Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(=O)=O.CC(C)=O.[C:13](#[N:15])[CH3:14].[CH2:16]1[N:27]2[C:28]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[CH:23]=[N:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=32)[CH2:17]1>O1CCCC1>[CH2:16]1[N:27]2[C:28]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[CH:23]([CH2:14][C:13]#[N:15])[NH:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=32)[CH2:17]1
Reactant: C1=Nc2ccccc2N2CCc3cccc1c32
Reactant: CC#N
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: N#CCC1Nc2ccccc2N2CCc3cccc1c32
Reaction time: 2 h
Yield: 78.7 %

Procedure:
n-Butyllithium (10 ml of a 2.5M solution) and tetrahydrofuran (THF, 10 ml) were placed in a 250 ml 3-neck flask under nitrogen and chilled to -60° C. (dry ice/acetone). Acetonitrile (1 g) in tetrahydrofuran (10 ml) was added in one portion. A precipitate formed in a short time. Thirty minutes thereafter, a solution of 1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (4.5 g) in tetrahydrofuran (20 ml) was added. The cold bath was then removed and the reaction mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate (350 ml) and poured into saturated ammonium chloride solution (500 ml). The organic phase was separated and washed with brine (50%, 500 ml). The insolubles were collected by filtration. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to a solid. The solids were combined and purified by flash chromatography (silica, 80 g, eluted with dichloromethane) to afford 4.2 g of product. Recrystallization from a large volume of ethanol/isopropanol gave 2.48 g of crystalline product, m.p. 218°-220° C.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][C:8]3[N:9]2[CH:12]=[N:13][N:14]=3)=[CH:4][CH:3]=1.[SH:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=[O:26].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]1([C:6]2[C:5]3[C:10](=[CH:11][C:2]([S:21][C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=[O:26])=[CH:3][CH:4]=3)[N:9]3[CH:12]=[N:13][N:14]=[C:8]3[CH:7]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1cccc(S)c1
Reactant: Ic1ccc2c(-c3ccccc3)cc3nncn3c2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(O)c1cccc(Sc2ccc3c(-c4ccccc4)cc4nncn4c3c2)c1
Temperature: 70 °C

Procedure:
8-Iodo-5-phenyl-[1,2,4]triazolo[4,3-a]quinoline (250 mg, 0.67 mmol), 3-mercaptobenzoic acid (120 mg, 0.81 mmol), iPr2NEt (0.36 mL, 2.1 mmol), Pd2dba3 (15 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (19 mg, 0.03 mmol) were dissolved in 1,4-dioxane and degassed with N2. The reaction was then sealed and heated to 70° C. for 30 minutes, followed by cooling to room temperature, filtration, and concentration to give the desired product, 11a.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=3)(=[O:19])=[O:18])[CH:15]=2)[NH:10][CH:9]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][S:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[CH2:7][CH2:6][NH:5][C:1](=[O:3])[CH3:2])(=[O:19])=[O:18])=[CH:26][CH:25]=1)[CH3:29]
Reactant: CC(=O)Cl
Reactant: CCOc1ccc(NS(=O)(=O)c2ccc3[nH]cc(CCN)c3c2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1ccc(NS(=O)(=O)c2ccc3[nH]cc(CCNC(C)=O)c3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (0.6 ml) was added dropwise to a stirred solution of the product of Example 4 (3.1 g) in dry dimethylformamide (20 ml) containing triethylamine (3.3 ml) and the resulting suspension stirred at room temperature for 30 min. The suspension was partitioned between hydrochloric acid (2 N, 100 ml) and ethyl acetate (2×100 ml) and the combined extracts were washed with sodium carbonate (2 N, 100 ml) dried (MgSO4) and evaporated in vacuo to give an oil. The oil was purified by flash chromatography eluted with chloroform:methanol (19:1) to give the title compound as a foam (0.8 g), a sample of which (0.4 g) was crystallised from a mixture of ethyl acetate and hexane to give the title compound as a crystalline solid (0.3 g) m.p. 173°-175°.
Reaction SMILES: C(NC1C=C([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][CH:20]=2)C=CC=1Cl)(=O)C1C=CC=CC=1.CC1CNCC(C)N1>>[C:18]([NH2:17])(=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(Cl)nc1
Agent: CC1CNCC(C)N1
Product: NC(=O)c1cccnc1

