Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[C:5]([Cl:12])[N:4]=1)#[N:2].Cl>C(O)C>[C:1]([C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([Cl:12])[N:4]=1)#[N:2]
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: N#Cc1nc(Cl)ccc1N
Temperature: 0 °C
Yield: 87.2 %

Procedure:
Added 4 g (21.8 mmol) of 2-cyano-3-nitro-6-chloropyridine into concentrated hydrochloric acid (15.00 mL) and ethanol (45.00 mL), then the solution was stirred thoroughly. 4.27 g (76.3 mmol) of reduced iron powder was added in batches to the mixture under a speed that maintained a slight boiling in the flask. The mixture was heated under reflux for 30 min, poured into ice-water (650 mL), stirred, and filtered. Sufficient aether was added to the filter cake and the mixture was stirred thoroughly and filtered. The filtrate was dried with anhydrous magnesium sulfate. The filtrate was adjusted to alkaline with concentrated ammonia first, then filtered and extracted with ether for 3 times. The combined solution of the organic phase and ether solution was dried with anhydrous magnesium sulfate before combined, and then filtered and evaporated under reduced pressure to yield 2.92 g of yellow solid product with a recovery rate of 87.42%.
Reaction SMILES: [CH:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:17][Cl:18].O>C1COCC1.CCCCCC>[Cl:18][CH2:17][C:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCBr
Reactant: N#CC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: N#CC1(CCl)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
A solution of cyclopentanecarbonitrile (14.3 g, 150 mmol) in THF (25 ml) was added dropwise to a stirred solution of lithium diisopropylamide (158 mmol) in THF (150 ml) and hexane (100 ml), under dry nitrogen, keeping the temperature below -65°. After 0.5 h, the solution was warmed to ambient temperature and added to a stirred solution of bromochloromethane (49.4 ml, 750 mmol) in THF (50 ml) keeping the temperature below -65°. The solution was allowed to warm to ambient temperature and, after 18 h, poured into water (500 ml). The aqueous mixture was extracted with CHCl3 (3×250 ml). The extracts were washed with 2N HCl (100 ml) and H2O (100 ml), dried (MgSO4), and evaporated under reduced pressure to give an oil which was distilled to give a pale yellow oil (8.9 g) b.p. 96° at 10 mmHg.
Reaction SMILES: N#N.[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][C:12]#[N:13])[O:8][CH2:7][CH2:6][O:5]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>CCOCC.O>[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(CCCC#N)OCCO1
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CC1(CCCCN)OCCO1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-(2-methyl-[1,3]dioxolan-2-yl)-butyronitrile (2.23 g, 14.4 mmol) in dry Et2O (2.5 mL) was added to a suspension of LiAlH4 (1.36 g, 35.9 mmol) in dry Et2O (50 mL). The reaction mixture was stirred at reflux for 3 h, cooled down to rt and treated with water (2 mL), 15% aq. NaOH (2 mL) and water (4 mL). The precipitate was filtered off and washed with Et2O. The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a light brown oil. LC-MS-conditions 02: tR=0.32 min; [M+H]+=160.29.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:13][Li]>C(OCC)C>[CH2:1]([C:5]1[S:9][C:8]([C:10](=[O:12])[CH3:13])=[CH:7][CH:6]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)Cc1ccc(C(=O)O)s1
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)c1ccc(CC(C)C)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-isobutyl-thiophene-2-carboxylic acid (550 mg, 2.99 mmol) in diethyl ether (20 mL), a solution of methyl lithium (3.75 mL, 1.6 M in diethyl ether) is slowly added at rt. The reaction mixture is stirred at rt for 1 h before it is carefully washed twice with water, dried over MgSO4, filtered and evaporated to give the title compound (336 mg) as a slightly yellow oil, LC-MS: tR=0.91 min, [M+1]+=183.07.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH3:31][O:32][CH2:33][CH3:34]>>[CH3:31][O:32][CH2:33][CH2:34][O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOC
Agent: [Cl-]
Agent: [Na+]
Product: COCCOCCCc1c[nH]cn1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 7 mmol of 2-methoxyethane chloride are treated as described in Example 5.
Reaction SMILES: [C:1]([NH:9][C@H:10]1[CH2:14][N:13]([C:15](=[O:25])[CH2:16][NH:17]C(OC(C)(C)C)=O)[C@H:12]([C:26]([OH:28])=[O:27])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29].O>CC(C)=O>[ClH:29].[NH2:17][CH2:16][C:15]([N:13]1[CH2:14][C@H:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11][C@H:12]1[C:26]([OH:28])=[O:27])=[O:25]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Temperature: 50 °C
Yield: 97.3 %

