Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=2[CH3:19])=[C:6]([CH3:20])[N:5]=[C:4]([C:21]2[C:26]([CH2:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:29][CH3:30])[N:3]=1.CC1(C)C(C)(C)OB([C:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH:40]=2)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:27]([C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:29][CH3:30])[C:21]=1[C:4]1[N:3]=[C:2]([C:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[CH2:41][CH:40]=2)[C:7]([CH2:8][O:9][C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=2[CH3:19])=[C:6]([CH3:20])[N:5]=1)[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCc1cccc(CC)c1-c1nc(C)c(COc2cc(C(C)C)ccc2C)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1-c1nc(C)c(COc2cc(C(C)C)ccc2C)c(C2=CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 80 °C

Procedure:
To a solution of 4-chloro-2-(2,6-diethylphenyl)-5-((5-isopropyl-2-methylphenoxy)methyl)-6-methylpyrimidine (423 mg, 1 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Wustrow and Wise, Synthesis, 1991, 993) (371 mg, 1.2 mmol) in anhydrous DMF (5 mL) is added K2CO3 (414 mg, 3 mmol). The mixture is bubbled with N2 for 15 min and PdCl2dppf (28 mg) is added. The mixture is then heated under N2 at 80° C. for 16 h. After cooling to room temperature, the mixture is diluted with ether, washed with water and brine. The organic layer is dried over anhydrous MgSO4, concentrated and purified by silica gel column chromatography to provide the title product. [mass expected (569.8); mass found (M+1: 570.6)].
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1.C(=O)([O-])[O-].[K+].[K+].CC(O)C>[Pd].O>[S:21]1[CH:25]=[CH:24][C:23]([C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)=[CH:22]1
Reactant: OB(O)c1ccsc1
Reactant: Ic1ccc(Oc2ccc(N3CCOCC3)cc2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: c1cc(-c2ccc(Oc3ccc(N4CCOCC4)cc3)cc2)cs1
Yield: 35.3 %

Procedure:
The title compound (25 mg, 35%) was prepared by treating 4-[4-(4-Iodo-phenoxy)-phenyl]-morpholine (80 mg, 0.21 mmol) from Example 24 with thiophene-3-boronic acid (35 mg, 0.25 mmol) in the presence of 10% Pd/C (10 mg), potassium carbonate (87 mg, 0.68 mmol), 2-propanol (4 mL) and water (0.4 mL) by using the procedure described in step 2 of Example 16: MS (ESI) m/z 338 (M+H); 1H NMR (400 MHz, CDCl3) δ 3.13 (t, J=4.8 Hz, 4H), 3.87 (t, J=4.8 Hz, 4H), 6.91-7.01 (m, 6H), 7.34-7.38 (m, 3H), 7.51-7.53 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH2:34]([CH2:36][NH2:37])[OH:35]>C1COCC1.CCOC(C)=O>[OH:35][CH2:34][CH2:36][NH:37][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[CH:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][N:11]=2)[CH:15]=1)(=[O:21])=[O:22]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)NCCO)c3)c2)n1
Temperature: 25 °C
Yield: 21 %

Procedure:
The title compound was prepared from the solution of 3-[6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (example 346 step 2) (ca. 0.2 g, 0.41 mmol) by treatment with excess ethanolamine in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.045 g, 21%) as a white solid. MS (ISP) 514.0 [(M+H)+]; mp 103° C. (dec.).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Cl:7][CH2:8][CH2:9][CH:10]([C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=1)[C:11](O)=[O:12]>CN(C=O)C.C(Cl)Cl>[Cl:7][CH2:8][CH2:9][CH:10]([C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=1)[C:11]([Cl:4])=[O:12]
Reactant: O=C(O)C(CCCl)c1cc(F)c(F)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(CCCl)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
oxalyl chloride (0.63 mL) and DMF (1 drop) were added to a solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid (1.17 g) in methylene chloride (30 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 4-chloro-2-(3,4,5-trifluorophenyl)butyryl chloride. A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyryl chloride in THF (5 mL) was added to a solution of tert-butyl carbazate (600 mg) and triethylamine (3.1 mL) in THF (20 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was added to a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.35 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C@@H:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][C@H:21]3[OH:29])[C:13]2=[N:12][C:11]=1[CH3:30])=[O:9].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH:8]([C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C@@H:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][C@H:21]3[O:29][S:32]([CH3:31])(=[O:34])=[O:33])[C:13]2=[N:12][C:11]=1[CH3:30])=[O:9]
Reactant: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cccn2c1C=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3OS(C)(=O)=O)cccn2c1C=O

