Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:23]([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)=[O:24])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1>[CH2:34]([N:22]([CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:7])(=[O:8])[NH2:5])=[CH:20][CH:19]=1)[C:23]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)=[O:24])[CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)N1CCc2ccccc21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(=O)N1CCc2ccccc21
Yield: 93.3 %

Procedure:
A solution of 59 mg (0.11 mmole) of 1-[N-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-N-pentylcarbamoyl]indoline (from Step A), 20 μL of anisole, and 0.5 mL of anhydrous TFA was stirred at room temperature for 16 hours. The residue obtained after evaporation of excess TFA was flash chromatographed over silica gel (elution with 0.5% MeOH--CH2Cl2) to give 49 mg (89%) of the title compound as a hard gum, homogeneous by TLC (95:5 MeOH--CH2Cl2); FAB-MS m/e 478 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.[OH:23][C@H:24]1[C@H:28]([OH:29])[CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C>CC(O)C.CCOC(C)=O>[OH:23][C@H:24]1[C@H:28]([OH:29])[CH2:27][N:26]([C:2]2[C:11]([C:12]#[N:13])=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:21][CH3:22])[CH:8]=3)[N:3]=2)[CH2:25]1
Reactant: O[C@@H]1CNC[C@H]1O
Reactant: COc1ccc2nc(Cl)c(C#N)c(-c3cccc(F)c3)c2c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc2nc(N3C[C@@H](O)[C@H](O)C3)c(C#N)c(-c3cccc(F)c3)c2c1
Temperature: 150 °C
Reaction time: 72 h

Procedure:
A solution of 2-chloro-4-(3-fluorophenyl)-6-methoxyquinoline-3-carbonitrile (61.0 mg, 0.20 mmol), (3R,4R)-3,4-dihydroxypyrrolidine (43 mg, 0.42 mmol) and triethylamine (0.055 mL, 0.42 mmol) in 3 mL of 2-propanol was heated in a sealed tube at 120° C. for 3 days. The temperature was raised to 150° C. After 3 days, additional portions of (3R,4R)-3,4-dihydroxypyrrolidine (40 mg) and triethylamine (0.055 mL) were added. After a total of 11 days, the solution was cooled and diluted with EtOAc. The organic layer was washed with saturated NaHCO3 solution and brine, and dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by recrystallization from EtOAc/hexane (40 mg, 54%). Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C21H19FN3O3 (M+M+): 380.1405. Found 380.1401.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][CH:9]=[CH:8][CH:7](O[Si](C)(C)C)[C:6]=1[C:16]([O:18][CH3:19])=[O:17])=[O:4].[CH2:20]([O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:32][C:31]2[CH:30]=[CH:29][C:28]([O:27][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:34][CH:33]=2)=[C:9]([NH:32][C:31]2[CH:30]=[CH:29][C:28]([O:27][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:34][CH:33]=2)[CH:10]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1=C(C(=O)OC)C(O[Si](C)(C)C)C=CC1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Nc2ccc(OCc3ccccc3)cc2)c(Nc2ccc(OCc3ccccc3)cc2)cc1C(=O)OC

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-his (trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 4.8 g (24 mmol) of 4-benzyloxyaniline in 24 ml of glacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 20 ml of 1N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is dissolved while hot in ethyl acetate and filtered, then allowed to crystallize at 0°. The crystalline residue is chromatographed on silica gel with ethyl acetate/hexane 3:2 and the product fractions are concentrated by evaporation and recrystallized from ethyl acetate/hexane, yielding the title compound in the form of beige crystals, FAB-MS: 589 [M+ +H].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[OH:10][CH:11]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:12][CH2:13][C@@H:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]#[CH:22])[CH2:16][C@@H:15]1[C:23]([O:25][CH3:26])=[O:24].O>C(N(CC)CC)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:10][CH:11]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:12][CH2:13][C@@H:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]#[C:22][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)[CH2:16][C@@H:15]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: Fc1cc(F)cc(Br)c1
Reactant: C#CCN1CC[C@@H](CCC(O)c2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 80 °C

