Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.CO.[BH4-].[Na+]>>[NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([OH:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1nc(C2CCC(=O)CC2)ccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(=O)c1nc([C@H]2CC[C@H](O)CC2)ccc1N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-amino-N-methyl-6-(4-oxocyclohexyl)pyridine-2-carboxamide (Compound 232B, 53 mg, 0.21 mmol) in MeOH (3 mL, 70 mmol) was cooled to 0° C. and treated with sodium borohydride (8.1 mg, 0.21 mmol). The mixture was stirred at 0° C. for 20 minutes. The reaction was quenched with sat. aq. NH4Cl (1 mL) and concentrated. The residue was taken up in 1 mL H2O and EtOAc (30 m). The layers were separated. The aqueous layer was saturated with salt and washed again with ˜20 mL of EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude solid was taken up in DCM, treated with silica and concentrated. This silica was loaded into a sample column and purified on an ISCO Combiflash unit (0-7% MeOH/DCM) to isolate the product as a mixture of predominantly trans isomer. 1H NMR (400 MHz, CHLOROFORM-d) δ 1.37-1.57 (m, 4H), 1.92-2.01 (m, 2H), 2.07-2.16 (m, 2H), 2.55 (tt, J=11.87, 3.54 Hz, 1H), 2.99 (d, J=5.05 Hz, 3H), 3.63-3.77 (m, 1H), 5.81 (br. s., 2H), 6.95 (d, J=8.40 Hz, 1H), 7.04 (d, J=8.40 Hz, 1H), 8.11 (br. s., 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[C:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28].O>CN(C)C=O>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[C:22]1[S:26][C:25](=[O:27])[N:24]([CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[C:23]1=[O:28]
Reactant: ClCCCCSc1cccc2nccn12
Reactant: O=C1NC(=O)C(=Cc2cccs2)S1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1SC(=Cc2cccs2)C(=O)N1CCCCSc1cccc2nccn12
Temperature: 80 °C

Procedure:
To a solution of 1.81 g (7.5 mmol) of 5-(4-chlorobutylthio)imidazo[1,2-a]pyridine and 1.59 g (7.5 mmol) of 5-(2-thienylmethylene)thiazolidine-2,4-dione in 70 ml of N,N-dimethylformamide, 1.12 ml (7.5 mmol) of 1,8-diazabicyclo[5.4.0-7-undecene was added, followed by heating at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=2/1→1/1→ethyl acetate). The resulting crude crystal was purified by recrystallization (solvent, chloroform/diethyl ether) to yield 1.54 g (49.5%, light yellow crystal) of the desired product.m.p. 116.0°-117.0° C.; 1H-NMR (CDCl3, 200 MHz) δ 1.64-1.92 (4H, m), 3.03 (2H, t, J=7.0 Hz), 3.76 (2H, t, J=7.0 Hz), 6.92 (1H, dd, J=1.0, 7.0 Hz), 7.15 (1H, dd, J=7.2, 9.2 Hz), 7.21 (1H, dd, J=3.8, 5.2 Hz), 7.42 (1H, d, J=3.6 Hz), 7.58 (1H, d, J=9.0 Hz), 7.68 (1H, d, J=5.0 Hz), 7.70 (1H, d, J=1.4 Hz), 7.85 (1H, s), 8.05 (1H, s); IR (KBr) 1728, 1678, 1599, 1369, 1128, 773, 727 cm-1 ; Anal. Calcd for C19H17N3O2S3 : C, 54.92; H, 4.12; N, 10.11. Found: C, 54.67, H, 4.18; N, 10.03
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]([OH:16])=[O:15])[CH:12]2[CH2:17][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]([O:39][CH2:40][C:41]([C:43]1[CH:44]=[CH:45][C:46]2[C:52]3[CH:53]=[CH:54][C:55]([C:57](=[O:60])[CH2:58]Br)=[CH:56][C:51]=3[CH2:50][O:49][CH2:48][C:47]=2[CH:61]=1)=[O:42])=[O:38])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]([O:16][CH2:58][C:57]([C:55]2[CH:54]=[CH:53][C:52]3[C:46]4[CH:45]=[CH:44][C:43]([C:41](=[O:42])[CH2:40][O:39][C:37]([CH:33]5[CH2:34][CH2:35][CH2:36][N:32]5[C:30]([O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:31])=[O:38])=[CH:61][C:47]=4[CH2:48][O:49][CH2:50][C:51]=3[CH:56]=2)=[O:60])=[O:15])[CH:12]2[CH2:17][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc2c(c1)COCc1cc(C(=O)CBr)ccc1-2
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc2c(c1)COCc1cc(C(=O)COC(=O)C3C4CCC(C4)N3C(=O)OC(C)(C)C)ccc1-2
Reaction time: 10 h
Yield: 80.7 %

