Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([C:32]3[C:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[O:44][CH3:45])=[N:34][O:35][C:36]=3[CH3:37])=[O:31])[CH2:26][CH2:25]2)=[CH:4][C:5]([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[BH4-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[C:3]([N:24]2[CH2:25][CH2:26][N:27]([C:30]([C:32]3[C:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[O:44][CH3:45])=[N:34][O:35][C:36]=3[CH3:37])=[O:31])[CH2:28][CH2:29]2)=[CH:4][C:5]([NH:12][C:13](=[O:23])[C:14]2[CH:15]=[CH:16][C:17]([N:20]([CH3:21])[CH3:22])=[CH:18][CH:19]=2)=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: COC(=O)c1cc(Cl)c(N2CCN(C(=O)c3c(-c4ccccc4OC)noc3C)CC2)cc1NC(=O)c1ccc(N(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(N(C)C)cc3)c(CO)cc2Cl)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a solution of methyl 5-chloro-2-(4-(dimethylamino)benzamido)-4-(4-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carbonyl)piperazin-1-yl)benzoate (108 mg, 0.171 mmol) in MeOH (1 mL) and THF (3 mL) at room temperature was added sodium borohydride (32.3 mg, 0.854 mmol). The resulting reaction mixture was stirred at 40° C. for 2 hours. The product was purified by preparative HPLC(CH3CN/H2O-10 nM ammonium acetate) to give 90 mg (81% yield) of N-(4-Chloro-2-(hydroxymethyl)-5-(4-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carbonyl)piperazin-1-yl)phenyl)-4-(dimethylamino)benzamide. 1H-NMR (CDCl3, 400 MHz): δ 9.39 (1H, s), 8.03 (1H, s), 7.84 (2H, d, J=8.8 Hz), 7.58 (1H, dd, J1=7.5 Hz, J2=1.8 Hz), 7.52-7.45 (1H, m), 7.14 (1H, s), 7.11-6.99 (2H, m), 6.74 (2H, d, J=9.0 Hz), 4.71 (2H, s), 3.82 (3H, s), 3.77 (2H, s), 3.23 (2H, s), 2.97 (2H, s), 3.07 (6H, s), 2.57 (3H, s), 2.46 (2H, s).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CC=CCN.C(N(CC)CC)C.[CH3:23][N:24]1C[CH2:27][CH2:26][C:25]1=O>O>[CH2:25]([N:24]([CH3:23])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH:26]=[CH2:27]
Reactant: CN1CCCC1=O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC=CCN
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCN(C)c1ccc([N+](=O)[O-])cc1
Yield: 96 %

Procedure:
A mixture of p-fluoronitrobenzene (2.8 g, 20 mmol), N-methylallylamine (2.10 g, 30 mmol), triethylamine (2.0 g, 20 mmol), and N-methyl-2-pyrrolidinone (NMP) (20 ml) was heated to 60°-70° C. for 5 hours in an oil bath. The mixture was diluted with distilled water (100 ml) and extracted twice with ether. The extracts were washed with distilled water and brine solution, dried over potassium carbonate and concentrated to an oil. The oil was distilled via Kugelrohr apparatus (forecut taken up to 90° C. discarded, 110°-125° C., 0.1 mm Hg) to give 3.70 g (96%) N-allyl-N-methyl-4-nitroaniline. As is, this material failed to undergo clean hydrosilation, possibly due to residual N-methyl-2-pyrrolidinone present. The remaining material was chromatographed on silica with hexane-ethyl acetate (10:1) and distilled again via Kugelrohr apparatus to give a yellow oil that underwent clean hydrosilation.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH2:22])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1>[Pd].CO.CCOC(C)=O>[O:18]1[CH2:19][CH2:20][C@:15]2([C:4]3[C:5](=[N:6][CH:7]=[CH:2][CH:3]=3)[O:8][C:9]3[C:14]2=[CH:13][C:12]([NH2:22])=[CH:11][CH:10]=3)[N:16]=[C:17]1[NH2:21]
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1ncc(Br)cc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A 15-mL flask was charged with (S)-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.015 g, 0.042 mmol) and 10% palladium on carbon (0.075 g, 0.706 mmol). The material was suspended in MeOH (1.5 mL) and EtOAc (0.5 mL). The reaction was stirred for 2 h at rt under an atmosphere of hydrogen. The mixture was filtered through Celite, rinsing with 10% MeOH-dcm, and the filtrate was concentrated to afford crude (S)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (8 mg, 0.028 mmol).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[C:25]1([NH:35]N)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>CN(C=O)C.C(O)(=O)C>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:35]([C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27][CH:26]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: NNc1cccc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4ccccc34)n2)c1

