Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:21])[CH2:10][CH2:11][C@@H:12]([OH:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:22](Cl)[O:23][CH3:24].CCN(C(C)C)C(C)C>C(Cl)Cl>[Si:1]([O:8][C@H:9]([CH3:21])[CH2:10][CH2:11][C@@H:12]([O:20][CH2:22][O:23][CH3:24])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/[C@H](O)CC[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)/C=C/[C@@H](CC[C@@H](C)O[Si](C)(C)C(C)(C)C)OCOC
Reaction time: 8 h

Procedure:
To a stirred solution of the compound (30, ethyl(4R,7R,E)-7-((tert-butyldimethylsilyl)oxy)-4-hydroxyoct-2-enoate) in dry CH2Cl2 solvent, MOMCl (2 equiv), DIPEA (3 equiv) were added and stirred for 8 h. On completion of the reaction (by checking TLC), the organic layer was extracted in DCM, washed with brine, dried over anhydrous Na2SO4. The solvent was removed in vacuum, concentrated and subjected for chromatographic separation. The eluent was allowed to come in a solution of pet ether:EtOAC=90:10 as a pale yellow liquid [α]25=+23.22 (c 1.24, CHCl3); 1H NMR (200 MHz, CDCl3): δ 6.69-6.80 (dd, 1H), 5.96 (d, 1H), 4.57 (m, 2H), 4.14 (m, 3H), 3.81 (m, 1H), 1.40 (t, 3H), 1.23 (d, 2H), 0.84 (s, 9H), −0.4 (s, 6H); 13C NMR (CDCl3, 50 MHz): 166.04, 147.76, 121.95, 94.48, 75.04, 68.07, 60.37, 55.55, 34.94, 30.78, 25.92, 23.85, 18.12, 14.28, −4.29; −4.67.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12])[CH3:2].[CH3:13][O:14]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:13]=[O:14])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12])[CH3:2]
Reactant: COC(Cl)Cl
Reactant: CCN1C(=O)Cc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCN1C(=O)Cc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 252 h
Yield: 76 %

Procedure:
To a solution of 32.2 g. (0.2 mole) of 1-ethyloxindole in 200 ml. of methylene chloride was added 44 ml. (0.4 mole) of titanium tetrachloride followed by 22.6 ml. (0.25 mole) of dichloromethyl methyl ether. The reaction was stirred for 10.5 days at 25° C. followed by the addition of additional titanium tetrachloride and dichloromethyl methyl ether every 48 hours. The reaction was poured onto 1 l. of ice and water and extracted with methylene chloride. Concentration of the dried extract gave the crude product which was recrystallized from diethyl ether, 28.6 g. (76% yield), m.p. 126°-127° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](N)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.ClC1C=CC(C(Cl)=O)=CN=1.[Cl:22][C:23]1[CH:39]=[CH:38][C:26]([C:27]([NH:29]C2C=CC(I)=C(C)C=2)=[O:28])=[CH:25][N:24]=1>>[Cl:22][C:23]1[CH:39]=[CH:38][C:26]([C:27]([NH:29][C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][N:2]3[CH3:1])=[CH:6][CH:7]=2)=[O:28])=[CH:25][N:24]=1
Reactant: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Reactant: Cn1ccc2cc(N)ccc21
Agent: O=C(Cl)c1ccc(Cl)nc1
Product: Cn1ccc2ccc(NC(=O)c3ccc(Cl)nc3)cc21

