Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][N:6]=2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)=[CH:16][C:15]=1[C:12]#[C:11][C:8]1[CH:9]=[N:10][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[N:6][CH:7]=1
Reactant: C#Cc1cnc(NC2CC2)nc1
Reactant: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(I)c4)[nH]c3c2)CC1
Product: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(C#Cc5cnc(NC6CC6)nc5)c4)[nH]c3c2)CC1

Procedure:
The title compound was synthesized from N-cyclopropyl-5-ethynylpyrimidin-2-amine and 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1 H-benzo[d]imidazole in a manner similar to that described for in Example 1. The title compound was obtained as a brown solid. Mp:160-162° C.; 1H NMR (300 MHz, CDCl3) δ: 8.43-8.45 (2 H, d, J=6.0 Hz), 8.12-8.15 (1 H, d, J=6.0 Hz), 7.58-7.60 (1 H, d, J=6.0 Hz), 7.52 (1 H, s), 7.45-7.47 (1 H, d, J=6.0 Hz), 7.38-7.40 (1 H, d, J=6.0 Hz), 7.15-7.17 (1 H, d, J=6.0 Hz), 5.80 (1 H, s), 3.60 (2 H, s), 2.80 (8 H, brs), 2.59 (3 H, s), 1.35-1.39 (1 H, m), 0.82-0.88 (2 H, m), 0.58-0.60 (2 H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C28H29ClN7: 498.2167. found: 498.2163.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1F)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH3:21][O:22][CH2:23][C@@H:24]([NH2:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[NH:26][C@@H:24]([CH3:25])[CH2:23][O:22][CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC[C@H](C)N
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Product: COC[C@H](C)Nc1cc(F)ccc1C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
A mixture of 2,4-difluoro-benzoic acid tert-butyl ester (30 g, 140.05 mmol) and (S)-2-methoxy-1-methyl-ethylamine (100 mL) was stirred at 65° C. for 2 days. A satured solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3×). The organic phase was washed with water (2×), brine, dried over sodium sulfate filtered and evaporated to dryness to obtain a crude, which was purified by column chromatography on silica gel (exane-EtOAc 9:1). The title compound (33.38 g, 84%) was obtained as oil.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:13][C:12](=[O:14])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([Mg]Br)#[CH:16]>O1CCCC1>[C:1]([O:9][CH:10]1[CH2:13][C:12]([C:15]#[CH:16])([OH:14])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#C[Mg]Br
Reactant: O=C1CC(OC(=O)c2ccccc2)C1
Solvent: C1CCOC1
Product: C#CC1(O)CC(OC(=O)c2ccccc2)C1
Temperature: -76 °C
Reaction time: 0.5 h

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure A. Into a 25-mL three neck-round bottle flask, was placed a solution of 3-oxocyclobutyl benzoate (380 mg, 2.0 mmol, 1.00 equiv) in tetrahydrofuran (10 mL). Ethynylmagnesium bromide (0.5 M in tetrahydrofuran, 6 mL) was added dropwise, then resulting solution was stirred for 30 min at −76° C. When the mixture was warmed to room temperature in air, quenched by addition of saturated aqueous ammonium chloride (5 mL), the organic layer was washed by brine (10 mL), dried and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6). This resulted in 300 mg (69%) of 3-ethynyl-3-hydroxycyclobutyl benzoate as a white solid. 1H-NMR: (300 MHz, CDCl3, ppm) δ 8.100-8.000 (m, 1H), 7.610-7.500 (t, 1H), 7.499-7.380 (m, 2H), 5.160-5.040 (m, 1H), 3.150-3.010 (m, 2H), 2.610-2.470 (m, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1)=O>>[F:19][C:16]([F:18])([F:17])[C:13]1[N:11]2[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Reactant: N#Cc1ccc(C=O)cc1
Product: N#Cc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4c3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine with 4-formylbenzonitrile was carried out according to General Synthetic Method 9. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]piperazin-1-yl]methyl]benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[C:28]([N:30]([CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH3:31])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[CH:14]=2)[NH:9][N:8]=1)=[O:5].[O:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1.C(O)(C(F)(F)F)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>C(Cl)Cl>[F:24][C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([F:25])[CH:21]=1)[CH2:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:6][C:4](=[O:5])[C:3]1[CH:26]=[CH:27][C:28]([N:30]([CH2:32][CH2:33][CH2:34][N:35]([CH3:36])[CH3:37])[CH3:31])=[CH:29][C:2]=1[NH:1][CH:41]1[CH2:42][CH2:43][O:38][CH2:39][CH2:40]1
Reactant: CN(C)CCCN(C)c1ccc(C(=O)Nc2n[nH]c3ccc(OCc4cc(F)cc(F)c4)cc23)c(N)c1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCN(C)c1ccc(C(=O)Nc2n[nH]c3ccc(OCc4cc(F)cc(F)c4)cc23)c(NC2CCOCC2)c1
Yield: 46.5 %

