Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]1[CH2:31][CH2:32][N:33]([CH2:20][CH2:19][CH2:18][C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:34][CH2:35]1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)c1C

Procedure:
77 mg (81%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (64 mg, 0.231 mmol), 1-(2,3-dimethylphenyl)piperazine (40 mg, 0.210 mmol), DIPEA (0.037 mL, 0.210 mmol) and NaBH(OAc)3 (156 mg, 0.735 mmol).
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:13])[C@H:4]([NH:11][CH3:12])[CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.CCN(C(C)C)C(C)C.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]=1[CH3:33]>C(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:11]([C@@H:4]([C@H:3]([O:2][CH3:1])[CH3:13])[CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH3:12])=[O:29])=[CH:26][C:25]=1[CH3:33]
Reactant: Cc1cc(C(=O)Cl)ccc1F
Reactant: CN[C@H](CN1CCCC1)[C@@H](C)OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H](C)[C@@H](CN1CCCC1)N(C)C(=O)c1ccc(F)c(C)c1
Yield: 73.6 %

Procedure:
To a solution of (2R,3R)-3-methoxy-N-methyl-1-(pyrrolidin-1-yl)butan-2-amine (Compound M6) (80 mg, 0.43 mmol) in DCM (1.5 mL) was DIPEA (0.090 mL, 0.52 mmol) and 4-fluoro-3-methylbenzoyl chloride (0.061 mL, 0.43 mmol) added. The resultant mixture was stirred at rt overnight. The mixture was diluted with DCM (5 mL), washed with NaHCO3 (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (102 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][N+:14]([O-])=O)=[CH:8][C:4]=1[C:5]([O-:7])=[O:6].[ClH:17].[H][H].[CH3:20]O>[Pd]>[ClH:17].[NH2:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([O:7][CH3:20])=[O:6]
Reactant: [H][H]
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1C(=O)[O-]
Reactant: CO
Agent: [Pd]
Agent: Cl
Product: COC(=O)c1cc(CCN)ccc1OC

Procedure:
To a solution of 0.429 g (1.81 mmol) of 2-methoxy-5-(2-nitrovinyl)benzoate in 18 mL of methanol was added 0.75 mL of 12 N HCl followed by 50 mg of 10% palladium on carbon. The mixture was stirred for 3 h under a balloon hydrogen atmosphere then degassed with nitrogen and filtered. Evaporation gave methyl 5-(2-aminoethyl)-2-methoxybenzoate hydrochloride as a sticky oil.
Reaction SMILES: [NH2:1][CH:2]([CH3:42])[CH2:3][O:4][C@@H:5]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([NH:14][C@@H:15]([CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:16][N:17]([CH3:27])[C:18](=[O:26])[O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:13])[CH2:7]1.CCN(C(C)C)C(C)C.Cl[C:53]([O:55][CH3:56])=[O:54]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:56][O:55][C:53]([NH:1][CH:2]([CH3:42])[CH2:3][O:4][C@@H:5]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([NH:14][C@@H:15]([CH2:28][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:16][N:17]([CH3:27])[C:18](=[O:26])[O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:13])[CH2:7]1)=[O:54]
Reactant: CC(N)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of crude 2-(trimethylsilyl)ethyl (2S)-2-((3R)-3-((1R)-(2-aminopropoxy)(3-chlorophenyl)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate (0.1340 g), obtained as, described above, DMAP (0.151 g), DIPEA (2 mL), and methyl chloroformate (0.483 g) in CH2Cl2 was stirred at rt for 2 d. After the reaction mixture was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC to give 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((R)-(2-(methoxycarbonylamino)propoxy)(3-chlorophenyl)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate. MS ESI +ve m/z 705 (M+Na).
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:36][CH2:37][CH2:38][C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=1>>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][C:13](=[O:15])[N:14]1[CH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]#[N:44])=[CH:45][CH:46]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Reactant: N#Cc1ccc(CCCBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCc1ccc(C#N)cc1)Cc1ccccc1

