Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]1([S:12]Cl)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC>[C:6]1([S:12][C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1cc[nH]c1
Reactant: ClSc1ccccc1
Solvent: CCOCC
Product: c1ccc(Sc2ccc[nH]2)cc1
Yield: 5.7 %

Procedure:
Pyrrole (2.0 g., 30 mmoles) was dissolved in 20 ml. of ether. Benzenesulfenyl chloride (4.5 g., 30 mmoles) was added dropwise at such a rate that the purple color of the reagent was discharged. A slightly exothermic reaction was noted. After addition was complete (10 minutes), the reaction was evaporated to an oil (5.7 g.). The oil was chromatographed on approximately 180 ml. of silica gel, eluted with ethyl acetate-1/hexane-7. Middle fractions, evaporated to dryness, afforded 2-phenylthiopyrrole (300 mg.).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH3:26])[C:19](=[O:27])[CH2:18]3)=[C:13]([F:28])[CH:12]=2)[CH2:6]1)=[N+]=[N-].[C:29](OCC)(=[O:31])[CH3:30]>>[F:28][C:13]1[CH:12]=[C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][NH:1][C:29](=[O:31])[CH3:30])[O:9][C:8]2=[O:10])[CH:16]=[CH:15][C:14]=1[N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH3:26])[C:19](=[O:27])[CH2:18]1
Reactant: CCOC(C)=O
Reactant: COCCN1CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1=O
Product: COCCN1CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5R)-5-Azidomethyl-3-(3-fluoro-4-{4-(2-methoxyethyl)-3-oxopiperazin-1-yl}phenyl)oxazolidin-2-one (750 mg) was dissolved in ethyl acetate (15 ml), and the solution purged with argon. Palladium (10% on carbon, 150 mg) was added, followed by acetic anhydride (0.36 ml) and the mixture stirred at ambient temperature under hydrogen confined in a balloon for 2 hours. The mixture was filtered through celite, evaporated to dryness, and chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated, to give N-(5S)-[3-(3-fluoro-4-{4-(2-methoxyethyl)-3-oxopiperazin-1-yl}phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (228 mg).
Reaction SMILES: [CH:1]1[C:9]2[N:8]3[C:10]([CH:13]4[CH:18]([CH3:19])[CH2:17][CH2:16][N:15](C(OCC5C=CC=CC=5)=O)[CH2:14]4)=[CH:11][N:12]=[C:7]3[CH:6]=[N:5][C:4]=2[NH:3][CH:2]=1.[H][H]>[Pd].CCO>[CH3:19][CH:18]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[C:10]1[N:8]2[C:9]3[CH:1]=[CH:2][NH:3][C:4]=3[N:5]=[CH:6][C:7]2=[N:12][CH:11]=1
Reactant: [H][H]
Reactant: CC1CCN(C(=O)OCc2ccccc2)CC1c1cnc2cnc3[nH]ccc3n12
Agent: [Pd]
Solvent: CCO
Product: CC1CCNCC1c1cnc2cnc3[nH]ccc3n12
Yield: 83.9 %

Procedure:
A mixture of benzyl 3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylpiperidine-1-carboxylate (0.55 g, 1.4 mmol) and palladium on carbon (10%, 0.38 g, 0.36 mmol) in EtOH (25 mL) was hydrogenated at room temperature under an atmospheric pressure of hydrogen for about 20 h. The catalyst was removed by filtration through a Celite® pad and the filtrate was concentrated in vacuo to give 8-(4-methylpiperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.30 g, 83%) as a yellow amorphous solid: LC/MS (Table 2, Method a) Rt=0.93 min; MS m/z: 256 (M+H)+.