Procedure:
6-Chloro-N-(1-methyl-1H-indol-6-yl)-nicotinamide was prepared from 1-methyl-1H-indol-5-ylamine (prepared as described in J. Med. Chem. 2007, 5509) and 6-chloronicotinoyl chloride in a manner similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after purification with a silica gel column and 0.0-30% EtOAc in hexanes gradient. H1 NMR (300 MHz, chloroform-d) d ppm 3.79 (s, 3H), 6.44 (d, J=3.0 Hz, 1H), 6.94 (dd, J=10.2, 8.4 Hz 1H), 7.04 (d, J=3.0, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.89 (s, 1H), 8.05 (s, 1H), 8.16 (dd, J=10.2, 8.4 Hz, 1H), 8.87 (apparent s, 1H)
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[CH:4][N:3]=1.[Li].FC1C([O:15][S:16]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)(=O)=[O:17])=C(F)C(F)=C(F)C=1F.[OH-].[Na+]>C1COCC1.O>[S:6]1[C:2]([NH:1][S:16]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)(=[O:17])=[O:15])=[N:3][CH:4]=[N:5]1
Reactant: Nc1ncns1
Reactant: COC(=O)c1ccc(S(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ncns2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
To a solution of 5-amino-1,2,4-thiadiazole (58 mg, 0.574 mmol, 1.1 eq) in THF (5 ml) was added, 1,1,3,3,3-Hexanemethyldisilazane lithium salt (LiHMDS, 1M in THF, 1.15 ml, 1.2 mmol, 2.2 eq) and the reaction mixture stirred at 50° C. for 5 minutes. Methyl 4-[(pentafluorophenoxy)sulfonyl]benzoate (Preparation 28, 196 mg, 0.513 mmol, 1 eq) was added and the reaction monitored. On the disappearance of the starting materials the reaction mixture was quenched with water (5 ml), diluted with ethyl acetate (10 ml), washed with saturated sodium hydrogen carbonate, dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in dioxane (5 ml) and a solution of sodium hydroxide (100 mg, 2.5 mmol, 4.3 eq) in water (2 ml) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate (5 ml) and water (5 ml), the aqueous phase was acidified with concentrated HCl, extracted into ethyl acetate (10 ml), dried over sodium sulphate, filtered and evaporated in vacuo. The crude material was triturated with DCM to yield the title compound as a pale yellow solid (64 mg, 0.22 mmol, 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:9])=[O:5].[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>ClCCl>[Br:30][C:27]1[CH:28]=[CH:29][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[C:3]([CH:26]=1)[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH2:16][CH2:17]1)=[O:9])=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Br)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(Br)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 4-[[N-[2-amino-5-bromobenzoyl]glycyl]aminomethyl]-1-(4-chlorobenzyl)piperidine (25 mg, 0.05 mmol) with methanesulfonyl chloride (0.0045 mL), triethylamine (0.026 mL) and dichloromethane (2 mL) was stirred at room temperature for 17 hours. The resulting reaction mixture was purified by column chromatography (SiO2), loaded onto a Varian™ SAX column and washed with methanol (5 mL). The obtained crude product was eluted with a 0.1 M methanol solution of HCl (5 mL) and concentrated to thereby provide 4-[[N-[5-bromo-2-(methylsulfonylamino)benzoyl]glycyl]aminomethyl]-1-(4-chlorobenzyl)piperidine (Compd. No. 1581) (5.4 mg, 19%). ESI/MS m/e 573.0 (M++H, C23H28BrClN4O4S).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:17][C:18]2[O:22][C:21]([C:23]([O:25]CC)=O)=[N:20][CH:19]=2)[CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])=[C:5]([CH3:28])[CH:4]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:32][CH2:31]1.C[Al](C)C.C1(C)C=CC=CC=1>ClCCCl>[CH:14]1([N:13]([CH2:17][C:18]2[O:22][C:21]([C:23]([N:40]3[CH2:39][CH2:38][N:37]([CH2:36][CH:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)[CH2:42][CH2:41]3)=[O:25])=[N:20][CH:19]=2)[S:10]([C:6]2[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:28])(=[O:11])=[O:12])[CH2:16][CH2:15]1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: CCOC(=O)c1ncc(CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Agent: C[Al](C)C
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cnc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)o2)C2CC2)c(C)c1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of ethyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](cyclopropyl)amino}methyl)-1,3-oxazole-2-carboxylate (25 mg, 0.07 mmol) and 1-(N-methylpiperidin-4-yl-methyl)piperazine (26 mg, 0.13 mmol) in DCE (1 mL) was added trimethylaluminium 2M in toluene (65 μL, 0.13 mmol) and the mixture stirred at 60° C. for 1.5 h. The reaction mixture was washed with saturated aqueous NaHCO3 and extracted with DCM. The organic extract was dried over MgSO4, and concentrated in vacuo. The residue was purified by FCC eluting with 95:4.5:0.5 NH3/MeOH/DCM. This afforded the title compound as a colourless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.CO[CH:20]1[CH2:24][CH2:23][CH:22](OC)O1.O.[OH-].[Na+]>C(O)(=O)C>[N:17]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[CH:20]=[CH:24][CH:23]=[CH:22]2)[CH2:11][CH2:10]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: COC1CCC(OC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: c1cnc(N2CCN(CCCCn3cccc3)CC2)nc1
Yield: 45.3 %

