Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[NH:10][NH2:11].[BH3-]C#N.[Na+]>CO.C([O-])(O)=O.[Na+].CCOC(C)=O>[C:14]([O:13][C:9]([NH:10]/[N:11]=[CH:1]/[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=CCCCCC=O
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCCCC/C=N/NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
To a solution of 54 (68 mg, 0.610 mmol) and tert-butyl carbazate (81 mg, 0.613 mmol) in MeOH (5 mL) was added ground molecular sieves (115 mg, 3 Å). The mixture was stirred for 3 h after which it was filtered through celite and evaporated. The residue was dissolved in dry THF (3 mL) and AcOH (3 mL). NaBH3CN (95 mg, 1.51 mmol) was added and the solution was stirred over night. The reaction mixture was diluted with saturated NaHCO3 solution (6 mL) and EtOAc (6 mL). The organic phase was washed with brine, saturated NaHCO3, brine, dried over MgSO4 and evaporated. The cyanoborane adduct was hydrolyzed by treatment with MeOH (3 mL) and 2 M NaOH (1.9 mL). The mixture was stirred for 2 h and the MeOH was evaporated. H2O (5 mL) and DCM (5 mL) were added and the water phase was extracted three times with DCM. The combined organic phases were dried and evaporated. Purification by flash column chromatography (toluene/ethyl acetate 9:1 with 1% triethylamine and toluene/ethyl acetate 6:1 with 1% triethylamine) provided the title compound (85 mg, 61%) as an oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]1([CH:25](O)[CH3:26])[CH2:24][CH2:23][CH2:22][CH2:21]1.CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:46]1[C:54]2[C:49](=[CH:50][C:51]([C:55]3[N:59]=[CH:58][N:57](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:56]=3)=[CH:52][CH:53]=2)[C:48]([C:79]2[CH:80]=[C:81]([OH:85])[CH:82]=[CH:83][CH:84]=2)=[N:47]1.Cl>O1CCCC1>[NH:56]1[C:55]([C:51]2[CH:50]=[C:49]3[C:54](=[CH:53][CH:52]=2)[NH:46][N:47]=[C:48]3[C:79]2[CH:84]=[CH:83][CH:82]=[C:81]([O:85][CH2:26][CH2:25][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:80]=2)=[N:59][CH:58]=[N:57]1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(O)N1CCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCN2CCCC2)cc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 46 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), pyrrolidinylethanol (0.310 mL, 2.65 mmol) and diethylazodicarboxylate (0.418 mL, 2.65 mmol) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 0.662 mmol). The mixture was stirred at ambient temperature for 23 h and poured into aqueous 6 N hydrochloric acid (30 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ether (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (30 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica pretreated with 2% triethylamine/ethyl acetate followed by 0–20% methanol/ethyl acetate. The desired fractions were concentrated, dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated which gave the title compound (0.114 g, 46% yield). 1H NMR (CD3OD) δ 8.72 (s, 1H), 8.34 (s, 1H), 8.09 (dd, 1H), 7.67 (d, 1H), 7.62 (d, 1H), 7.57 (m, 1H), 7.47 (t, 1H), 7.04 (m, 1H), 4.26 (t, 2H), 3.02 (t, 2H), 2.73 (m, 4H), 1.87 (m, 4H). ES-MS (m/z) 375 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:29])=O.CN(C)C=O>CCCCCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=1[C:5]([Cl:29])=[O:6]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Cl

Procedure:
