Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]([NH:24]CC4C=CC(OC)=CC=4)=[CH:21][C:22]=3[CH3:23])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:24][C:20]1[N:19]=[CH:18][C:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=3)[CH2:10][CH2:11]2)=[O:16])=[C:22]([CH3:23])[CH:21]=1
Reactant: COc1ccc(CNc2cc(C)c(C(=O)N3CCN(c4ncc(C)cc4C)CC3)cn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N)cc3C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (840 mg) described in Preparation Example 146 was added 4-methoxybenzylamine (2 mL), and the mixture was stirred at 160° C. for 2.5 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. To the obtained residue was added diethyl ether, and the insoluble material was collected by filtration to give [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl][6-(4-methoxybenzylamino)-4-methylpyridin-3-yl)methanone (790 mg). The obtained [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl][6-(4-methoxybenzylamino)-4-methylpyridin-3-yl)methanone (790 mg) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (13 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give (6-amino-4-methylpyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone. The obtained (6-amino-4-methylpyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone and triethylamine (0.75 mL) were dissolved in dichloromethane (10 mL), 3-chloropropane-1-sulfonyl chloride (0.49 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (7 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.32 mL) was added, and the mixture was stirred at room temperature for 4.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl][6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-methylpyridin-3-yl]methanone. The obtained [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl][6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-methylpyridin-3-yl]methanone was dissolved in dichloromethane, 1N hydrogen chloride/diethyl ether was added, and the precipitate was collected by filtration to give the title compound (385 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]=[C:9]=[S:10])=[O:7].[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=[C:19]([NH2:26])[C:18]=2[N:17]=[C:16]1[CH2:27][O:28][CH2:29][CH3:30]>>[NH2:26][C:19]1[C:18]2[N:17]=[C:16]([CH2:27][O:28][CH2:29][CH3:30])[N:15]([CH2:14][CH2:13][CH2:12][NH:11][C:9]([NH:8][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[S:10])[C:23]=2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=1
Reactant: O=C(N=C=S)c1ccco1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCN
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCNC(=S)NC(=O)c1ccco1

Procedure:
Using the method of Examples 94-105, 2-furoylisothiocyanate was reacted with 1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 431.1846.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([CH3:24])[N:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:21]3[CH:22]=[C:17]([Cl:16])[N:18]=[C:19]([CH3:24])[N:20]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2cc(O)ccc12
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cccc2cc(Oc3cc(Cl)nc(C)n3)ccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A suspension of 6.0 g (29.7 mMol) 6-hydroxy-naphthalene-1-carboxylic acid methyl ester (see Step 3.1), 7.6 g (46.6 mMol) 4,6-dichloro-2-methylpyrimidine and 13.9 g (65 mMol) K3PO4 in 50 ml NMP is stirred for 4 days at rt. The mixture is poured into ½ l water and the title compound filtered off, washed with water and dried (HV, 80° C.): HPLC: tRet=17.2.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17][OH:18]>CS(C)=O>[F:12][C:11]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17][OH:18]
Reactant: OCCNCCO
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N(CCO)CCO)c(C(F)(F)F)c1
Temperature: 140 °C
Yield: 8 %

Procedure:
2-Fluoro-5-nitrobenzotrifluoride (5.0 g; 23.9 mmol) and 6.0 g (57.1 mmol) of diethanolamine were dissolved solved in 30 ml of DMSO, followed by stirring under heat at 140° C. for 5 hours. The reaction mixture was extracted with ethyl acetate and the extract was then dried over magnesium sulfate. The brown oil so obtained was purified by chromatography on a silica gel column (chloroform/ methanol=10/1), whereby 565 mg of the title compound were obtained as yellow powder (yield: 8%).
Reaction SMILES: Cl.[SH:2][CH2:3][CH2:4][NH2:5].[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH:7]=O>>[S:2]1[CH2:3][CH2:4][NH:5][CH:7]1[C:6]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: NCCS
Reactant: CCOC(=O)C=O
Agent: Cl
Product: CCOC(=O)C1NCCS1
Yield: 84.2 %