Procedure:
Analogous to the procedure described for Compound 1A, Step D, the anion derived from 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-pyrrolidin-2-one (262.8 mg, 0.756 mmol) and NaHMDS (0.83 mL, 0.83 mmol) was reacted with 4-(3-bromo-propyl)-benzonitrile (186 mg, 0.832 mmol) at 70° C. for 24 h. Purification by medium pressure chromatography (5:1 hexanes:EtOAc to 1:1 hexanes:EtOAc to 1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzonitrile (257.6 mg). 1H NMR (CDCl3) δ 7.56 (m, 2H), 7.26 (m, 5H), 7.13 (m, 2H), 3.85 (m, 1H), 3.62 (m, 1H), 3.48 (m, 1H), 2.93 (m, 1H), 2.82-2.60 (m, 4H), 2.29 (m, 2H), 1.88-1.25 (m, 7H); MS 491.5 (M+1).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH:13]1([CH2:19][CH:20]([NH:24][C:25](=[N:27][S:28]([CH3:31])(=[O:30])=[O:29])C)[C:21]([OH:23])=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[NH2:32][C@@H:33]([CH2:45][CH3:46])[CH:34]([C:36]1[O:37][C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1)[OH:35].CN1CCOCC1>C(Cl)Cl.Cl>[O:37]1[C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=[C:36]1[CH:34]([OH:35])[C@@H:33]([NH:32][C:21](=[O:23])[CH:20]([NH:24][CH:25]=[N:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:19][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH2:45][CH3:46]
Reactant: CC(=NS(C)(=O)=O)NC(CC1CCCCC1)C(=O)O
Reactant: CC[C@H](N)C(O)c1nc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@H](NC(=O)C(CC1CCCCC1)NC=NS(C)(=O)=O)C(O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 91.1 %

Procedure:
A mixture of ethyldimethylaminopropyl carbodiimide hydrochloride (0.198 g, 1.14 mmol), hydroybenzotriazole (0.114 g, 0.742 mmol), 3-cyclohexyl-2-(1-methanesulfonyliminoethylamino)-propionic acid (0.205 g, 0.742 mmol) and 2(S)-amino-1-benzoxazol-2-ylbutan-1-ol (0.153 g, 0.743 mmol) in methylene chloride (6 mL) was cooled in an ice bath and then N-methylmorpholine (0.155 g, 1.55 mmol) was added to the reaction mixture which was then stirred at room temperature for 40 min. The reaction mixture was diluted with ice water and dilute hydrochloric acid and the product extracted with ethyl acetate. The extracts were washed with aqueous sodium bicarbonate, then brine, then dried over magnesium sulfate and evaporated to give of N-[1(S)-(benzoxazol-2-ylhydroxymethyl)propyl]-3-cyclohexyl-2-[(methanesulfonyliminomethyl)-amino]propionamide (0.314 g). Exact mass 464.21. Found: M+H=465.3, M+Na=487.3, M−H=463.1.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[C:22]=[O:23]>CO>[O:30]([C:27]1[CH:26]=[CH:25][C:24]([NH:21][C:22](=[O:23])[NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[CH:29][CH:28]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)Nc1ccc(Oc2ccccc2)cc1
Reaction time: 18 h

Procedure:
To a solution of (R)-aminocarnitine (27 mg, 0.17 mmol) and diisopropylethylamine (88 uL, 0.51 mmol) in MeOH (2 mL) was added 1-isocyanato-4-phenoxybenzene (71 mg, 0.34 mmol) and the reaction stirred for 18 h. The MeOH was removed in vacuo and the residue stirred with 1:1 ether/EtOAc. Impurities were dissolved in the ether/EtOAc and discarded and the remaining material was taken up into 90:10 CH2Cl2/MeOH and then loaded onto a short SiOH plug. The title compound was eluted by increasing MeOH content in 10% steps to 60%. The compound was then taken up into 90:10 CH2Cl2/MeOH and filtered through a plug of celite which gave after drying the title compound as a white powder (10 mg, 16%). 1H NMR (400 MHz, CD3OD) δ 7.37-7.30 (m, 4H), 7.07 (t, 1H, J=7.2 Hz), 6.95-6.92 (m, 4H), 4.73-4.71 (m, 1H), 3.80-3.54 (m, 2H), 3.26 (s, 9H), 2.81-2.68 (m, 2H); MS ESI 372.2 [M+H]+, calcd for [C20H25N3O4+H]+ 372.43.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[C:9]([C:22]([F:25])([F:24])[F:23])[CH:8]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C.O>[N:16]1([S:13]([C:10]2[CH:11]=[CH:12][C:7]([C:26](=[O:28])[CH3:27])=[CH:8][C:9]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=S(=O)(c1ccc(Br)cc1C(F)(F)F)N1CCOCC1
Reactant: CC(=O)OC(C)=O
Agent: CC(C)[Mg]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(S(=O)(=O)N2CCOCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
A solution of isopropylmagnesium chloride (2M in THF, 10 ml, 20.04 mmol) was added drop wise to a solution of the product obtained in step 1 (5.00 g, 13.36 mmol) in THF (30 ml) at −10° C. The mixture was stirred at this temperature for 1 h and then added drop wise to acetic acid anhydride (12.6 ml, 133.60 mmol) at −15° C. The reaction mixture was stirred at 0° C. for 2 h and allowed to warm up slowly to RT. Water (100 ml) was added and the reaction mixture was stirred at 60° C. for 15 min. The mixture was diluted with ethyl acetate at RT, neutralized with aqueous NaHCO3, washed with brine, dried over sodium sulphate and evaporated. Purification of the crude product by silica gel chromatography using ethyl acetate/n-heptane gave the desired product (2.00 g, 44%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([NH:27][CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2cccc(F)c2)c1C#N
Reactant: NCc1ccccn1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccn2)nc(N)nc1-c1cccc(F)c1

