Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[C:3]=1[CH3:14].[CH3:15][NH2:16].O>C(#N)C>[Cl:13][C:4]1[C:3]([CH3:14])=[C:2]([NH:16][CH3:15])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)c(C)c1Cl
Reactant: CN
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cnc(Cl)c(C)c1NC
Temperature: 50 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
To a solution of ethyl 4,6-dichloro-5-methylnicotinate (2.6 g, 11.1 mmol) in acetonitrile (60 mL) was added dropwise 40% methylamine in water (689 mg, 22.2 mmol, 60 mL), and the mixture was stirred at 50° C. for 72 h. LCMS monitored the reaction was completed. The reaction mixture was concentrated and extracted with ethyl acetate (100 mL). The organic layer was separated, combined, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (petroleum ether: ethyl acetate=2:1) to get the title compound (2.05 g, 81%) as a colorless oil. MS (ES+) C10H13ClN2O2 requires: 228, 230. found: 229, 231 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH2:16]([NH2:22])[C@@H:17]1[O:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>>[CH2:16]([NH:22][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])[C@@H:17]1[O:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: NC[C@H]1CCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC[C@H]2CCCO2)c1Cl
Yield: 96.6 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (993 mg, 3.41 mmol), (2R)-tetrahydrofurfurylamine (0.36 mL, 3.49 mmol) and triethylamine(0.72 mL, 5.17 mmol) were reacted to form the desired product (1.17 g, 97%). EI-MS m/z 353(M-H)−.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:3])[NH2:2].[OH:18]O.O>S(=O)(=O)(O)O>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][OH:18])=[O:16])(=[O:3])[NH2:2]
Reactant: OO
Reactant: NC(=O)NCCCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: NC(=O)NCCCCCCCCCCC(=O)OO
Temperature: 15 °C

Procedure:
61.6 g (0.25 mol) of N-carbamoyl-11-aminoundecanoic acid are dissolved in 74.4 g of sulfuric acid (96% strength by weight) and the solution is cooled to 15° C. 23.8 g (0.6 mol) of hydrogen peroxide (85% strength by weight) are added dropwise with cooling at such a rate that the internal temperature can be maintained between 15 and 20° C. The reaction mixture is subsequently stirred with occasional cooling at 20° C. internal temperature for 1 h and then cooled down to 10° C., 200 ml of water are added dropwise, and the precipitated peroxycarboxylic acid is filtered off with suction. The filter cake is washed with water until free of mineral acid and is dried at 40° C. under an aspirator vacuum.
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[S:10][C:9]=2[CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])=[CH:32][CH:33]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=3)[S:10][C:9]=2[CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.4 %

Procedure:
To a mixture of 4-[(cyclohexyl{2-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-3-yl}methyl)amino]benzoic acid (300 mg) synthesized in Example 280-(4), ethyl β-alaninate hydrochloride (117 mg), 1-hydroxybenzotriazole monohydrate (117 mg) and triethylamine (106 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (146 mg), and the mixture was stirred at room temperature for 5 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (212 mg, 61%) as a white solid.
Reaction SMILES: BrBr.[C:3]([O-])(=O)[CH3:4].[Na+].[C:8]1([CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[S:18])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])O.[Na+]>CO.CC(C)CC(=O)C>[CH2:9]([C:3]1[N:19]=[C:17]([NH:16][CH2:15][CH2:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:18][CH:4]=1)[CH:8]([CH3:14])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: NC(=S)NCCc1ccccc1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: CO
Product: CC(C)Cc1csc(NCCc2ccccc2)n1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of 4-methyl-2-pentanone (2.00 g) in methanol (10 mL) was added bromine (3.20 g) at −30° C. The mixture was allowed to warm to room temperature and stirred until the red color of bromine disappeared. To the obtained colorless solution were added sodium acetate (3.20 g) and N-(2-phenylethyl)thiourea (1.80 g) and the mixture was stirred with heating under reflux for 4 hr. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added to the reaction mixture and the mixture was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9-2:1 in volume ratio) to give the title compound (1.15 g, yield 41%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][C:26](C)([CH3:29])[CH2:27][OH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][C@@H:26]([CH3:29])[CH2:27][OH:28])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(N)CO
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)N[C@@H](C)CO)cn1
Yield: 94 %