Procedure:
To a slurry of (2S,4R)-4-benzamido-1-(2-(tert-butoxycarbonyl-amino)acetyl)pyrrolidine-2-carboxylic acid (650.2 g) in acetone (4.1 L) was added conc. hydrochloric acid (322 g). The reaction mixture was heated to 50° C. over 15 min and stirred at 50° C. The reaction was monitored for completion by HPLC. Water (520 g) was added. The mixture was heated to reflux to dissolve the solid coating. The resulting clear solution was cooled to 40° C. Acetone (7.0 L) was added over 15 min while temperature was maintained at 30-40° C. The mixture was cooled to room temperature over 30 min, and stirred until a white slurry was formed. Additional acetone (7.0 L) was added over 10 min. The mixture was stirred overnight at about 22-24° C. The precipitated solids were filtered through a Buchner funnel lined with polypropylene and washed with acetone (2×2 L), was dried on the funnel to give 530 g (93.8%) of product as a monohydrate. LC area purity was 99.7%. 1H NMR (DMSO-d6, δ, ppm, for two conformers): 8.77 (d, J=7 Hz, 0.8H), 8.71 (d, J=7 Hz, 0.2H), 8.68-7.95 (br, 2H), 7.92-7.83 (m, 2H), 7.59-7.43 (m, 3H), 4.87-4.79 (m, 0.2H), 4.68-4.54 (m, 0.8H), 4.54-4.44 (m, 1H), 4.0-3.47 (m, 4H), 2.47-2.12 (m, 2H). HRMS calc. for C14H18N3O4 (M+H): 292.1297. found: 292.1294.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][S:10][C:9]2=[S:14])=[CH:4][CH:3]=1.C(C(CC)(CC)C([O-])([O-])[O-])C.[C:26]([O:29][C:30](=O)[CH3:31])(=O)[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:26]([O:29][CH2:30][CH3:31])[CH3:27])[S:10][C:9]2=[S:14])=[CH:6][CH:7]=1
Reactant: O=C1CSC(=S)N1c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Agent: CCC(CC)(CC)C([O-])([O-])[O-]
Product: CCOC(C)=C1SC(=S)N(c2ccc(Cl)cc2)C1=O

Procedure:
A mixture of 50 g. (0.2 m.) of the above-prepared rhodanine and 140 g. (0.86 m.) of triethylorthoacetate in 350 ml. of acetic anhydride is refluxed for four hours. The cooled reaction solution is filtered and the product is washed with 100 ml. of 70% aqueous acetic acid to yield 3-(4'-chlorophenyl)-5-(1'-ethoxyethylidene)-rhodanine, m.p. 168°-171°C.
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[C:25]([CH3:27])([CH3:26])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:28]([O:30]C)=[O:29])[CH:22]=4)[NH:17]3)=[CH:12][CH:11]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]3[C:25]([CH3:27])([CH3:26])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:28]([OH:30])=[O:29])[CH:22]=4)[NH:17]3)=[CH:14][CH:15]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C3CCCCC3)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NC(=O)C2CCCCC2)cc1
Yield: 95 %

Procedure:
To a mixture of methyl 2-(4-(cyclohexanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (53 mg, 0.11 mmol) in methanol (3 mL) and water (1.5 mL) was added a solution of sodium hydroxide (123 mg, 2.83 mmol.) in water (1.5 mL). The resultant mixture was heated for reflux until the complete of the reaction (monitored by thin layer chromatography). The methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=1. The precipitates were collected by filtration to afford 2-(4-(cyclohexanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid, yellow solid, 50 mg, 95% Yield; MS (ESI+APCI) M+1=429.11.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.[Sn](Cl)Cl>CCO>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Yield: 72.9 %