Procedure:
2-Amino-N-[5-(3,5-difluoro-benzyloxy)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-benzamide (150 mg, 0.29 mmol) in DCM (4 mL) was treated, at 4° C., under a nitrogen atmosphere, with tetrahydro-4H-pyran-4-one (0.34 mL, 0.37 mmol), TFA (0.23 mL, 2.95 mmol) and finally with tetramethylammonium triacetoxyborohydride ((204 mg, 0.74 mmol). After 1.5 hours DCM, was added (25 mL) and the organic layer was washed with water (25 mL), saturated NaHCO3 solution (25 mL) and brine. After drying over anhydrous sodium sulfate, removal of the solvent and purification of the crude over silica gel (DCM: 7N NH3 in MeOH 9:1), 80 mg of title compound were obtained in 46% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:32][CH2:33][C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:23][CH:24]=1)=[O:35]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
1.7 g of 1-(4-aminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine and 0.55 g of triethylamine are introduced into 25 ml of methylene chloride. A solution of 0.6 g of chloroacetyl chloride is added dropwise thereto. The dark solution is left to stand overnight, diluted with 50 ml of methylene chloride, washed with 1N sodium hydroxide solution, dried over magnesium sulfate and concentrated by evaporation. The crystallisate so obtained is recrystallised from acetone, yielding 1-(4-chloroacetylaminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 146°-147°.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:34])[CH3:33]
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Reactant: CC(=O)Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A170) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[OH:13])(=[O:4])[CH:2]=[CH2:3].[CH:14]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH:14]([N:27]1[CH2:32][CH2:31][N:30]([CH2:3][CH2:2][C:1]([NH:5][C:6]2[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=2[OH:13])=[O:4])[CH2:29][CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CC(=O)Nc1cc(C)ccc1O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCO
Product: Cc1ccc(O)c(NC(=O)CCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
A solution of the compound (1) (1.52 g, 8.58 mmol) and 1-benzhydrylpiperazine (4.33 g, 17.2 mmol) in ethanol (14 ml) was heated under reflux for 3 hours. The solvent was distilled off from the reaction mixture, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel to give a colorless glassy substance (2). Yield 3.47 g (94%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][O:13][CH3:14])=[CH:7][C:6]=1[NH2:15])(=[O:3])[CH3:2].[CH3:16][O:17][C:18]([N:20]=[C:21]=[S:22])=[O:19]>CC(C)=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][O:13][CH3:14])=[CH:7][C:6]=1[NH:15][C:21]([NH:20][C:18]([O:17][CH3:16])=[O:19])=[S:22])(=[O:3])[CH3:2]
Reactant: COCSc1ccc(NC(C)=O)c(N)c1
Reactant: COC(=O)N=C=S
Solvent: CC(C)=O
Product: COCSc1ccc(NC(C)=O)c(NC(=S)NC(=O)OC)c1