Procedure:
As described for example 254, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) was converted, using L-alaminol instead of 2-amino-2-methyl-1-propanol, to the title compound (110 mg, 94%) which was obtained as a white solid. MS: m/e=402.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[N:5]=[C:4]2[N:16]([CH3:19])[N:17]=[CH:18][C:3]=12.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][O:14][C:11]1[N:10]=[CH:9][C:8]([C:6]2[N:5]=[C:4]3[N:16]([CH3:19])[N:17]=[CH:18][C:3]3=[C:2]([O:30][C:27]3[CH:26]=[CH:25][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:29][CH:28]=3)[CH:7]=2)=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: COc1ccc(-c2cc(Cl)c3cnn(C)c3n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3cnn(C)c3n2)cn1
Temperature: 150 °C
Yield: 79.5 %

Procedure:
To 4-chloro-6-(6-methoxypyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (0.32 g) and 4-(methylsulfonyl)phenol (0.40 g) in DMF (6 mL) was added potassium carbonate (0.80 g) and nitrogen was bubbled through the solution for 5 min. The reaction mixture was then heated in a microwave reactor at 150° C. for 1 h. The resulting product was purified by silica gel chromatography (0-30% EtOAc in hexane) to afford 117 (0.38 g). MS (ESI) m/z 411.1 (M+1)+
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1Cl)[CH2:6][N+:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12.[Br-].COC1C=CC=CC=1C[N+]1C=CN2C=CC=CC=12.[Cl-:39].COC1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12.[I-].C(C1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12)#N.[Br-].BrC1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12.[Br-].FC1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12.[Cl-].C1(C2C=C(C=CC=2)C[N+]2C=CN3C=CC=CC=23)C=CC=CC=1.[Cl-].S(C1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12)(=O)(=O)N.[Cl-].CS(C1C=CC=CC=1C[N+]1C=CN2C=CC=CC=12)(=O)=O.[Br-].FC(F)(F)C1C=CC(C[N+]2C=CN3C=CC=CC=23)=CC=1>>[Cl-:2].[Cl:39][C:4]1[C:3]([Cl:2])=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][N+:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12
Reactant: Clc1ccc(C[n+]2ccn3ccccc32)cc1Cl
Agent: Brc1cccc(C[n+]2ccn3ccccc32)c1
Agent: COc1cccc(C[n+]2ccn3ccccc32)c1
Agent: COc1ccccc1C[n+]1ccn2ccccc21
Product: Clc1cccc(C[n+]2ccn3ccccc32)c1Cl