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-chloronicotinamide (0.15 mmol) was used in general procedure 3 with 2,6-dimethylpiperazine (0.77 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-(3S-,5R)-3-5-dimethylpiperazine-1-yl)nicotinamide. MS (Q1) 464.0 (M)+
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].FC(F)(F)C(O)=O.[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18]>C(OCC)C>[C:15]([O:4][CH2:3][C@@H:2]([C:5]([OH:7])=[O:6])[NH2:1])(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: N[C@@H](CO)C(=O)O
Reactant: CCCC(=O)Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)OC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
L-Serine (10.5 g, 0.10 mol) was added with stifling to trifluoroacetic acid (70 ml) and the resultant solution was decanted from the insoluble material. Butyryl chloride (13.5 ml, 0.123 mol) was then added to the solution and the mixture was stirred for 1 h at room temperature. Upon the addition of diethyl ether (20 ml), a white solid precipitated which redissolved upon stirring. The reaction vessel was sealed and left to stand overnight in a refrigerator. Further diethyl ether (60 ml) was added to the cold solution with stirring. The resultant fine white precipitate was collected by filtration, washed with diethyl ether, and dried under vacuum to afford 13.4 g (60.0 mmol, 63%) of 2020371, m.p. 165-168° C. (dec.). 1H NMR (300 MHz, d6-DMSO) δ 0.80 (t, J 7 Hz, 3H), 1.46 (m, 2H), 2.24 (m, 2H), 4.21 (br s, 1H), 4.38 (m, 2H), 8.75 (br s, 3H). 13C NMR (75.5 MHz, d6-DMSO) δ 13.5, 18.1, 35.1, 57.7, 62.1, 168.3, 173.0. m/z 176.1 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[C:15]1[C:16](=[O:30])[NH:17][CH:18]([CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([O:28][CH3:29])[CH2:24][CH2:23]2)[C:19]=1[OH:20].CCN(CC)CC>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:5]([O:4][C:2](=[O:3])[O:20][C:19]1[CH:18]([CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([O:28][CH3:29])[CH2:26][CH2:27]2)[NH:17][C:16](=[O:30])[C:15]=1[C:9]1[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=1[CH3:7])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: CON1CCC(CC2NC(=O)C(c3cc(C)ccc3C)=C2O)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)NC1CC1CCN(OC)CC1
Reaction time: 0.5 h

Procedure:
Ethyl chloroformate (72 mg, 0.67 mmol) was added dropwise to a solution of 3-(2,5-dimethyl-phenyl)-4-hydroxy-5-(1-methoxy-piperidin-4-ylmethyl)-1,5-dihydro-pyrrol-2-one (220 mg, 0.67 mmol), Et3N (94 mg, 0.9 mmol) and DMAP (30 mg, 0.25 mmol) in 10 ml of THF at room temperature. The mixture was stirred for 30 min and concentrated to dryness in vacuo. The residue was purified by column chromatography on silica gel. Yield: 150 mg of carbonic acid 4-(2,5-dimethyl-phenyl)-2-(1-methoxy-piperidin-4-ylmethyl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl ester ethyl ester (title compound P1.1) as a gum.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=2[OH:13])=[CH:2]1.O1CCCC1>CO.[C].[Pd]>[CH3:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[C:7]=1[OH:13]
Reactant: Cc1cccc(-c2ccoc2)c1O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(C2CCOC2)c1O
Reaction time: 48 h
Yield: 93.8 %

Procedure:
2-(furan-3-yl)-6-methylphenol (Compound 6-9) (173 mg, 0.70 mmol) and palladium carbon (25 mg, 15%) were dissolved in methanol:tetrahydrofuran=1 mL:1 mL, followed by stirring under hydrogen balloon for 48 hours. After the completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate=3:1) to obtain 2-methyl-6-(tetrahydrofuran-3-yl)phenol (117 mg, 93%).
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([NH2:9])=[O:8])#[N:5].CN(C)[CH:12]=[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1)[CH:14]=O>CO>[CH3:22][C:18]1[CH:17]=[C:16]([C:13]2[CH:14]=[C:6]([C:4]#[N:5])[C:7](=[O:8])[NH:9][CH:12]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc(C(C=O)=CN(C)C)c1
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(-c2c[nH]c(=O)c(C#N)c2)c1