To a stirred solution of 2-Methoxy-6-pentadecylbenzoic Acid (6.5 g, 16 mmol) in hexane (60 mL) were added thionyl chloride (2.5 g, 21 mmol) and N,N-dimethylformamide (0.5 mL). The reaction mixture was heated to reflux for 1 h After the reaction was complete, the solvent was evaporated under reduced pressure to yield the desired 2-Methoxy -6-pentadecylbenzoyl Chloride, which was redissolved in dichloromethane (50 mL) and used for the condensation with anilides.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:18][C:17]1[CH:19]=[CH:20][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Product: CC(C)c1ccc(NCc2ccc(Cl)cc2Cl)cc1
Yield: 89.2 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 2,4-dichlorobenzaldehyde (1.8 g) and 4-isopropylaniline (1.4 g) as starting materials, [(2,4-dichlorophenyl)methyl](4-isopropylphenyl)amine (2.7 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:46])[NH:34][C:35]4[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=4[F:45])=[C:28]([F:47])[CH:27]=3)[CH:9]=[C:10]([C:11]([CH:13]3[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.Cl>O1CCOCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:34][C:35]4[CH:40]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:38]=[CH:37][C:36]=4[F:45])=[O:46])=[C:28]([F:47])[CH:27]=3)[CH:9]=[C:10]([C:11]([CH:13]3[O:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)c2cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c3c(N)ncnn23)C1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncnn2c(C(=O)C3CNCCO3)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 2-({4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}carbonyl)morpholine-4-carboxylate (50 mg, 0.076 mmol) in 1,4-dioxane (1 mL) was treated with 4N HCl (200 μL) in 1,4-dioxane and stirred at rt for 4 h. The reaction was concentrated then diluted with EtOAc and saturated NaHCO3 solution. The organic layer was dried (MgSO4) and concentrated. The crude residue was triturated with EtOAc and filtered. A yellow solid was isolated (24 mg, 57%). 1H-NMR (CD3OD) δ 8.65 (d, J=8.2 Hz, 1 H), 8.32 (t, J=8.5 Hz, 1 H), 8.09 (s, 1 H), 7.48 (s, 1 H), 7.34-7.29 (m, 4 H), 5.26 (dd, J1=9.6 Hz, J2=2.6 Hz, 1 H), 4.65-4.60 (m, 1H), 4.00 (dt, J1=11.6 Hz, J2=2.5 Hz, 1 H), 3.82-3.75 (m, 1 H), 2.89-2.86 (m, 2 H), 2.75 (dd, J1=12.8 Hz, J2=9.6 Hz, 1 H); MS [M+H]+=562.1; LCMS RT=2.66 min.
Reaction SMILES: Cl.C(OC(N[C@H](C(N[C@@H](CC1C=CC=CC=1)[C@H](O)C(N1C[C@@H](Cl)C[C@H]1C(NC(C)(C)C)=O)=O)=O)CC(=O)N)=O)C1C=CC=CC=1.Cl.[NH2:47][C@H:48]([C:53]([NH:55][C@@H:56]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C@H:57]([OH:73])[C:58]([N:60]1[CH2:71][C@@H:70]([Cl:72])[CH2:69][C@H:61]1[C:62]([NH:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[O:59])=[O:54])[CH2:49][C:50](=[O:52])[NH2:51].[N:81]1[C:90]2[C:85](=[CH:86][CH:87]=[CH:88][CH:89]=2)[N:84]=[CH:83][C:82]=1[C:91](O)=[O:92].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CO.CN(C)C=O>[N:81]1[C:90]2[C:85](=[CH:86][CH:87]=[CH:88][CH:89]=2)[N:84]=[CH:83][C:82]=1[C:91]([NH:47][C@H:48]([C:53]([NH:55][C@@H:56]([CH2:74][C:75]1[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=1)[C@H:57]([OH:73])[C:58]([N:60]1[CH2:71][C@@H:70]([Cl:72])[CH2:69][C@H:61]1[C:62]([NH:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[O:59])=[O:54])[CH2:49][C:50](=[O:52])[NH2:51])=[O:92]
Reactant: O=C(O)c1cnc2ccccc2n1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1cnc2ccccc2n1
Reaction time: 3 h

Procedure:
