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22](=[NH:23])[NH:32][OH:33])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: NO
Reactant: Cl
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2cnc(C#N)cn2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2cnc(C(=N)NO)cn2)cc1Cl
Temperature: 70 °C
Yield: 67.1 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-cyano-pyrazin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionamide (prepared as in Example 22, 151 mg, 0.34 mmol) in ethanol (2 mL) and water (1 mL) was treated with hydroxylamine hydrochloride (28 mg, 0.40 mmol) and sodium carbonate (35 mg, 0.34 mmol). The reaction was heated at 70° C. for 3 h. At this time, the reaction was concentrated in vacuo and then extracted with 10% methanol/chloroform 3×30 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 20/80 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-[5-(N-hydroxycarbamimidoyl)-pyrazin-2-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (110 mg, 68%) as a white solid: mp 137.2-140.5° C.; (ES)+-HRMS m/e calcd for C20H24ClN5O5S (M+H)+ 482.1260. found 482.1263.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:21]([CH:23]1[CH:28]([CH3:29])[CH:27]([CH2:30][O:31][Si](C)(C)C)[CH2:26][CH2:25][C:24]1=[O:36])[CH3:22].Cl>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:24]2([OH:36])[CH2:25][CH2:26][CH:27]([CH2:30][OH:31])[CH:28]([CH3:29])[CH:23]2[CH2:21][CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc(OCc2ccccc2)cc1
Reactant: CCC1C(=O)CCC(CO[Si](C)(C)C)C1C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC1C(C)C(CO)CCC1(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-Benzyloxy4-iodo-benzene (5.70 g, 18.37 mmol) was dissolved in anhydrous THF (36 mL) at −10° C. Isopropyl magnesium chloride (1.0 M, 18.37 mL) was added and the mixture was stirred for 3 h. A solution of 2-ethyl-3-methyl-4-trimethylsilanyloxymethyl-cyclohexanone (12.0 g in 50 mL THF) was added slowly over 30 min by syringe pump. The reaction mixture was stirred for 30 min at 25° C. and then refluxed for 30 min. The reaction mixture was then cooled to 25° C., HCl (1.0 N, 80 mL) was added slowly, followed by addition of ethyl acetate (100 mL). The organic layer was washed with H2O (100 mL), dried over MgSO4 and purified on SiO2 (10˜15% ethyl acetate/hexane) to yield 1-(4-benzyloxy-phenyl)-2-ethyl-4-hydroxymethyl-3-methyl-cyclohexanol.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:9]=1[C:10]([OH:12])=O.CN(C=O)C.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[NH2:17][C:14]1[CH:15]=[CH:16][C:8]([F:7])=[C:9]([CH:13]=1)[C:10]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:12]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Nc1ccc(F)c(C(=O)Nc2ccccc2)c1
Yield: 92.6 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.39 mmol), 2-fluoro-5-nitrobenzoic acid (5.00 g, 27.01 mmol), DMF (1.0 mL, 12.92 mmol), and aniline (5.0 mL, 54.88 mmol) to afford the pure product (5.76 g); m.p. 120-122° C.