Procedure:
To the solution of 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (100 mg, 0.42 mmol) and triethylamine (50 μl, 0.36 mmol) in acetonitrile (2 ml) was added a solution of pyrrolidine-1,2-dicarboxylic acid 2-{2-[9-(2-bromo-acetyl)-5,7-dihydro-dibenzo[c,e]oxepin-3-yl]-2-oxo-ethyl}ester 1-tert-butyl ester (136 mg, 0.24 mmol) in DMF (4 ml). The mixture was stirred for 10 hours, and the solvent was evaporated. The mixture was diluted with EtOAc, and washed with water and brine, and was dried with sodium sulfate. Concentration gave 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{9-[2-(1-tert-butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-5,7-dihydro-dibenzo[c,e]oxepin-3-yl}-2-oxo-ethyl)ester 2-tert-butyl ester (142 mg). m/z: 731.3 (M−H)−, 755.2 (M+Na)+.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19](O)=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:45][C@@H:46]([C:59]([NH:61][C@H:62]([C:70]([O:72][CH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)=[O:71])[CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:60])[CH2:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:50]([CH:57]=[O:58])[CH:49]=1>C(Cl)Cl.CN(C=O)C>[NH:1]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C@H:2]([C:19]([NH:45][C@@H:46]([C:59]([NH:61][C@H:62]([C:70]([O:72][CH2:73][C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1)=[O:71])[CH2:63][C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)=[O:60])[CH2:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:50]([CH:57]=[O:58])[CH:49]=1)=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2)cc1
Reactant: N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc3cn(C=O)c4ccccc34)C(=O)N[C@@H](Cc3ccccc3)C(=O)OCc3ccccc3)c2)cc1
Yield: 83.4 %

Procedure:
To a solution of Boc-His(Tos)-OH (0.81 g) in methylene chloride (10 ml) were added NMM (0.22 ml) and isobutyl chloroformate (0.26 ml) successively at -15° C., and the mixture was stirred for ten minutes. On the other hand, a solution of HCl.H-D-Trp(CHO)-Phe-OBzl (1.00 g) in DMF (20 ml) was cooled at -30° C. and thereto was added NMM (0.22 ml). This solution was added to the above mentioned mixture and stirred for two hours at -30° C. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with 2% hydrochloric acid, water, 2% sodium hydrogencarbonate, water and saturated sodium chloride solution, and dried over magnesium sulfate. After evaporation, the residue was subjected to column chromatography on silica gel (100 g) and eluted with a mixture of chloroform and methanol (100:1). The fractions containing the object compound were combined and evaporated. The residue was pulverized with n-hexane, filtered, washed with n-hexane and dried to give Boc-His(Tos)-D-Trp(CHO)-Phe-OBzl (1.42 g).
Reaction SMILES: [CH:1]1([CH:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[NH:11][C:10]([O:9][CH:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH3:8])=[O:25])=[CH:18][CH:19]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)C1CCCCC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)C4CCCCC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-cyclohexyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C(NS(C1C=CC=CC=1B(O)O)(=O)=O)(C)(C)C.BrC1C=CC(C2N=CC(N)=NC=2)=C(OC)C=1.[NH2:34][C:35]1[N:36]=[CH:37][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48]([S:53]([NH:56]C(C)(C)C)(=[O:55])=[O:54])=[CH:49][CH:50]=[CH:51][CH:52]=3)=[CH:43][C:42]=2[O:61]C)=[N:39][CH:40]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:34][C:35]1[N:36]=[CH:37][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48]([S:53]([NH2:56])(=[O:55])=[O:54])=[CH:49][CH:50]=[CH:51][CH:52]=3)=[CH:43][C:42]=2[OH:61])=[N:39][CH:40]=1
Reactant: COc1cc(-c2ccccc2S(=O)(=O)NC(C)(C)C)ccc1-c1cnc(N)cn1
Agent: BrB(Br)Br
Agent: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Agent: COc1cc(Br)ccc1-c1cnc(N)cn1
Solvent: ClCCl
Product: Nc1cnc(-c2ccc(-c3ccccc3S(N)(=O)=O)cc2O)cn1
Temperature: 25 °C