0.6 ml of 1N aqueous hydrochloric acid was added to a solution of 300 mg (0.48 mmol) of (4S)-1-[(2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-4-chloro-L-prolinamide (prepared as described in Example 1) in methanol, and a stream of hydrogen was bubbled through the mixture at atmospheric pressure for 3 hours in the presence of 60 mg of 10% w/w palladium-on-charcoal, to remove the benzyloxycarbonyl group. The whole of the resulting (4S)-1-[(2S,3S)-3--asparaginylamino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-4-chloroprolinamide hydrochloride and 99 mg (0.57 mmol) of 2-quinoxalinecarboxylic acid were dissolved in 5 ml of dimethylformamide, and 93 mg (0.57 mmol) of diethyl cyanophosphate and 144 mg (1.44 mmol) of triethylamine under ice-cooling were added to this solution. The resulting mixture was stirred for 3 hours, after which it was concentrated by evaporation under reduced pressure. The residue was mixed with a 10% w/v aqueous solution of sodium hydrogencarbonate and then extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography, using a 10:1 by volume mixture of methylene chloride and methanol as the developing solvent, to give 140 mg of the title compound as a colorless powder, melting at 132°-134° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH:13]2[CH2:19][CH:18]3[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:15]([CH2:16][CH2:17]3)[CH2:14]2)=[CH:7][CH:6]=1)=[O:4].C=O.[C:30](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]([CH3:30])[CH:13]2[CH2:14][CH:15]3[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:18]([CH2:17][CH2:16]3)[CH2:19]2)=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(CNC2CC3CCC(C2)N3C(=O)OC(C)(C)C)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(CN(C)C2CC3CCC(C2)N3C(=O)OC(C)(C)C)cc1
Reaction time: 17 h
Yield: 76.8 %

Procedure:
A solution of 1,1-dimethylethyl 3-[[[4-(methoxycarbonyl)phenyl]methyl]amino]-8-azabicyclo[3.2.1]octane-8-carboxylate (2.1 g, 5.7 mmol) and formaldehyde (1 mL of 37% solution in water) in dichloroethane (20 mL) was stirred as acetic acid (0.37 g, 6.9 mmol) and sodium triacetoxyborohydride (1.7 g, 8 mmol) were added. The reaction was stirred for 17 hours. The reaction was treated with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2×). The combined organic extracts were dried and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexane gave 1.7 g of 1,1-dimethylethyl 3-[[[4-(methoxycarbonyl)phenyl]methyl]methylamino]-8-azabicyclo[3.2.1]octane-8-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]([OH:9])[CH3:8])[S:5][CH:6]=1.C1C(=O)N([Br:17])C(=O)C1>CN(C=O)C.O>[Br:17][C:6]1[S:5][C:4]([CH:7]([OH:9])[CH3:8])=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc(C(C)O)n1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(C)O)sc1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of 1-(4-methylthiazol-2-yl)ethanol of preparation 95 (3.3 g, 22.9 mmol) in DMF (80 mL) was added NBS (4.47 g, 25.2 mmol), and the mixture was stirred at 50° C. for 2 hours. TLC (petroleum ether:EtOAc 3:1) indicated the reaction was completed. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (80 mL×3). The combined organic extracts were washed with brine (80 mL×3), dried over sodium sulfate, and concentrated in vacuum to give the residue which was purified by a silica gel column eluting with petroleum ether:EtOAc=25:1-5:1 to give the title compound as a yellow solid (3.7 g, 74%).