Procedure:
To a solution of 5-bromo-2-chloro-3-nitropyridine (4.24 g, 17.86 mmol) in EtOH (89 ml) was added Tin(II) chloride (16.9 g, 89.0 mmol) at room temperature. The mixture was refluxed for 1 hour, and then cooled to room temperature, filtered through a Celite pad and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was treated with saturated aq. NaHCO3, and extracted with EtOAc. The combined organic layers were washed brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=3:1) to give 5-bromo-2-chloropyridin-3-amine (2.7 g, 73%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 5.89 (2H, brs), 7.30 (1H, d, J=2.0 Hz), 7.66 (1H, d, J=2.4 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:19]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[O:14])=[CH:15][CH:16]=1)[CH3:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino)benzaldehyde (250 mg, 1.13 mmol, synthesized at Example 278 (1)) in 2.3 mL of dry N,N-dimethylformamide was added sodium hydride (59 mg, 55%, 1.4 mmol) under nitrogen at 0° C. After the reaction mixture was stirred at room temperature for 30 min, methyl iodide (105 μL, 1.69 mmol) was added with additional stirring overnight. After quench with saturated NH4Cl aqueous solution, the mixture was extracted with diethyl ether. The extract was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 60/40) to obtain the title compound (210 mg, 79%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Si:19]([CH3:24])([CH3:23])[CH2:20][CH2:21]O.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([O:17][CH2:21][CH2:20][Si:19]([CH3:24])([CH3:23])[CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCO
Reactant: CC(C)(C)OC(=O)NC1CCCCC1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCCC1C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a mixed liquid of 2.00 g of (1RS,2SR)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid and 40 ml of dichloromethane were added 1.41 ml of 2-(trimethylsilyl)ethanol, 0.40 g of DMAP, and 2.21 g of WSC in this order, followed by stirring at room temperature for 60 hours. After evaporating the solvent, ethyl acetate was added thereto, followed by washing with water, a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated to obtain 2.82 g of 2-(trimethylsilyl)ethyl(1RS,2SR)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate as a colorless oily substance.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH:47]3[CH2:49][CH2:48]3)(=[O:46])=[O:45])=[C:40]([CH:50]3[CH2:52][CH2:51]3)[CH:39]=2)/[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.CC1(C)[O:58][C@@H:57]([CH2:59][N:60]2[CH:64]=[CH:63][C:62]([NH2:65])=[N:61]2)[CH2:56][O:55]1>ClCCl.N1C=CC=CC=1.O>[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH:47]3[CH2:48][CH2:49]3)(=[O:46])=[O:45])=[C:40]([CH:50]3[CH2:51][CH2:52]3)[CH:39]=2)/[C:35]([NH:65][C:62]2[CH:63]=[CH:64][N:60]([CH2:59][C@H:57]([OH:58])[CH2:56][OH:55])[N:61]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CC1(C)OC[C@H](Cn2ccc(N)n2)O1
Reactant: O=C(O)/C(=C/C1CCCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccn(C[C@H](O)CO)n1)/C(=C/C1CCCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
To a solution of triphenylphosphine (320 mg) in dichloromethane (10 mL) was added N-bromosuccinimide (217 mg) under ice-cooling, followed by stirring for 15 minutes under ice-cooling. A solution of (2E)-3-cyclopentyl-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]acrylic acid (200 mg) in dichloromethane (10 mL) was added thereto under ice-cooling, followed by stirring at room temperature for 0.5 hour. A solution of 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-3-amine (142 mg) in dichloromethane (5 mL) and pyridine (0.09 mL) were added thereto at room temperature, followed by stirring at room temperature overnight. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:2). To a solution of the obtained oily substance in THF (15 mL) was added 1 M hydrochloric acid (15 mL), followed by stirring overnight. Saturated brine was added thereto, followed by extraction with a solvent (chloroform:isopropyl alcohol=4:1). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform:methanol=1:0-20:1) to obtain (2E)-3-cyclopentyl-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-{1-[(2S)-2,3-dihydroxypropyl]-1H-pyrazol-3-yl}acrylamide (197 mg) as a white amorphous substance.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([C:4](=[O:14])[CH2:5][C:6](=[N:8][CH2:9][CH2:10]N(C)C)[CH3:7])[CH3:3].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:23][N:24]([CH3:29])[CH2:25]CCN>>[CH3:15][C:2]([CH3:1])([C:4](=[O:14])[CH2:5][C:6](=[N:8][CH2:9][CH2:10][CH2:23][N:24]([CH3:29])[CH3:25])[CH3:7])[CH3:3]
Reactant: CC(CC(=O)C(C)(C)C)=NCCN(C)C
Reactant: CN(C)CCCN
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CC(CC(=O)C(C)(C)C)=NCCCN(C)C
Yield: 89 %

