Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C:8](=O)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CNC(=O)C1.Br[Br-]Br.C(=O)(O)[O-].[Na+].BrC(Br)=O.C([O:33][C:34](=[O:49])[CH2:35][CH2:36][N:37]([CH2:41][C:42]1[S:43][C:44]([CH2:47][CH3:48])=[CH:45][CH:46]=1)[C:38]([NH2:40])=[S:39])(C)(C)C>CO.C1COCC1>[CH:1]1([CH2:7][C:8]2[N:40]=[C:38]([N:37]([CH2:41][C:42]3[S:43][C:44]([CH2:47][CH3:48])=[CH:45][CH:46]=3)[CH2:36][CH2:35][C:34]([OH:49])=[O:33])[S:39][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)CC1CCCCC1
Reactant: CCc1ccc(CN(CCC(=O)OC(C)(C)C)C(N)=S)s1
Agent: O=C(Br)Br
Agent: O=C([O-])O
Agent: O=C1CCCN1
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(CN(CCC(=O)O)c2nc(CC3CCCCC3)cs2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 167.4 %

Procedure:
Cyclohexylacetone (300 mg, 2.14 mmol) in MeOH (5 mL) was treated with pyrrolidone hydrotribromide (1.3 g, 4.28 mmol) and the reaction was stirred at RT overnight. To the resulting solution of crude alpha-bromoketone in MeOH (without workup) was directly added solid sodium bicarbonate to neutralize the acid formed in the bromination step. To this neutralized bromoketone mixture was added 3-[1-(5-ethyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (150 mg) in THF (2 mL) and the reaction was stirred for 1 h at RT. The solvent was removed at reduced pressure and the residue was dissolved in water and ethyl acetate. The aq portion was extracted two times with EtOAc, and the combined organic portion was washed with brine and then dried over sodium sulfate. Solvent removal under reduced pressure gave the crude product which was partially purified by silica gel chromatography (eluent: 10:1 hexanes:EtOAc) to give the aminothiazole derivative (300 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C@H:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH3:16][N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1.[ClH:36].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:36].[CH3:16][N:17]([CH3:35])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)[C:13]([C@H:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:22][CH:23]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: COc1ccc2c(c1)[C@H](C(=O)O)CCC2
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)[C@H](C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1)CCC2

Procedure:
(R)-7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.65 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.0 g) were reacted and treated in the same manner as in Example 12. The obtained solid was dissolved in ethyl acetate. Thereto was added 4 mol/L-HCl/ethyl acetate (1 mL). The solvent was evaporated under reduced pressure. The precipitated solid was recrystallized twice from ethanol to give (R)—N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride ½ ethanol (0.20 g).
Reaction SMILES: Cl.[S:2]1[C:6]([NH2:7])=[CH:5][N:4]=[CH:3]1.[Br:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]1[CH2:24][CH2:23][O:22][C:21]2[CH:25]=[C:26]([S:29](Cl)(=[O:31])=[O:30])[CH:27]=[CH:28][C:20]1=2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][C:10]=1[N:19]1[CH2:24][CH2:23][O:22][C:21]2[CH:25]=[C:26]([S:29]([NH:7][C:6]3[S:2][CH:3]=[N:4][CH:5]=3)(=[O:30])=[O:31])[CH:27]=[CH:28][C:20]1=2
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Reactant: Nc1cncs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cncs1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.7 %