Reaction SMILES: C[O:2][C:3]1[C:8]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]#N.C(OC(=O)C)(=[O:22])C>I.C(O)(=O)C>[C:11]1([CH3:16])[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:9][C:8]1[C:3]2[O:2][C:18](=[O:22])[CH2:17][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(CC#N)cccc1Sc1ccccc1C
Agent: I
Solvent: CC(=O)O
Product: Cc1ccccc1Sc1cccc2c1OC(=O)C2

Procedure:
A solution of 2-[2-methoxy-3-(o-tolylthio)phenyl]acetonitrile (5.9 g) in hydriodic acid (58%, 15 ml) and acetic acid (30 ml) was refluxed under heating for 17 hours. After concentration, water and aqueous sodium hydrogen sulfite were added to the residue and extracted with diethyl ether. The extract was washed with dil. aqueous sodium hydrogen sulfite and water in turn and evaporated. To the residue was added a solution of potassium hydroxide (2 g) in methanol (50 ml), and the mixture was refluxed under heating for 2 hours. Methanol was distilled off under reduced pressure, and the residue was dissolved in water, washed with diethyl ether, acidified with conc. hydrochloric acid and then extracted with diethyl ether. The extract was washed with water, dried and exaporated under reduced pressure to give crude 2-[2-hydroxy-3-(o-tolylthio)phenyl]acetic acid (4.2 g). To this product was added acetic anhydride (5 ml), and the mixture was refluxed under heating. The reaction mixture was evaporated, and the resultant oily residue was crystallized with ethanol to give pale yellow needles of 7-(o-tolylthio)-2,3-dihydrobenzofuran-2-one (1.58 g), mp. 108°-109° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:34])[CH:7]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:8]1[C:9]([CH3:28])=[N:10][C:11]2[S:12][C:13]3[CH2:14][O:15][CH2:16][CH2:17][C:18]=3[C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)C>C(O)C.O1CCCC1>[C:30]([O:29][CH:7]([C:8]1[C:9]([CH3:28])=[N:10][C:11]2[S:12][C:13]3[CH2:14][O:15][CH2:16][CH2:17][C:18]=3[C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:6]([OH:34])=[O:5])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3sc4c(c23)CCOC4)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Aqueous sodium hydroxide (2N, 2 mL, 4 mmol) was added to a stirred solution of tert-Butoxy-(2-methyl-4-p-tolyl-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl)-acetic acid ethyl ester (66 mg, 0.15 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) and the reaction was stirred for 2 hours at 60° C. The reaction was concentrated in vacuo until only the aqueous remained. The pH was adjusted to 2 by the addition of 2N aqueous HCl. The resulting solid was collected by filtration and purified by preparative HPLC to afford the title compound. LCMS 3.63 min, ES+/AP+ 425.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:11]3[CH2:14][O:13][CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:17][S:18]([C:21]1[C:29]2[C:24](=[CH:25][N:26]=[CH:27][CH:28]=2)[NH:23][N:22]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:11]3[CH2:14][O:13][CH2:12]3)[C:7]([CH2:9][N:23]3[C:24]4=[CH:25][N:26]=[CH:27][CH:28]=[C:29]4[C:21]([S:18]([CH3:17])(=[O:19])=[O:20])=[N:22]3)=[N:8][C:4]=2[CH:3]=1
Reactant: ClCc1nc2cc(Cl)ccc2n1C1COC1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2COC2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-oxetan-3-yl-1H-benzoimidazole and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:21])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:6]=[N:7][CH:8]=1.[F:22][C:23]([F:30])([F:29])[CH2:24][S:25](Cl)(=[O:27])=[O:26]>>[Cl:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([C:18]#[N:19])=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][S:25]([CH2:24][C:23]([F:30])([F:29])[F:22])(=[O:27])=[O:26])[CH:8]=[N:7][CH:6]=3)[N:10]2[CH3:21])=[CH:15][CH:14]=1
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)CC(F)(F)F
Product: Cn1c(-c2cncc(CNS(=O)(=O)CC(F)(F)F)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
2-(5-Aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 186e) and 2,2,2-trifluoro-ethanesulfonyl chloride are processed according to the method described in Example 186f to give 2,2,2-trifluoro-ethanesulfonic acid [5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]amide. 1H NMR (400 MHz, MeOD) δ ppm 3.84 (s, 3H), 4.29 (q, J=9.6 Hz, 2H), 4.54 (s, 2H), 7.39 (dd, J=8.6, 1.8 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.78 (d, J=1.8 Hz, 1H), 8.18 (t, J=2.0 Hz, 1H), 8.81 (d, J=2.0 Hz, 1H), 8.83 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 443.0557 [(M+H)+ Calcd for C18H15N4O2F3SCl: 443.0556].