Procedure:
8.5 ml triethylamine is added, while stirring and excluding any moisture, to 10 g 3-formyl-8-(2-(trans)-hydroxy-2,3-dihydro-1-indenyloxy)-2-methyl-imidazo[1,2-a]pyridine, suspended in 200 ml dry dichloromethane. This is cooled in an icebath and 5 ml methane sulfonyl chloride dissolved in 10 ml dry dichloromethane is added dropwise. This is stirred for 1 hour while cooling with ice, and the solution is poured onto icewater and extracted several times with dichloromethane. The organic phases are washed with water and dried, and the solvent is stripped off in vacuo. The yellowish residue is stirred with diethyl ether, filtered off under suction and dried. 12 g of the title compound of m.p. 158°-160° C. is obtained. By analogous methods 2-methyl-8-(2-(trans)methylsulfonyloxy-2,3-dihydro-1-indenyloxy)-imidazo[1,2-a]pyridine is obtained from 2-methyl-8-(2-(trans)-hydroxy-2,3-dihydro-1-indenyloxy)-imidazo[1,2-a]pyridine and methane sulfonyl chloride. M.p. 122°-125° C. (decomposition).
Reaction SMILES: CCN(CC)CC.Cl.[CH3:9][C:10]1[S:11][C:12]([NH2:15])=[CH:13][N:14]=1.[CH3:16][C:17](OC(C)=O)=[O:18]>C(Cl)Cl>[CH3:9][C:10]1[S:11][C:12]([NH:15][C:17](=[O:18])[CH3:16])=[CH:13][N:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncc(N)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cnc(C)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of Et3N (1.4 ml, 10 mmol) and 2-methylthiazol-5-amine hydrochloride (1 g, 6.6 mmol) in DCM (30 mL) was added Ac2O (0.94 mL, 10 mmol). The mixture was stirred at room temperature for 3 h. The reaction solution was concentrated, deposited onto silica gel and loaded onto a silica gel column and eluted with EA to give the title compound (0.8 g, yield: 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Br[CH2:23][CH:24](OC)OC.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:14]3[CH:23]=[CH:24][N:1]=[C:2]3[CH:3]=[C:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[CH:12]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(N)n2)cc1
Reactant: COC(CBr)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc3nccn23)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 48.6 %

Procedure:
To a solution of tert-butyl 2-amino-6-(4-methylphenyl)isonicotinate (57 mg, 0.2 mmol) in N,N-dimethylformamide (1.3 mL) were added 2-bromo-1,1-dimethoxyethane (33.9 mg, 0.2 mmol) and 4-methylbenzenesulfonic acid (5.2 mg, 0.03 mmol). The mixture was heated to 90° C. After 18 h, the mixture was filtered. The filtrate was purified by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.025% trifluoroacetic acid) gave the title compound (30 mg): LC-MS [M+1]=309.2.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C1([Hg][C:22](Br)([Cl:24])[Cl:23])C=CC=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:22]2([Cl:24])[Cl:23])=[CH:13][CH:14]=1
Reactant: ClC(Cl)(Br)[Hg]c1ccccc1
Reactant: COC(=O)C=COc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: COC(=O)C1C(Oc2ccc(Cl)cc2)C1(Cl)Cl
Reaction time: 4 h