Reaction SMILES: [C:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=[O:5])[CH2:2][CH2:3][CH3:4].[ClH:19].[H][H].CC(C)=O>O1CCOCC1.[Pd]>[ClH:19].[C:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCC(=O)Oc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CCCC(=O)Oc1ccc(N)cc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
10 g of 2-butanoyloxy-5-nitro-benzoic acid, 8.5 ml of dioxane, 1.5 ml of HCl 4M solution in dioxane and 1.0 g of Pd/C at 5% were loaded into a 300 ml reactor at 16±2° C. After two vacuum-nitrogen cycles, the reactor was saturated with hydrogen at 10 bar and kept at 16±2° C. for 6 hours. At the end, nitrogen atmosphere was restored in the reactor and the reaction mixture was added with 125 ml of acetone at 25° C. The suspension was stirred at 25° C. for 30 minutes to obtain the dissolution of the undissolved product and the carbon suspension was filtered on a celite panel which was then washed with 60 ml of acetone. The resultant solution was then evaporated under vacuum at 30° C. and the solid residue was dried under vacuum at 35° C. for 4 hours to obtain 10 g of the expected product (99% yield).
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][C:9]1[S:29][C:12]2=[N:13][C:14]([CH3:28])=[CH:15][C:16]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)(=[O:20])=[O:19])=[C:11]2[C:10]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)(=O)=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([S:18]([NH:17][C:16]2[CH:15]=[C:14]([CH3:28])[N:13]=[C:12]3[S:29][C:9]([C:8]#[C:7][CH2:6][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:10]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=4)[C:11]=23)(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: C1COCCN1
Reactant: COc1cccc(-c2c(C#CCOS(C)(=O)=O)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C#CCN3CCOCC3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of 3-{4-{[(3-chlorophenyl)sulfonyl]amino}-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-2-yl}-2-propyn-1-yl methanesulfonate (Description 77) (14 mg, 0.024 mmol) and morpholine (21.14 μl, 0.243 mmol) in THF (221 μl) was stirred at 60° C. for 1 h. The mixture was evaporated to dryness and the residue purified on silica, eluting with a gradient of 0-10% 2M NH3 in MeOH in DCM, to afford the title compound (12 mg). LCMS (A) m/z: 568 [M+1]+, Rt 1.02 min (acidic).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[CH2:28][CH3:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20](O)[CH:19]=2)=[CH:8][N:7]=1.P(Cl)(Cl)([Cl:32])=O.Cl.N>C(#N)C.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[CH2:28][CH3:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:32])[CH:19]=2)=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1ccc(Nc2ncc(CCc3ccnc(O)c3)c3ccccc23)cc1Br
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CC#N
Product: CCc1ccc(Nc2ncc(CCc3ccnc(Cl)c3)c3ccccc23)cc1Br
Temperature: 65 °C
Reaction time: 48 h

Procedure:
Under a N2 atmosphere, 150 mg (0.334 mmol) of 1-(3-bromo-4-ethyl-anilino)-4-[2-(2-hydroxy-pyridin-4-yl)-ethyl]-isoquinoline (Ex. 32a) in 5 ml of acetonitrile are mixed with 76 μl (0.83 mmol) of phosphorus oxychloride and 0.17 ml (0.68 mmol) of 4 N HCl in dioxane, and stirred at 65° C. A further 76 μl of phosphorus oxychloride is added after 12 h, and stirring continues for 48 h at 65° C. The mixture is cooled to RT, 4 ml of 10% NH3 solution added, and it is partitioned between 3 portions of EtOAc, 2 portions of water and brine. Drying (Na2SO4), concentrating by evaporation and chromatography on silica gel (acetone/methylene chloride 3:2) yield 1-(3-bromo-4-ethyl-anilino)-4-[2-(2-chloro-pyridin-4-yl)ethyl]-isoquinoline; FAB-MS: (M+H)+=466/468; HPLC(gradient20-100) tRef=13.4.
