Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClN1C2C=CC=CC=2N=N1.N1C2C=CC=CC=2N=N1.[C:20]([O:24][C:25](=[O:30])[NH:26][CH2:27][CH2:28][SH:29])([CH3:23])([CH3:22])[CH3:21].NC(N)=S.[CH3:35][C:36]([SH:39])([CH3:38])[CH3:37]>C(Cl)Cl.C1COCC1>[C:36]([S:39][S:29][CH2:28][CH2:27][NH:26][C:25](=[O:30])[O:24][C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:38])([CH3:37])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: CC(C)(C)S
Agent: Cln1nnc2ccccc21
Agent: NC(N)=S
Agent: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCSSC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
1-Chloro-1H-benzo[d][1,2,3]triazole (1.73 g, 11.28 mmol) and 1H-benzo[d][1,2,3]triazole (0.67 g, 5.64 mmol) were dissolved in DCM (24.0 ml) under a nitrogen atmosphere, the mixture was cooled to −78° C., and a solution of tert-butyl(2-mercaptoethyl)carbamate (Compound 6a) (1.00 g, 5.64 mmol) in DCM (3.0 ml) was added dropwise. Following stirring at 78° C. for 10 minutes, a suspension of thiourea (1.29 g, 16.92 mmol) in THF (6.0 ml) was added and the mixture was further stirred for 10 minutes. A solution of 2-methylpropane-2-thiol (0.76 g, 8.46 mmol) in DCM (3.0 ml) was then added dropwise, and the mixture was stirred with warming to room temperature for 20 hours. The solid in the reaction solution was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=4:1) to afford the title compound (1.15 g, 77%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li:14])CCC>CCCCC.CCCCCC>[Li:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1Br
Reactant: [Li]CCCC
Solvent: CCCCC
Solvent: CCCCCC
Product: [Li]c1ccccc1OC
Reaction time: 9 h

Procedure:
2-Bromoanisole (97.0 g, 0.52 mol, 1.0 eq) was dissolved in 150 ml pentane. A 1.6M solution of n-butyllithium (0.52 mol, 1.0 eq) in 325 ml hexane was slowly added drop wise with vigorous stirring and cooling with an ice bath. A white suspension formed which was stirred for a further 3 hours at 0° C., then for 9 hours at room temperature. The white solid was filtered off and washed with pentane (4×30 ml). After drying under vacuum, 2-lithioanisole was isolated as a fine white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:19][C@H:20]([C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1)[CH3:21]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:19][C@H:20]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[CH:24][CH:23]=2)[CH3:21])=[O:9])[C:5]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)cnc1Oc1cncc(Cl)c1
Reactant: C[C@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1cncc(Cl)c1)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-[(5-chloropyridin-3-yl)oxy]nicotinic acid (step 1) and tert-butyl 4-[(1S)-1-aminoethyl]benzoate (step 3 of Example 44): 1H-NMR (CDCl3) δ 8.56 (1H, d, J=2.7 Hz), 8.55–8.54 (1H, m), 8.42–8.41 (1H, m), 8.13 (1H, d, J=2.7 Hz), 7.99–7.96 (2H, m), 7.80–7.82 (1H, m), 7.58 (1H, t, J=2.3 Hz), 7.42–7.39 (2H, m), 5.42–5.31 (1H, m), 1.62–1.58 (12H, m); MS (ESI) m/z 488 (M+H)+, 486 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:26]([F:29])([F:28])[F:27])([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.[NH2:38][CH2:39][C:40]([NH:42][CH2:43][CH3:44])=[O:41].C(N(CC)CC)C>CN(C=O)C.C1COCC1>[CH2:43]([NH:42][C:40](=[O:41])[CH2:39][NH:38][C:4](=[N:5][OH:6])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[CH2:15][C:14]([C:26]([F:29])([F:27])[F:28])([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[O:13][N:12]=2)=[CH:10][C:2]=1[CH3:1])[CH3:44]
Reactant: Cc1cc(C2=NOC(c3cccc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C=NO
Reactant: CCNC(=O)CN
Agent: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)CNC(=NO)c1ccc(C2=NOC(c3cccc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C
Temperature: 75 °C
Yield: 55.4 %