Procedure:
3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and naphthalen-1-yl-hydrazine (2 eq) were dissolved in a sealed tube in DMF with 2 drops acetic acid and irradiated in MW at 120° C. for 15 min. The solvent of the reaction mixture was removed and the crude product was purified by preparative HPLC yielding the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C1COCC1.[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:25]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])=[O:7])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: O=C=NCc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)NNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred suspension of 4-chlorobenzoic acid, hydrazide (10.4932 g, 6.1508×10-2 mole) and dry THF (240 mL) was warmed with a heat gun until it was homogenous. To this stirred solution was added benzyl isocyanate (7.8 ml, 6.3×10-2 mole). After stirring overnight at room temperature, the reaction was diluted with ether. The precipitate was collected by filtration, washed with a little ether, and dried by suction Crystallization from ethanol afforded small colorless needles 15.69 g (84%), mp 244°-246° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.[H-].[Na+].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][CH:32]=2)[O:27][CH:28]=1.O>CN(C=O)C>[CH2:37]([C:34]1[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]4[CH:6]=[CH:7][N:8]=[C:4]4[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=3)[N:25]=2)=[CH:32][CH:33]=1)[CH3:38]
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Reactant: CCc1ccc(/C=C/c2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnc4CCO)cc3)co2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl ]butyl]phenol (260 mg) in DMF (4 ml), 60% oily sodium hydride (44 mg) was added under ice cooling. After stirring at room temperature for 30 minutes, (E)-4-chloromethyl-2-[2-(4-ethylphenyl)ethenyl]oxazole (272 mg) was added under ice cooling. After stirring overnight at room temperature, water was added under ice cooling. The precipitate was collected by filtration and washed with water. The precipitate was dissolved in ethyl acetate and dried (magnesium sulfate), after which it was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to yield the titled compound (297 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[C:27](=[O:36])[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:22][CH2:21]2)=[O:19])[C:13]([O:15]C)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([NH:17][C:18]([N:20]2[CH2:21][CH2:22][CH:23]([C:26]3[C:27](=[O:36])[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24][CH2:25]2)=[O:19])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: COC(=O)[C@@H](Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](NC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn[nH]c12
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of (R)-methyl 3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propanoate (2.44 g, 5 mmol) in THF (50 mL) was added a solution of lithium hydroxide (420 mg, 10 mmol) in water (15 mL) at room temperature. After 1 h, most of the THF was removed and neutralized with 1.0 M hydrogen chloride to give (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propanoic acid as a white solid in 95% yield. 1H-NMR (CD3OD) δ 7.97 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.60 (s, 1H), 7.51-7.48 (m, 2H), 7.33 (d, J=8 Hz, 1H), 7.27-7.24 (m, 1H), 7.12 (s, 1H), 4.61-4.58 (m, 1H), 4.14-4.08 (m, 2H), 3.76-3.73 (m, 2H), 3.13-2.84 (m, 4H), 2.54 (s, 3H), 1.90-1.84 (m, 4H), 1.48-1.34 (m, 2H); MS (ESI) 474 (M+H) ; Rf=1.89.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6](OCC)(=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Li])CCC>CCCCCC.C1CCCCC1>[O:12]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: c1cscn1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: CCOC(=O)C(=O)c1nccs1