Procedure:
1.0 G. of 1-acetamido-2-amino-4-methoxymethylthiobenzene in 30 ml. acetone is treated overnight with 2 g. methoxy carbonyl isothiocyanate at room temperature. The solution is concentrated and the residue triturated with ether. Recrystallization affords 2-acetamido-1-(3-methoxycarbonyl-2-thioureido)-5-methoxymethylthiobenzene.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH3:14].[Br:15][C:16]1[CH:17]=[C:18]([C:28](O)=O)[N:19]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[Br:15][C:16]1[CH:17]=[C:18]([C:28]2[O:12][C:11](=[O:13])[C:10]3[C:2](=[C:3]([CH3:14])[CH:4]=[C:5]4[CH:6]=[N:7][NH:8][C:9]4=3)[N:1]=2)[N:19]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Cc1cc2cn[nH]c2c(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 700 mg (3.66 mmol) of 6-amino-5-methyl-1H-indazole-7-carboxylic acid in 26 mL of anhydrous acetonitrile is added 1.11 g (3.66 mmol) of 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid followed by 1.3 mL (16.2 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 1.0 mL (12.9 mmol) of methanesulfonyl chloride is added drop wise. The mixture is stirred at ambient temperature for 16 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated, washed with cold water and dried. The pale yellowish product obtained (1.6 g) is engaged in the next step; LC/MS:459/461 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[N:40][CH:39]=[CH:38][N:37]=1)CCC>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:36]4[CH:41]=[N:40][CH:39]=[CH:38][N:37]=4)=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1c2cc(Cc3ccc(-c4cnccn4)nc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Temperature: 25 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one (Example 1, 0.050 g, 0.12 mmol) in 1 mL of dioxane under an atmosphere of nitrogen was added 2-(tributylstannyl)-pyrazine (0.175 g, 0.475 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.014 g, 0.012 mmol). The mixture was irradiated in a microwave reactor at 160° C. for 1 h, cooled to rt, and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 464.9 for [M+H]: 1H NMR (400 MHz, CD3OD) δ 9.84 (s, 1H), 9.51 (s, 1H), 9.32 (d, J=6.2 Hz, 1H), 8.84 (d, J=6.2 Hz), 8.75-8.64 (m, 4H), 8.41 (d, J=8.2 Hz, 1H), 8.34 (s, 1H), 7.96-7.94 (m, 1H), 4.86 (s, 2H), 4.16 (br s, 1H), 2.19 (br s, 1H), 2.03 (br s, 1H), 1.96-1.86 (m, 3H), 1.56-1.42 (m, 4H).
Reaction SMILES: [C:1]([NH:4][C:5]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].N[C:15]1(CC(O)=O)CCCCC1.CC#N.O.CC#N>O>[C:1]([NH:4][C:5]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:15]1)(=[O:3])[CH3:2]
Reactant: NC1(CC(=O)O)CCCCC1
Reactant: CC(=O)NC1(CC(=O)O)CCCC1
Solvent: CC#N
Solvent: O
Product: CC(=O)NC1(CC(=O)O)CCCCC1

Procedure:
The title compound is prepared analogously as described for (1-acetylamino-cyclopentyl)-acetic acid from (1-amino-cyclohexyl)-acetic acid. MS (LC-MS): [M+H]+=200.1. (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 0.81 min.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:26][C@H:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH:18]=3)[N:14]([CH2:28][CH2:29][CH3:30])[CH2:13]1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[NH2:11][C@H:12]1[CH2:26][C@H:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH:18]=3)[N:14]([CH2:28][CH2:29][CH3:30])[CH2:13]1
Reactant: CCCN1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCN1C[C@@H](N)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21

Procedure:
12 g (ca 30 mM) of 8α-benzyloxycarbonylamino)-6-n-propylergoline obtained from step (d) and 1.5 g palladium on charcoal (10% by weight) in 500 ml ethanol are hydrogenated at normal pressure until hydrogen uptake ceases. The mixture is filtered and concentrated. This resultant heading compound is crystallised from methanol.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH2:18][C:19](=[O:36])[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[CH2:23][CH2:22]2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1)=O.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[CH:37]1([NH:40][CH2:1][C:3]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH2:18][C:19](=[O:36])[NH:20][CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])[CH2:25][CH2:26]3)[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH:4]=2)[CH2:39][CH2:38]1
Reactant: COc1ccccc1CN1CCC(NC(=O)CN(Cc2cc(C=O)ccn2)C(=O)OC(C)(C)C)CC1
Reactant: NC1CC1
Product: COc1ccccc1CN1CCC(NC(=O)CN(Cc2cc(CNC3CC3)ccn2)C(=O)OC(C)(C)C)CC1