Reaction SMILES: N12CCCN=C1CCCC[CH2:2]2.[CH3:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[NH:24][C:25]([NH:27][S:28]([N:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])(=[O:30])=[O:29])=[O:26])[CH3:14].CI>C(#N)C>[CH3:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25](=[O:26])[N:27]([S:28]([N:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])(=[O:30])=[O:29])[CH3:2])[CH3:14]
Reactant: CCCCN(CCCC)S(=O)(=O)NC(=O)Nc1c(C(C)C)cccc1C(C)C
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CC#N
Product: CCCCN(CCCC)S(=O)(=O)N(C)C(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.6 mL, 10.7 mmol) was added dropwise to a solution of N-[2,6-bis(1-methylethyl)phenyl]-N'-[(dibutylamino)sulfonyl]urea (4.0 g, 9.7 mmol) and methyl iodide (1.52 g, 10.7 mmol) in 100 mL acetonitrile at -15° C. The resulting mixture was warmed to room temperature and stirred for 16 hours. Concentrated in vacuo and partitioned between 1N HCl and ethyl acetate. The organic layer was dried with MgSO4, filtered, and concentrated to give an orange oil. Chromatography gave the title compound as a clear oil; 1H NMR (DMSO-d6) θ 8.57 (s, 1H), 7.31-7.15 (m, 3H), 3.33-3.21 (m, 7H), 3.05 (heptet, 2H), 1.57-1.46 (m, 4H), 1.35-1.20 (m, 4H), 1.13 (d, 12H), 0.90 (t, 6H). ##STR14##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@@H]4CCCNC4)ncnc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC[C@@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 50.4 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3R)-piperidin-3-yl]-9H-purin-6-amine (20 mg, 0.046 mmol, 1 eq.) in 2 mL of dichloromethane was added methanesulfonyl chloride (0.007 mL, 0.091 mmol, 2 eq.) and triethylamine (0.02 mL, 0.137 mmol, 3 eq.). The mixture was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 12 mg (51%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3R)-1-methanesulfonylpiperidin-3-yl]-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81-2.18 (m, 4 H) 2.77-2.94 (m, 3 H) 3.07-3.29 (m, 2 H) 3.42 (br. s., 1 H) 3.82 (d, J=9.89 Hz, 1 H) 4.68 (br. s., 1 H) 6.13 (br. s., 1 H) 7.12-7.65 (m, 8 H) 8.48 (s, 1 H), [M+H]+ 517.8.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11].FC(F)(F)S(O[C:18]1[C:19]2[CH2:39][N:38]([C:40](=[O:42])[CH3:41])[CH2:37][CH2:36][C:20]=2[N:21]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[O:35][CH:34]=[N:33][CH:32]=3)=[CH:27][CH:26]=2)[N:23]=1)(=O)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O>>[OH:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:2]([CH3:1])[C:18]1[C:19]2[CH2:39][N:38]([C:40](=[O:42])[CH3:41])[CH2:37][CH2:36][C:20]=2[N:21]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[O:35][CH:34]=[N:33][CH:32]=3)=[CH:27][CH:26]=2)[N:23]=1
Reactant: CNCc1ccccc1CO
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(C)Cc3ccccc3CO)c2C1
Yield: 15.3 %

Procedure:
1-(4-((2-(Hydroxymethyl)benzyl)(methyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (12.3 mg, 15.3%) was prepared from (2-((methylamino)methyl)phenyl)methanol and 6-acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-y1 trifluoromethanesulfonate (example 88a) according to the general procedure for amine substitution of tosylate on pyrimidines.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)[CH:13]=[CH:14][C:15]=2[N+:16]([O-])=O)=[O:8])=[CH:5][CH:4]=1.C([OH:32])(C)C>C(Cl)Cl>[NH2:16][C:15]1[CH:14]=[CH:13][C:12]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:32])=[CH:21][CH:20]=2)=[CH:11][C:10]=1[NH:9][C:7](=[O:8])[C:6]1[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CC(C)O
Reactant: COc1ccc(C(=O)Nc2cc(-c3ccc(SC)cc3)ccc2[N+](=O)[O-])cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(-c3ccc(S(C)=O)cc3)ccc2N)cc1
Yield: 57 %

Procedure:
