Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:22])[CH:15]=[C:16](I)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:26]([OH:29])[C:27]#[CH:28]>C(NCC)C.C(Cl)Cl.[Cu]I.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:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:22])[CH:15]=[C:16]([C:28]#[C:27][CH2:26][OH:29])[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)cc(F)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)cc(F)c21

Procedure:
A mixture of N-(4-chlorobenzyl)-8-fluoro-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 14 (0.600 g), propargyl alcohol (0.11 mL, 1.90 mmol), CuI (0.048 g, 0.25 mmol), and PdCl2(PPh3)2 (0.178 g, 0.25 mmol) in diethylamine (42.5 mL) and CH2Cl2 (50 mL) are warmed to 65° C. overnight. The reaction mixture is then concentratred in vacuo. Column chromatography (elution with 5-10% MeOH/CH2Cl2) gave the title compound as a solid.
Reaction SMILES: [N:1]12[CH2:8][C:5]([CH2:9][OH:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.C([Li])CCC.CCCCCC.N1([C:27]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[N:30]=2)=[O:28])C=CNC1>O1CCCC1>[N:1]12[CH2:8][C:5]([CH2:9][O:10][C:27]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]([CH3:38])[N:30]=3)=[O:28])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: OCC12CCCN(CC1)C2
Reactant: Cn1nc(C(=O)N2C=CNC2)c2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nc(C(=O)OCC23CCCN(CC2)C3)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
A cooled (0° C.) solution of 1-azabicyclo[3.2.1]oct-5-ylmethanol (1.70 g, 12 mmol) in anhydrous tetrahydrofuran (15 mL) under nitrogen was treated (via syringe) with 2.45N n-butyllithium/hexane (12 mmol), then stirred at room temperature for thirty minutes and concentrated in vacuo to remove all hexane. Anhydrous tetrahydrofuran (15 mL) was added, followed by 3-(3H-imidazol-1-ylcarbonyl)-1-methyl-1H-indazole (2.49 g, 11 mmol), and the mixture was stirred under nitrogen at room temperature for 18 hours, then at 60° C. for three hours, and concentrated in vacuo. The residue was partitioned between 1.0N sodium carbonate (75 mL) and toluene (125 mL) containing some 2-propanol, and the organic layer was set aside. The aqueous solution was extracted with toluene (2×50 mL) containing some 2-propanol, and the combined organic solution was rinsed with water to remove imidazole, then dried azeotropically with toluene. The residue was filtered through alumina (eluted with 15% methanol/tetrahydrofuran), concentrated in vacuo, and triturated from ether/petroleum ethers (30°-60°), then recrystallized from ether/petroleum ethers (30°-60°) to afford 1.75 g (53%) of the product as a colorless solid; mp 93°-95° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5](=[O:15])[CH2:6][CH:7]([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH2:9].C1(C)C=CC(S([N:26]=[N+:27]=[N-])(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:16])[C:4](=[N+:26]=[N-:27])[C:5](=[O:15])[CH2:6][CH:7]([O:10][Si:11]([CH3:13])([CH3:14])[CH3:12])[CH:8]=[CH2:9]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: C=CC(CC(=O)CC(=O)OC)O[Si](C)(C)C
Solvent: CCN(CC)CC
Product: C=CC(CC(=O)C(=[N+]=[N-])C(=O)OC)O[Si](C)(C)C
Yield: 83 %

Procedure:
In accordance with the process of Example 2, 3-oxo-5-trimethylsilyloxy-6-heptenoic acid methyl ester (360 mg; 1.47 m mol), p-toluenesulfonyl azide(290 mg; 1.47 m mol) and triethylamine (150 mg; 147 m mol) were used as starting materials to obtain 330 mg of 2-diazo-3-oxo-5-trimethylsiloxy-6-heptenoic acid methyl ester as yellow oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.Cl.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][NH2:48])[CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:48][CH2:47][CH2:46][N:43]3[CH2:42][CH2:41][N:40]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=4)[CH2:45][CH2:44]3)=[O:29])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCCN1CCN(c2ccccn2)CC1
Reactant: O=C(O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1)NCCN1CCN(c2ccccn2)CC1