Procedure:
From 2-amino-4-(3-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-picolylamine in DME. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:21][CH:22]([CH3:26])[C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:21][CH:22]([CH3:26])[C:23]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:24]
Reactant: CC(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cl)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a mixture of tert-butyl piperazine-1-carboxylate (2.0 g, 11 mmol) in methylene chloride (20 mL) was added triethylamine (3.0 mL, 21 mmol) followed by 2-chloropropanoyl chloride (1.5 g, 12 mmol) drop-wise at 0° C. The reaction was stirred for 1 h, quenched with water, and extracted with dichloromethane. The combined organic layers were washed with water, brine, dried over magnesium sulfate and then evaporated to dryness to provide the crude product (3 g, 101%). LCMS calculated for C8H14ClN2O3 (M-Bu+H)+: m/z=221.1; Found: 221.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10]([CH3:18])([CH2:12][CH2:13][C:14](Cl)([CH3:16])[CH3:15])[CH3:11]>>[Br:1][C:2]1[C:3]([OH:8])=[CH:4][C:5]2[C:10]([CH3:18])([CH3:11])[CH2:12][CH2:13][C:14]([CH3:16])([CH3:15])[C:6]=2[CH:7]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Oc1ccccc1Br
Product: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Yield: 78.4 %

Procedure:
In a manner similar to that of Example 36(a), by reaction of 67.14 g (388.0 mmol) of 2-bromophenol with 71.10 g (388.0 mmol) of 2,5-dichloro-2,5-dimethylhexane, 86.13 g (78%) of the expected product are obtained in the form of a white solid with a melting point of 90–94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:21]([N:23]([CH2:35][CH3:36])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:22]>C(#N)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11]([N:32]3[CH2:33][CH2:34][CH:29]([CH2:28][CH2:27][O:26][CH2:25][CH2:24][N:23]([CH2:21][CH3:22])[CH2:35][CH3:36])[CH2:30][CH2:31]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: CCN(CC)CCOCCC1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Solvent: CC#N
Product: CCN(CC)CCOCCC1CCN(C(=O)N2c3cc(Cl)ccc3C(=O)Nc3cccnc32)CC1
Yield: 43 %

Procedure:
Prepared analogously to Example 4 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[2-[2-(diethylamino)ethoxy]ethyl]piperidine in a yield of 43% of theory. Colourless crystals, m.p. 145°-146° C. (acetonitrile), Rf 0.39 (conditions as in Example 54).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=3)[CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:22][NH2:23]>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:23][CH3:22])=[CH:16][CH:15]=3)[CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)nc1-c1cc(-c2ccc(CCl)cc2)no1
Reactant: CN
Solvent: CCO
Product: CNCc1ccc(-c2cc(-c3nc(Br)cnc3N)on2)cc1
Temperature: 70 °C

Procedure:
Trifluoroacetic Acid (2.500 mL) was added to a solution of tert-butyl N-[5-bromo-3-[3-[4-(chloromethyl)phenyl]isoxazol-5-yl]pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (500 mg, 0.8836 mmol) in dichloromethane (20.00 mL) and the mixture was stirred at ambient temperature for 10 minutes. The reaction mixture was concentrated in vacuo to give 5-bromo-3-[3-[4-(chloromethyl)phenyl]isoxazol-5-yl]pyrazin-2-amine (323.1 mg, assumed 100% yield) which was used as such in next step. LC/MS m/z 365.4 [M−H]− Step 2: 5-bromo-3-[3-[4-(chloromethyl)phenyl]isoxazol-5-yl]pyrazin-2-amine was dissolved in ethanol, methanamine in ethanol (2.495 g, 3.300 mL, 26.51 mmol) was added and the mixture was stirred at 70° C. in a microwave. The reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. Combined organic extract was dried (MgSO4) and concentrated in vacuo yielding 5-bromo-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine as an oil that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH:11][CH:12]([CH3:14])C)[C:5]=2[S:4][CH:3]=1.[N:15]1([CH2:20]CCN)[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH:11][CH2:12][CH2:14][CH2:20][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:5]=2[S:4][CH:3]=1
Reactant: NCCCN1CCCC1
Reactant: CC(C)Nc1ncnc2c(Br)csc12
Product: Brc1csc2c(NCCCN3CCCC3)ncnc12