Following the same procedure as described in Example 10, step 2 (scheme 10), but substituting compound 120 for compound 209, the title compound 210 was obtained in 57% yield [after column chromatography (5% isopropanol in DCM)].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([CH3:27])=[CH:25][N:24]=[CH:23][C:22]=1[CH3:28].[CH3:31][NH:32][CH2:33][CH2:34][OH:35]>>[CH3:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH3:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]([CH2:33][CH2:34][OH:35])[CH3:31])[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: CNCCO
Reactant: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCN(C)CCO

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 6) and and 2-(methylamino)ethanol following the procedure outlined in Example 18, Step 2 (modifications: 22° C., 60 h). 1H NMR (300 MHz, DMSO-d6):):δ: 9.67 (s, 1H), 8.42 (s, 3H), 7.91 (d, J=9 Hz, 1H), 7.04 (s, J=7 Hz, 1H), 4.55 (s, 1H), 4.31 (s, 1H), 3.98 (t, J=6.6 Hz, 5H), 3.46 (s, 2H), 2.40-2.28 (m, 4H), 2.15 (s, 9H), 1.75 (m, 2H), 1.35 (m, 6H). MS (ESI) 469.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH3:14])[CH:8]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[N:13]([C:10]1[C:9]([CH3:14])=[CH:8][C:7]([O:6][CH3:5])=[N:12][CH:11]=1)=[C:1]=[S:2]
Reactant: COc1cc(C)c(N)cn1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C)c(N=C=S)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
Thiophosgene (8.9 mL, 120 mmol) was added dropwise to a stirred mixture of 6-methoxy-4-methylpyridin-3-amine (13.8 g, 99.8 mmol) in tetrahydrofuran (100 mL) and saturated aqueous sodium hydrogen carbonate (150 mL) at 0° C., and the mixture was stirred at 0° C. for 2 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with n-hexane to give the title compound as a colorless powder (10.6 g, 58.8 mmol, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:38]1C(C)=CC=C[C:39]=1C.CN.O1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](=[O:25])[NH:38][CH3:39])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1cccc(C)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.8 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, a 2.0 M solution of methylamine in tetrahydrofuran (59 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-propionamide (11 mg, 21%) as a white solid: ESI-LRMS m/e calcd for C22H29ClN4O4S [M+] 480.2, found 481.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.09-1.20 (m, 2H, CH2), 1.46-1.96 (m, 8H, 4×CH2), 2.17-2.29 (m, 1H, CH), 2.62 (t, J=6.3 Hz, 2H, COCH2), 2.75 (d, J=4.9 Hz, 3H, CONCH3), 3.27 (s, 3H, SO2CH3), 3.55 (t, J=7.6 Hz, 1H, CH), 4.31 (t, J=6.3 Hz, 2H, NCH2), 5.48 (brm, 1H, NH), 6.58 (d, J=2.3 Hz, 1H, Ar), 7.30 (d, J=2.3 Hz, 1 H, Ar), 7.46 (dd, Jo=8.2, Jm=1.6 Hz. 1H, Ar), 7.60 (d, Jm=1.6 Hz, 1H, Ar), 7.88 (s, 1 H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][CH2:39][CH:40]=O)[CH2:34][CH2:33]2)[CH2:28][CH2:27]1)#[N:25]>COC(C)(C)C.O>[CH3:2][O:3][CH:4]=[CH:40][CH2:39][CH2:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([C@H:29]2[CH2:28][CH2:27][C@H:26]([C:24]#[N:25])[CH2:31][CH2:30]2)[CH2:37][CH2:36]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#C[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=O)CC2)CC1
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: O
Product: COC=CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C#N)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.11 g of methoxymethyl-triphenylphosphonium chloride were suspended in 60 ml of tert.butyl methyl ether while gassing with argon and treated at room temperature within 2 minutes with 1.26 g of potassium tert.butylate. The suspension was stirred at room temperature for a further 1 hour, then cooled to 0° C. and treated dropwise within 5 minutes with a solution of 1.98 g of 3-[trans-4-(trans-4-cyanocyclohexyl)cyclohexyl]propionaldehyde in 25 ml of tert.butyl methyl ether. The reaction mixture was stirred at 0° C. for a further 45 minutes, then diluted with 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulfate, filtered and concentrated. Chromatographic purification of the crude product (5.1 g) on silica gel at 0.5 bar with ethyl acetate/petroleum ether (vol. 5:95) gave 2.0 g of trans-4-[trans-4-(4-methoxy-3-butenyl)cyclohexyl]cyclohexanecarbonitrile as a colorless milky oil.