Procedure:
A mixture of 4 g (17 mmol) of 2-[4(4-aminobutyl)-1-piperazinyl]pyrimidine and 3.3 g of 2.5-dimethoxytetrahydrofuran in 10 ml of acetic acid is refluxed for 1 hour. The reaction mixture is poured into cold water, neutralised with 10% sodium hydroxide solution and extracted with chloroform, the extract is dried and evaporated and 2.2 g of 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl}pyrrole are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[O:16])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:29]C(O)=O.C1(P([N:47]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[OH-].[Na+]>C1COCC1>[NH2:47][CH2:29][CH:7]1[C:6]2[C:28](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=2)[C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[O:16])[CH2:11][CH2:10]2)[CH2:8]1
Reactant: O=C(O)CC1CC2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCC1CC2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 3.5 %

Procedure:
A 100-mL of flask was charged with (±)-2-(7-bromo-1′-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (30 mg, 0.06 mmol) dissolved in THF (3 mL) and treated with TEA (2 mL). Then diphenylphosphoryl azide (18 mg, 0.066 mmol) was added dropwise slowly. The mixture was stirred for 3 h at rt. 1 N aq NaOH solution (3 mL) was added and the reaction mixture was reflux overnight. The solvent was removed in vacuo and the aqueous residue was extracted with CH2Cl2 (3×5 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give (±)-2-adamantyl 3-(aminomethyl)-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (1 mg, 4%). LC-MS Method 5 tR=1.175 min, m/z=475; 1H NMR (400 MHz, MeOD): δ=0.71-0.83 (m, 3H), 1.46-1.57 (m. 2H), 1.61-1.81 (m, 6H), 1.81-2.06 (m, 11H), 2.39-2.51 (m, 1H), 2.83-3.00 (m, 2H), 3.41-3.57 (m, 2H), 4.07-4.14 (m, 1H), 4.79 (m, 1H), 6.99-7.10 (m, 2H), 7.37 (m, 1H), 7.95-8.30 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:20](=[O:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Solvent: CO
Solvent: C1CCOC1
Product: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Temperature: -50 °C
Reaction time: 0.67 h
Yield: 74.3 %