Procedure:
In the manner described in Example 6, a solution of 13.7 g. of sodium methoxide and 10.7 g. of cyanoacetamide in 250 ml. of methanol and 24.0 g. of 3-(dimethylamino)-2-(3-methylphenyl)-2-propenal is refluxed overnight to give 12.0 g. of the product of the Example as a yellow solid, m.p. 254.5°-260° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][CH2:13][CH2:14]Br)[CH3:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:10]([O:12][CH2:13][CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[CH3:11]
Reactant: CCOCCBr
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1ccc(CO)cc1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture of 4-hydroxybenzyl alcohol (3.00 g), 2-bromoethyl ethyl ether (4.1 ml), potassium carbonate (6.68 g) and DMF (30 ml) was stirred at 90° C. for 3 days. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:2→1:1) to obtain 4-(2-ethoxyethoxy)benzyl alcohol (2.45 g) as a light yellow, oily substance.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1)[C:7]([NH2:9])=[O:8].C=O.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O.N>[CH3:1][N:2]([CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1)[C:7]([NH2:9])=[O:8])[CH3:28]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CNCc1cc(C(N)=O)ccc1Oc1ccc(SC)c(C(F)(F)F)c1
Agent: C=O
Agent: N
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CSc1ccc(Oc2ccc(C(N)=O)cc2CN(C)C)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 79 %

Procedure:
The amide from example 177 (105 mg, 0.28 mmol) was suspended in DCM (3 mL) and treated with formaldehyde (37% aqueous, 35 μL, 0.425 mmol). The mixture was stirred for 30 minutes (dissolution had occurred by this stage) and then treated with sodium tri(acetoxy)borohydride (120 mg, 0.567 mmol). The reaction was stirred overnight and then diluted with water (5 mL), basified with 880 ammonia (1 mL) and extracted with DCM (3×10 mL). The combined organic extracts were washed with brine (5 mL), dried (MgSO4) and evaporated to a white solid. Purification by flash chromatography [SiO2; DCM, MeOH, 880 NH3 (95:5:0.5)] afforded the title amide as a white powder (85 mg, 78%); Free base: δH (CDCI3, 400 MHz) 2.24 (6 H, s), 2.46 (3 H, s), 3.50 (2 H, s), 5.47-6.15 (2 H, brm), 6.85 (1 H, d), 7.03 (1 H, d), 7.23 (1 H, s), 7.35 (1 H, d), 7.71 (1 H, d), 7.90 (1 H, s); MS m/z (TS+) 385 (MH+)
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[CH2:27][CH2:28][CH2:29][C:30]([OH:32])=O)=[C:21]([C:34]([O:36]C)=[O:35])[CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[CH2:27][CH2:28][CH2:29][C:30]([N:3]([CH2:1][CH3:2])[C:4]2[CH:5]=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:7]=[CH:8][C:9]=2[CH3:10])=[O:32])=[C:21]([CH:20]=1)[C:34]([OH:36])=[O:35]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CCCC(=O)O
Reactant: CCNc1cc(-c2ccc(F)cc2)ccc1C
Product: CCN(C(=O)CCCC(=O)Nc1ccc(Cl)cc1C(=O)O)c1cc(-c2ccc(F)cc2)ccc1C

Procedure:
Using the same method as in Example 15-(i), N-ethyl-4′-fluoro-4-methylbiphenyl-3-amine was reacted with the 5-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-5-oxopentanoic acid to give 5-chloro-2-((5-[ethyl(4′-fluoro-4-methylbiphenyl-3-yl)amino]-5-oxopentanoyl)amino)benzoic acid.methyl ester (yield: 62%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:18])[CH:24]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)o1
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2cccc(Cl)c2)o1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and 3-chlorophenylboronic acid, using tetrakis(triphenylphosphine)palladium(0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The product-containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M in diethyl ether) was added and the solution was evaporated. After drying under vacuum, the hydrochloride salt of the title compound was obtained as a colourless solid; MS (ES+) 331 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[N+](=[CH2:13])=[N-]>CO.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:13])=[O:9]
Reactant: O=C(O)c1cnccc1Cl
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cnccc1Cl
Yield: 85 %