Procedure:
A mixture of methyl 3-(4-chlorophenoxy)-2-propenoate (30 mmol), phenyl(bromodichloromethyl)mercury (30 mmol) and 50 ml benzene are heated under reflux, with stirring, for 4 hr, followed by TLC of the product. The mixture is then filtered and the solvent removed, giving methyl 3-(4-chlorophenoxy)-2,2-dichlorocyclopropanecarboxylate, which is then hydrolyzed and reacted with m-phenoxybenzyl bromide to give m-phenoxybenzyl 3-(4-chlorophenoxy)-2,2-dichlorocyclopropanecarboxylate.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][NH:7][NH2:8])[CH3:2].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:21][C:17]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[C:15](=[O:14])[CH:16]=1
Reactant: CCc1cccc(CNN)c1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCc1cccc(Cn2[nH]c(N)cc2=O)c1
Reaction time: 8 h

Procedure:
14.2 g of 3-ethylbenzylhydrazine were added dropwise to a solution of 15.1 g of β-amino-β-ethoxyacrylic acid ethyl ester and a pinch of p-toluenesulphonic acid in 80 ml of ethanol, in the course of which the temperature rose from 22° to 30°. After stirring overnight, the solvent was distilled off in vacuo and the solid residue was recrystallised from ethanol. The product was the compound identified above. Melting point: 73°, 5 g (24%).
Reaction SMILES: [Br:1][C:2]1[N:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[N:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[N:15]=2)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)(=[O:26])C>>[Br:1][C:2]1[N:12]=[CH:11][CH:10]=[C:9]([C:13]([C:14]2[N:15]=[C:16]([O:22][CH3:23])[CH:17]=[C:18]([O:20][CH3:21])[N:19]=2)=[O:26])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1c(Cc2nc(OC)cc(OC)n2)ccnc1Br
Product: CCOC(=O)c1c(C(=O)c2nc(OC)cc(OC)n2)ccnc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.28 g of ethyl 2-bromo-4-[(4,6-dimethoxy-2-pyrimidinyl)methyl]nicotinate, 3.61 g of SeO2 and 100 ml of glacial acetic acid are combined under nitrogen, heated to 110° for 1.5 hrs and slowly cooled to RT still under nitrogen. The mixture is filtered, washed through with 10 ml of acetic acid and the filtrate evaporated to remove the acetic acid. 100 ml of methylene dichloride is added to the residue and the mixture washed twice with 100 ml of sat. aqueous NaHCO3. The CH2Cl2 phase is filtered and evaporated and the residue digested with 25 ml of 25% ethyl acetate/hexane at 50° for 15 mins. This solution is then poured onto a silica gel column and eluted with 3×125 ml of 25% ethyl acetate/hexane. Evaporation of combined fractions 1 and 2 yields the title product mp 98°-99°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.C(OC(=O)C)(=O)C.C(N(CC)CC)C.Cl>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=2)[C:21]([OH:23])=[O:22])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(C=C(C(=O)O)c2ccc(O)cc2)cc(OC)c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 138.7 %