Procedure:
1-(3,5-dichlorobenzyl)imadazo[ 1,2-a]pyridinium chloride; 1-(3,4-dichlorobenzyl)-imidazo[1,2-a]pyridinium bromide; 1-(2-methoxybenzyl)imidazo[1,2-a]pyridinium bromide; 1-(3-methoxybenzyl)imidazo[1,2-a]pyridinium chloride; 1-(3-cyanobenzyl)imidazo[1,2-a]pyridinium iodide; 1-(3-bromobenzyl)imidazo[1,2-a]pyridinium bromide; 1-(3-fluorobenzyl)imidazo[1,2-a]pyridinium bromide; 1-(3-phenylbenzyl)imidazo[1,2-a]pyridinium chloride; 1-(3-sulfamoylbenzyl)imidazo[1,2-a]pyridinium chloride; 1-(2-methylsulfonylbenzyl)imidazo[1,2-a]pyridinium chloride; 1-(4-trifluoromethylbenzyl)imidazo[1,2-a]pyridinium bromide; and 1-(3-furfuryl)imidazo[1,2-a]pyridinium bromide.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH:22]1[C:32]2[CH2:31][NH:30][C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[NH:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.C1(C2C=CC(C(Cl)=O)=CC=2)CCCCC1>ClCCl.CN(C)C=O>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:30]3[CH2:31][C:32]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[NH:27][C:28]4[CH:36]=[CH:35][CH:34]=[CH:33][C:29]3=4)=[O:13])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1ccc(C2CCCCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2ccccc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
To a suspension of 4-cyclohexylbenzoic acid (10.0 g) in dichloromethane (75 mL) was added oxalyl chloride (10.0 g) followed by N,N-dimethylformamide (2 drops). The mixture was stirred at room temperature overnight and then all volatiles were removed in vacuo to provide the crude acid chloride (11.0 g). 5,11-Dihydro-10H-dibenzo[b,e][1,4]diazepine (1.96 g) in dichloromethane (50 mL) containing N,N-diisopropylethyl amine (1.3 g) was reacted with the crude 4-cyclohexylbenzoyl chloride prepared as described above (2.22 g). The reaction mixture was kept at room temperature overnight, then washed with water and saturated aqueous sodium bicarbonate. The solution was dried over anhydrous sodium sulfate and filtered through a short column of Magnesol® which was eluted with several additional volumes of dichloromethane. The total effluent was refluxed with the gradual addition of hexane until crystallization was noted. Cooling and filtration afforded the title compound as colorless crystals (1.28 g), m.p. 175-176° C.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([NH:12][C:13]([O:15][CH3:16])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)C.[Li+].[OH-]>C1COCC1.CO.C(Cl)Cl>[CH3:16][O:15][C:13]([NH:12][CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[C:4]([OH:17])=[O:3])=[O:14]
Reactant: CCOC(=O)C(NC(=O)OC)c1ccccn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)NC(C(=O)O)c1ccccn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of Methoxycarbonylamino-pyridin-2-yl-acetic acid ethyl ester (0.26 g, 1.1 mmol) in THF (6.0 mL) and MeOH (2.0 mL) was added aqueous LiOH (2.5 M, 2.2 mL, 5.5 mmol). The solution was stirred at room temperature for 1.5 h. The reaction was diluted with CH2Cl2 and washed with aqueous ammonium chloride and brine. The aqueous layers were combined and concentrated. The resulting solid was triterated with MeOH and filtered. The filtrated was concentrated and triterated a second time with MeOH. Concentration of the filtrate provided Methoxycarbonylamino-pyridin-2-yl-acetic acid which was used crude in the next step. LCMS-ESI+: calc'd for C9H10N2O4: 210.06 (M+); Found: 210.98 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[C:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([O-:10])=[O:9].ClC(OCC(C)C)=O.[F:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]([NH2:45])[CH3:44])=[CH:39][CH:38]=1>ClCCl>[N+:8]([C:11]1[C:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:45][CH:43]([C:40]1[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=1)[CH3:44])=[O:16])([O-:10])=[O:9]
Reactant: CC(N)c1ccc(F)cc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)c1cccc([N+](=O)[O-])c1OCc1ccccc1)c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 57.6 %

Procedure:
2.4 g (0.011 mol) of triethylamine are added at −10° C. to a solution of 3 g (0.011 mol) of 3-nitro-2-benzyloxybenzoic acid in 40 ml of dichloromethane. After the mixture has been stirred for 5 minutes, 2.8 g (0.011 mol) of isobutyl chloroformate are added dropwise at −10° C., and the mixture is stirred for a further 30 minutes. A solution of 1.53 g (0.011 mol) of 1-(4-fluorophenyl)-ethylamine in 10 ml of dichloromethane is added at −10° C., and stirring is continued for 12 hours without further cooling. The mixture is treated with sodium halogen carbonate solution, and the organic phase is separated off, washed with water and dried over sodium sulphate. After the solvent has been distilled off, 2.5 g (56% of theory) of 3-nitro-2-benzyloxy-N-[1-(4-fluorophenyl)-ethyl)-benzamide are obtained as an oil.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:28])[C@@H:8]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH:1]1([O:6][C:7](=[O:28])[C@@H:8]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(OC1CCCC1)[C@@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)N[C@H](C(=O)OC2CCCC2)c2ccccc2)cc1
Reaction time: 24 h
Yield: 92.6 %