Procedure:
4-Chloronicotinic acid, prepared as described by W. C. J. Ross in J. Chem. Soc. (C), 1816 (1966), (2.54 g, 16.1 mmol) in methanol (30 mL) at 0° C. was treated with diazomethane in ether until gas evolution ceased; the ice bath was removed halfway through the esterification. The excess diazomethane was removed with a nitrogen stream and the solvent was removed under reduced pressure. The residue was taken up in saturated sodium bicarbonate solution and extracted with ethyl acetate (2×). The combined organic extracts were washed with 1M aqueous sodium hydroxide solution (2×) and brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford 2.35 g (85%) of the title compound as a yellow oil. A portion (1.47 g) was distilled at b.p. 75°-85° C. at ~1 mm mercury to afford 1.15 g as a pale yellow crystalline solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:16][C:15]([C:17]#[N:18])=[N:14][N:13]=2)[CH2:8][CH2:7]1.[N-:25]=[N+:26]=[N-:27].[Na+].Cl.[NH+]1C=CC=CC=1.Cl>CN1C(=O)CCC1>[N:18]1[NH:25][N:26]=[N:27][C:17]=1[C:15]1[S:16][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([O:5][C:4]3[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=3[C:2]([F:1])([F:23])[F:24])[CH2:7][CH2:8]2)=[N:13][N:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1nnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Agent: Cl
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccccc1OC1CCN(c2nnc(-c3nn[nH]n3)s2)CC1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
A suspension of 5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazole-2-carbonitrile (4.99 g, 14.1 mmol), NaN3 (4.65 g, 71.5 mmol) and pyridinium hydrochloride (3.43 g, 29.7 mmol) in NMP (50 mL) was heated at 130° C. for 18 h. The reaction mixture was cooled to room temperature and poured into aqueous 0.5 N HCl, extracted with EtOAc, washed three times with aqueous 0.5 N HCl, and with aqueous brine solution. The organic layer was dried (Na2SO4) and filtered. Evaporation of the solvent was followed by trituration in a mixture of MeOH/Et2O/heptane (1:1:6) (v/v) with stirring for 4 h at room temperature. After this time, the suspension was cooled with an ice-water bath and the title compound was collected by filtration as a white solid. The material was dried under high vacuum by heating at 50° C. for 1-2 h.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C@H:11]2[CH2:16][N:15]3[CH2:17][CH2:18][N:19](C(OCC4C=CC=CC=4)=O)[CH2:20][C@H:14]3[CH2:13][N:12]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:38]>CO.[Pd]>[CH3:1][C:2]1[C:10]([C@H:11]2[CH2:16][N:15]3[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]3[CH2:13][N:12]2[C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:38]
Reactant: Cc1c([C@H]2CN3CCN(C(=O)OCc4ccccc4)C[C@H]3CN2C(=O)OC(C)(C)C)ccc2c1COC2=O
Agent: [Pd]
Solvent: CO
Product: Cc1c([C@H]2CN3CCNC[C@H]3CN2C(=O)OC(C)(C)C)ccc2c1COC2=O
Reaction time: 8 h