Procedure:
To a mixture of 3,5-dimethoxybenzaldehyde (120 g, 0.72 mol) and p-hydroxyphenyl acetic acid (110 g, 0.72 mol) was added acetic anhydride (240 mL) and triethylamine (161 mL, 1.6 equiv.). This non-homogeneous mixture on heating becomes homogeneous at ˜70° C. After being stirred at 130° C. for 4 hr, the mixture was cooled to room temperature. HCl (15%, 500 mL) was added to the reaction mixture slowly in 30 min keeping temperature below 5-10° C. The solid was dissolved in 3N aqueous NaOH (1.2 L) and stirred for 0.5 hr. The filtrate was acidified, maintaining a temperature at 25-30° C., with conc. HCl (˜700 mL) to pH 1. The precipitated product was filtered and washed with water to give crude product (˜300 g, wet cake). The crude product was dissolved by heating in ethanol and recrystallized by adding equal volume of water. The product was dried overnight in a vacuum oven at 40° C. Yield: 161 g, 74%. Analysis: 1HNMR (DMSO-d6): δ 12.48 (br, 1H), 9.42 (s, 1H), 7.59 (s, 1H), 6.95 (d, J=8.0 Hz, 2H), 6.76 (d, J=8.0 Hz, 2H), 6.35 (t, J=2.2 Hz, 1H), 6.27 (d, J=2.2 Hz, 2H), 3.56 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[NH2:19][CH2:20][CH2:21][OH:22].C(N(CC)CC)C>CC(O)C>[CH3:18][S:17][C:13]1[N:12]=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:19][CH2:20][CH2:21][OH:22])=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=[CH:15][N:14]=1
Reactant: NCCO
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CSc1nccc(-c2n[nH]c3nc(NCCO)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (590 mg, 2.12 mmol) in 2-propanol (20 mL) was added 2-aminoethanol (142 mg, 2.33 mmol) followed by triethylamine (235 mg, 2.33 mmol). The reaction mixture was stirred at reflux for 16 hours and the solvent was then removed under reduced pressure. The residue was washed with 2-propanol (1 mL) and dried by evaporation to afford 2-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-ethanol. (Yield 0.7 g, crude). LC-MS: [M+H]+ 304.
Reaction SMILES: [CH:1]([C:3]1([CH3:17])[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH3:16])[C:7]=2[S:6][CH2:5][CH2:4]1)=O.[CH3:18][NH2:19]>C1C=CC=CC=1.CO>[CH3:17][C:3]1([CH:1]=[N:19][CH3:18])[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH3:16])[C:7]=2[S:6][CH2:5][CH2:4]1
Reactant: Cn1c2c(c3ccccc31)C(C)(C=O)CCS2
Reactant: CN
Solvent: CO
Solvent: c1ccccc1
Product: CN=CC1(C)CCSc2c1c1ccccc1n2C
Reaction time: 2 h

Procedure:
To a solution of the product (2.0 g) of the above (1) in benzene (20 ml) is added a 30% solution (14 ml) of methylamine in methanol. The solution is stirred for 2 hours and evaporated to give 4,9-dimethyl-4-methyliminomethyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (IR: νmaxCHCl3 1660 cm-1). The product is dissolved in methanol (20 ml) and sodium borohydride (930 mg) is added thereto on ice bath. The mixture is stirred at room temperature for 1 hour and evaporated to remove the solvent. The residue is extracted with ether after addition of some pieces of ice and a 10% aqueous solution of sodium hydroxide. The ethereal extract is again extracted with hydrochloric acid. The extract is made alkaline with an aqueous solution of sodium hydroxide and extracted with ether. The extract is washed with a saline solution, dried and evaporated to give an oil. Crystallization from hydrochloric acid--ethanol gives the hydrochloride (2.06 g) of the title compound melting at 274° C. (decomp.). Yield: 86%.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22].[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Cl>CN(C=O)C>[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[Cl:24])[C:14]1=[O:22]
Reactant: COC(=O)CCCCCCCn1c(=O)[nH]c2ccccc21
Reactant: ClCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)n(Cc2ccccc2Cl)c2ccccc21

Procedure:
The product is produced as described in example 1 from 0.72 g. of NaH (80% suspension in mineral oil), 7 g. of 8-(2-oxobenzimidazolin-1-yl)-caprylic acid methyl ester, 100 cc. of DMF, 3.9 g. of 2-chlorobenzylchloride and 0.72 g. of NaJ. Eluant of chromatographic purification: hexane/ethylacetate.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:27]=[CH:26][C:14]([O:15][CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[F:35][C:36]([F:42])([F:41])[S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:24][CH:22]([S:19]([NH:18][CH2:17][CH:16]([O:15][C:14]1[CH:26]=[CH:27][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][NH:2][S:37]([C:36]([F:42])([F:41])[F:35])(=[O:39])=[O:38])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)[CH3:25])(=[O:21])=[O:20])[CH3:23]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCN)cc2)cc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCNS(=O)(=O)C(F)(F)F)cc2)cc1
Yield: 38.5 %