Procedure:
22.6 g of mercaptoethylamine hydrochloride and 20.4 g of ethyl glyoxylate are heated with 100 g of 3A molecular sieves on a water bath for 45 min. The mixture is filtered, the filtrate is evaporated in vacuo, the residue is filtered through silica gel and the product is crystallized from methylene chloride/tert.-butyl methyl ether. 27 g of the thiazolidine derivative are obtained. ##STR17##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[OH:13]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([O-:13])=[CH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2ncccc2c1
Reactant: OO
Solvent: CC(=O)O
Product: COc1ccc2c(ccc[n+]2[O-])c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
6-Methoxy quinoline (15 g, 0.094 mol) was dissolved in acetic acid (97 ml) and treated with hydrogen peroxide (37 ml). The mixture was stirred to 100° C. for 2 hours. After evaporation to dryness 100 ml of water was added to the residue until a precipitate appears. Filtration and washing with water gives a yellow precipitate that is dried under vacuum to yield 13.5 g of the title compound as a light yellow solid (82%). MS (m/e): 176.3 (M+H)+.
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)=[CH:28][CH:27]=3)[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1.C(Cl)Cl>CO>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]4[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]4)=[CH:28][CH:27]=3)[C:10]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(OCCCCC3CCNCC3)cc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1c1ccc(OCCCCC2CCNCC2)cc1

Procedure:
A mixture of (3RS,4RS)-7-methoxymethoxy-3-(4-(methoxymethoxy)phenyl)-3-methyl-4-[4-(4-piperidylbutyloxy)phenyl]chroman (325 mg, 0.56 mmol) p-toluenesulfonic acid (1.42 g, 5.6 mmol) and methanol was stirred at reflux for 12 h. After cooling, the mixture was extracted with ethyl acetate, dried over MgSO4, and filtered. The filtrate was evaporated under reduced pressure, and the concentrate thus obtained was subjected to silica gel column chromatography (CH2Cl2:methanol=10:1) to give 160 mg (yield. 58%) of a white foamy solid.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][N:9](C(OC(C)(C)C)=O)[C:8]=2[C:19]([O:21]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:24][NH2:25]>O>[C:1]1([C:7]2[CH:11]=[CH:10][NH:9][C:8]=2[C:19]([NH:24][NH2:25])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: COC(=O)c1c(-c2ccccc2)ccn1C(=O)OC(C)(C)C
Solvent: O
Product: NNC(=O)c1[nH]ccc1-c1ccccc1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A solution of 1-tert-butyl 2-methyl 3-phenyl-1H-pyrrole-1,2-dicarboxylate (7.00 g, 23.0 mmol) in hydrazine monohydrate (30.0 mL, 617 mmol) was heated at 100° C. for 12 h. The reaction mixture was cooled to room temperature and diluted with water (100 mL). The solid precipitated was filtered through a Büchner funnel and dried under reduced to pressure to yield 3-phenyl-1H-pyrrole-2-carbohydrazide (3.80 g, 81.0%) as a white solid. LCMS method B-3: retention time 1.54 min, [M+1]=202.0. 1H NMR (400 MHz, DMSO-d6) δ ppm: 4.32 (s, 2H), 6.23 (d, J=2.8 Hz, 1H), 6.88 (d, J=2.8 Hz, 1H), 7.21-7.26 (m, 1H), 7.32-7.36 (m, 2H), 7.44-7.47 (m, 2H), 8.37 (s, 1H), 11.40 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[CH2:17]([O+](CC)CC)[CH3:18]>ClC(Cl)C>[CH2:17]([O:8][C:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[NH:9])[CH3:18]
Reactant: CC[O+](CC)CC
Reactant: NC(=O)c1ccc(Br)s1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(Cl)Cl
Product: CCOC(=N)c1ccc(Br)s1
Temperature: 90 °C

