Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[CH2:11]([O:13][C:14]([C@H:16]1[C@@H:21]([NH2:22])[C@H:20]2[CH2:23][C@@H:17]1[CH2:18][CH2:19]2)=[O:15])[CH3:12].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH2:11]([O:13][C:14]([C@H:16]1[C@@H:21]([NH:22][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([F:10])=[C:2]([Cl:1])[CH:3]=2)[C@H:20]2[CH2:23][C@@H:17]1[CH2:18][CH2:19]2)=[O:15])[CH3:12]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
3-Chloro-4-fluoro-benzaldehyde (0.710 mL, 4.48 mmol) and 10 drops glacial acetic acid were added sequentially to a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 0.82 g, 4.47 mmol) in methanol (15 mL) at 25° C. Sodium cyanoborohydride (0.709 g, 11.3 mmol) was added, and the reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0 to 35% ethyl acetate in hexanes) to afford the desired product, (1S,2R,3S,4R)-3-(3-chloro-4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (1.12 g, 3.44 mmol, 77%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.04-1.16 (2H, m), 1.18-1.24 (2H, m), 1.29 (3H, t, J=7.4 Hz), 1.44-1.61 (2H, m), 1.91-1.94 (1H, m), 2.27-2.28 (1H, m), 2.42-2.43 (1H, m), 2.60 (1H, d, J=7.7 Hz), 2.91 (1H, d, J=8.8 Hz), 3.64 (1H, d, J=13.9 Hz), 3.79 (1H, d, J=14.2 Hz), 4.14 (2H, q, J=7.0 Hz), 7.02-7.06 (1H, m), 7.13-7.17 (1H, m), 7.36-7.38 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:8])=[C:5]([N+:28]([O-])=O)[CH:4]=1.[Sn](Cl)Cl.C(O)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:28][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:27]=[CH:26][C:6]=1[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:15][CH:16]=[C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:18][CH2:19]1)=[O:8]
Reactant: COc1ccc(C(=O)NCCCCN2CC=C(c3ccccc3)CC2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccc(C(=O)NCCCCN2CC=C(c3ccccc3)CC2)c(N)c1
Yield: 58.3 %

Procedure:
A mixture of 4-methoxy-2-nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide (1 g), tin(II) chloride (1.39 g) and ethanol (20 ml) was stirred under reflux for 0.5 hour. After cooling, sat. sodium bicarbonate solution was added and the mixture was diluted with chloroform (50 ml). A chloroform layer was separated, washed in turn with water and brine, dried over magnesium sulfate and evaporated. Crude residue (0.93 g) was chromatographed on a silica gel [13 g, chloroform and methanol (50:1-20:1, V/V) as an eluent] to give 2-Amino-4-methoxy-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide (0.54 g).
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)N.C(O)(=O)C>O>[Cl:7][C:8]1[CH:14]=[C:13]([NH:6][C:2]([CH3:1])=[CH:3][C:4]#[N:5])[CH:12]=[CH:10][CH:9]=1
Reactant: Nc1cccc(Cl)c1
Reactant: C/C(N)=C\C#N
Solvent: O
Solvent: CC(=O)O
Product: CC(=CC#N)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Aminocrotonitrile (5.0 g, 60.9 mmol), 3-chloroaniline (8.55 g, 66.99 mmol) and acetic acid (6.22 g, 103.5 mmol) are dissolved in water (20 ml). The reaction mixture is stirred at room temperature for 60 minutes and the precipitate is isolated.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)[C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:9].[CH2:24]([N:27]([CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH:31]=O)[CH2:25][CH3:26].C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:33]([N:27]([CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29][CH2:30][CH2:31][N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:8](=[O:9])[N:7]([CH2:18][C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)[CH2:6][C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:13][CH2:14]1)[CH2:34][CH3:35]
Reactant: CCCN(CCC)CCCC=O
Reactant: O=C(NCC1CCNCC1)N(Cc1ncc[nH]1)Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCCN1CCC(CNC(=O)N(Cc2ncc[nH]2)Cc2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
Under an argon atmosphere, to a methanol (2.3 mL) solution of the compound (73 mg) obtained in Example 10, 4-(dipropylamino)butanal (39 mg) and trimethyl orthoformate (49 mg) were added at 0° C. The reaction solution was stirred at room temperature for 2 hours. To the reaction solution, sodium borohydride (17 mg) was added at 0° C., followed by stirring for one hour. The reaction solution was concentrated under reduced pressure, and then an aqueous 5N sodium hydroxide solution (10 mL) was added to the residue. The aqueous layer was extracted twice with chloroform (30 mL). The combined organic layer was dried over anhydrous magnesium sulfate. After removing the anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (dichrolomethane:methanol:28% aqueous ammonia=10:1:0→80:10:1) to obtain the title compound (37 mg) having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:9][C:8]([CH3:20])=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[NH2:23][N:24]1[C:28]([NH2:29])=[N:27][N:26]=[C:25]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>CCO>[CH3:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:9][C:8]([CH3:20])=[C:7]2[C:3]=1[C:4]1[C:5]([NH:6]2)=[N:29][C:28]2=[N:27][N:26]=[C:25]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[N:24]2[N:23]=1
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Reactant: Cc1cc(OCCN2CCOCC2)c(C)c2c1NC(=O)C2=O
Solvent: CCO
Product: Cc1cc(OCCN2CCOCC2)c(C)c2c1[nH]c1nc3nnc(Cc4ccc(O)cc4)n3nc12
Temperature: 120 °C
Reaction time: 72 h
Yield: 26.4 %