Procedure:
The title compound was prepared from [5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid (Example 2c) and 2-(4-pyridin-2-yl-piperazin-1-yl)-ethylamine tetrahydrochloride (Reference Example 5) according to the method described in Example 1e. MS (EI) 637.3 (MH+).
Reaction SMILES: [Cl:1][N:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:20][CH:19]=[N:18][CH:17]=3)=[C:12]([O:21][CH3:22])[CH:11]=2)[NH:3]1.[CH3:23][NH2:24].C1COCC1>C(COC)OC>[Cl:1][N:2]1[N:7]=[C:6]([NH:24][CH3:23])[CH:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:20][CH:19]=[N:18][CH:17]=3)=[C:12]([O:21][CH3:22])[CH:11]=2)[NH:3]1
Reactant: COc1cc(NC2=CC(Cl)=NN(Cl)N2)ccc1-c1cnco1
Reactant: CN
Solvent: COCCOC
Solvent: C1CCOC1
Product: CNC1=NN(Cl)NC(Nc2ccc(-c3cnco3)c(OC)c2)=C1
Reaction time: 3 h
Yield: 77 %

Procedure:
2,4-Dichloro-6-(4-oxazol-5-yl-3-methoxyphenylamino)triazine 214A (1.8 g, 5.4 mmol) was suspended in dimethoxyethane (50 mL). 2 M Methylamine in THF (27 mL, 54 mmol) was added dropwise and the reaction mixture stirred for 3 h. The crude product was filtered and triturated with ethanol (20 mL) and dried to yield 1.37 g (77%) of the title compound. LCMS Condition A retention time=2.61 min (>95%), M+H+=333.16 (100%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][O:12][C:13]=1[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[NH:16][N:15]=1.[Br:23]C1C=CC(F)=NC=1>>[Br:23][C:20]1[CH:21]=[C:22]2[C:14]([C:13]3[O:12][N:11]=[CH:10][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])=[N:15][NH:16][C:17]2=[N:18][CH:19]=1
Reactant: Fc1ccc(Br)cn1
Reactant: Fc1cccc(-c2cnoc2-c2n[nH]c3ncccc23)c1F
Product: Fc1cccc(-c2cnoc2-c2n[nH]c3ncc(Br)cc23)c1F

Procedure:
5-Bromo-3-(4-(2,3-difluorophenyl)isoxazol-5-yl)-1H-pyrazolo[3,4-b]pyridine was prepared according to the method described for the preparation of 3-(4-(2,3-difluorophenyl)isoxazol-5-yl)-1H-pyrazolo[3,4-b]pyridine starting with 5-bromo-2-fluoropyridine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)[N:4]=[N:3]1.P(Br)(Br)[Br:16]>ClCCl>[Br:16][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[CH:8][CH:9]=1
Reactant: Cn1cc(-c2ccc(CO)cc2)nn1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Cn1cc(-c2ccc(CBr)cc2)nn1
Temperature: 20 °C
Reaction time: 16 h
Yield: 77.3 %

Procedure:
To a solution of [4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]methanol (3.40 g) in dichloromethane (130 mL) was added dropwise phosphorus tribromide (23.0 g) under ice-cooling, and the mixture was stirred at 20° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, the residue was poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (×3). The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.50 g) as a mixture with phosphine oxide. This mixture was diluted with tert-butyl methyl ether, and the mixture was stirred at 20° C. for 16 hr. The precipitate was collected by filtration, and dried under reduced pressure to give the title compound (3.40 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])[CH:19]([CH3:21])[CH3:20].C(OCC)(=O)C>C(#N)C>[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([N:15]1[CH2:14][CH2:13][N:12]([C:9]2[CH:10]=[CH:11][C:5]3[S:4][C:3]([CH3:2])=[N:7][C:6]=3[CH:8]=2)[CH2:17][CH2:16]1)=[O:26])[CH:19]([CH3:21])[CH3:20]
Reactant: Cc1nc2cc(N3CCNCC3)ccc2s1
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1nc2cc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OCC(C)C)CC3)ccc2s1