Procedure:
The title compound was prepared in a manner similar to that described in Example 589 using (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid and 5-(4-bromo-2-methoxyphenyl)pyrazin-2-amine. After the coupling, the tert-butyl group and methyl group were removed by treating a solution consisting of 4′-(5-aminopyrazin-2-yl)-N-(tert-butyl)-3′-methoxy-[1,1′-biphenyl]-2-sulfonamide (48 mg, 0.12 mmol) and DCM (2 mL), with BBr3 (0.14 mL, 1 M in DCM) at −78° Celsius. The reaction mixture was warmed to room temperature. After the starting material was consumed the reaction mixture was poured into saturated NH4Cl (10 mL) and extracted with DCM (3×10 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated to dryness. The resultant residue was subjected to HPLC purification to provide the title compound. MS (ESI): mass calcd. for C16H14N4O3S, 342.38; m/z found, 343.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 8.18 (dd, J=7.9, 1.4, 1H), 7.93 (d, J=1.4, 1H), 7.80 (d, J=8.2, 1H), 7.64-7.57 (m, 1H), 7.57-7.48 (m, 1H), 7.39 (dd, J=7.6, 1.3, 1H), 7.12 (dd, J=8.1, 1.9, 1H), 7.09-7.03 (m, 1H), 4.38 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[NH:10][C:11]1[NH:15][C:14]2[CH:16]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH:22]3[CH2:26][N:27]([CH3:29])[CH3:28])[C:18]([Cl:20])=[CH:19][C:13]=2[N:12]=1.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:4][C:3]=1[NH:10][C:11]1[NH:15][C:14]2[CH:16]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH:22]3[CH2:26][N:27]([CH3:29])[CH3:28])[C:18]([Cl:20])=[CH:19][C:13]=2[N:12]=1
Reactant: CN(C)CC1CCCN1c1cc2[nH]c(Nc3cc(CN)ccc3Cl)nc2cc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CN(C)CC1CCCN1c1cc2[nH]c(Nc3cc(CNC(=O)C(C)(C)C)ccc3Cl)nc2cc1Cl

Procedure:
The title compound was prepared analogously to example 3 step (e) from 4-chloro-3-[5-chloro-6-(2-dimethylaminomethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine (30 mg), pivaloyl chloride (10 μL, 0.06 mmol) and TEA (70 μL, 0.54 mmol) in THF (2 mL).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)[CH2:10][CH:11]([CH3:16])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH2:38].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH:38][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([CH:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:10][CH:11]([CH3:16])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:25][CH:24]=1
Reactant: COC(=O)CCN
Reactant: CCCCC(C)CC(Sc1ccc(Br)cc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(C)CC(Sc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a mixture of 4-[1-(4-bromo-phenylsulfanyl)-3-methyl-heptyl]benzoic acid (1700 mg, 4.18 mmol) in methylene chloride (42 mL) are added triethyl amine (1.75 mL, 12.53 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (875 mg, 6.27 mmol) and EDCI (2408 mg, 12.53 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving 3-{4-[1-(4-bromo-phenylsulfanyl)-3-methyl-heptyl]-benzoylamino}-propionic acid methyl ester (1.640 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:14][C:15]1[CH:20]=[C:19]([C:21]2[NH:30][C:29](=[O:31])[C:28]3[C:23](=[CH:24][C:25](F)=[CH:26][C:27]=3[O:32][CH3:33])[N:22]=2)[CH:18]=[C:17]([CH3:35])[N:16]=1.O>CS(C)=O.C(O)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:25]1[CH:24]=[C:23]2[C:28]([C:29](=[O:31])[NH:30][C:21]([C:19]3[CH:18]=[C:17]([CH3:35])[N:16]=[C:15]([CH3:14])[CH:20]=3)=[N:22]2)=[C:27]([O:32][CH3:33])[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOCc1ccccc1
Reactant: COc1cc(F)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(OCCOCc2ccccc2)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-benzyloxy-ethanol (1.15 g, 10.0 mmol) in dimethyl sulfoxide (4 mL), sodium hydride (60% suspension in mineral oil, 0.20 g, 5.0 mmol) was added in portions and the reaction mixture was stirred at room temperature for 20 minutes. To this reaction mixture was added 2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one (0.30 g, 1.0 mmol) and the reaction mixture was stirred at 85° C. for 24 hours. Water was added, and the mixture was acidified to pH approximately 4-5 with acetic acid and the precipitated solid was filtered to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; eluting with hexane and ethyl acetate 10:1) to obtain the title compound as a white solid. Yield: 0.140 g (32.4%). MP 178-180° C. MS (ES) m/z: 432.18 (M++1). 1H NMR (400 MHz, CDCl3): δ 10.90 (s, 1H), 7.69 (s, 2H), 7.29-7.40 (m, 5H), 6.85 (d, J=2.0 Hz, 1H), 6.59 (d, J=2.0 Hz, 1H), 4.66 (s, 2H), 4.29 (m, 2H), 3.97 (s, 3H), 3.89 (m, 2H), 2.66 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][OH:6].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:6][CH2:5][CH2:4][CH:3]([C:2]([F:11])([F:12])[F:1])[CH2:7][CH2:8][CH2:9][CH3:10])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC(CCO)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reaction time: 2 h
Yield: 92 %