Procedure:
To a solution of 2-Methyl-4-[5-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-4,5-dihydro-isoxazol-3-yl]-benzaldehyde oxime (250 mg) in DMF (8 mL) was added N-chloro succinimide (84 mg) and heated to 75° C. for 1 h. After cooling, the reaction mixture was poured onto ice-water and extracted with EtOAc. The combined organic layers were washed with water, dried (Na2SO4) and concentrated in vacuo to ¼ of the original volume to obtain the crude hydroxamic acid chloride. This mixture was added to a solution of 2-amino-N-ethyl-acetamide (61 mg) and triethylamine (0.15 mL, 0.11 g) in THF (8 mL) and stirred at room temperature over night. After concentration in vacuo, the mixture was purified by chromatography on silica gel to obtain the title compound (171 mg, 55%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.[BH3-]C#N.[Na+].N>C(O)C.C(O)(=O)C>[CH:15]1([NH:18][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
1 g (5 mmol) of tert-butyl 4-oxopiperidine-1-carboxylate is dissolved in 40 mL of ethanol with 10% of acetic acid. 0.28 mL (4.2 mmol) of cyclopropylamine is added. After 30 minutes, 0.53 g (36 mmol) of NaBH3CN is added and the reaction medium is stirred for one hour at room temperature. The reaction is stopped by addition of aqueous ammonia solution and the organic products are then extracted with ethyl acetate. The organic phase is dried and then evaporated. The crude product obtained is chromatographed on silica gel (eluent: 55/45 heptane/ethyl acetate). 0.8 g of tert-butyl 4-cyclopropylamino-piperidine-1-carboxylate in the form of a colourless oil is obtained in a yield of 79%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([O:39][CH3:40])[C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[N:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1>CO.Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[N:24][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[C:22]([O:39][CH3:40])[CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)cnc1N1CCNCC1
Yield: 68.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxypyridin-2-yl)piperazine-1-carboxylate (91 mg, 0.156 mmol) was deprotected in methanol/HCl in dioxane (5/5 ml) to afford 52 mg (56% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.727-8.722 (d, 1H), 8.626-8.622 (d, 1H), 8.29 (s, 1H), 8.19-8.18 (d, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.75-7.74 (d, 1H), 7.37-7.35 (q, 1H), 7.12-7.10 (d, 1H), 7.02-6.99 (m, 2H), 5.44 (s, 2H), 4.03 (s, 3H), 3.78-3.74 (t, 4H), 3.39-3.32 (m, 4H). MS: m/z=484.3 (M+1), HPLC: 97.58% in method A.
Reaction SMILES: [N:1]#[C:2][NH2:3].C([O:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=1[N:16]=[C:17]=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Br:25])C=C>C(#N)C>[OH:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=1[NH:16][C:17]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Br:25])=[N:3][C:2]#[N:1]
Reactant: N#CN
Reactant: C=CCOc1cc(C#N)ccc1N=C=Nc1ccccc1Br
Solvent: CC#N
Product: N#CN=C(Nc1ccc(C#N)cc1O)Nc1ccccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.6 %

Procedure:
To a stirred mixture of cyanamide (560 mg, 13.33 mmol) and Huinig's base (2.6 ml) in acetonitrile was added a solution of N-(2-Allyloxy-4-cyanophenyl)-N′-(2-bromophenyl)-carbodiimide (600 mg, 1.69 mmol) in acetonitrile (30 ml) dropwise. The reaction was stirred at rt for 15 min, then the solvent was removed under reduced pressure and the residue hydrolyzed with 0.5 M sodium dihydrogen phosphate. Ethyl acetate extractions of the aqueous mixture were washed with 0.5 M sodium dihydrogen phosphate and brine. After drying (MgSO4) filtration and evaporation under reduced pressure afforded a crude tan solid (500 mg). This was chromatographed on silica gel (50/50 ethyl acetate/hexane) to give the title compound (455 mg, 95%). MS(ES−) m/e 394, 396 [M−H]−
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:9]2)=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][O:26][C:27]1[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[C:28]1[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=1[O:26][CH2:25][CH2:24][N:20]1[CH2:19][CH2:18][CH:17]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:8]([CH2:7][C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=2)[CH2:22][CH2:21]1
Reactant: Clc1ccc(Cn2cc(C3CCNCC3)c3cccnc32)s1
Reactant: COC(=O)c1ccccc1OCCCl
Product: COC(=O)c1ccccc1OCCN1CCC(c2cn(Cc3ccc(Cl)s3)c3ncccc23)CC1
Yield: 33.2 %