Procedure:
Prepared in analogy to example 1.1(b) from 2-methyl-5-piperazin-1-yl-benzothiazole hydrochloride and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a brownish solid.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].Cl.C(N(C(C)C)CC)(C)C.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>C(#N)C>[CH2:25]([S:27]([N:6]1[CH2:5][C:4](=[CH:3][C:1]#[N:2])[CH2:7]1)(=[O:29])=[O:28])[CH3:26]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CC(=CC#N)C1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (9, 1000 g, 5.2 mol) in acetonitrile (7 L) and a 3 N aqueous HCl solution (7 L) was stirred at room temperature for 18 h. When HPLC showed that all the starting material (9) was consumed, the reaction mixture was concentrated under reduced pressure to dryness. The residue, which contains the crude desired deprotection product (10), was then suspended in acetonitrile (12 L) and the resulting suspension was cooled to 0-5° C. Diisopropyethylamine (DIEA, 3.14 L, 18.03 mol, 3.5 equiv) was then slowly added while keeping the internal temperature below 5° C. The resulting homogeneous solution was allowed to cool down to 0° C. and ethane sulfonyl chloride (EtSO2Cl, 730 mL, 7.73 mol, 1.5 equiv) was added over 1 h while keeping the internal temperature below 5° C. The resulting reaction mixture was allowed to gradually warm to room temperature and stirred at room temperature for overnight. When HPLC showed that the reaction was complete, the reaction mixture was concentrated under reduced pressure to a volume of approximately 2 L. The bath temperature of the rotary evaporator is set to not exceed 45° C. The concentrated residue was then diluted with dichloromethane (CH2Cl2, 10 L) and the resulting dichloromethane solution was washed with aqueous sodium chloride solution (10 L). The aqueous phase was back extracted with dichloromethane (CH2Cl2, 5 L). The combined organic layers were dried over anhydrous sodium sulfate (Na2SO4) and the residue was absorbed onto silica gel (SiO2, 1 Kg) under reduced pressure. The bath temperature of the rotary evaporator was set to not exceed 45° C. The material was then loaded onto a silica gel column (SiO2, 2.5 Kg) and eluted with 20-60% ethyl acetate in heptane to afford 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (11, 882 g, 968.4 g theoretical, 91% yield) as off-white solids. For 11: 1H NMR (CDCl3, 300 MHz) δ 5.46 (m, 1H), 4.77 (m, 2H), 4.70 (m, 2H), 3.05 (q, 2H), 1.39 (t, 3H) ppm; C7H10N2O2S (MW, 186.23), LCMS (EI) m/e 187 (M++H).
Reaction SMILES: [Na].[S:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:4]=[N:3]1.[N:12](OCCC(C)C)=[O:13]>CO>[OH:13][N:12]=[C:7]([C:5]1[CH:4]=[N:3][S:2][CH:6]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1cnsc1
Reactant: CC(C)CCON=O
Agent: [Na]
Solvent: CO
Product: COC(=O)C(=NO)c1cnsc1
Yield: 61 %

Procedure:
A solution of sodium (1.01 g.) in absolute methanol (10 ml.) was dropwise added over 15 minutes with stirring and ice-cooling to a solution of methyl 2-(isothiazol-4-yl)acetate (6.30 g.) and isopentyl nitrite (10.6 g.) in absolute methanol (63 ml.). The mixture was stirred for 30 minutes at the same temperature and for 3 hours at ambient temperature. The reaction mixture was concentrated and the residue was poured into a mixture of ethyl acetate (50 ml.) and water (50 ml.) The aqueous layer was separated and the ethyl acetate layer was extracted twice with 1N aqueous solution of sodium hydroxide (20 ml. and 10 ml.). The extracts and the aqueous layer separated above were combined, adjusted to pH 1 with 10% hydrochloric acid and extracted twice with ethyl acetate (70 ml. and 50 ml.). The extracts were washed with a 5% aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give methyl 2-hydroxyimino-2-(isothiazol-4-yl)acetate (anti isomer) (4.55 g.), mp 110° to 112° C.
Reaction SMILES: CS([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=O)=O.BrC1C=C[C:23]([S:26](C)(=[O:28])=[O:27])=CC=1>>[CH3:23][S:26]([C:10]1[CH:5]=[CH:6][C:7]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][OH:18])=[CH:15][CH:16]=2)=[CH:8][CH:9]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CO)cc2)c1
Product: CS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1