Procedure:
In a procedure analogously to 2,2-dimethyl-5-(dimethylaminoethyl-imino)-3-hexanone, starting with 2,2-dimethylhexa-3,5-dione (19.27 g, 136 mmol), Na2SO4 (13 g, 92 mmol), and 3-(dimethylamino)propylamine (15.72 g, 154 mmol). A yellow liquid was obtained via a short-path vacuum distillation apparatus after removal of all volatiles. The yield is 89%.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([CH2:8][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=[N:5][C:4]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:3]1[C:20]#[N:21].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>CN(C=O)C.ClCCl>[C:29]([N:17]1[CH2:16][CH2:15][N:14]([C:4]2[N:5]=[C:6]([CH2:8][C:9]3[CH:13]=[CH:12][S:11][CH:10]=3)[NH:7][C:2](=[O:1])[C:3]=2[C:20]#[N:21])[CH2:19][CH2:18]1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: N#Cc1c(N2CCNCC2)nc(Cc2ccsc2)[nH]c1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2nc(Cc3ccsc3)[nH]c(=O)c2C#N)CC1

Procedure:
50 mg (0.17 mmol) of 6-oxo-4-(piperazin-1-yl)-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are dissolved together with 34 mg (0.33 mmol) of triethylamine in DMF and stirred with 14.3 mg (0.18 mmol) of acetyl chloride at RT overnight. The mixture is then diluted with dichloromethane and washed with water. The organic phase is separated off and dried over sodium sulphate and the residue is flash-chromatographed on silica gel (mobile phase: dichloromethane/methanol 100:1, 80:1, 60:1). 42 mg (74% of theory) of the title compound are obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[N+:37]([O-])=O)=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1>[Ni].[Pt]>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[NH2:37])=[CH:29][CH:30]=3)(=[O:23])=[O:24])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccc(-c3ccccc3[N+](=O)[O-])cc2)CC1
Agent: [Ni]
Agent: [Pt]
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccc(-c3ccccc3N)cc2)CC1

Procedure:
Prepared from N-[1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethyl]-2'-nitro-4-biphenylyl-sulphonamide in the presence of platinum/charcoal or Raney nickel and under a hydrogen pressure of 3 bar analogously to Example 22.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:8][N:9]([CH3:11])[CH:10]=2)[N:7]=1.[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:22][CH:23]([OH:41])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:22][CH:23]([OH:41])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:2]2[CH:3]=[CH:4][C:5]3[C:6](=[N:8][N:9]([CH3:11])[CH:10]=3)[N:7]=2)[CH:27]=1
Reactant: CC1(C)OB(c2cccc(OCC(O)CN3CCc4ccccc4C3)c2)OC1(C)C
Reactant: Cn1cc2ccc(Cl)nc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc2ccc(-c3cccc(OCC(O)CN4CCc5ccccc5C4)c3)nc2n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 2.4 %