Procedure:
By General Procedure A from tert-butyl N-[(4-formylpyridin-2-yl)methyl]-N-[({1-[(2-methoxyphenyl)methyl]piperidin-4-yl}carbamoyl)methyl]carbamate and cyclopropylamine. Purification by column chromatography (CH2Cl2/MeOH/NH4OH, 90:10:1) gave the title compound as a colorless glue. 1H NMR (300 MHz, CDCl3): δ 9.40 (br s, 1H), 8.62 (2S, 1H; rotamer), 8.40 (s, 1H), 7.50-7.40 (m, 2H), 7.38 (m, 1H), 7.20 (m, 1H), 7.00-6.80 (m, 2H), 4.58 & 4.48 (2S, 2H; rotamer), 4.00-3.60 (m, 8H), 3.18-2.99 (m, 4H), 2.40-2.20 (m, 2H), 1.80 (m, 2H), 1.70 (m, 2H), 1.40 & 1.20 (2S, 9H; rotamer), 1.00 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]3[O:40][CH:39]=[CH:38][C:37]=3[CH:41]=2)O1.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[O:40]1[C:36]2[CH:35]=[CH:34][C:33]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)=[CH:41][C:37]=2[CH:38]=[CH:39]1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4occc4c3)n2n1
Temperature: 110 °C
Yield: 34.8 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 80 mg, 0.232 mmol), 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (73.6 mg, 0.302 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16 mg, 22 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.774 mL of 1,4-dioxane and 0.387 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (60-70% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (34.4 mg, 35%). 1H NMR (DMSO-d6) δ: 11.13 (s, 1H), 8.36 (d, J=1.5 Hz, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.89-8.00 (m, 4H), 7.78 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.6 Hz, 2H), 7.10 (dd, 1H), 6.34 (s, 1H), 5.13 (s, 1H), 2.35 (s, 3H), 1.39 (s, 6H); ESI-MS: m/z 452.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([F:8])[CH2:5][N:4]1[C:9]([NH:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([NH2:23])=[O:22])[CH:13]=1)=[O:10].[Cl:24][C:25]1[C:26]([F:33])=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>ClC(Cl)C>[Cl:24][C:25]1[C:26]([F:33])=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([F:8])[CH2:5][N:4]1[C:9]([NH:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([NH2:23])=[O:22])[CH:13]=1)=[O:10]
Reactant: O=Cc1cccc(Cl)c1F
Reactant: NC[C@@H]1C[C@@H](F)CN1C(=O)Nc1cn(C(N)=O)c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: NC(=O)n1cc(NC(=O)N2C[C@H](F)C[C@H]2CNCc2cccc(Cl)c2F)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-[((2S,4R)-2-Aminomethyl-4-fluoro-pyrrolidine-1-carbonyl)-amino]-indole-1-carboxylic acid amide (50 mg, 0.157 mmol) and 3-chloro-2-fluorobenzaldehyde (25 mg, 0.157 mmol, prepared as described in Scheme B11) were mixed in dichloroethane (1 mL), sodium triacetoxyborohydride (46.5 mg, 0.22 mmol) was added and the mixture was stirred at RT under nitrogen for 2 days. 3-Chloro-2-fluorobenzaldehyde (25 mg, 0.157 mmol) and triacetoxyborohydride (46.5 mg, 0.219 mmol) were added to complete the reaction. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue diluted in MeOH was purified by SiliaPrep Tosic Acid-1 g (SPE-R60530B-06S from Silicycle), the column was washed with 10 mL of MeOH and the compound released with 10 mL of 2M ammonia in MeOH to give after concentration the desired material which was further purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19×50 mm, eluent: 20% to 100% CH3CN in H2O in 15 min, CH3CN and H2O containing 0.1% HCOOH, flow: 20 mL/min) to give after lyophilization of the purified fractions the desired material as a formic acid salt. MS (LC-MS): 462.1/464 [M+H]+, 460/462 [M−H]−; tR (HPLC, conditions f): 1.54 min.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([OH:12])[C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl>ClCCl>[OH:12][C@@H:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:11]
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Reactant: C1COCCN1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: O=C([C@@H](O)Cc1ccccc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A sample of (S)-3-phenyllactic acid (1, 21 g, 126 mmol) is dissolved in dichloromethane (300 mL) and treated with morpholine (55 g, 631 mmol). The reaction is cooled in an ice/water bath and a solution of PyBOP (72 g, 139 mmol) in dichloromethane (200 mL) is added dropwise through a pressure equalizing funnel. The reaction mixture is stirred overnight and allowed to warm to room temperature. After addition of 110 mL of 4 M HCl, the reaction mixture is filtered and the organics are separated. The aqueous layer is extracted twice with dichloromethane and discarded. The combined organics are dried over MgSO4 and the solvent is removed. The resulting material is chromatographed on silica gel and eluted with ethyl acetate to afford 20.65 g (68% yield) of (S)-2-hydroxy-1-morpholin-4-yl-3-phenyl-propan-1-one (2) as an oil; HPLC-MS calculated for C13H17NO3 (M+H+) 236.1, found 236.4.