Procedure:
A flask containing thiazol-5-amine hydrochloride (0.093 g, 0.684 mmol), 4-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (INTERMEDIATE C, 0.284 g, 0.622 mmol), and THF (4.15 mL) was cooled to 0° C. LHMDS (1.0 M in THF) (1.866 mL, 1.866 mmol) was added dropwise and the reaction was stirred for 5 minutes at 0° C. The reaction was quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel column chromatography (40 g, gradient elution 0 to 100% EtOAc:Heptane) to afford 4-(2-bromo-4-(trifluoromethyl)phenyl)-N-(thiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.083 g, 0.160 mmol) as an orange oily solid. 1H NMR (400 MHz, DMSO-d6) δ=10.66 (s, 1 H), 8.69 (d, J=0.9 Hz, 1 H), 8.21 (d, J=1.6 Hz, 1 H), 7.91 (dd, J=1.5, 8.3 Hz, 1 H), 7.75 (d, J=7.8 Hz, 1 H), 7.35 (d, J=0.9 Hz, 1 H), 7.12 (d, J=2.2 Hz, 1 H), 7.05 (dd, J=2.2, 8.6 Hz, 1 H), 6.24 (d, J=8.6 Hz, 1 H), 4.37 (d, J=17.2 Hz, 2 H), 3.85-3.63 (m, 2 H). m/z (ESI) 520.2 (M+H)+.
Reaction SMILES: [S:1]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[S:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Br:15])=[CH:10][CH:9]=1)([C:4]([F:5])([F:6])[F:7])(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(c1ccc(CBr)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
A stirred solution of 22.4 g (0.1 mole) of 4-triflyltoluene, 178 g (0.1 mole) of N-bromosuccinimide, and 0.48 g (0.2 mole %) of benzoyl peroxide in carbon tetrachloride is heated at reflux for 20 hours. After cooling to room temperature, the reaction is diluted by the addition of carbon tetrachloride, and the solid byproducts are removed by filtration. The filtrate is concentrated in vacuo, and the product is purified by recrystallization from benzene.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([N:16]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:18][CH2:19][OH:20])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:40].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:17][CH2:18][C:19]([OH:40])=[O:20])[S:21]([C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)C1(N(CCCO)S(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 1 h

Procedure:
A solution of the crude 1-[[4-(4-fluorophenoxy)benzenesulfonyl]-(3-hydroxypropyl)amino]cyclopentanecarboxylic acid benzyl ester (235 grams) in acetone (2 L) was cooled in an ice bath and treated with Jones reagent (about 200 mL) until an orange color persisted. The mixture was stirred from 0° C. to room temperature over 1 hour. After quenching excess oxidant with isopropanol (10 mL), the mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken up in ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated to afford a solid which was triturated with a mixture of diethyl ether and hexane to provide 1{(2-carboxyethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentane carboxylic acid benzyl ester as a white solid (147 grams).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1.[NH2:20][CH2:21][CH2:22][NH:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25]>C(O)(C)C>[CH3:27][N:26]([CH3:28])[C:24]([NH:23][CH2:22][CH2:21][NH:20][CH2:15][CH:14]([OH:16])[CH2:13][O:12][C:11]1[CH:17]=[CH:18][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH:2]([CH3:19])[CH3:1])=[CH:9][CH:10]=1)=[O:25]
Reactant: CN(C)C(=O)NCCN
Reactant: CC(C)COCCOc1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: CC(C)COCCOc1ccc(OCC(O)CNCCNC(=O)N(C)C)cc1

Procedure:
8 g of 3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)-1,2-epoxypropane and 14 g of N-2-aminoethyl-N',N'-dimethylurea was warmed (60°-70° C.) in 150 ml of isopropanol over night. The mixture was evaporated and the residue dissolved in ethyl acetate. The ethyl acetate phase was washed with water (twice), fresh water was then added and pH lowered to 5 with hydrochloric acid. Fresh ethyl acetate was then added to the water phase and pH was rised to 9.5. The organic phase was separated off, dried, and evaporated. The residue was recrystallized from a small amount of ethyl acetate. Yield 3 g. M.p. 75° C. (base). The structure was determined using NMR-analysis.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:32])[N:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)=[C:19]([CH3:33])[CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[OH-].[Na+]>C(O)C>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:34])=[O:2])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:32])[N:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)=[C:19]([CH3:33])[CH:18]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)c(C)c1)NC(=O)c1c(C)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C[C@H](NC(=O)c2c(C)cccc2Cl)C(=O)O)ccc1-c1cn(C)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To a suspension of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester (0.083 mmol, 40 mg) in ethanol (1 mL) was added aqueous 1.0 N sodium hydroxide (0.2 mL) at room temperature. The mixture was stirred for 2 h at room temperature. Then, the ethanol was removed under reduced pressure and the residue was diluted with water (5 mL). The aqueous solution was washed with diethyl ether (20 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted into ethyl acetate (2×25 mL). The combined organic extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate afforded 34 mg (87% yield) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine as an amorphous white solid. ES-HRMS m/e calcd for C24H24ClN3O5 (M+Na) 492.1295, found 492.1301.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([F:19])[CH:18]=1)[N:15]=[CH:14][C:13]([C:20]([O:22]CC)=O)=[C:12]2[OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>C(Cl)(Cl)Cl.CO>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([F:19])[CH:18]=1)[N:15]=[CH:14][C:13]([C:20]([NH:32][CH2:31][C:30]1[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][CH:29]=1)=[O:22])=[C:12]2[OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(F)cc(SCc3ccccc3)cc2c1O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(SCc3ccccc3)cc2c1O
Yield: 95 %