Procedure:
The title compound (130 mg, 38%, slow crystallizing-foam) was prepared from (2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (250 mg, 0.664 mmol, prepared in example 39), methylene chloride (4.5 mL, anhydrous), triethylamine (0.09 mL, 0.664 mmol), and trifluoromethanesulfonyl chloride (0.07 mL, 0.664 mmol) in a manner analogous to the procedure described in Example 40.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[C:5]([CH3:8])=[N:6][CH:7]=1.C([O:17]C(=O)N(C1C(C)=NC=C(Br)C=1)CC)(C)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[C:5]([CH3:8])=[N+:6]([O-:17])[CH:7]=1
Reactant: Cc1ncc(Br)cc1OC(C)C
Reactant: CCN(C(=O)OC(C)(C)C)c1cc(Br)cnc1C
Product: Cc1c(OC(C)C)cc(Br)c[n+]1[O-]

Procedure:
The title compound was synthesized in a similar manner as described for Stage 155.1.4 using 5-bromo-3-isopropoxy-2-methyl-pyridine (Stage 84.1.2, 2.108 mmol) as replacement for (5-bromo-2-methyl-pyridin-3-yl)-ethyl-carbamic acid tert-butyl ester to give the title compound as a slowly crystallizing orange solid. (HPLC: tR 2.75 min (Method A); M+H=246, 248 MS-ES).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:28][CH:29]([N:31]=[C:32]=[O:33])[CH3:30].O>ClCCl>[CH:29]([NH:31][C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1)=[O:33])([CH3:30])[CH3:28]
Reactant: CN(Cc1cccc(-c2ccc(N)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: CC(C)N=C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)NC(=O)Nc1ccc(-c2cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To an ice-cooled solution of tert-butyl (2-{[(4′-aminobiphenyl-3-yl)methyl](methyl)amino]-2-oxoethyl}carbamate (200 mg) in dichloromethane (4 ml) was added 2-propyl isocyanate (55 mg), followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by stirring, and the organic layer was purified by silica gel column chromatography (2% MeOH/CHCl3) to obtain tert-butyl {2-[({4′-[(isopropylcarbamoyl)amino]biphenyl-3-yl}methyl)(methyl)amino]-2-oxoethyl}carbamate (240 mg) as a colorless oil.
Reaction SMILES: [H-].[Na+].C1COCC1.[C:8]([O:12][C:13](=[O:21])/[CH:14]=[CH:15]/[C:16]1[CH:20]=[CH:19][NH:18][CH:17]=1)([CH3:11])([CH3:10])[CH3:9].[Br:22][C:23]1[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=1>O>[C:8]([O:12][C:13](=[O:21])/[CH:14]=[CH:15]/[C:16]1[CH:20]=[CH:19][N:18]([S:28]([C:26]2[S:27][C:23]([Br:22])=[CH:24][CH:25]=2)(=[O:30])=[O:29])[CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.53 g NaH (60%) with 40.0 ml THF is cooled down to −30° C. and 3.1 g (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester are added. During the addition it is liberated a gas. The solution is stirred at ambient temperature for 0.5 h. Then 5.0 g of 5-bromothiophene-2-sulfonylchloride is added by -30° C. The mixture is stirred at ambient temperature for 24 h. The NaH is hydrolyzed with water and the solution is extracted with ethyl acetate. The title compound is isolated by flash chromatography. By this method 4.5 g of colorless crystals are obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:15][CH:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH:12]1[CH2:24][CH:25]=[CH2:26])=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:24]([CH:12]1[CH2:13][CH:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][N:11]1[C:9](=[O:10])[CH:8]([NH2:7])[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1)[CH:25]=[CH2:26]
Reactant: C=CCC1CC(OCc2ccccc2)CN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCC1CC(OCc2ccccc2)CN1C(=O)C(N)Cc1ccc(F)cc1

Procedure:
[2-(2-Allyl-4-benzyloxy-pyrrolidin-1-yl)-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester, 53, (0.67 g, 1.4 mmol) is dissolved in methylene chloride (21 mL), and trifluoroacetic acid (9 mL) is added. The reaction mixture is stirred for 1 hourr and then concentrated in vacuo. MeOH (40 mL) is added and the solvent is removed in vacuo to afford the desired product in approximately quanitative yield as a viscous oil which is used without further purification.