Procedure:
A mixture of 4,7-dimethyl-5-(2-morpholin-4-yl-ethoxy)-1H-indole-2,3-dione (121.6 mg, 0.4 mmol) and 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol (82 mg, 0.4 mmol) in EtOH (15 mL) was heated with stirring in a pressure tube at 120° C. for 72 h. The solvent was removed and the residue was purified with a flash silica gel chromatography (CH2Cl2:MeOH:NH4OH=100:7:0.7) to give the title compound as a pink solid (50 mg, 27%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](/[C:11](=[N:13]/[OH:14])/[NH2:12])=[C:4]2[CH:3]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].N12CCCN=C1CCCCC2>O1CCOCC1.Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]([C:11]3[NH:12][C:23](=[O:24])[O:14][N:13]=3)=[C:4]2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2/C(N)=N/O)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3ccc(Br)cc3c2-c2noc(=O)[nH]2)cc1
Yield: 78.1 %

Procedure:
A mixture of Example 19G (0.74 g, 2.049 mmol), 1,1′-carbonyldiimidazole (0.365 g, 2.254 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.340 mL, 2.254 mmol) in dioxane (10 mL) was refluxed for 1 hour, cooled and diluted with 1 M aqueous HCl. The resulting solid was collected by filtration, washed with water and dried. The solid was triturated twice with 1% methanol in dichloromethane to give the title compound (0.62 g, 78%). MS (ESI+) m/z 387/389 (M+H)+.
Reaction SMILES: [Cu:1](Cl)Cl.[Na].[C:5]([O-:8])(=[O:7])[CH3:6].[Na+].[C:10]([O-:15])(=[O:14])[CH2:11][CH2:12][CH3:13].[Na+]>>[C:5]([O-:8])(=[O:7])[CH3:6].[Cu+2:1].[C:10]([O-:15])(=[O:14])[CH3:11].[C:10]([O-:15])(=[O:14])[CH2:11][CH2:12][CH3:13].[Cu+2:1].[C:10]([O-:15])(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: Cl[Cu]Cl
Agent: CC(=O)[O-]
Agent: CCCC(=O)[O-]
Agent: [Na+]
Product: [Cu+2]

Procedure:
It is not necessary that the copper(II) carboxylate be added directly to the reaction mixture. For example, when copper(II) chloride and the sodium salt of a carboxylic acid, e.g., sodium acetate or sodium butyrate, are charged to the reaction vessel, the corresponding copper(II) carboxylate, e.g., copper(II) acetate or copper(II) butyrate, are formed in situ in the reaction mixture. Preferably, the copper(II) salt is dried before use to remove any water of crystallization and obtain substantially anhydrous salt.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)=O.[CH2:12]([O:14][C:15](=[O:18])[CH2:16]Br)[CH3:13]>>[CH2:12]([O:14][C:15]([CH2:16][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:2]1=[O:1])=[O:18])[CH3:13]
Reactant: Oc1cccnc1O
Reactant: CCOC(=O)CBr
Agent: O=C=O
Product: CCOC(=O)Cn1cccc(O)c1=O
Temperature: 140 °C