Procedure:
A solution of 3.93 g of of ethyl 6-(benzylsulfanyl)-8-fluoro-4-hydroxy-3-quinolinecarboxylate in 8.8 g of 4-chlorobenzylamine is heated at 165° C. under argon for 16 h, then cooled and diluted with CHCl3 and MeOH. The solution is washed with dil. HCl, dried (Na2SO4), and concentrated under reduced pressure to a yellow solid. Flash chromatography on silica using 3-6% MeOH in CH2Cl2 affords 4.73 g (95%) of 6-(benzylsulfanyl)-N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide as a yellow solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:26](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:26][N:19]1[CH2:18][CH2:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)([C:22]#[N:23])[CH2:21][CH2:20]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCNCC1
Agent: C=O
Agent: [Na+]
Product: CN1CCC(C#N)(c2ccc(OCCCN3CCCC3)cc2)CC1
Yield: 76 %

Procedure:
The title compound (80 mg, 76%) was prepared from 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-4-carbonitrile, formaldehyde and sodium triacetoxyborohydride similarly to the procedure used for example 54. 1H NMR (400 MHz, CD3OD) δ 1.81-1.85 (m, 4H), 1.97-2.15 (m, 6H), 2.37 (s, 3H), 2.45 (t, 2H), 2.58-2.62 (m, 4H), 2.68 (t, 2H), 2.99 (d, 2H), 4.04 (t, 2H), 6.96 (d, 2H), 7.42 (d, 2H). LRMS APCI+ m/z 328 [MH]+. Microanalysis: Found: C, 73.01; H, 8.94; N, 12.81%. C20H29N3O requires C, 73.36; H, 8.93; N, 12.83%.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:17]([C:19]1[N:29]([CH2:30][C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[CH:34]=[O:35])[C:22]2=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]2[N:20]=1)[CH3:18].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Si:8]([O:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([CH:34]([C:33]2[CH:36]=[CH:37][CH:38]=[C:31]([CH2:30][N:29]3[C:22]4=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]4[N:20]=[C:19]3[CH2:17][CH3:18])[CH:32]=2)[OH:35])=[CH:3][CH:4]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(C=O)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(C(O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 65.8 %

Procedure:
4-Bromobenzyloxy-tert-butyldimethylsilane (1.23 g, 4.08 mmol) obtained in Step 1 was dissolved in THF (30 mL) and the flask was filled with argon. The reaction mixture was cooled to −78° C., and a 1.57 mol/L n-butyl lithium-hexane solution (2.60 mL, 4.09 mmol) was added thereto, followed by stirring at same temperature for 5 minutes. A solution of 3-(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)benzaldehyde (0.800 g, 2.72 mmol) obtained in Step 2 in THF (5 mL) was dropped into the mixture for 15 minutes, followed by stirring at −78° C. for 1 hour. The reaction mixture was added with a saturated aqueous ammonium chloride solution to terminate the reaction, and diluted with ethyl acetate. The organic layer was separated from the aqueous layer, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:2) to obtain [4-(tert-butyldimethylsilyloxymethyl)phenyl][3-(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)phenyl]methanol (0.923 g, yield 66%).
Reaction SMILES: [Cl:1][C:2]1[C:27]([OH:28])=[CH:26][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)=[CH:11][C:10]=3[CH2:23][CH2:24][CH3:25])=[N:7][O:8][C:4]=2[CH:3]=1.[C:29]([O:34]C)(=[O:33])[C@@H:30]([CH3:32])O>>[Cl:1][C:2]1[C:27]([O:28][C@@H:30]([CH3:32])[C:29]([OH:34])=[O:33])=[CH:26][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)=[CH:11][C:10]=3[CH2:23][CH2:24][CH3:25])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)[C@@H](C)O
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2cc(Cl)c(O)cc12
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2cc(Cl)c(O[C@@H](C)C(=O)O)cc12