Procedure:
This compound was prepared following the procedure described in example 4, part E starting with 2.8 g (6.5 mmol) of 1-(5-chloro-thiophen-2-ylmethyl)3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 1.5 g (7.2 mmol) of methyl 2-(2-chloroethoxy)benzoate. After standard work-up and purification, 1.1 g (33% yield) of 2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-yl}ethoxy)benzoic acid methyl ester were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4ccccc4OC)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4ccccc4OC)cc3)c2cc1OC
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(2-methoxyphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 447 (M++1)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[NH:16][C:15]([CH3:22])([CH3:21])[CH:14]=[C:13]4[CH3:23])[CH:10]([OH:24])[O:9][C:5]=2[CH:6]=[CH:7][CH:8]=1.[CH2:25]([Si](C)(C)C)[CH:26]=[CH2:27]>>[CH2:27]([O:24][CH:10]1[C:11]2=[C:12]3[C:17](=[CH:18][CH:19]=[C:20]2[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9]1)[NH:16][C:15]([CH3:21])([CH3:22])[CH:14]=[C:13]3[CH3:23])[CH:26]=[CH2:25]
Reactant: COc1cccc2c1-c1ccc3c(c1C(O)O2)C(C)=CC(C)(C)N3
Reactant: C=CC[Si](C)(C)C
Product: C=CCOC1Oc2cccc(OC)c2-c2ccc3c(c21)C(C)=CC(C)(C)N3

Procedure:
treating 10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno [3,4-f]quinolin-5-ol with allyltrimethylsilane and a Lewis acid to provide 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline; and
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]([F:13])([F:12])[F:11])[NH:9][NH:8]2)[CH:2]=1.C(N(CC)CC)C.ClOC(C)(C)C.S([O-])([O-])=O.[Na+].[Na+]>C(O)C>[C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]([F:11])([F:13])[F:12])[N:9]=[N:8]2)[CH:2]=1
Reactant: Cc1cccc(C2(C(F)(F)F)NN2)c1
Agent: CC(C)(C)OCl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cccc(C2(C(F)(F)F)N=N2)c1
Reaction time: 0.08 h
Yield: 80 %

Procedure:
To a cold stirring solution of 3-m-tolyl-3-trifluoromethyl-diaziridine (2.0 g, 10 mmol. prepared using the methods described in Doucet-Personeni C. et al., J. Med. Chem., 2001, 44, 3203 and Nassal, M. Liebigs Ann. Chem. 1983, 1510-1523 or in Stromgaard, K et al., J. Med. Chem., 2002, 45, 4038-46) in ethanol (20 mL) was added triethylamine (1.5 g, 15 mmol). To this mixture was added tert-butyl hypochlorite (3.25 g, 30 mmol), and the mixture stirred for 5 min. This mixture was poured into 10% aqueous sodium sulfite (100 mL), and extracted with ether. The ether extract was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, pentane) to provide 1.6 g (Yield 80%) of the title compound. 1H NMR (300 MHz, CDCl3) δ ppm: 2.33 (3 H, s) 6.90-7.03 (2 H, m) 7.15-7.31 (2 H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([O:26]C)=O)=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:31][C:30]3[CH:32]=[C:33]([F:37])[C:34]([F:36])=[CH:35][C:29]=3[F:28])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1cc(F)c(F)cc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(F)c(F)cc3F)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Yield: 38.9 %