Procedure:
2,3-Dihydroxypyridine (5 g) is suspended in ethylbromoacetate (20 ml) and the mixture heated in a sealed tube for 24 hours at 140° C. The tube is then cooled in solid CO2 and opened. The contents are subjected to rotary evaporation at 50° C. to yield a yellow solid. Recrystallisation of this solid from water yields 1-ethoxycarbonylmethyl-3-hydroxypyrid-2-one as white crystals (5.4 g), m.p. 141°-151° C.; νmax (nujol) 1645, 1720 cm-1 ; δ(d6DMSO), 1.0 (t, 3H), 4.0 (q, 2H), 4.55 (s, 2H), 5.95 (t, 1H), 6.6 (d, 1H), 7.05 (d, 1H).
Reaction SMILES: Cl[C:2]1C(F)=C(NC2C3C(=CC(OC)=C(CN(C)[C@H](C(N)=O)CCOC)C=3)N=CN=2)C=CC=1.[C:33]([O:37][C:38]([NH:40][C@H:41]([C:46]([OH:48])=[O:47])[CH2:42][CH2:43][O:44][CH3:45])=[O:39])([CH3:36])([CH3:35])[CH3:34].C(OC(N[C@H](C(O)=O)COC)=O)(C)(C)C>>[C:33]([O:37][C:38]([N:40]([CH3:2])[C@H:41]([C:46]([OH:48])=[O:47])[CH2:42][CH2:43][O:44][CH3:45])=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: COCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COCC[C@@H](C(N)=O)N(C)Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Agent: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: COCC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C

Procedure:
The N2,O-dimethyl-L-homoserinamide used as starting material was prepared by methylating N-(tert-butoxycarbonyl)-O-methyl-L-homoserine using an analogous method to that described in Example 7 for the methylation of N-(tert-butoxycarbonyl)-O-methyl-L-serine, to give N-(tert-butoxycarbonyl)-N,O-dimethyl-L-homoserine; 1H NMR spectrum: (DMSO d6, 100° C.) 1.40 (s, 9H), 1.91 (m, 1H), 2.09 (m, 1H), 2.75 (s, 3H), 3.24 (s, 3H), 3.34 (m, 2H), 4.44 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]=[C:7]([S:9][CH2:10][C:11]3[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][N:12]=3)[NH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-:24].[K+].[K+].ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO.O>[Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]=[C:7]([S:9]([CH2:10][C:11]3[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][N:12]=3)=[O:24])[NH:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccnc(CSc2nc3cc(Cl)c(Cl)cc3[nH]2)c1C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1ccnc(CS(=O)c2nc3cc(Cl)c(Cl)cc3[nH]2)c1C

Procedure:
A solution of 1.0 g of 5,6-dichloro-2-[[(4-methoxy-3-methyl-2-pyridyl)methyl]thio]benzimidazole in 150 ml of methylene chloride and 30 ml of methanol was treated with 0.5 g of potassium carbonate. 0.6 g of m-chloroperbenzoic acid was added thereto at -30° while stirring, whereupon the solution was stirred for an additional 5 minutes and subsequently poured into a mixture of 20 ml of saturated sodium bicarbonate solution and 20 ml of water. The separated organic phase was dried over sodium sulfate, treated with 0.5 ml of triethylamine and evaporated in a vacuum. Crystallization from methylene chloride-methanol-ether yielded 5,6-dichloro-2-[[(4-methoxy-3-methyl-2-pyridyl)methyl]sulfinyl]benzimidazole of melting point 173°.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)#[CH:10].O>C(NCC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[C:10][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:12][CH:13]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: Nc1ccccc1I
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCNCC
Product: Cc1ccc(C#Cc2ccccc2N)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 86.8 %

Procedure:
To 2-iodoaniline (2.19 g, 10.0 mmol) in diethylamine (40 ml) were added 4-ethynyltoluene (1.16 g, 10.0 mmol), bis(triphenylphosphine) palladium(II) chloride (702 mg, 1.00 mmol) and copper iodide (190 mg, 1.00 mmol) successively, and the mixture was stirred for 6 hours at 50° C. After adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography to give the subject compound (1.80 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].C(O[CH:12]=[C:13]([CH3:16])[CH:14]=O)C>>[CH3:16][C:13]1[CH:12]=[N:1][C:2]2[N:6]([N:5]=[CH:4][C:3]=2[C:7]#[N:8])[CH:14]=1
Reactant: CCOC=C(C)C=O
Reactant: N#Cc1cn[nH]c1N
Product: Cc1cnc2c(C#N)cnn2c1