Procedure:
Compound 78A was prepared in a similar manner to the synthesis of compound 69A by substituting propan-2-amine with 3-(pyrrolidin-1-yl)propan-1-amine: APCI (+)LC/MS: 342 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([O:38]CC3C=CC=CC=3)=[C:17]([CH:37]=2)[C:18]([NH:20][C:21]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[O:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl>C(OCC)(=O)C.CO.[C].[Pd]>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([OH:38])=[C:17]([CH:37]=2)[C:18]([NH:20][C:21]2[CH:30]=[C:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[O:19])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(C(C)=O)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(C(C)=O)CC2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution mixture of the obtained methyl 2-(5-(2-(4-acetylpiperazin-1-yl)ethoxy)-2-(benzyloxy)benzamido)-4-phenylbenzoate in ethyl acetate (1.5 mL) and methanol (1.5 mL), 10% palladium-carbon (0.15 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour and 30 minutes. Chloroform and methanol were added to the reaction mixture. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.083 g of methyl 2-(5-(2-(4-acetylpiperazin-1-yl)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoate as a light yellow solid.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH2:10]([O:12][C:13](=[O:29])[C:14]([CH3:28])([CH3:27])[CH2:15][CH2:16][CH2:17][CH:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[CH3:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:10]([O:12][C:13](=[O:29])[C:14]([CH3:28])([CH3:27])[CH2:15][CH2:16][CH2:17][CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[CH2:5]1)[CH3:11]
Reactant: c1cc2c(s1)CCNC2
Reactant: CCOC(=O)C(C)(C)CCCC(Br)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCCC(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 70 °C
Yield: 34.1 %

Procedure:
4,5,6,7-tetrahydro-thieno[3,2-c]pyridine hydrochloride (2.5 g, 8.8 mmol) was mixed with sodium hydroxide (2.7 g) in water (80 mL). The corresponding free amine was extracted with dichloromethane (3×20 mL), which was dried over Na2SO4, filtered, and concentrated to provide 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (1.22 g). 4,5,6,7-Tetrahydro-thieno[3,2-c]pyridine (1.22 g, 8.8 mmol) and 6-bromo-6-(2-chlorophenyl)-2,2-dimethylhexanoic acid ethyl ester (2.5 g, 8.8 mmol) were combined in DMF (90 mL) and potassium carbonate (1.82 g, 13.2 mmol) was added. The mixture was heated to 70° C. for 1 h and then 60° C. overnight. The mixture was cooled to room temperature and water (100 mL) was added. The product was extracted with diethyl ether (3×150 mL). The combined ether extracts were washed with water (3×80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate/heptane=1/10) to provide 6-(2-chlorophenyl)-6-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5yl)-2,2-dimethylhexanoic acid ethyl ester (Compound Ie, 1.26 g, 42.04%) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.49 (d, 1H, J=7.8 Hz), 7.37 (d, 1H, J=8.1 Hz), 7.26-7.14 (m, 2H), 7.05 (d, 1H, J=5.4 Hz), 6.70 (d, 1H, J=5.4 Hz), 4.19 (dd, 1H, J=8.7, 4.5 Hz), 4.02 (q, 2H, J=7.2 Hz), 3.81 (d, 1H, J=14.4 Hz), 3.47 (d, 1H, J=14.4 Hz), 2.88-2.66 (m, 1.95-1.74 (m, 2H), 1.52-1.46 (m, 2H), 1.13 (t, 3H, J=7.2 Hz), 1.15-1.08 (m, 2H), 1.07 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 177.63, 139.16, 134.91, 134.21, 133.55, 129.53, 129.03, 128.03, 126.81, 124.46, 122.65, 63.47, 60.33, 50.73, 48.04, 42.31, 41.04, 33.48, 26.14, 25.58, 25.12, 21.07, 14.44. MS (GC-CI): Calculated for C23H30ClNO2S (MH)+: 420.1758; found 420.1725.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:32][C:33]1[CH:38]=[C:37]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[O:12])=[CH:21][CH:20]=3)[CH:16]=[C:17]2[C:22]([N:24]2[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]2)=[O:23])[CH:36]=[CH:35][CH:34]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(Cl)c1)N1CCN(C2CCC2)CC1
Yield: 10 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless solid (10%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:15])[C:9]=1[NH:16]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C.C(OC(C)C)(C)C>C(OCC)(=O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:15])[C:9]=1[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nccc(Cc2ccccc2)c1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: COc1nccc(Cc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
To a solution of tert-butyl (4-benzyl-2-methoxypyridin-3-yl)carbamate (25.4 g) in ethyl acetate (202 mL) was added 4N hydrogen chloride/ethyl acetate solution (202 mL) at room temperature, and the mixture was stirred overnight at room temperature, and then at 50° C. for 1 hr. To the reaction mixture was added diisopropyl ether at room temperature, and the obtained precipitate was collected by filtration, and washed with diisopropyl ether. Saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane) to give the title compound (8.8 g).