Procedure:
The title compound was prepared following the procedure described for Example-137 using methyl 2-[(2,6-dichlorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-6, 0.200 g, 0.493 mmol) and 2,4,5-trifloro aniline (0.108 g, 0.740 mmol), trimethyl aluminium (2M solution in toluene) (0.071 g, 0.986 mmol) and dry toluene (5.0 mL) to afford 0.100 g of the desired product. 1HNMR (DMSO-d6): δ 1.55 (s, 6H), 3.11 (s, 2H), 7.21 (m, 2H), 7.53 (m, 2H), 7.73 (q, J=7.8 Hz, 1H), 8.48 (m, 1H), 10.11 (bs, 1H), 11.00 (s, 2H); MS [M+H]+: 521.14.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([NH:8][S:9]([C:12]1[CH:22]=[CH:21][C:15]2[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=2[CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1.O>[CH3:6][CH:5]([CH3:7])[C@@H:4]([NH:8][S:9]([C:12]1[CH:22]=[CH:21][C:15]2[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=2[CH:13]=1)(=[O:11])=[O:10])[C:3]([OH:23])=[O:2]
Reactant: COC(=O)[C@H](NS(=O)(=O)c1ccc2nc(SC)sc2c1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc2s1

Procedure:
(2R)-3-methyl-2-[(2-methylthiobenzthiazol-6-sulfonyl)amino]butanoic acid methylester (0.35 g, 0.9 mmol) was dissolved in THF/H2O (2 mL/2 mL), and added LiOH (0.16 g, 5 equi.). After the reaction soluton was refluxed for 6 hours, the solution was distilled under reduced pressure and treated with 1N HCl. The product was extracted with ethylacetate (10 mL). The separated organic phase was washed with NaCl solution, dried over MgSO4, distilled under reduced pressure and dried under vacuum, to prepare the titled compound, (2R)-3-methyl-2-[(2-methylthiobenzthiazol-6-sulfonyl)amino]butanoic acid (54 mg, 23%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[N:4][CH:3]=1.C([Li])CCC.[I:16]I>C1COCC1>[I:16][N:4]1[CH:5]=[C:6]2[S:10][CH2:9][CH:8]=[C:7]2[C:2]([Cl:1])=[CH:3]1
Reactant: Clc1cncc2sccc12
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: ClC1=CN(I)C=C2SCC=C12
Temperature: 25 °C
Yield: 51.8 %

Procedure:
In a 500 mL round-bottomed flask 120 mL of tetrahydrofuran and with 13 grams of 4-chloro-thieno[3,2-d]pyridine (76.6 mmol) were cooled to −78° C. To the stirring solution was added n-butyllithium (191.6 mmol, 2.5M in hexane) was added dropwise over a 20 minute period. After stirring an additional 20 minutes iodine (48.3 g, 191.6 mmol) in 80 mL of THF was added dropwise such that the internal temperature did not exceed −78° C. After the addition was complete the reaction was allowed to slowly warm to room temperature. The reaction mixture was quenched by diluting with chloroform and extracting with H2O (2×250 mL), followed by extraction of the combined aqueous material with CHCl3 (1×100 mL). The organic portions were then washed with Na2S2O3 (2×200 mL), H2O (2×200 mL), dried over MgSO4, filtered and dried. The resulting residue was suspended in a minimal amount of chloroform and an excess of ether was added. The solid obtained was filtered and washed with ether. The mother liquor was concentrated and another crop of material was isolated in the same fashion. The two crops of crystals were combined to afford 11.8 g (52%) of 6-iodo-4-chloro-thieno[3,2-d]pyridine that was greater than 90% pure. 1H NMR (400 MHz, CDCl3) δ8.51 (d, 1H), 7.83 (s, 1H), 7.24 (d, 1H). LC-MS: 295.9, 297.9 (MH+); HPLC RT: 6.45 min.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[N:4]([CH3:13])[C:5]([C:8]([O:10]CC)=O)=[N:6][N:7]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([NH:22][C:8]([C:5]1[N:4]([CH3:13])[C:3]([N:2]([CH3:1])[CH3:14])=[N:7][N:6]=1)=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1nnc(N(C)C)n1C
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: CN(C)c1nnc(C(=O)NCc2ccccc2)n1C
Yield: 34.5 %