Procedure:
This compound was prepared in a manner analogous to the preparation of (3′-methanesulfonyl-biphenyl-4-yl)-methanol (WO 01/70753, Example 27) using 1-bromo-4-methanesulfonyl-benzene as the starting material. LCMS found for C14H15O3S (M+H)+: m/z=263.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:8]=[C:9]([C:14]2[O:15][C:16]([CH3:19])=[N:17][N:18]=2)[CH:10]=[CH:11][C:12]=1[CH3:13].[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl>O1CCCC1.O>[CH3:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]2[O:15][C:16]([CH3:19])=[N:17][N:18]=2)=[CH:8][C:7]=1[B:20]([OH:25])[OH:21]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1nnc(-c2ccc(C)c(I)c2)o1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccc(C)c(B(O)O)c2)o1
Temperature: -10 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
Isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 10 mL, 20.0 mmol) was added dropwise over 20 minutes to a stirred solution of 2-(3-Iodo-4-methylphenyl)-5-methyl-1,3,4-oxadiazole (preparation 55c, 4.0 g, 13.3 mmol) in tetrahydrofuran (40 mL) at −10° C. The mixture was stirred for 1 hour at −10° C. then triisopropyl borate (4.71 mL, 20.0 mmol) was added dropwise over 10 minutes and the mixture was stirred for 1 hour at −10° C. Then, the mixture was warmed to room temperature and stirred overnight. Water was then added, the mixture was cooled by means of an ice-water bath and the pH was adjusted to 3-4 with 2M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was triturated with diethyl ether and the solid was filtered and dried to give the title compound (1.92 g, 66%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:14][CH2:15][CH2:16][CH3:17])=[N:8][C:9](SC)=[N:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])O.[Na+].C(O[CH2:27][CH3:28])(=O)C>CN1CCCC1=O.ClC1C=CC=C(C(OO)=O)C=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:14][CH2:15][CH2:16][CH3:17])=[N:8][C:9]([NH:14][CH2:15][CH2:16][C:28]2[CH:27]=[CH:9][N:8]=[CH:7][CH:6]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCCNc1nc(SC)ncc1C(=O)OCC
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-(methylthio)-4-(propylamino)pyrimidine-5-carboxylic acid ethyl ester (A1, 9.0 g) in N-methylpyrrolidone (88 mL), meta-chloroperbenzoic acid (70 to 75% wt, 10.8 g) was added portionwise under ice cooling, and the mixture was stirred at room temperature for 45 minutes. To the reaction mixture, meta-chloroperbenzoic acid (70 to 75% wt, 2.5 g) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in N-methylpyrrolidone (35 mL), N,N-diisopropylethylamine (11.9 mL) and 4-(2-aminoethyl)pyridine (6.3 mL) were added at room temperature, and the mixture was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, and then poured into water (400 mL). The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxylic acid ethyl ester (A2, 9.2 g) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC1C=CC=CC=1)=O)[C:6](=[O:20])[C:5]2([C:31]1[C:32]([O:37][CH2:38][CH3:39])=[N:33][CH:34]=[CH:35][CH:36]=1)[O:21][C:22]([O:24]C1C=CC=CC=1)=O.[CH3:40][N:41]1[CH2:46][CH2:45][CH:44]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:43][CH2:42]1.C1COCC1>ClCCl>[CH3:40][N:41]1[CH2:42][CH2:43][CH:44]([N:47]2[CH2:52][CH2:51][N:50]([C:22]([O:21][C:5]3([C:31]4[C:32]([O:37][CH2:38][CH3:39])=[N:33][CH:34]=[CH:35][CH:36]=4)[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][C:6]3=[O:20])=[O:24])[CH2:49][CH2:48]2)[CH2:45][CH2:46]1
Reactant: CCOc1ncccc1C1(OC(=O)Oc2ccccc2)C(=O)N(C(=O)Oc2ccccc2)c2ccc(Cl)cc21
Reactant: CN1CCC(N2CCNCC2)CC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOc1ncccc1C1(OC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
A mixture of 1.29 g (2.37 mmol) of phenyl 5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-3-phenoxycarbonyloxy-2,3-dihydroindole-1-carboxylate, 1.73 g (9.46 mmol) of 1-(1-methylpiperidin-4-yl)piperazine and 10 ml of dry THF was stirred at room temperature for 72 hours. The reaction mixture was diluted with dichloromethane and extracted with water and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was stirred with diethyl ether. 963 mg of the title compound were obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([CH3:14])[N:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH3:13].C(N(CC)CC)C>C(O)C.[Pd]>[CH3:14][N:4]1[C:3](=[O:15])[CH:2]=[C:7]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])[CH:6]=[N:5]1
Reactant: Cc1nccn1-c1cnn(C)c(=O)c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nccn1-c1cnn(C)c(=O)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 82.2 %