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]1[N:20]([CH3:21])[N:19]=[N:18][N:17]=1)=[C:7]2[C:11]([OH:13])=[O:12].[S:22]([C:26]1[N:27]([CH2:31][C:32](Cl)=[O:33])[CH:28]=[CH:29][N:30]=1)([CH3:25])(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>O.[Na].CC(C)=O>[C:11]([C:7]1[N:8]2[CH:3]([S:4][CH2:5][C:6]=1[CH2:14][S:15][C:16]1[N:20]([CH3:21])[N:19]=[N:18][N:17]=1)[CH:2]([NH:1][C:32](=[O:33])[CH2:31][N:27]1[CH:28]=[CH:29][N:30]=[C:26]1[S:22]([CH3:25])(=[O:24])=[O:23])[C:9]2=[O:10])([OH:13])=[O:12]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: CS(=O)(=O)c1nccn1CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cn3ccnc3S(C)(=O)=O)C2SC1
Temperature: 4 °C
Yield: 3.8 %

Procedure:
Acetone (200 cc.) is added to a solution of 7-amino-2-carboxy-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (18.4 g.) in water (110 cc.) and sodium bacarbonate (9.41 g). The mixture is cooled to about 4° C., and (2-mesyl-imidazol-1-yl)-acetyl chloride (12.4 g.) in acetone (50 cc.) is added dropwise while keeping the pH at 7 by adding a saturated aqueous solution of sodium bicarbonate. After having allowed reaction to take place for 1 hour, the acetone is removed under reduced pressure (20 mm.Hg). The pH is brought to 2.5 by adding 6 N hydrochloric acid; a solid precipitates. Ethyl acetate (100 cc.) is added, the mixture is stirred, and then the solid is filtered off and washed with ethyl acetate (500 cc.). The combined organic filtrates are dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm.Hg). A residue (8.7 g.) is obtained and is taken up in a saturated aqueous solution of sodium bicarbonate (100 cc.). The aqueous phase is washed with ethyl acetate (100 cc.) and then acidified to pH 5 by adding 6 N hydrochloric acid; a slight amount of insoluble matter is filtered off and then the filtrate is acidified to pH 2.5: a product precipitates. Extraction is effected using ethyl acetate (800 cc.), and the organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm.Hg). The residue is stirred with acetonitrile (40 cc.) and the solid formed is collected to yield 2-carboxy-7-[(2-mesyl-imidazol-1-yl)-acetamido] -3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene (1.08 g.), m.p. approx. 230° C., [α]D20 = -42°± 1 (c= 0.87, dimethylformamide).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[O:13][CH2:14][O:15][C:11]=2[C:10]2[CH2:9][NH:8][CH2:7][CH2:6][C:5]=2[CH:4]=1.[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22](O)=[O:23])([CH3:18])[CH3:17]>>[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([N:8]1[CH2:7][CH2:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:12]3[O:13][CH2:14][O:15][C:11]=3[C:10]=2[CH2:9]1)=[O:23])([CH3:18])[CH3:17]
Reactant: COc1cc2c(c3c1OCO3)CNCC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: COc1cc2c(c3c1OCO3)CN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)CC2

Procedure:
Prepared in analogy to example 1.1 from 4-methoxy-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-h]isoquinoline (CA [110103-21-4]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 448.3 (M+H+).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[C:25]([CH3:26])=[CH:24][S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: Cc1csc2nc(-c3ccncc3)nc(Cl)c12
Reactant: NCCc1ccccc1
Product: Cc1csc2nc(-c3ccncc3)nc(NCCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-4-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-phenethylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:19]([C:14]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=2)(=[O:21])=[O:20])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COc1nc(Br)cnc1N
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.15 g) and 3,4-dichlorobenzenesulphonyl chloride (0.15 g). Yield 0.09 g.