Procedure:
0.48 g of 3-trifluoromethyl-1-heptanol was dissolved in 0.79 g of pyridine, and the solution was cooled with ice, followed by addition of 0.5 g of p-toluenesulfonyl chloride, stirring for 2 hours under cooling with ice and stirring for 2 hours at room temperature. After the reaction, the product was acidified with 2N-hydrochloric acid and extracted with methylene chloride. The resultant methylene chloride solution was washed with water and dried with magnesium sulfate, and the solvent was distilled off, whereby 3-trifluoromethylheptyl p-toluenesulfonate was obtained in an amount of 0.82 g (yield: 92%) and showed: [α]D23 +0.5, [α]43523 +2.2 (c 2, methylene chloride).
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12]C)[CH2:6][CH2:5]1.Br[C:38]1[S:39][C:40]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])=[CH:41][N:42]=1.C(OC(C)C)(=O)C>>[OH:1][C:2]([CH3:35])([CH3:36])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:38]3[S:39][C:40]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])=[CH:41][N:42]=3)=[CH:18][CH:19]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN(C)C(=O)c1cnc(Br)s1
Solvent: CC(=O)OC(C)C
Product: C[C@@H](c1ccc(-c2ncc(C(=O)N(C)C)s2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 2-bromo-N,N-dimethylthiazole-5-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.215 min, m/z=450.1; 1H NMR (CD3OD) 0.92 (s, 3H), 1.22 (s, 3H), 1.53 (d, 3H), 2.11 (s, 2H), 2.19-2.28 (m, 1H), 2.40-2.58 (m, 2H), 3.00-3.31 (m, 4H), 5.56 (m, 1H), 7.02 (d, 2H), 7.26-7.39 (m, 5H), 7.69 (d, 2H), 8.08 (s, 1H). The compound was dissolved in refluxing isopropyl acetate and allowed to cool slowly to rt to afford a solid with mp 110-111.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:14][CH2:13][C@H:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[N:11]2[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCCC1.[Ni]>[O:33]1[CH2:34][CH2:35][N:30]([C:27]2[CH:28]=[CH:29][C:24]([N:11]3[C@@H:12]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[CH2:13][CH2:14][C@@H:10]3[C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)=[CH:25][CH:26]=2)[CH2:31][CH2:32]1
Reactant: O=[N+]([O-])c1ccc([C@H]2CC[C@H](c3ccc([N+](=O)[O-])cc3)N2c2ccc(N3CCOCC3)cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc([C@H]2CC[C@H](c3ccc(N)cc3)N2c2ccc(N3CCOCC3)cc2)cc1
Yield: 44 %