Procedure:
The phenol from Step 6 of Example 5 (0.42 g, 1.0 mmol) and methyl (R)-lactate (0.16 g, 1.5 mmol) was reacted according the general procedure described in Step 11 of Example 1 to give the title compound as a white solid.
Reaction SMILES: C1(O)C=CC=CC=1.[C:8]([O:12][C:13](=[O:27])[C@H:14]([CH:24]([CH3:26])[CH3:25])[NH:15]C(OCC(Cl)(Cl)Cl)=O)([CH3:11])([CH3:10])[CH3:9].O.C(=O)=O>CC(C)=O.[Co].[Li].C1C=CC2C(=C3N=C4N=C(C5C=CC=CC=54)N=C4NC(C5C=CC=CC=54)=NC4=NC(C5C=CC=CC=54)=NC=2N3)C=1>[C:8]([O:12][C:13](=[O:27])[C@H:14]([CH:24]([CH3:25])[CH3:26])[NH2:15])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)[C@H](NC(=O)OCC(Cl)(Cl)Cl)C(=O)OC(C)(C)C
Agent: [Co]
Agent: O=C=O
Agent: [Li]
Solvent: CC(C)=O
Solvent: O
Solvent: Oc1ccccc1
Product: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 75 %

Procedure:
5.4 g (6.0 mmols) of lithium -cobalt-phthalocyanine in 30 ml of absolute acetone, 1 g (about 10 mmols) of phenol and 700 mg (2.0 mmols) of 2,2,2-trichloroethoxycarbonyl-L-valine tert.-butyl ester are stirred for 1 hour at 20° C. 10 ml of water saturated with CO2 are added to the deep green solution, CO2 and air are passed into the mixture for 5 minutes and the mixture is left to stand for 30 minutes. Cobalt phthalocyanine is filtered off and rinsed with water and acetone, the acetone is stripped off from the filtrate and the residual aqueous phase is extracted with CH2Cl2. Stripping of the combined CH2Cl2 extracts (after drying over Na2SO4) gives L-valine tert.-butyl ester which is contaminated with traces of PcC and contains diacetone alcohol. Purification via the hydrocitrate gives 260 mg (75% yield).
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][SH:4].C(=O)([O-])[O-].[K+].[K+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:28])[C:20]([N:25]([CH3:27])[CH3:26])([CH3:24])[CH2:21][CH:22]=[CH2:23])=[CH:15][CH:14]=1>CC(N(C)C)=O>[SH:4][CH2:3][CH2:2][CH2:1][S:5][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:28])[C:20]([N:25]([CH3:27])[CH3:26])([CH3:24])[CH2:21][CH:22]=[CH2:23])=[CH:15][CH:14]=1
Reactant: SCCCS
Reactant: C=CCC(C)(C(=O)c1ccc(F)cc1)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C=CCC(C)(C(=O)c1ccc(SCCCS)cc1)N(C)C
Temperature: 50 °C
Reaction time: 12 h