Procedure:
Prepared from thiazole and diethyl oxalate using Method KE-A. In this case the temperature was held at −35° C. and n-butyllithium in hexane was used in place of sec-butyllithium in cyclohexane.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1)([O-:10])=[O:9].O>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Yield: 50 %

Procedure:
Monomethylpiperazine (15 mL) and tetrahydrofuran (60 mL) were placed in a 200 mL eggplant shaped flask, and a solution of 4-nitrobenzylchloride (8.58 g, 50 mmol) in tetrahydrofuran was added dropwise to the mixture at room temperature while stirring. After finishing the instillation, the mixture was stirred at room temperature for 24 hours. The reaction mixture was mixed with distilled water, and the precipitated solids were collected by filtration and dried under reduced pressure to obtain the title compound (5.9 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:27])[N:11]([C@H:22]2[CH2:25][C@@H:24]([OH:26])[CH2:23]2)[C:12]2[N:13]([N:18]=[C:19]([CH3:21])[N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[N+](=[C:38]([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N-]>C([O-])(=O)C.[Rh+2].C([O-])(=O)C.C(Cl)Cl>[C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10](=[O:27])[N:11]([C@@H:22]3[CH2:25][C@H:24]([O:26][CH:38]([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:23]3)[C:12]3[N:13]([N:18]=[C:19]([CH3:21])[N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[C:2]([F:1])[CH:3]=1)#[N:35]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](O)C2)c2nc(C)nn12
Reactant: CCOC(=O)C(C)=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](OC(C)C(=O)OCC)C2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3′-fluoro-4′-{[4-(cis-3-hydroxycyclobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (659 mg), rhodium(II) acetate (dimer) (31 mg) and methylene chloride (5 mL) was added dropwise ethyl 2-diazopropanoate (359 mg) under an argon atmosphere at 70° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel chromatography [eluent: hexane/ethyl acetate=90/10→70/30 (volume ratio)] to give the title compound as a colorless amorphous compound (553 mg, 69%).
Reaction SMILES: [CH3:1][N:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[NH:3]1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>ClCCl>[CH3:1][N:2]1[N:3]=[C:4]([Cl:9])[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[NH:7]1
Reactant: C1COCCN1
Reactant: CN1N=C(Cl)C=C(Cl)N1
Solvent: ClCCl
Product: CN1N=C(Cl)C=C(N2CCOCC2)N1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
2-Methyl-4,6-dichlorotriazine (256 mmol) is dissolved in dichloromethane (200 mL) and chilled to −78° C. in an inert atmosphere. Morpholine (550 mol) dissolved in dichloromethane (100 mL) is added slowly. The reaction is allowed to warm to room temperature while stirring overnight. The organic layer is washed with saturated ammonium chloride (2×100 mL), dried with sodium sulfate, and evaporated to give 2-methyl-4-chloro-6-morpholino-triazine.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:8]([CH3:20])=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([CH2:16][C:17]([O-:19])=[O:18])[CH2:11][CH2:10]2.Cl[CH2:22]Cl>>[OH:6][C:7]1[C:8]([CH3:20])=[C:9]2[C:13](=[CH:14][CH:15]=1)[C@@H:12]([CH2:16][C:17]([O:19][CH3:22])=[O:18])[CH2:11][CH2:10]2
Reactant: COc1ccc2c(c1C)CCC2CC(=O)[O-]
Reactant: ClCCl
Agent: BrB(Br)Br