Procedure:
The product from Example 98A in tetrahydrofuran (20 mL) was added to Ra-Ni (water wet, A-7000, 0.8 g, 12.63 mmol) in a 50 mL pressure bottle and stirred for 2 hours at ambient temperature under 30 psi of hydrogen. The mixture was filtered through a nylon membrane and concentrated to afford the title compound (0.31 g, 44%). MS (DCI) m/z 415 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[OH:25].Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH3:17][C:18]1[CH:23]=[C:22]([CH:21]=[C:20]([CH3:24])[C:19]=1[OH:25])[C:8]([C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: Cc1cccc(C)c1O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cc(C(=O)c2ccc([N+](=O)[O-])cc2)cc(C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
To a stirring solution of p-nitrobenzoyl chloride (76.1 g, 0.410 mol) in 250 mL nitrobenzene were added 82 g of AlCl3 (0.62mol). To this mixture a solution of 50 grams of 2,6-dimethylphenol (0.41 mole) in 250 mL nitrobenzene was added dropwise over a period of 45 minutes, and the resulting mixture was stirred 16 hours at room temperature. The reaction was poured into 2L of 3% HCl and ice and extracted 3×1L with Et2O (i.e., three times with 1L each time of diethyl ether). The combined ethereal layers were washed with lL of saturated NaHCO3, then extracted 2×1L with 10% NaOH. The combined basic extracts were acidified with concentrated HCl to give a white precipitate; filtration followed by recrystallization from CH3OH/H2O gave 37 g (33%) of white powder consistent with the desired product by TLC, IR, mass spectroscopy, NMR and elemental analysis, m.p. 182.5-184.5.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:7])[CH:4]([CH3:6])[CH3:5].[H-].[Na+].C(O[C:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:26][N:25]=1)[CH:19]=[CH:18]2)=O)C>C1COCC1>[C:40]([O:39][C:37]([N:34]1[CH2:33][CH2:32][CH:31]([O:30][C:27]2[CH:26]=[N:25][C:24]([N:20]3[C:21]4[C:17](=[CH:16][C:15]([C:13]5[O:1][N:2]=[C:3]([CH:4]([CH3:6])[CH3:5])[N:7]=5)=[CH:23][CH:22]=4)[CH:18]=[CH:19]3)=[CH:29][CH:28]=2)[CH2:36][CH2:35]1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)C(N)=NO
Reactant: CCOC(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1noc(-c2ccc3c(ccn3-c3ccc(OC4CCN(C(=O)OC(C)(C)C)CC4)cn3)c2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 22.6 %

Procedure:
To a stirred solution of N′-hydroxyisobutyrimidamide (0.10 g, 1.0 mmol) in dry THF (10 mL), NaH (0.078 g, 3.26 mmol) was added and stirred at 60° C. for 2 h. The reaction contents were brought to room temperature, Ethyl-1-(5-((1-(tert-butoxycarbonyl)piperidin-4-yl) oxy) pyridin-2-yl)-1H-indole-5-carboxylate (0.205 g, 0.440 mmol) was added and stirred at 60° C. for 3 h. The reaction was quenched by methanol at 0° C. and concentrated in vacuo. The resultant residue was dissolved with ethyl acetate and washed with water, the organic layer was separated, concentrated in vacuo and the resulting residue was purified by flash column chromatography to give the title compound (0.050 g, 10.16%).
Reaction SMILES: [S:1]=[C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[NH:3]1.CI.[OH-].[Na+].[C:13](O)(=O)C>O>[CH3:13][S:1][C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[N:3]=1
Reactant: CC(=O)O
Reactant: O=c1[nH]ncc(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSc1cn[nH]c(=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound 9a (30 g, 232 mmol) and CH3I (15.9 ml, 255 mmol) are placed in 300 ml of water. 18.6 g of NaOH (465 mmol) are added and the mixture is stirred for 1 h at room temperature. The reaction mixture, cooled on a bed of ice, is neutralized using 27 ml of acetic acid and then extracted with dichloromethane. The organic phases are dried (MgSO4) and then concentrated to dryness. After recrystallizing from ether, 29.9 g of compound 9b are isolated.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[CH:14])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=1[F:24]>>[C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:20]3[CH:21]=[CH:22][C:17]([F:16])=[C:18]([F:24])[CH:19]=3)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cnc2cc(C(C)(C)C)nn2c1
Reactant: Fc1ccc(I)cc1F
Product: CC(C)(C)c1cc2ncc(C#Cc3ccc(F)c(F)c3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=312.2 (M+H+), can be prepared in accordance with the general method of example 1 from 2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 1,2-difluoro-4-iodobenzene.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:18][O:19][C:20](=[O:26])[C@@H:21]([CH:23]([CH3:25])[CH3:24])[NH2:22].C([BH3-])#N.[Na+]>>[CH3:18][O:19][C:20](=[O:26])[C@@H:21]([CH:23]([CH3:25])[CH3:24])[NH:22][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: COC(=O)[C@H](N)C(C)C
Reactant: N#Cc1ccccc1-c1ccc(C=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)[C@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C

Procedure:
The starting material can be obtained, for example, analogously to Example 1b): Reaction of 4.0 g of 2'-cyanobiphenyl-4-carbaldehyde, 19.3 g of molecular sieve 5 A, 3.8 g of (D)-valine methyl ester hydrochloride and 1.43 g of sodium cyanoborohydride yields N-[(2'-cyanobiphenyl-4-yl)methyl]-(D)-valine methyl ester after flash chromatography (N3). (TLC: N2) Rf : 0.56.