Procedure:
To a solution of 3.30 g (14.7 mmol) of 4-chloro-2-methyl-5-(2-methyl-imidazol-1-yl)-2H-pyridazin-3-one in 60 ml of ethanol at 50° C. were added 2.44 ml (1.78 g, 17.6 mmol) of triethylamine and 0.312 g of Pd 10%/C. The suspension was stirred under hydrogen atmosphere for 15 h at 50° C. The catalyst was filtered off and washed twice with 10 ml of ethanol. The filtrate was concentrated in vaccuo, and taken up in 50 ml of methylene chloride. The organic phase was washed four times with water, dried and concentrated to yield the title compound (2.30 g, 12.09 mmol, 82%) as a white crystalline solid, MS: m/e=191.2 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)N1CCNCC1

Procedure:
348.5 g of 1-benzyl-4-tert-butyl piperazine are dissolved in 1200 cc of 99% ethanol and 10 g of a 5% palladium/charcoal catalyst are added to the resulting solution. The solution is subsequently shaken in a hydrogenation apparatus, in a hydrogen atmosphere (1 atmosphere) and at room temperature, until the take up of hydrogen is complete. Filtration is subsequently effected, the filtrate is concentrated by evaporation in a vacuum and the residue is distilled in a vacuum. 1-tert-butyl piperazine is obtained in the form of a colourless oil, having a B.P. of 66°-70° at 12 mm of Hg, which crystallizes upon standing. The crystals have a M.P. of 35°-40°.
Reaction SMILES: N.C([N:9]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]1=[O:23])C1C=CC=CC=1.CCO>C1COCC1>[NH:14]1[CH2:15][CH2:16][C:11]2([C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:9][C:10]2=[O:23])[CH2:12][CH2:13]1
Reactant: O=C1N(Cc2ccccc2)c2ccccc2C12CCNCC2
Agent: N
Solvent: C1CCOC1
Solvent: CCO
Product: O=C1Nc2ccccc2C12CCNCC2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
At −78° C., to liquid NH3 (20 ml) is added dropwise a solution of 1-benzylspiro[indole-3,4′-piperidin]-2(1H)-one (2 mmol) in THF (30 ml) and the mixture is stirred at −78° C. for 10 min. Li (42 mg, 6 mmol) is added in 3 portions and the resulting dark blue solution is stirred at −78° C. for 2 h. Anhydrous EtOH (1 ml) is added dropwise and the mixture is allowed to warm to rt overnight. Solvent is removed in vacuo and the resulting title compound (a light yellow solid) is used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:10][CH:9]([OH:11])[CH2:8][NH:7]1)=[O:5].Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].Cl>C(#N)C>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][N:7]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])=[O:5]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: COC(=O)C1CC(O)CN1
Agent: Cl
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@H](O)CN1c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 22 h
Yield: 98.9 %

Procedure:
A suspension of 2S,4S)-4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (4.0 g, 1.0 eq) in acetonitrile (55 mL) was treated with TEA (3.8 g, 1.36 eq) and 1-chloro-2-nitrobenzene (4.1 g, 1.05 eq). A solution formed, followed by rapid formation of a white precipitate. The mixture was stirred at 60° C. for 22 h then poured over HCl 1N (60 mL) and extracted several times with ether. The combined organic extracts were dried over sodium sulfate and evaporated. Purification by flash chromatography on silica gel with an heptane/ethyl acetate gradient yielded the title compound as a white solid (5.8 g, 79%).