Product: COC(=O)C[C@H]1CCc2c1ccc(O)c2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1.0 M solution of boron tribromide in dichloromethane (16.2 mL, 16.2 mmol) was added to an ice-cold solution methyl (R or S)-(5-methoxy-4-methyl-indan-1-yl)acetate (1.52 g, 6.49 mmol, from Step F) in dichloromethane (5 mL). The cooling bath was removed and the reaction mixture stirred at ambient temperature. After 1 hr, the reaction mixture was slowly transferred to an ice-cold solution of methanol (50 mL). Methanol was removed in vacuo, and the residue was partitioned between EtOAc and sat. NaH2PO4. The organic layer was washed with H2O, brine, and dried over MgSO4. The mixture was filtered, concentrated in vacuo and purified by flash chromatography (5, 10% EtOAc/hexanes) on SiO2 to afford 1.22 g of the title compound as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.71-1.78 (m, 1H), 2.16 (s, 3H), 2.35-2.44 (m, 2H), 2.71-2.79 (m, 2H), 2.86-2.90 (m, 1H), 3.54 (p, 1H, J=7.3 Hz), 3.72 (s, 3H), 4.83 (s, 1H), 6.61 (d, 1H, J=8.0 Hz), 6.85 (d, 1H, J=8.0 Hz).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1B(O)O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:2]1[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(NC2CCOCC2)n1
Reactant: OB(O)c1ccncc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: Nc1ncc(-c2ccncc2Cl)c(NC2CCOCC2)n1
Temperature: 130 °C
Yield: 91.1 %

Procedure:
A mixture of compound 33 (2.03 g, 7.43 mmol), 3-chloropyridin-4-ylboronic acid (3.51 g, 22.3 mmol), and Pd(PPh3)2Cl2 (0.522 g, 0.743 mmol) in dioxane (44 ml) in a pressure vessel was purged with N2 for 20 minutes and to this mixture was added aq. Na2CO3 (1 M, 22 mL) by syringe. The reaction was further purged with N2 for another 20 minutes and then heated to 130° C. for 12 hours. DCM was added to the reaction and the mixture was washed with water and brine. The organic layer was dried with sodium sulfate and concentrated to provide compound 34 (2.07 g, crude, 98%) which was used in the next reaction without further purification. LCMS-ESI (POS), M/Z, M+1: Found 306.1, Calculated 306.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[S:35][C:34]([C:36](O)=[O:37])=[N:33][CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:34]4[S:35][C:31]([CH3:30])=[CH:32][N:33]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cnc(C(=O)O)s1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ncc(C)s2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 70 mg, 0.18 mmol) and 5-methylthiazole-2-carboxylic acid (30 mg, 0.21 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=[O:5].[OH:21][CH2:22][CH2:23][O:24][C:25]1[C:32]([CH3:33])=[CH:31][C:28]([CH:29]=O)=[CH:27][C:26]=1[CH3:34]>C(O)C.[Cu](Cl)Cl>[OH:21][CH2:22][CH2:23][O:24][C:25]1[C:32]([CH3:33])=[CH:31][C:28]([C:29]2[N:6]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=3)[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:1]=2)=[CH:27][C:26]=1[CH3:34]
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: Nc1ccccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: Cl[Cu]Cl
Solvent: CCO
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(C(F)(F)F)cc2)cc(C)c1OCCO
Temperature: 25 °C

Procedure:
To a solution of 2-amino-N-(4-trifluoromethyl-phenyl)-benzamide (0.19 g, 0.68 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.16 g, 0.81 mmol) in anhydrous ethanol (15 mL) was added anhydrous copper (II) chloride (0.273 g, 2.03 mmol). The reaction mixture was stirred at reflux for 16 hours under nitrogen and then cooled to room temperature. Ethanol was evaporated under reduced pressure. The residue was taken in ethyl acetate (100 mL). The organic phase was washed with water (2×75 mL), then brine (75 mL), and dried over anhydrous Na2SO4. Solvent was evaporated; crude compound was purified by column chromatography (silica gel 230-400 mesh; 2:3:5 ethyl acetate, hexanes and CH2Cl2 as eluent) to give the title compound as a white solid. Yield: 0.17 g (55%). MP 160-161° C. 1H-NMR (400 MHz, CDCl3): δ 8.34 (d, J=8.00 Hz, 1H), 7.84-7.82 (m, 2H), 7.62-7.53 (m, 3H), 7.31 (d, J=8.40 Hz, 2H), 6.97 (s, 2H), 3.93-3.89 (m, 2H), 3.80 (t, J=5.20 Hz, 2H), 2.15 (s, 6H), 2.07 (t, J=6.40 Hz, 1H).