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)(=[O:18])[CH3:17].C(N(CC)CC)C.Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([NH:15][S:26]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:16](=[O:18])[CH3:17])=[CH:25][CH:24]=3)(=[O:28])=[O:27])=[CH:14][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCN1CCc2ccc(N)cc2CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN1CCc2ccc(NS(=O)(=O)c3ccc(NC(C)=O)cc3)cc2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
400 mg (1.96 mmol) of 3-propyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-amine and 1.86 mmol of 4-acetylaminobenzenesulfonyl chloride were dissolved in 20 ml of tetrahydrofuran at room temperature, 0.82 ml (5.87 mmol) of triethylamine was added dropwise, and the mixture was stirred at room temperature overnight. After the solvent had been evaporated off, 20 ml of water were added, and the mixture was acidified with 1 mol of hydrochloric acid and extracted with 50 ml of diethyl ether. The aqueous phase was made basic at pH 9-10 with 1 mol of sodium hydroxide solution and then extracted with diethyl ether. The residue obtained after drying with sodium sulfate and after removal of the solvent was converted into the hydrochloride with ethereal hydrochloric acid. Yield: 280 mg (35% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:40])[C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[C:18]([O:30][CH2:31][CH2:32][C:33]3[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[H][H]>CC(=O)OCC.[Pd]>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:40])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:30][CH2:31][CH2:32][C:33]3[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=3)[CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C1(NC(=O)c2ccc(OCc3ccccc3)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1(NC(=O)c2ccc(O)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Yield: 45.2 %

Procedure:
The compound of step 3 of example 253 (800 mg, 1.49 mmol) was dissolved in EA (15 ml) and hydrogenated in the presence of palladium (10%) on charcoal (200 mg) at a hydrogen pressure of 5 bar and room temperature for 6 h. The mixture was filtered over silica gel and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield 300 mg of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:9][CH2:8]1.[C:23]([OH:32])(=[O:31])[CH:24]([CH:26]([C:28]([OH:30])=[O:29])[OH:27])[OH:25]>CO.O>[C:28]([C@@H:26]([C@H:24]([C:23]([OH:32])=[O:31])[OH:25])[OH:27])([OH:30])=[O:29].[C:28]([C@@H:26]([C@H:24]([C:23]([OH:32])=[O:31])[OH:25])[OH:27])([OH:30])=[O:29].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[NH:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:11][CH2:12]1
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: c1ccc(N2CCN(Cc3nc4ccccc4[nH]3)CC2)nc1
Solvent: CO
Solvent: O
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O

Procedure:
2-[(4-Pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole (4.00 g, 13.6 mmol) in methanol (20 mL) and H2O (20 mL) was treated with (L) tartaric acid (4.09 g, 27.2 mmol). The resulting solid was filtered, washed with methanol (10 mL), and dried under reduced pressure to provide the title compound as a solid. Elemental analysis calc'd for C25H31N5O12: C, 50.59; H, 5.26; N, 11.80; O, 32.35. Found: C, 50.48; H 5.27; N, 11.78; O, 32.41. DSC: sharp endotherm at 206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][C:12]([O:15][C:16](=[O:27])[NH:17][CH2:18][CH2:19][C@@H:20]([OH:26])[C:21]1[S:22][CH:23]=[CH:24][N:25]=1)([CH3:14])[CH3:13].[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.CCCC(C)C>[CH3:14][C:12]([O:15][C:16](=[O:27])[NH:17][CH2:18][CH2:19][C@@H:20]([O:26][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[C:21]1[S:22][CH:23]=[CH:24][N:25]=1)([CH3:11])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1nccs1
Reactant: N#Cc1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC[C@@H](Oc1cc(Cl)ccc1C#N)c1nccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
To a solution of 4-chloro-2-fluorobenzonitrile (156 mg, 1 mmol) and [(3R)-3-hydroxy-3-(2-thiazolyl)propyl]carbamic acid 1,1-dimethylethyl ester (258 mg, 1 mmol) in dry dimethylformamide (3 ml), was added sodium hydride (60% dispersion in oil, 40 mg, 1 mmol) and the mixture was stirred at room temperature for 16 h. The reaction was quenched with methanol and partitioned between ethyl acetate and water. The combined extracts were washed with water (3×25 ml) and saturated brine solution, dried (magnesium sulphate) and concentrated in vacuo to leave a crude yellow gum. Flash chromatography (silica, 15% ethyl acetate in isohexane) gave 345 mg of a white solid (86%).