Procedure:
To a solution of the title compound of Step D ((0.46 g, 0.88 mmol) in methanol (30 mL) was added palladium on carbon (10%, 0.094 g, 0.088 mmol) and the mixture was subjected to hydrogenation at rt overnight. After filtration the filtrate was concentrated to give the title compound. LC/MS: (M+1)+: 388.10.
Reaction SMILES: CC1(C)COC2(CCC(CCN[C@H](C3C=CC(C(F)(F)F)=CC=3)C)(O)CC2)OC1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CC1(C)CO[C:46]2([CH2:69][CH2:68][C:49]3([O:54][C:53](=[O:55])[N:52]([C@H:56]([C:58]4[CH:63]=[CH:62][C:61]([C:64]([F:67])([F:66])[F:65])=[CH:60][CH:59]=4)[CH3:57])[CH2:51][CH2:50]3)[CH2:48][CH2:47]2)[O:45]C1>>[F:67][C:64]([F:65])([F:66])[C:61]1[CH:62]=[CH:63][C:58]([C@@H:56]([N:52]2[CH2:51][CH2:50][C:49]3([CH2:68][CH2:69][C:46](=[O:45])[CH2:47][CH2:48]3)[O:54][C:53]2=[O:55])[CH3:57])=[CH:59][CH:60]=1
Reactant: C[C@@H](c1ccc(C(F)(F)F)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Agent: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(C(F)(F)F)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: C[C@@H](c1ccc(C(F)(F)F)cc1)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
The title compound is prepared from 3,3-dimethyl-9-{2-[(S)-1-(4-trifluoromethyl-phenyl)-ethylamino]-ethyl}-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 12,12-dimethyl-3-[(S)-1-(4-trifluoromethyl-phenyl)-ethyl]-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained after that is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound, too. Yield: 67% of theory; LC (method 6): tR=1.28 min; Mass spectrum (ESI+): m/z=356 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([C:19](=[O:21])[NH2:20])=[C:4]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:6][N:5]2[C:17]=1[Cl:18].C1C2N(C=CC=2)C=CN=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:19]([C:3]1[C:2]([C:36]2[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)=[C:17]([Cl:18])[N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:4]=12)(=[O:21])[NH2:20]
Reactant: CC(C)(C)OC(=O)N1CCn2c(Cl)c(Br)c(C(N)=O)c2C1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2c(C(N)=O)c3n(c2Cl)CCN(C(=O)OC(C)(C)C)C3)cc1
Temperature: 100 °C
Yield: 77.9 %

Procedure:
To a mixture under nitrogen of 4.00 g (10.6 mmol) of tert-butyl 7-bromo-8-carbamoyl-6-chloro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate under N2 with the bromo derivative of pyrrolo[1,2-a]pyrazine, 1.77 g (11.6 mmol) of 4-methoxyphenylboronic acid and 10.3 g (31.7 mmol) of caesium carbonate in a mixture of 80 ml of tetrahydrofuran and 4 ml of water is added 0.863 g (1.06 mmol) of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (CAS 72287-26-4). The mixture is heated at 100° C. for 20 hours and, after cooling, the medium is then diluted with ethyl acetate and filtered through Celite. The filtrate is washed with water, the organic phase is dried over sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on a column of 40 g of silica gel, eluting with 5 to 100% ethyl acetate in dichloromethane, to give 3.35 g of tert-butyl 8-carbamoyl-6-chloro-7-(4-methoxy-phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate after crystallization from ethyl acetate and drying.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[NH:15][N:14]=[C:13]([C:16](O)=[O:17])[C:12]=1[N+:19]([O-:21])=[O:20])([CH3:10])([CH3:9])[CH3:8].C[N:23](C)C=O>ClCCl>[C:7]([C:11]1[NH:15][N:14]=[C:13]([C:16]([NH2:23])=[O:17])[C:12]=1[N+:19]([O-:21])=[O:20])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)c1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (10.2 ml, 117 mmol) was added dropwise to a suspension of 5-tert-butyl-4-nitro-1H-pyrazol-3-carboxylic acid (6 g, 28 mmol) in dichloromethane (55 ml) containing dimethylformamide (0.1 ml) under nitrogen at 0° C. The reaction was stirred at 0° C. for 0.5 hours, allowed to warm to room temperature and stirred for a further 1.5 hours. The solvent was removed under reduced pressure, the residue was azeotroped with dichloromethane (50 ml) and the residue was dissolved in dichloromethane (100 ml). Ammonia gas was bubbled into the solution for 45 minutes and the reaction was stirred under nitrogen at room temperature for 18 hours, concentrated under reduced pressure and the residue was dissolved in ethyl acetate (250 ml). After washing with water (100 ml) and brine (100 ml) the organic phase was filtered, the filtrate was dried over MgSO4 and concentrated under reduced pressure to give 5-tert-butyl-4-nitro-1H-pyrazol-3-carboxylic acid amide (4.0 g) as a light brown solid. 1H NMR (400 MHz, DMSO-D6): δ=12.90-13.08 (1H, brs), 7.78-7.86 (1H, brs), 7.49-7.60 (1H, brs), 1.30 (9H, s) (electrospray): m/z [M+H]+ 213, [M+Na]+ 235, [M−H]+ 211.