Procedure:
The 5-bromo-thiophene 2-carboxylic acid amide (2BW) (7 g, 34.1 mmols) was dissolved in dichloroethane (170 ml). Triethyloxonium hexafluorophosphate (10.16 g, 40.97 mmols) was added and the resulting mixture was refluxed for 1 hr at 90° C. The reaction mixture was concentrated under reduced pressure, and was taken directly to next step.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][S:9][C:10]2[NH:11][C:12]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C[OH:24]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:8][S:9]([C:10]2[NH:11][C:12]3[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[O:24])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: Cc1cccnc1CSc1nc2ccc(C(F)(F)F)cc2[nH]1
Solvent: ClCCl
Product: Cc1cccnc1CS(=O)c1nc2ccc(C(F)(F)F)cc2[nH]1
Reaction time: 1 h

Procedure:
6.7 g of 2-[[(3-methyl-2 -pyridyl)methyl]thio]-5-(trifluoromethyl)benzimidazole are dissolved in 250 ml of methylene chloride and 20 ml of methanol and then cooled to -20°. 4.7 g of m-chloroperbenzoic acid, recrystallized from methylene chloride/petroleum ether, are then introduced within 10 minutes. The solution is stirred further at -20° for 60 minutes and then poured into a mixture of 100 ml of 2N sodium carbonate solution and ice. The organic phase is washed neutral with water, dried over sodium sulphate and evaporated in vacuo. Crystallization from methylene chloride/methanol/petroleum ether gives 2-[[(3-methyl-2-pyridyl)methyl]sulphinyl]-5 -(trifluoromethyl)benzimidazole of melting point 156°-158°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:15])=[O:7]
Reactant: COc1cccc(C(=O)O)c1C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cccc(C(=O)Cl)c1C
Yield: 86.3 %

Procedure:
To 3-methoxy-2-methylbenzoic acid (454 g, 2.73 moles) in 1300 mL chloroform containing 20 g dimethyl formamide at 65° C., thionyl chloride (390 g) was added dropwise over 6 hours, whereupon the solvent was removed by evaporation at a reduced pressure. The residue (512 g) was distilled at 110° C. at 1-2 mm Hg to give 3-methoxy-2-methylbenzoyl chloride (435 g).
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH2:15][CH3:16])[N:9]2[CH:17]=[CH:18][CH:19]=[C:8]2[C:7]=1[OH:20])=[O:5])C.[NH2:21][CH2:22][C:23]([O-:25])=[O:24].[Na+]>>[CH2:13]([N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:5])=[C:7]([OH:20])[C:8]2=[CH:19][CH:18]=[CH:17][N:9]12)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCn1c(=O)c(C(=O)OCC)c(O)c2cccn21
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: CCCCn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cccn21

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-butyl-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 308 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:15][OH:16])([CH3:14])[CH2:9]1)=O)(C)(C)C.[ClH:17]>C(Cl)Cl.O1CCOCC1>[ClH:17].[CH3:14][C:10]1([CH2:15][OH:16])[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC1(CO)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(CO)CCCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.20 g (0.87 mmol) of (rac)-3-hydroxymethyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester was dissolved in 5 ml of CH2Cl2, treated at 0° C. with a solution of HCl in dioxane (2.18 ml, 4 M in dioxane) and stirred for 2 h at RT. The reaction was then concentrated to dryness and re-evaporated with toluene to afford the title product (0.17 g, quant.) as white solid. MS: 130.1 (MH+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26]1>>[O:25]1[CH:29]=[CH:28][C:27]([C:30]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:31])=[CH:26]1
Reactant: O=C(Cl)c1ccoc1
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)c1ccoc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.061 mMol) 3-furoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23]([CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])[C@@H:22]([OH:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](COS(C)(=O)=O)[C@@H](O)C1
Temperature: 25 °C
Yield: 33.1 %