Procedure:
By the procedure described in Example 2, 5.40 g of 5-amino-4-pyrazolecarbonitrile is reacted with 5.70 g of 3-ethoxy-2-methylacrolein in 25 ml of glacial acid to give the desired product as colorless prisms, mp 193°-194° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11](C=O)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:30][C:31]([F:35])([F:34])[S:32]Cl>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([S:32][C:31]([F:35])([F:34])[F:30])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(C=O)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: FC(F)(F)SCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(-c2cc(SC(F)(F)F)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
To a stirred mixture of 1.5 g (5 m mole) of 4,5-bis(4-methoxyphenyl)pyrrole-2-carboxaldehyde and 1.3 g sodium carbonate in 10 ml ether/10 ml THF at -78° was added 0.8 g of trifluoromethanesulfenyl chloride. The mixture was allowed to warm to room temperature with a dry-ice condenser attached to keep the trifluoromethanesulfenyl chloride from escaping. Excess trifluoromethanesulfenyl chloride was added and the mixture was stirred overnight at room temperature. The mixture was filtered and the filtrate concentrated by rotary evaporation. The residue was purified by chromatography on 300 g Silic AR CC-7, eluting with toluene, to give 0.75 g (39%) of product, identical to that obtained by Method A.
Reaction SMILES: [OH-].[Ca+2:2].[OH-].[C:4]([O:10][CH3:11])(=[O:9])[CH2:5][C:6]([CH3:8])=[O:7]>>[C:4]([O:10][CH3:11])(=[O:9])[CH2:5][C:6]([CH3:8])=[O:7].[Ca:2]
Reactant: [Ca+2]
Agent: COC(=O)CC(C)=O
Agent: [OH-]
Product: [Ca]
Reaction time: 5 h

Procedure:
444 g (6 mol) of calcium hydroxide was added to the kneader used in Comparative Example 1, and stirred. Thereafter, 1,532 g [13.2 mol, calcium hydroxide/methyl acetoacetate=1/2.2 (molar ratio)] of methyl acetoacetate was added dropwise to the kneader over 3 hours. The reaction temperature was between 36 and 58° C. After completion of the dropping, at a temperature of from 58 to 62° C., the reaction mixture was stirred and mixed for aging for 5 hours until the reaction was complete. The resulting product was warmed under a flow of nitrogen gas. When the temperature reached 62° C., the product was subjected to the drying step, and dried at 110 to 122° C. for 18 hours until the product attained a moisture content of 0.65% by weight. Thereafter, the dried product was cooled to give 1,618 g of white calcium methyl acetoacetate [yield 97.9 mol % (calcium hydroxide basis), purity 98.1% by weight].
Reaction SMILES: [CH2:1]([NH:10][C:11](=[O:26])[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O>O>[C:4]1([C:2]2[O:26][C:11]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][CH2:19]3)=[N:10][CH:1]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(CCN1CCN(c2ccccc2)CC1)NCC(=O)c1ccccc1
Solvent: O
Product: c1ccc(-c2cnc(CCN3CCN(c4ccccc4)CC3)o2)cc1
Temperature: 140 °C

Procedure:
N-Phenacyl-3-(4-phenylpiperazine-1-yl)-proponamide (4.03 g; 0.011 mole) was mixed with polyphosphoric acid (36 g) and stirred and heated at 140° C. for 30 minutes. The mixture was dissolved in water (100 ml), cooled, and extracted (2 × 30 ml chloroform). The extracts were discarded and the aqueous phase basified to pH 9 with 50% aqueous NaOH solution. The emulsion formed was extracted with 3 × 100 ml chloroform, the extracts dried and evaporated. The crystalline residue was recrystallised from 60°-80° C. petroleum ether. Yield 2.6 g m.p. 84°-5° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([N:11]2[CH2:12][CH:13]3[CH2:14][N:15]([C:28](=[O:31])[CH2:29][CH3:30])[CH2:16][CH:17]3[CH2:18]2)=[O:10])=[CH:7][CH:8]=1
Reactant: O=C(c1ccc(Br)cc1)N1CC2CNCC2C1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)N1CC2CN(C(=O)c3ccc(Br)cc3)CC2C1
Temperature: 0 °C
Reaction time: 14 h
Yield: 99.5 %