Procedure:
Under an argon flow, 8-benzyloxy-5-(2-bromoacetyl)-1H-quinolin-2-one (374 g, 1.00 mol) was suspended in dehydrated tetrahydrofuran (3.8 L), CBS catalyst (27.8 g) was added thereto, and the mixture was stirred at −55 to −45° C. for 40 minutes. After adding dropwise a 0.9 M tetrahydrofuran solution of borane-tetrahydrofuran complex (1.27 L) at the same temperature, the reaction mixture was gradually warmed to 0° C. After adding methanol (1.3 L) dropwise, insoluble matter was removed by filtration and washed with tetrahydrofuran. The filtrate and the washing were mixed and concentrated under reduced pressure. To the residue was added purified water (6.3 L), and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration and washed with purified water. Further, the precipitate was suspension-washed with ethyl acetate (4.8 L), collected by filtration, and dried under reduced pressure to obtain 8-benzyloxy-5-((R)-2-bromo-1-hyroxyethyl)-1H-quinolin-2-one (278 g). 1H-NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 8.08 (d, J=10.0 Hz, 1H), 7.37-7.45 (m, 5H), 7.28 (d, J=8.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.72 (d, J=10.0 Hz, 1H), 5.33 (dd, J=9.0 Hz, 4.0 Hz, 1H), 5.19 (s, 2H), 3.71-3.74 (m, 2H)
Reaction SMILES: [C:1]([N:8]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[C:30]([N:37]([CH2:40][CH2:41][CH2:42]Br)[CH2:38][CH3:39])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].O>O1CCOCC1>[CH2:38]([N:37]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:40][CH2:41][CH2:42][N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][N:8]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:39]
Reactant: CCN(CCCBr)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCN(CCc1ccccn1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CCCN(CCCN(CCc1ccccn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To a solution of 1.85 g (5.1 mmol) of N,N'-di-BOC-N-[2-(2-pyridyl)-ethyl]-1,3-propanediamine in 20 ml of dioxane there are added, with stirring, 0.4 g (10 mmol) of sodium hydride dispersion (approximately 60% in oil; Fluka, Buchs, Switzerland) and, after 20 minutes, a solution of 1.23 ; (6 mmol) of N-BOC-N-ethyl-3-bromo-propylamine in 2 ml of dioxane. The reaction mixture is stirred at 50° C. for 18 hours, a further 0.4 g (10 mmol) of sodium hydride dispersion (approximately 60%) and 1.23 g (6 mmol) of N-BOC-N-ethyl-3-bromo-propylamine are added at 25° C., the mixture is stirred at 50° C. for a further 18 hours and is then coded to room temperature, 50 ml of water are added, and the reaction mixture is extracted with methylene chloride. The methylene chloride extract is dried over sodium sulfate and concentrated by evaporation. and the residue is purified by flash chromatography on silica gel having a particle size of 0.04-0.063 mm using tert-butyl methyl ether. After concentration of the product-containing fractions by evaporation, the title compound is obtained in the form of an oil, Rf value=0.37 (silica gel/tert-butyl methyl ether).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]([F:36])([F:35])[C:22]1[O:26][N:25]=[C:24]([C:27]2[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=2)[N:23]=1>>[C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH:19][C:32]([C:30]4[S:31][C:27]([C:24]5[N:23]=[C:22]([C:21]([F:36])([F:20])[F:35])[O:26][N:25]=5)=[CH:28][CH:29]=4)=[O:33])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Reactant: O=C(O)c1ccc(-c2noc(C(F)(F)F)n2)s1
Product: O=C(NCC1(c2nc(-c3ccccc3)cs2)CCOCC1)c1ccc(-c2noc(C(F)(F)F)n2)s1
Yield: 22 %

Procedure:
This compound was synthesized from (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiophene-2-carboxylic acid as described in example 8 step 6 (25 mg, yield 22%): 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=7.3 Hz, 2H), 7.78 (m, J=4.0 Hz, 1H), 7.62 (br s, 1H), 7.53-7.48 (m, 4H), 7.42-7.38 (m, 1H), 3.97-3.91 (m, 2H), 3.86 (d, J=5.5 Hz, 2H), 3.78-3.73 (ddd, J=11.6 Hz, 7.5 Hz, 3.5 Hz, 2H), 2.33-2.27 (ddd, J=13.6 Hz, 7.0 Hz, 3.5 Hz, 2H), 2.06-1.99 (ddd, J=13.8 Hz, 7.3 Hz, 3.3 Hz, 2H). MS (ESI) m/z: Calculated for C23H19F3N4O3S2: 520.09. found: 521.0 (M+H)+.
Reaction SMILES: [CH2:1](NCCCC)CCC.C(O)(=O)C.C=O.[CH3:16][CH:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH:19]=[O:20]>C1(C)C=CC=CC=1>[CH3:16][CH:17]([CH:21]([CH3:23])[CH3:22])[C:18](=[CH2:1])[CH:19]=[O:20]
Reactant: CCCCNCCCC
Reactant: CC(C)C(C)CC=O
Agent: C=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=C(C=O)C(C)C(C)C
Temperature: 70 °C

Procedure:
Dibutylamine (34 g), acetic acid (15.78 g), and formaldehyde (230 g) were charged to a reaction flask and heated to 70° C. 3,4-Dimethyl-pentanal (500 g) was fed over 2 hours and aged for another hour. The reaction mixture was cooled down and toluene (200 mL) was added. The reaction mixture was sequentially washed with water (2 L), sodium carbonate solution (1 L), and brine (1 L) to provide the crude product 3,4-dimethyl-2-methylene-pentanal.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[C:26](=[S:28])[NH2:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:30][C:31](=O)[CH3:32]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[C:26]1[S:28][CH:30]=[C:31]([CH3:32])[N:27]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](C(N)=S)C1
Reactant: CC(=O)CCl
Solvent: c1ccccc1
Product: Cc1csc([C@@H]2C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]2NC(=O)OCc2ccccc2)n1
Temperature: 75 °C
Yield: 44.9 %