Procedure:
A mixture of (S)-(4-Nitro-benzenesulfonylamino)-phenyl-acetic acid cyclopentyl ester (5.29 g, 13.1 mmol) and 10% Pd/C (5.0 g) in EtOAc (350 ml) was hydrogenated under balloon pressure at room temperature for 24 h. The Pd/C catalyst was filtered off through a pad of celite. The filtrate was concentrated under reduced pressure to yield the required product (4.54 g, 92% yield). LCMS purity 100%, m/z 375 [M++H]+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].N1C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[C:22](=[O:23])[NH:21][N:20]=[C:19]1[C:24]1[S:40][C:27]2[C:28]3[CH:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][C:29]=3[O:30][CH2:31][CH2:32][C:26]=2[CH:25]=1>C1COCC1.O>[NH2:3][CH2:2][CH2:1][NH:4][C:37]([C:34]1[CH:35]=[CH:36][C:28]2[C:27]3[S:40][C:24]([C:19]4[N:18]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=5[Cl:11])[C:22](=[O:23])[NH:21][N:20]=4)=[CH:25][C:26]=3[CH2:32][CH2:31][O:30][C:29]=2[CH:33]=1)=[O:38]
Reactant: O=C(Cl)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Reactant: NCCN
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: NCCNC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a solution of ethane-1,2-diamine (82 mg, 1.36 mmol) and pyridine (0.5 mL) in 5 mL of THF was slowly added 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonyl chloride (ca. 417 mg, ca. 0.91 mmol) in 20 mL of THF at 0° C. The mixture was stirred at room temperature overnight, diluted with water and purified by preparative HPLC to afford 66 mg of 533, isolated yield: 20%. ESI-MS: 482. 1H NMR (DMSO-d6, 400 MHz): δ 8.74 (s, 1H, NH), 8.37 (s, 1H, NH), 7.74-7.47 (m, 7H, ArH), 6.47 (s, 1H, ═CH), 4.19 (t, J=4.8 Hz, 2H, CH2), 3.40-3.36 (m, 4H, 2CH2), 2.98 (t, J=5.2 Hz, 2H, CH2), 2.86 (t, J=6.0 Hz, 2H, CH2).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:9]1[CH:8]=[CH:7][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: OCCCCBr
Product: BrCCCCOc1ccc2ccccc2c1

Procedure:
This example was prepared by substituting 3-bromopropanol with 4-bromobutanol and substituting 1-naphthol with 2-naphthol in EXAMPLE 31A.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=CC=C[C:8]=2OC)[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16].NC1N(C(C)C)N=CC=1C#N>>[NH2:1][C:2]1[N:6]([CH:7]([CH3:8])[CH3:12])[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16]
Reactant: COc1ccccc1-n1ncc(C(N)=O)c1N
Agent: CC(C)n1ncc(C#N)c1N
Product: CC(C)n1ncc(C(N)=O)c1N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxamide but substituting 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile provided the title compound. 400 MHz 1H NMR (CDCl3) δ 7.67 (s, 1H), 4.40-4.33 (m, 1H), 1.37 (d, J=6.6 Hz, 6H). MS: (M+H m/z=169.1).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][C@H:13]2[C@H:11]([CH2:12]2)[C@H:10]1[CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=O)(C)(C)C>O1CCOCC1>[C@H:11]12[CH2:12][C@H:13]1[CH2:14][NH:9][C@@H:10]2[CH2:15][NH:16][C:17](=[O:22])[C:18]([F:19])([F:21])[F:20]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNC(=O)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)C(F)(F)F
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
A solution of HCl in dioxane (4 M, 30 mL) is added to a solution of (1S,2S,5R)-2-[(2,2,2-Trifluoro-acetylamino)-methyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (31.6 mmol) in dioxane (30 mL) and the mixture is stirred for 60 min at RT and for 30 min at 45° C. The solvents are removed in vacuo and the obtained solid is washed twice with a small volume of dioxane to give the desired product which is used without further purification in the next step.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.O>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=1
Reactant: O=C1CCNCC1
Reactant: COc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 65 °C