Procedure:
Methanesulfonyl chloride (180 μL, 23 mmol) was added dropwise to a CH2Cl2 solution of triethylamine (400 μL, 29 mmol) and (3R,4R)-1-tert-butoxycarbonyl-3-hydroxy-4-(hydroxymethyl)pyrrolidine (1) (2 g, 9.2 mmol) at 0° C. and the resulting solution allowed to warm to room temperature. The reaction was diluted with CH2Cl2, washed with water, brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to afford (3R,4R)-1-tert-butoxycarbonyl-3-hydroxy-4-(mesyloxymethyl)pyrrolidine (900 mg) as an oil. Without further purification the product was dissolved in DMF (10 mL) and stirred with sodium thiomethoxide (400 mg, 5.7 mmol) at room temp. overnight. The reaction was diluted with toluene washed with water, brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to afford (3R,4S)-1-tert-butoxycarbonyl-3-hydroxy-4-(methylthiomethyl)pyrrolidine (600 mg, 2.4 mmol) as a syrup, which was not further characterised. (3R,4S)-1-tert-Butoxycarbonyl-3-hydroxy-4-(methylthio)pyrrolidine was dissolved in MeOH (5.0 mL) and cHCl (1.0 mL) and concentrated in vacuo to afford (3R,4S)-3-hydroxy-4-(methylthiomethyl)pyrrolidine hydrochloride (48) as a syrup (442 mg, 26% overall yield for three steps). 13C NMR (D2O) δ 73.5, 51.5, 48.6, 45.2, 34.3, 14.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:23][C:24](=[O:28])[N:25]([CH3:27])[CH3:26])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)OCC[O:13]1.O1CCCC1.Cl>[Cl-].[Na+].O>[C:12]([CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:23][C:24](=[O:28])[N:25]([CH3:27])[CH3:26])=[CH:3][C:2]=1[Cl:1])(=[O:13])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)C(=O)Nc1ccc(OCCCC2(c3ccccc3)OCCO2)c(Cl)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)Nc1ccc(OCCCC(=O)c2ccccc2)c(Cl)c1
Reaction time: 8 h

Procedure:
A mixture of 3-{3-chloro-4-[3-(2-phenyl-1,3-dioxolan-2-yl)propoxy]phenyl}-1,1-dimethylurea (2.03 g; 0.005 mol), tetrahydrofuran (10 ml) and 10% aqueous hydrochloric acid (2 ml) is stirred overnight. The reaction mixture is poured into brine (100 ml) and extracted with methylene chloride. The organic layer is washed with water, dried and evaporated to afford the product: 1.69 g of an off-white solid. Recrystallization from a toluene-hexane mixture (50 ml) yields 1.33 g of cream colored needles, m.p. 129°-130° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1.N#N.C([Sn](CCCC)(CCCC)[C:37]([O:39][CH2:40][CH3:41])=[CH2:38])CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:40]([O:39][C:37]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]([CH3:28])[CH3:29])[CH2:23]3)=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1)=[CH2:38])[CH3:41]
Reactant: CN(C)[C@H]1CCN(c2cnc3ccc(Sc4nnc5ccc(Br)cn45)cc3c2)C1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: CN(C)C=O
Product: C=C(OCC)c1ccc2nnc(Sc3ccc4ncc(N5CC[C@H](N(C)C)C5)cc4c3)n2c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 13.9 %

Procedure:
The solution of (81.1) (256.5 mg, 0.546 mmol) and PdCl2(PPh3)2 (38.4 mg, 0.055 mmol) in DMF (10 ml) was bubbled by N2 for 5 min. Tributyl(1-ethoxyvinyl)stannane (296 mg, 0.820 mmol) was added. The reaction tube was flushed by N2 for 5 min again and sealed. The sealed-tube was stirred at 85° C. for 16 h. The mixture was evaporated to dryness and the residue was purified by flash chromatography (CombiFlash, ISCO, eluent MeOH/DCM from 0 to 10%) to afford the title compound (35 mg, yield 13.91%). LCMS (method A): [M+H]+=461.2, tR=1.96 min.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[C:9]1(CCCN)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([NH:2][CH2:3][CH2:4][CH2:5][CH:5]2[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NCCCc1ccccc1
Reactant: CN1CCC(=O)CC1
Product: c1ccc(NCCCC2CCNCC2)cc1