Procedure:
To a solution of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-carbamothioylcyclohexylcarbamate (0.5 g, 0.0012 mol) in dry benzene (20 mL) under nitrogen was added chloroacetone (0.34 g, 0.0036 mol) and the reaction mixture was heated at 75° C. over night. Benzene was removed under vacuum and the crude was extracted with ethyl acetate. The organic layer was washed with brine, concentrated and purified by recrystallisation from ether to give 0.24 g (44%) of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-(4-methylthiazol-2-yl)cyclohexylcarbamate as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 1.65 (m, 3H), 1.78 (m, 2H), 2.19 (m, 2H), 2.42 (s, 3H), 3.49 (m, 1H), 3.70 (m, 1H), 4.05 (m, 1H), 5.04 (s, 2H), 5.29 (bs, 1H), 6.75 (s, 1H), 7.34 (m, 5H); 13H NMR (400 MHz, CDCl3) δ 16.4, 27.4, 27.8, 32.7, 41.9, 46.5, 49.7, 66.0, 78.5, 112.3, 127.3, 127.4, 127.8, 135.9, 151.8, 154.6, 155.2, 169.2. MS found: (M+H)+=446.
Reaction SMILES: [Cl-].[Na+:2].Cl[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])(=[O:6])=[O:5].[OH2:16]>>[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([O-:12])=[O:11])([OH:16])(=[O:6])=[O:5].[Na+:2]
Reactant: O
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: [Cl-]
Agent: [Na+]
Product: O=C([O-])c1cccc(S(=O)(=O)O)c1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 90.9 %

Procedure:
360 g of 26.4% strength sodium chloride solution, prepared from 95.0 g of sodium chloride and 265.0 g of water, and 332 g of crude 3-(chlorosulfonyl)benzoic acid (water content: 39.2%) (corresponding to 201.8 g (0.92 mol) of 100% 3-(chlorosulfonyl)benzoic acid) are introduced into a 1 l four-neck flask fitted with stirrer, internal thermometer and reflux condenser. The reaction mixture is heated to 100° C. and stirred for a further 45 minutes at this temperature. The mixture is then allowed to cool over about 1 hour to 40° C. Subsequently it is cooled with an ice bath to <5° C. and stirred for a further 30 minutes at this temperature. The precipitated product is filtered off with suction and washed with 256 g of 5% strength sodium chloride solution, prepared from 12.8 g of sodium chloride and 243.2 g of water and cooled to 5° C., in two portions. The filter cake is dried at 100° C./100 torr (13.16 kPa). 196.3 g of sodium 3-sulfobenzoate are obtained with a purity of 95% and a sodium chloride content of 3.9% (corresponding to 186.5 g (0.83 mol) of 100% sodium 3-sulfobenzoate). The yield is 90.9% of theoretical. 345 g of mother liquor and 318 g of wash liquor are produced.
Reaction SMILES: Cl.[CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([O:31]CC2C=CC=CC=2)=[C:26]([NH:28][CH:29]=[O:30])[CH:27]=1)[OH:21].CO.C(Cl)(Cl)[Cl:42]>CO.[Pd]>[ClH:42].[CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26]([NH:28][CH:29]=[O:30])[CH:27]=1)[OH:21]
Reactant: ClC(Cl)Cl
Reactant: O=CNc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=CNc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1O

Procedure:
According to the procedures as given in Example 2, the compound of Example 22 (in a solution of 40 mg of the compound in 5.8 ml of methanol) was subjected to a hydrogenolysis using 10% palladium/carbon black (27 mg), whereby the above-identified compound (28.1 mg) was obtained. Rf=0.08 (methanol/chloroform of 1/10).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[C:21](F)=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31]C1C=CC(Cl)=CC=1C[Mg]Cl>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[C:20]([Cl:31])[CH:19]=[CH:18][C:17]=2[Cl:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(Cc1c(F)cccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: Cl[Mg]Cc1cc(Cl)ccc1Cl
Product: OC(Cc1cc(Cl)ccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 18a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol, using 2,5-dichlorobenzyl magnesium chloride as starting material (available from Rieke Metals) was followed making non-critical variations, to yield the title compound. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+=442 @ Rt 3.48 min. major peak.