Procedure:
25.0 g (0.23 mol) of 1,3-propandithiol are dissolved in 80 ml of dry dimethylacetamide and 6.0 g of potassium carbonate are added. 10.0 g of 1-(4-fluorophenyl)-2-dimethylamino-2-methylpent-4-en-1-one in 20 ml of dry dimethylacetamide are added dropwise. The suspension is stirred at 50° C. for 12 h, the solid is filtered off. The excess 1,3-propanedithiol and dimethylacetamide are distilled off. To the residue toluene is added and the precipitate is filtered off. After toluene is distilled off, the residue is purified by column chromatography on silica gel with ethyl acetate-hexane (1:10) as eluent and an oily product is obtained. The structure is confirmed by the 1H-NMR-spectrum, measured in CDCl3. The signals (δ in ppm) are 1.18 (s,3H), 1.39 (t,1H), 2.00 (m,2H), 2.27 (s,5H), 2.42 (m, 1H), 2.66-2.72 (m,3H), 3.12 (t,2H), 4.83-4.93 (m,2H), 5.52 (m, 1H), 7.26 (d,2H), 8.38 (d,2H).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][C:2]12[CH2:10][OH:11].[F:12][C:13]([F:47])([F:46])[C:14]1[CH:15]=[C:16]([C:24]([CH3:45])([CH3:44])[C:25]([N:27]([C:29]2[CH:30]=[N:31][C:32](Cl)=[CH:33][C:34]=2[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[CH3:42])[CH3:28])=[O:26])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:17]=[C:16]([C:24]([CH3:45])([CH3:44])[C:25]([N:27]([C:29]2[CH:30]=[N:31][C:32]([N:6]3[CH2:5][CH2:4][N:3]4[CH2:7][CH2:8][CH2:9][C:2]4([CH2:10][OH:11])[CH2:1]3)=[CH:33][C:34]=2[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[CH3:42])[CH3:28])=[O:26])[CH:15]=[C:14]([C:13]([F:47])([F:12])[F:46])[CH:19]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OCC12CCCN1CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCCC3(CO)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C
Yield: 10.5 %

Procedure:
To a solution of hexahydropyrrolo[1,2-a]pyrazin-8a(6H)-ylmethanol (D67, 35 mg) in methyl sulfoxide (1.5 mL), 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (60 mg) and potassium carbonate (63 mg) were added. The resulting mixture was heated at 150° C. for 24 hours. The mixture was allowed to cool down to r.t and further D67 (17 mg) and potassium carbonate (15 mg) were added. The resulting mixture was heated at 150° C. for further 8 hours and then it was allowed to cool to r.t. and diluted with water (2 mL). The aqueous phase was extracted with ethyl acetate (3×2.5 mL). The combined organic extracts were dried and concentrated in vacuo to a residue which was purified twice by flash chromatography (first purification: EtOAc/Cycl from 80/20 to 100:0 then DCM/MeOH 95:5. Second purification: DCM/MeOH 98:2) to give the desired compound (7.7 mg) as yellow foam.
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.CON(C)[C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[CH3:36].O1CCOCC1>O.CCOC(C)=O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([C:29]([C:30]3[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=3)=[O:37])=[N:3][CH:4]=[C:5]([Cl:25])[CH:6]=2)(=[O:10])=[O:11])=[CH:13][CH:14]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: CON(C)C(=O)c1cccnc1C
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ncccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide (140 mg, 300 mmol) was placed in a dry 2-neck 10 mL round-bottom flask. The flask was evacuated and purged with nitrogen, followed by the addition of THF (1 mL). The homogeneous mixture was lowered to −5° C. and iPrMgCl (0.33 mL, 2.0 M) was added dropwise. Upon completion of the addition, the reaction was stirred 90 minutes, followed by the slow addition of N-methoxy-2,N-dimethyl-nicotinamide (135 mg, 750 mmol). The reaction was stirred overnight, during which the ice-bath warmed to room temperature. The following day, the reaction was quenched with a small quantity of MeOH and the solvents evaporated in vacuo. The residue was subsequently treated with 4.0 MHCl in dioxane (1 mL, 4.0 mmol) and H2O (0.33 mL), and then stirred at 80° C. for two hours. The resultant solution was diluted with EtOAc, washed with water, saturated sodium bicarbonate, and brine; dried with MgSO4, and evaporated employing reduced pressure. The crude residue was subsequently purified via automated flash chromatography to afford the desired sulfonamide: 1H NMR (400 MHz, CDCl3) δ 10.9 (s, 1H), 8.58 (d, 1H), 8.22 (d, 2H), 7.81 (d, 2H), 7.53-7.46 (m, 3H), 7.20-7.14 (m, 1H), 2.30 (s, 3H), 1.31 (s, 9H); MS (ES) M+H expect 444.1. found 444.5.