Procedure:
6 g (0.03 mole) of ethyl 5-dimethylamino-4-methyl-4H-1,2,4-triazol-3-yl-carboxylate and 4.28 g (0.04 mole) of benzylamine are heated in 80 ml of tetrahydrofuran at 200° C. at 20 bar. For working up, the mixture is evaporated in vacuo, and the residue is purified on silica gel by means of chromatography (eluent: toluene/ethanol 1:1). 2.68 g (35% of theory) of N-benzyl-5-dimethylamino-4-methyl-4H-1,2,4-triazol-3-yl-carboxamide of melting point 96° C.-98° C. are obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:8]1[C:9](=[O:21])[CH2:10][CH:11]([CH:15]2[CH2:20][CH2:19][CH2:18][S:17][CH2:16]2)[CH2:12][C:13]=1[OH:14])(=[O:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([C:8]1[C:9](=[O:21])[CH2:10][CH:11]([CH:15]2[CH2:20][CH2:19][CH2:18][S:17][CH2:16]2)[CH2:12][C:13]=1[O:14][C:1](=[O:3])[CH3:2])(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CC(=O)C1=C(O)CC(C2CCCSC2)CC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1=C(C(C)=O)C(=O)CC(C2CCCSC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.82 g (10.5 mmol) of acetyl chloride is added dropwise to a stirred solution of 2.54 g (10.0 mmol) of 2-acetyl-3-hydroxy-5-(tetrahydro-2H-thiopyran-3-yl)-cyclohex-2-en-1-one and 1.06 g (10.5 mmol) of triethylamine in 50 ml of dichloromethane. The mixture is stirred overnight at room temperature, and then is poured into 100 ml of ice-cold water. The organic layer is separated and washed with 20 ml of dilute sodium bicarbonate solution, followed by 50 ml of saturated sodium chloride solution. The washed extract is then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product can be purified by column chromatography employing tetrahydrofuran-hexane (1:2 by volume) as eluent to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[C:11]([NH2:17])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14]>C(O)(C)C.CC(O)=O.N1CCCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:12]([C:13](=[O:14])[CH3:15])[C:11]([NH2:17])=[O:16])=[CH:4][C:3]=1[F:10]
Reactant: CC(=O)CC(N)=O
Reactant: O=Cc1ccc(Cl)c(F)c1
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccc(Cl)c(F)c1)C(N)=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 67.8 %

Procedure:
A mixture of 4-chloro-3-fluorobenzaldehyde (2.47 g, 15.5 mmol), acetoacetamide (1.57 g, 15.5 mmol), AcOH (35 μL, 0.62 mmol) and piperidine (61 μL, 0.62 mmol) in isopropyl alcohol (30 mL) was stirred at room temperature for 2.5 days and evaporated under reduced pressure. The crude product was purified by a silica gel column (120 g) eluting from 50% to 80% EtOAc in hexanes to afford 2-(4-chloro-3-fluorobenzylidene)-3-oxobutanamide (2.54 g, 67.6%) as an off-white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=3)[CH:10]=2)=[O:5])=[CH:27][CH:28]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Product: O=C(c1ccc(F)cc1)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12l and 1-bromo-4-fluorobenzene
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([CH:20]=O)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1>>[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([CH:20]=[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])=[CH:17][CH:18]=2)[CH:13]=[CH:12]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: O=C1Cc2ccccc2N1
Product: O=C1Nc2ccccc2C1=Cc1ccc2[nH]ccc2c1
Yield: 59.5 %

Procedure:
2-Oxindole (133 mg, 1 mmol) was condensed with 1H-indole-5-carbaldehyde (145 mg, 1 mmol) using method B to give 155 mg (60%) of 3-(1H-indol-5-ylmethylene)-1,3-dihydroindol-2-one as a white solid.