Procedure:
1.3 (4-Bromo-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone hydrochloride (300 mg; 0.9 mmol) is dissolved in 5 ml of DCM, N-ethyldiiso-propylamine for synthesis (0.46 ml; 2.7 mmol) is added and then cooled to 0° C. Propionyl chloride for synthesis (0.095 ml; 1.09 mmol) is added dropwise followed by stirring at RT for 14 h. The reaction mixture is separated between DCM and water. The organic layer is separated, dried over MgSO4, filtered off and then reduced to dryness under vacuo to afford 316 mg (99.5%) 1-[5-(4-bromo-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propan-1-one 3 as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([I:34])[CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:28]([I:34])[CH:27]=1
Reactant: NCc1ccc(F)cc1I
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (4-fluoro-2-iodophenyl)methanamine. White solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.66 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2,), 4.57 (2H, d, J=6.6 Hz, NCH2), 7.05 (1H, m aromatic), 7.3-7.38 (3H, m, aromatics), 7.42 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 7.53 (2H, m, aromatics), 7.56 (1H, dd, J=2.6 Hz and J=8.0 Hz, aromatic), 8.05 (1 H, broad t, NH). HRMS (ESI+) calculated for C24H24FIN3O4 [M+H+]: 564.0796; found: 564.0809.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:43]1([C@H:47]([NH:54][CH3:55])[CH2:48][N:49]2[CH2:52][CH:51]([OH:53])[CH2:50]2)[CH2:46][CH2:45][CH2:44]1>C(Cl)Cl>[Cl:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:12]=1[C:13]([N:54]([C@@H:47]([CH:43]1[CH2:46][CH2:45][CH2:44]1)[CH2:48][N:49]1[CH2:50][CH:51]([OH:53])[CH2:52]1)[CH3:55])=[O:15]
Reactant: CN[C@H](CN1CC(O)C1)C1CCC1
Reactant: O=C(O)c1ccc(F)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc(F)cc1Cl)[C@H](CN1CC(O)C1)C1CCC1
Reaction time: 0.08 h
Yield: 51.1 %

Procedure:
DIPEA (0.183 mL, 1.05 mmol) was added to a stirred suspension of 2-chloro-4-fluorobenzoic acid (55 mg, 0.31 mmol) and TBTU (0.101 g, 0.31 mmol) in DCM (1 mL) at rt. The suspension was stirred for 5 min before it was cooled on an ice-bath. A solution of (S)-1-(2-cyclobutyl-2-(methylamino)ethyl)azetidin-3-ol (Compound Z2.1) (0.07 g, 0.35 mmol) in DCM (1 mL) was added over 3 min. The ice-bath was removed and the reaction was stirred at rt for 2 h. The reaction mixture was washed with NaHCO3 (8% aq., 3 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (54 mg, 45%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 1.41-2.1, 2.22-2.85, 3.06-3.59, 4.02-4.23, 4.46-4.60, 5.17-5.35, 7.23-7.72. HRMS (M+H)+: calculated 341.1432. found 341.1442.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[Cl:30][C:31]1[N:36]=[C:35]([Sn](CCCC)(CCCC)CCCC)[CH:34]=[CH:33][N:32]=1>CN(C=O)C.C(Cl)Cl.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.[Cu]I>[Cl:30][C:31]1[N:36]=[C:35]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][C:14]([NH:16][CH:17]([CH3:18])[CH3:19])=[N:13][N:12]=4)[CH:9]=3)[N:4]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=3)(=[O:22])=[O:21])[CH:3]=2)[CH:34]=[CH:33][N:32]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccnc(Cl)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 100 °C
Yield: 69 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (1.00 g, 1.914 mmol) and 2-chloro-4-(tributylstannyl)pyrimidine (0.966 g, 2.393 mmol) in DMF (5 mL) followed by tetrakis(triphenylphosphine)palladium (0.111 g, 0.096 mmol) and CuI (0.016 mL, 0.479 mmol). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The mixture was diluted with DCM and washed with water (3×50 mL) and brine. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 5-40% EtOAc in Hexanes) to give 5-(3-(2-chloropyrimidin-4-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (672 mg, 1.320 mmol, 69.0% yield) as a brown solid. MS (ESI, pos. ion) m/z: 509.0 (M+1).