Procedure:
KOH (8.44 g, 150 mmole), 5-methoxyindole (5.0 g, 34 mmole) and piperidine-4-one hydrochloride (10.53 g, 88.3 mmole) were suspended in methanol (50 ml) and heated for 8 hours at 65° C. under argon. Water (50 ml) was added dropwise at RT to the mixture over a period of 40 minutes. The solid thereby formed was filtered off, washed with water (3×20 ml) and recrystallised from methanol (20 ml). 5-methoxy-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole was obtained in a yield of 4.66 g (75%) as a yellow solid with an m.p. of 173°-175° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:16](=[O:18])(=[O:17])[NH:15][C:14](=[O:19])[CH2:13]1)[C:5](OC)=[O:6].[BH4-].[Li+]>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:9]=[CH:10][C:11]=1[CH:12]1[S:16](=[O:17])(=[O:18])[NH:15][C:14](=[O:19])[CH2:13]1
Reactant: COC(=O)c1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CC(c2ccc(CO)cc2Br)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of methyl 3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)benzoate (77.0 mg, 0.221 mmol) in tetrahydrofuran (6 mL) was added 2 M lithium tetrahydroborate in tetrahydrofuran (332 μL) at room temperature. The resulting solution was stirred at room temperature overnight. The reaction solution was diluted with methanol, and stirred for 0.5 h. The crude material was purified by preparative LCMS to give a white solid (65 mg, 92%). 1H NMR (400 MHz, CD3OD): δ 7.57 (s, 1H), 7.46 (m, 2H), 5.30 (dd, J=9.0, 5.9 Hz, 1H), 4.49 (s, 2H), 3.26 (m, 1H), 2.97 (dd, J=17.2, 5.7 Hz, 1H). LCMS found for C10H10BrNO4SNa (M+Na)+: m/z=342, 344.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:16])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])([CH3:4])[CH3:3].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>C(#N)C.P([O-])([O-])([O-])=O>[CH3:4][C:2]([O:5][C:6](=[O:16])[C@H:7]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH:8][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
An emulsion of L-phenylalanine 1,1-dimethylethyl ester (compound prepared at point A) (53.53 g; 242 mol), tert-butyl bromoacetate (37.3 mL; 254 mol) in acetonitrile (400 mL) and 2M buffer phosphate pH 8 (200 mL) is vigorously stirred at room temperature for 16 hours. After separation, the organic phase is evaporated and the residue is taken up into EtOAc; the aqueous phase is extracted with EtOAc (3×200 mL). The combined organic phases are washed with water (2×300 mL), saline solution (200 mL) and finally dried over Na2SO4. The crude is purified by flash chromatography (n-hexane/EtOAc 9:1 to 75:25). After removing the solvents under vacuum, the desired compound is obtained as a colourless oil (66.04 g; 196.90 mol).
Reaction SMILES: CN(C=O)C.[CH3:6][C@H:7]1[O:12][C@@H:11]([CH3:13])[CH2:10][NH:9][CH2:8]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:21]1[CH:26]=[CH:25][C:24]2=[N:27][C:28]([C:30]3[CH:31]=[CH:32][C:33]([C:43]([F:46])([F:45])[F:44])=[C:34]([NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=3)=[CH:29][N:23]2[N:22]=1>O>[CH3:13][C@H:11]1[O:12][C@@H:7]([CH3:6])[CH2:8][N:9]([C:21]2[CH:26]=[CH:25][C:24]3=[N:27][C:28]([C:30]4[CH:31]=[CH:32][C:33]([C:43]([F:44])([F:45])[F:46])=[C:34]([NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=4)=[CH:29][N:23]3[N:22]=2)[CH2:10]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(c2ccc3nc(-c4ccc(C(F)(F)F)c(NC(=O)C(C)(C)C)c4)cn3n2)C[C@H](C)O1
Temperature: 120 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
An 8 mL vial is charged with DMF (1 mL), cis-2,6-dimethylmorpholine (0.034 g), Cs2CO3 (0.130 g), and N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.0396 g, 0.1 mmol). The mixture is stirred at 120° C. for 16 hr, then diluted with H2O (5 mL) and extracted with Et2O (3 mL×2). Organics are dried and concentrated onto celite, purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (0.027 g, 57% yield). LCMS m/z=476.6 [M+H]+, tR=2.77 min. (compound same as Example 250)