Procedure:
0.138 g of tetrakis(triphenylphosphine)palladium, 0.046 g of cuprous iodide, and 0.42 cm3 of 1-bromo-3,5-difluorobenzene were added to a mixture, stirred at a temperature in the region of 20° C. under an inert atmosphere, of 0.95 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine -3-carboxylate in 9.5 cm3 of triethylamine. The mixture was heated at a temperature in the region of 80° C. for 3 hours. After cooling to approximately 20° C., the reaction mixture was taken up in 30 cm3 of ethyl acetate and 30 cm3 of water and stirred for 5 minutes. The organic phase was separated by settling, while the aqueous layer was extracted with 2 times 30 cm3 of ethyl acetate. The organic extracts were combined, washed with 3 times 30 cm3 of water, dried over sodium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 2.3 cm; 40 g), elution was carried out with pure ethyl acetate. 2 fractions of 100 cm3 were first collected and then 20-cm3 fractions were obtained. Fractions 8 to 40 were combined and evaporated under the above conditions. 0.967 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate was obtained in the form of a foam with an orange color.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]3[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[C:25](O)(=[O:29])[CH2:26][CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:15]([C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])=[CH:24][CH:23]=3)[N:17]([CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:10]=2[N:11]=1)#[N:16]
Reactant: CCCC(=O)O
Reactant: CC(C)(C)Cn1c(Cc2ccc(N)cc2)cc2cnc(C#N)nc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(=O)Nc1ccc(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a solution of 6-(4-amino-benzyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.3 mmol) in DMF (4 ml), butyric acid (0.36 mmol), water soluble carbodiimide (0.45 mmol) and 1-hydroxybenzotriazole hydrate (0.45 mmol) are added at 0° C. and then the reaction mixture is stirred at room temperature for 1 day. The reaction mixture is quenched with ammonium chloride and extracted with AcOEt. The organic layer is washed with brine, dried over sodium sulfate and evaporated in vacuo to give 129 mg of crude product. Purification of the residue by silica gel column chromatography affords the title compound in 96% yield. Rf=0.46 (n-hexane:AcOEt=1:1)
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>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.C([O-])([O-])=O.[Na+].[Na+].CCO>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1c(Cl)cnn(Cc2ccccc2)c1=O
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: Cc1ccccc1
Solvent: CCO
Product: COc1c(-c2ccc(Cl)cc2)cnn(Cc2ccccc2)c1=O
Temperature: 120 °C
Reaction time: 18 h
Yield: 100986.3 %

Procedure:
To a round bottom flask was added 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one (25.1 gm, 0.1 mmol), 4-chlorophenyl boronic acid (17.215 gm, 0.11 mmol), Pd(PPh3)4(9.24 gm, 0.008 mmol), toluene (200 ml), EtOH (200 ml) and 2.0N Na2CO3 (200 ml, 0.4 mmol). The reaction was purged with argon for 10 min. The reaction was then heated to 120° C. and stirred at this temperature for 18 hrs. After this time, the reaction was cooled to rt, poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (50 ml). The combined organic layers were washed with 1N NaOH (200 ml), water (200 ml) and saturated aqueous NaCl (200 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 330 gm silica gel) eluting with a gradient of 0-30% EtOAc/CH2Cl2 to give product 2-benzyl-5-(4-chlorophenyl)-4-methoxypyridazin-3(2H)-one (33 gm, 99% yield) as light yellow solid. HPLC retention time (method A) 3.740 min; LCMS (M+H)=327.2.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[OH-:16].[Na+].[C:18]1([OH:26])C=C(C)C=C(C)C=1>C1(C)C=CC=CC=1.O>[C:9]1([OH:16])([CH3:1])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]1[CH3:18].[C:1]([C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:2])[CH3:3].[CH2:18]=[O:26]
Reactant: Cc1cc(C)cc(O)c1
Reactant: [OH-]
Agent: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=O
Product: CC1C=CC=CC1(C)O