Procedure:
Starting materials: 1-Methyl-4-piperidone (1.1 ml, 7.4 mmol, 1.0 eq.), 3-phenylpropylamine (1.35 g, 1.0 eq.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH:8][CH2:9][CH:10]([CH3:12])[CH3:11])[S:5][CH:6]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21].C(N(CC)C(C)C)(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])(=[O:22])=[O:21])[S:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC(C)CNCc1cc(Br)cs1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(Cc1cc(Br)cs1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 13, step 2, (4-bromo-thiophen-2-ylmethyl)-isobutyl-amine was reacted with 2-chlorobenzenesulfonylchloride in presence of N,N-diisopropyl ethyl amine in dichloromethane to give N-(4-bromo-thiophen-2-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[Li]CCCC.[C:15]([C:17]1[CH:37]=[CH:36][C:20]([O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:35])([F:34])[C:29](OCC)=[O:30])=[N:26][CH:27]=2)=[CH:19][CH:18]=1)#[N:16]>C(OCC)C>[F:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[C:29](=[O:30])[C:28]([C:25]1[N:26]=[CH:27][C:22]([O:21][C:20]2[CH:19]=[CH:18][C:17]([C:15]#[N:16])=[CH:37][CH:36]=2)=[CH:23][CH:24]=1)([F:34])[F:35]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CCOC(=O)C(F)(F)c1ccc(Oc2ccc(C#N)cc2)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: N#Cc1ccc(Oc2ccc(C(F)(F)C(=O)c3ccc(F)cc3F)nc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1-bromo-2,4-difluorobenzene (0.724 g, 3.77 mmol) in diethyl ether (Et2O)(20 mL) under a N2 atmosphere was added n-BuLi (2.49 mL, 4.03 mmol) at −78° C. and the reaction mixture was stirred for 45 minutes. Ethyl 2-(5-(4-cyanophenoxy)pyridin-2-yl)-2,2-difluoroacetate (1.00 g, 3.1 mmol) in Et2O (5 mL) was added dropwise and the reaction was stirred at the same temperature for 1 h. The reaction mixture was carefully quenched with 1N HCl until the reaction mixture was acidic. The reaction mixture was allowed to warm to room temperature and was extracted with Et2O. The combined organic phases were dried (Na2SO4) and concentrated to afford the title compound as yellow solid that was used for the next step without further purification (1.0 g, 83% crude yield): 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J=2.7 Hz, 1H), 8.15-8.02 (m, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.74-7.65 (m, 2H), 7.53 (dd, J=8.6, 2.7 Hz, 1H), 7.16-7.06 (m, 2H), 7.05-6.96 (m, 1H), 6.84 (ddd, J=10.9, 8.6, 2.4 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −99.13 (d, J=13.5 Hz), −100.67 (d, J=14.9 Hz), −101.82 (dd, J=28.5, 14.2 Hz); ESIMS m/z 387 ([M+1]+).
Reaction SMILES: [CH:1](OC(=O)C)=[O:2].[NH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:9]=1[CH2:10][OH:11]>C1C=CC=CC=1.CCCCCC>[CH:1]([NH:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:9]=1[CH2:10][OH:11])=[O:2]
Reactant: Cc1cccc(N)c1CO
Reactant: CC(=O)OC=O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: Cc1cccc(NC=O)c1CO
Reaction time: 2 h
Yield: 84.9 %

Procedure:
Acetic formic anhydride (1.85 g) was added to a solution of 2-amino-6-methylbenzyl alcohol (2.74 g) in benzene (55 ml) at room temperature. After being stirred for 2 hours, the mixture was diluted with n-hexane (10 ml) and the precipitates were collected by filtration to give 2-formamido-6-methylbenzyl alcohol (2.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=1)[C:9]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:8]2)=[O:4].C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=1)[C:9]([C:26]([OH:28])=[O:27])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)cc(C(=O)OC(C)(C)C)n2Cc1cc(-c2ccc(Cl)s2)on1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)cc(C(=O)O)n2Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.5 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2,5-dicarboxylic acid 2-tert-butyl ester 5-methyl ester were dissolved in 300 ml trifluoro-acetic acid and stirred for 1 h at RT. Then 200 ml toluene were added and the solvents were removed under reduced pressure. This procedure was repeated three times, then the residue was dried in vacuo. Yield: 8.4 g.