Procedure:
To a solution of 6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine (220 mg, 1.313 mmol) in dioxane (8 ml) and H2O (2 mL) was added 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol (800 mg, 1.969 mmol), Pd(dppf)Cl2 (16 mg, 0.131 mmol) and K2CO3 (544 mg, 3.939 mmol) at 27° C. The reaction mixture was then stirred for 16 h at 100° C. until the reaction was shown to be complete by TLC analysis. The mixture was then concentrated to a crude material which was purified by prep-HPLC separation to give the desired product 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl)phenoxy)propan-2-ol as a white solid (13 mg, 2.4%). 1H NMR (400 MHz, MeOD): 8.13 (d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.80 (s 1H), 7.74 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.46 (dd, J1=J2=8.0 Hz, 1H), 7.29 (s, 1H), 7.20-7.15 (m, 3H), 7.07-7.05 (m, 2H), 4.35-4.32 (m, 1H), 4.24 (s, 3H), 4.21-4.15 (m, 2H), 3.98 (d, J=6.8 Hz, 2H), 3.80 (d, J=6.8 Hz, 2H), 3.08-2.86 (m, 6H). LCMS (m/z): 415.2 (M+1).
Reaction SMILES: C(OC(=O)COCC[C@H](O)C)(C)(C)C.[C:15]([O:19][C:20](=[O:28])[CH2:21][O:22][C@H:23]([CH3:27])[CH2:24][CH2:25][OH:26])([CH3:18])([CH3:17])[CH3:16].Cl[C:30]1[C:31]2[C:38]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[C:37]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[O:36][C:32]=2[N:33]=[CH:34][N:35]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:15]([O:19][C:20](=[O:28])[CH2:21][O:22][C@H:23]([CH3:27])[CH2:24][CH2:25][O:26][C:30]1[C:31]2[C:38]([C:39]3[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)=[C:37]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[O:36][C:32]=2[N:33]=[CH:34][N:35]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: C[C@H](CCO)OCC(=O)OC(C)(C)C
Agent: C[C@@H](O)CCOCC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC[C@@H](C)OCC(=O)OC(C)(C)C)c23)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 9 %

Procedure:
Put 455 mg (2.23 mmol) {[(3R)-3-hydroxybutyl]oxy}acetic acid tert.-butyl ester (which contains up to approx. 10% {[(1R)-3-hydroxy-1-methylpropyl]oxy}acetic acid tert.-butyl ester) under argon in 5 ml THF and cool to 0° C. Add 1.15 ml (2.23 mmol) of a 2 M solution of phosphazene base P2-tert.-butyl in THF and stir for a further 10 min at RT. Then cool to 0° C. again. Add 500 mg (1.49 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and stir overnight at RT. Then dilute with water, acidify with 10% aqueous citric acid solution and extract twice with ethyl acetate. Combine the ethyl acetate phases and wash once with satd. sodium chloride solution. Dry over magnesium sulphate and concentrate by evaporation. Purify the residue by chromatography on silica gel (solvent: cyclohexane/ethyl acetate 9:1). 450 mg (60.1% of theor.) of the target compound is obtained. 75 mg (9.0% of theor.) of (−)-{[(1R)-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-1-methylpropyl]oxy}acetic acid tert.-butyl ester is isolated as by-product (see Example 77).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:19])[C:10]=1[C:20]1[C:29]2[N:28]=[C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]3)[CH:26]=[N:25][C:24]=2[C:23]([C:39](O)=[O:40])=[CH:22][CH:21]=1>C(Cl)Cl.CO>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:39]([C:23]1[C:24]2[N:25]=[CH:26][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]3)=[N:28][C:29]=2[C:20]([C:10]2[C:9]([Cl:8])=[C:14]([O:15][CH3:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[Cl:19])=[CH:21][CH:22]=1)=[O:40]
Reactant: CCN1CCN(Cc2cnc3c(C(=O)O)ccc(-c4c(Cl)c(OC)cc(OC)c4Cl)c3n2)CC1
Reactant: Nc1ccccn1
Solvent: ClCCl
Solvent: CO
Product: CCN1CCN(Cc2cnc3c(C(=O)Nc4ccccn4)ccc(-c4c(Cl)c(OC)cc(OC)c4Cl)c3n2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 2-aminopyridine, 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carboxylic acid (Step 83.1) and stirring the reaction mixture for 2 days at rt. Title compound: ESI-MS: 581.0/583.2 [M+H]+; tR=3.62 min (System 1); TLC: Rf=0.45 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:13][CH2:14][CH2:15]Cl)[CH3:12]>>[CH2:11]([O:13][CH2:14][CH2:15][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1])[CH3:12]
Reactant: CCOCCCl
Reactant: Cc1nc2ccccc2[nH]1
Product: CCOCCn1c(C)nc2ccccc21
Yield: 82 %

Procedure:
1-(2-Ethoxyethyl)-2-methyl-1H-benzimidazole was synthesized as in Synthesis Example 1 except that an equimolar amount of 2-methylbenzimidazole was used instead of benzimidazole, and an equimolar amount of 2-chloroethyl ethyl ether was used instead of 2-chloroethyl methyl ether. Yield 82%.