Reaction SMILES: [C:1]([N:11]1[CH2:18][C@@H:17]2[C@@H:13]([CH2:14][N:15]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH2:31])[O:27][C:26]4=[O:32])=[CH:21][C:20]=3[F:33])[CH2:16]2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[C:1]([N:11]1[CH2:12][C@@H:13]2[C@@H:17]([CH2:16][N:15]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH:31][C:40](=[O:42])[CH3:41])[O:27][C:26]4=[O:32])=[CH:21][C:20]=3[F:33])[CH2:14]2)[CH2:18]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H]1CN(c2ccc(N3C[C@H]4CN(C(=O)OCc5ccccc5)C[C@H]4C3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CN(C(=O)OCc5ccccc5)C[C@H]4C3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a flame dried flask equipped with a nitrogen inlet is introduced (R)-[3-[4-[cis-3-(carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methanol (1.75 g, 3.84 mmol) and methylene chloride (100 mL) cooled to 0° C. Triethylamine (0.80 mL, 5.76 mmol) and methanesulfonyl chloride are added, stirred at 0° C. for 2 hours, and warmed to ambient temperature for 1 hour. The reaction is washed with water (30 mL), saturated sodium bicarbonate (30 mL), and saline (30 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude (R)-[[3-[4-[cis-3-(carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]methanesulfonate. (R)-[[3-[4-[cis-3-(Carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]methanesulfonate is combined in a resealable tube with THF (5 mL), isopropanol (5 mL), and concentrated ammonium hydroxide (10 mL) and heated to 95° C. for 10 hours. The reaction is diluted with methylene chloride (50 mL) and washed with saline (30 mL), dried over sodium sulfate, concentrated in vacuo to give (S)-[[3-[4-[cis-3-(carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]amine. The crude (S)-[[3-[4-[cis-3-(carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]amine (1.67 g, 3.67 mmol) is dissolved in methylene chloride (20 mL), cooled to 0° C. under nitrogen, pyridine (0.89 mL, 11.02 mmol) and acetic anhydride (0.43 mL, 4.59 mmol) are added, and the reaction is stirred 15 hours at ambient temperature. The reaction is diluted with methylene chloride (50 mL), washed with 1N HCl (25 mL), saturated sodium bicarbonate (25 mL), saline (25 mL), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 200 mL), eluting with chloroform/methanol (98/2). The appropriate fractions are combined (Rf =0.15, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 165-168° C.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=[O:14])[CH2:10][C:11]#[N:12])=[O:7])[CH2:2][CH2:3][CH3:4].[CH:16]1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C1COCC1.CO>[CH3:16][O:14][C:13](=[O:15])[C@@H:9]([CH2:10][C:11]#[N:12])[NH:8][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7]
Reactant: CCCCOC(=O)N[C@H](CC#N)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOC(=O)N[C@H](CC#N)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of N-butyloxycarbonyl-3-cyano-D-alanine (20.5 g, 97 mmol) and 4-dimethylaminopyridine (11.85 g, 97 mmol) in 150 mL THF and 33 mL methanol was added N,N'-dicyclohexylcarbodiimide (20 g, 97 mmol) and the solution was allowed to stir at room temperature for 2 hours. Insoluble material was removed by filtration and the solution was concentrated. The residue was taken up in ethyl acetate and the solution was washed with 5% citric acid, brine, NaHCO3 and brine, dried (MgSO4), and concentrated. Crystallization from ethyl acetate gave 18.8 g (85%) product. 1H-NMR: d (CDCl3) 5.48 (d, 1H); 4.54 (m, 1H); 3.84 (s, 3H); 2.98 (m, 2H); 1.44 (s, 9H). ES-MS: calcd M+1 229.2; found 229.0.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][C:11]3[CH:15]=[C:14]([C:16]([OH:18])=O)[S:13][C:12]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[NH:22][CH3:23]>>[Br:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][C:11]3[CH:15]=[C:14]([C:16]([N:22]([C:21]4[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=4[Cl:19])[CH3:23])=[O:18])[S:13][C:12]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CNc1ccccc1Cl
Reactant: O=C(O)c1cc2c(s1)-c1cccc(Br)c1OCC2
Product: CN(C(=O)c1cc2c(s1)-c1cccc(Br)c1OCC2)c1ccccc1Cl

Procedure:
Following Example 70 and General Procedure B, 114 was prepared from 7-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid and 2-chloro-N-methylaniline. MS: (ESI+) 450.0