Procedure:
Into a four-necked flask provided with a reflux condenser and a thermometer are charged p-tert-octylphenol (133.9 g, 0.65 mol), toluene (206 g), 88% paraform (23.6 g, 0.7 mol) and a 10 N-NaOH aqueous solution (8 ml). The mixture is reacted at 70° C. for 3 hours, and thereto is added 3,5-xylenol (42.7 g, 0.35 mol). The mixture is further reacted for 3 hours. After the reaction, water and toluene are simultaneously distilled off at 150° C. under reduced pressure (reduced degree: 30 mmHg or less) to give a solid xylenol/p-tert-octylphenol/formaldehyde co-polycondensate resin (Resin V).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:8](Cl)(=[O:12])[C:9]([CH3:11])=[CH2:10].Cl>O>[C:8]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: NCC(=O)O
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)C(=O)NCC(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
Glycine (75 g, 1 mol) is dissolved in 500 ml of 40 g (1 mol) of sodium hydroxide in the ice bath and the clear solution is reacted with 105 g (1 mol) of methacryloyl chloride and 40 g (1 mol) of sodium hydroxide in 150 ml of water simultaneously. The reaction temperature is kept below 5° C. throughout the addition. The reaction mixture is allowed to rise to room temperature and stirred at that temperature for three hours. The clear solution was titrated with 1N HCl to pH 3.0 and extracted with ethylacetate. The combined organic layer is dried over anhydrous magnesium sulfate and evaporated to leave 70 g (46%) of a crystalline material. Melting point 104° C. (literature 104°-105.5° C.). NMR (D2O), 5.7 gamma (s, 1H, =CH2), 5.4 gamma (s, 1H, =CH2), 4.0 gamma (s, 2H, CH2 ), 1.9 gamma (s, 3H, CH3). Purity by neutralization, 100.1%; purity by bromination, 100.8%.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][CH:23]([CH3:26])[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH3:26]
Reactant: CC(N)CO
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CC(CO)Nc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 71 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-amino-propan-1-ol according to the GPA affording 25 mg (71%) of a red powder. Rt=3.21 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([I:13])[C:7]1=[O:14].C([O-])([O-])=O.[K+].[K+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=2)=[C:8]([I:13])[C:7]1=[O:14]
Reactant: O=c1c(I)c(O)ccn1Cc1cccc(F)c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c(I)c(OCc2ccc(F)cc2)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-(3-fluorobenzyl)-4-hydroxy-3-iodopyridin-2(1H)-one (0.5 g, 1.44 mmol) in DMF (5 mL) was added K2CO3 (0.199 g, 1.44 mmol) followed by the addition of 4-fluorobenzyl bromide (0.189 mL, 1.51 mmol). The reaction mixture stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate (50 mL) and washed with water. The organic extracts were dried over anhydrous Na2SO4 and concentrated to dryness. 1H-NMR (CD3OD, 400 MHz) δ 7.75 (d, 1H, J=7.6 Hz), 7.49 (q, 2H), 7.34 (q, 1H), 7.11 (m, 5H), 6.40 (d, 1H, J=7.6 Hz), 5.26 (s, 2H), 5.19 (s, -2H); ES-HRMS m/z 454.0098 (M+H calculated for C19H15NO2F2I requires 454.0110).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[Cl:10])[NH2:6].N1C=CC=CC=1.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22]>ClCCl>[Cl:19][C:20]([Cl:25])([Cl:24])[C:21]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:3]([C:2]([F:1])([F:11])[F:12])[CH:4]=1)=[O:22]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)C(Cl)(Cl)Cl
Reaction time: 1 h
Yield: 90.2 %

Procedure:
The clear solution of 3-trifluoromethyl-4-chloroaniline (35 g, 0.1789 mol) and pyridine (36 ml, 0.447 mol) in dichloromethane (350 ml) was cooled at 0° C. to −5° C. and a solution of trichloro acetyl chloride (26 ml, 0.2326 mol) in dichloromethane (75 ml) was added drop wise maintaining temperature of the reaction mass below 0° C. The reaction mass was stirred for 1 hour below 0° C. and quenched with water (150 ml) below 5° C. The organic phase was separated and aqueous layer was reextracted with dichloromethane. The combined dichloromethane layer was then washed with water, dried over sodium sulfate and evaporated under vacuum to obtain (55 g) the desired product, i.e., 2,2,2-trichloro-N-(4-chloro-3-(trifluoromethyl)phenyl)acetamide.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][C@H:16]([NH:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.C(=O)(O)[O-:36].[Na+]>C(O)(C)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][C@H:16]([NH:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH3:17])=[CH:10][C:11]=2[C:13]([NH2:14])=[O:36])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(C[C@@H](C)NCCOc3ccccc3OCC(F)(F)F)cc(C#N)c21
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)N1CCc2cc(C[C@@H](C)NCCOc3ccccc3OCC(F)(F)F)cc(C(N)=O)c21

Procedure:
To a solution of (R)-(-)-1-acetyl-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carbonitrile (2.00 g) in isopropanol (4.2 ml) was added concentrated hydrochloric acid (4.2 ml) slowly with stirring under ice cooling, and the mixture was stirred for 40 minutes. The reaction mixture was neutralized by a saturated aqueous sodium bicarbonate solution, and extracted with methylene chloride. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 1.70 g of (R)-(-)-1-acetyl-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carboxamide melting at 144°-146° C.
Reaction SMILES: [CH2:1]1[C@H:7]2[NH:8][C@H:3]([CH2:4][CH:5]([OH:9])[CH2:6]2)[CH2:2]1.Br[CH2:11][CH2:12][CH2:13][F:14].C(N(CC)CC)C>CN(C=O)C>[F:14][CH2:13][CH2:12][CH2:11][N:8]1[CH:7]2[CH2:1][CH2:2][CH:3]1[CH2:4][CH:5]([OH:9])[CH2:6]2
Reactant: OC1C[C@H]2CC[C@@H](C1)N2
Reactant: FCCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1CC2CCC(C1)N2CCCF
Temperature: 60 °C
Reaction time: 10 h

Procedure:
A mixture of nortropine (381.6 mg), 1-bromo-3-fluoropropane (634.4 mg) and triethylamine (0.42 ml) in DMF (7.5 ml) was heated to 60° C. and stirred at this temperature for 10 h. The solvent was then removed in vacuo. The product with the molecular weight of 187.26 (C10H18FNO) was obtained in this way; MS (ESI): 188 (M+H+).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[Br:6][C:7]1[CH:8]=[CH:9][C:10]([OH:30])=[C:11]([CH:29]=1)[CH2:12][N:13]([C:16]1[N:21]=[N:20][C:19]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:30][CH2:2][CH2:3][CH2:4][CH3:5])=[C:11]([CH:29]=1)[CH2:12][N:13]([C:16]1[N:21]=[N:20][C:19]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2O)nn1
Reactant: CCCCI
Product: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2OCCCC)nn1

Procedure:
The title compound was prepared by reacting 1-iodobutane and butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxylate using a similar method to that of reference example 4.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][C:24]1[CH:25]=[CH:26][C:27]([N:33]2[N:37]=[CH:36][CH:35]=[N:34]2)=[C:28]([CH:32]=1)[C:29]([OH:31])=O.CCN(C(C)C)C(C)C.Cl.[NH:48]1[CH2:51][CH2:50][C@H:49]1[C:52]([O:54][CH3:55])=[O:53]>C(Cl)Cl.O>[CH3:55][O:54][C:52]([C@@H:49]1[CH2:50][CH2:51][N:48]1[C:29](=[O:31])[C:28]1[CH:32]=[C:24]([CH3:23])[CH:25]=[CH:26][C:27]=1[N:33]1[N:37]=[CH:36][CH:35]=[N:34]1)=[O:53]
Reactant: COC(=O)[C@@H]1CCN1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCN1C(=O)c1cc(C)ccc1-n1nccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TBTU (4.93 g, 15.4 mmol) was added to a rt solution of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid A-1-2 (2.40 mg, 11.8 mmol) and DIPEA (8.09 mL, 47.2 mmol) in DCM (24 mL) and after stirring for 15 min, (S)-methyl azetidine-2-carboxylate HCl (2.03 g, 13 mmol) was added and the resulting mixture was stirred at rt for 1 h. The rxn mixture was diluted with DCM and water, the layers were separated and the aq. layer was extracted with DCM (1×). The combined org. extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude was purified by FC (EtOAc/hept 5:1) to obtain the title compound A-2-1 as a white solid. LC-MS A: tR=0.70 min; [M+H]+=301.18.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](O)=[O:5].O=S(Cl)Cl.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(CC)CC>>[C:13]1([NH:12][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: CC(C)=CC(=O)O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC(C)=CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
A mixture of 3-methyl-but-2-enoic acid (100 g, 1 mol) and SOCl2 (119 g, 1 mol) was heated at reflux for 3 h. The excess SOCl2 was removed under reduced pressure. CH2Cl2 (200 mL) was added followed by the addition of aniline (93 g, 1.0 mol) in Et3N (101 g, 1 mol) at 0° C. The mixture was stirred at room temperature for 1 h and quenched with HCl (5%, 150 mL). The aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were washed with water (2×100 mL) and brine (100 mL), dried over Na2SO4 and concentrated to give 3-methyl-but-2-enoic acid phenylamide (120 g, 80%).
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=O.[CH2:7]([N:14]1[C:18]2[NH:19][C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:21]C(=O)C=2[N:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>ClCCl.CN(C=O)C>[CH2:7]([N:14]1[C:18]2[N:19]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[N:21]=[C:1]([Cl:6])[C:2]=2[N:16]=[N:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)c1nc(=O)c2nnn(Cc3ccccc3)c2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3)c2n1
Temperature: 35 °C
Reaction time: 0.75 h
Yield: 114.2 %

Procedure:
DMF over MS (105 g, 110 ml, 1.43 mol, Eq: 2.56) was charged in the reactor followed by Dichlormethane (1.46 kg, 1.1 l). The solution was heated to 35° C. and oxalylchloride (144 g, 97.6 ml, 1.11 mol, Eq: 2) was added over 1 h. After 45 min, a fine suspension of 3-benzyl-5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(4H)-one (161 g, 557 mmol, Eq: 1.00) in a mixture of dichlormethane (877 g, 662 ml) and DMF (41.8 g, 44.1 ml) was added over of 20 min. After 3 h, the reaction mixture was cooled to RT and slowly added to a cold (0-5° C.) half saturated aqueous NaHCO3 (1.76 l). The organic phase was separated and washed again with half saturated NaHCO3 (662 ml) followed by water (662 g, 662 ml). Then the org. phase was dried over MgSO4 and was concentrated under reduced pressure at 50° C./down to 10 mbar to give 192 g of a crude oil which does crystallize on standing. The crude 3-benzyl-5-tert-butyl-7-chloro-triazolo[4,5-d]pyrimidine was introduced in the next step without further purification.