Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:9]=1[C:10]([N:12]=[S:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:11].[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:41])[F:40])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1>C(#N)C>[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=3[Cl:22])=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:40])[F:41])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 6 h
Yield: 88.4 %

Procedure:
To a suspension of potassium carbonate (8.08 g, 58.5 mmol, 1.50 equiv.) and 2-amino-3,5-dichloro-N-(diethyl-λ4-sulfanylidene)benzamide (11.43 g, 38.98 mmol) in acetonitrile (100 mL) was added a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (15.8 g, 43.31 mmol, 1.10 equiv.) in acetonitrile (50 mL) at room temperature. After 6 h at this temperature, the solids were filtered off. The resulting filtrate was washed with water and dried over Na2SO4. After filtration, the filtrate was concentrated in vacuum and the resulting solids were crystallized from diisopropyl ether to yield the title compound (19.53 g, 88%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>>[CH2:18]([N:20]([CH2:21][CH3:22])[C:5](=[O:6])[C:4]1[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:3]=1[C:2]([F:17])([F:16])[F:1])[CH3:19]
Reactant: CCNCC
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1C(F)(F)F
Product: CCN(CC)C(=O)c1cc(C(F)(F)F)ccc1C(F)(F)F

Procedure:
N,N-Diethyl-2,5-bis(trifluoromethyl)benzamide was prepared from 2,5-bis(trifluoromethyl)benzoyl chloride and diethylamine according to General Method E1. The desired intermediate was isolated in quantitative yield (11.3 g) without additional purification.
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]([C:16]1[CH:17]=[N:18][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:20][CH:21]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].N1C=CN=C1.O>C(#N)C>[Cl:3][C:6]([C:16]1[CH:17]=[N:18][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:20][CH:21]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(O)(c1cnc(C(C)(C)C)nc1)C(C)(C)C
Reactant: O=S(Cl)Cl
Agent: c1c[nH]cn1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(Cl)(c1cnc(C(C)(C)C)nc1)C(C)(C)C
Temperature: 0 °C
Yield: 70.6 %

Procedure:
Thionyl chloride (0.57 g) was added dropwise to a solution of ethyl (RS)-2-hydroxy-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (0.2 g) and imidazole (0.32 g) in dry acetonitile (7 cm3), whilst the reaction temperature was maintained at 0° C. The mixture was allowed to warm to the ambient temperature and stirred for a period of sixteen hours, after which time it was poured into water, and extracted into dichloromethane. The combined organic extracts were washed with water, dried over anhydrous magnesium sulphate, passed through a short plug of silica, and concentrated by evaporation of the solvent under reduced pressure to give ethyl (RS)-2-chloro-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate as a yellow oil (0.15 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]([C:11]2([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[O:17])[CH2:14][CH:13](O)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.[C:30]1(=[O:44])[N:34]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][C:40](O)=[O:41])[C:33](=[O:43])[CH:32]=[CH:31]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][C:16]([C:11]2([C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=3)=[O:10])[CH2:14][CH:13]([C:40](=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35][N:34]3[C:30](=[O:44])[CH:31]=[CH:32][C:33]3=[O:43])[CH2:12]2)=[O:17])=[CH:21][CH:22]=1
Reactant: O=C(O)CCOCCN1C(=O)C=CC1=O
Reactant: COc1ccc(COC(=O)C2(C(=O)OCc3ccc(OC)cc3)CC(O)C2)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)C2(C(=O)OCc3ccc(OC)cc3)CC(C(=O)CCOCCN3C(=O)C=CC3=O)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of PMB-CB-OH (1.97 g, 4.91 mmol), 6-maleinimido-4-oxacaproic acid (1.57 g, 7.37 mmol) and triethylamine (2.04 ml, 8.64 mmol) is admixed with 2-chloro-1-methylpyridinium iodide (1.88 g, 7.37 mmol) in 30 ml anhydrous dichloromethane and stirred for three hours at room temperature. It is diluted with 140 ml dichloromethane, washed each time twice with 80 ml in hydrochloric acid, 80 ml water and once each time with 80 ml sodium chloride solution (saturated) and dried over magnesium sulfate. Subsequently the solvent is removed in a vacuum and the residue is purified by column chromatography (silica gel, chloroform/methanol 200:1). 2.89 g PMB-CB-1-Mal (99% of theory) is obtained as a colourless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].N1C=CC=CC=1.[CH3:13][C:14]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:33])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:15][CH2:16]Br>O1CCOCC1>[CH3:13][C:14]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:33])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:15][CH2:16][NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCBr
Reactant: CN(C)CCN
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCNCCN(C)C
Temperature: 0 °C
Yield: 33.4 %

Procedure:
4.4 g of N,N-dimethylethylenediamine was dissolved in 40 ml of dioxane. 5 ml of pyridine was added to the solution. 17.6 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl bromide was added thereto and the mixture was heated under reflux for 2 h and poured in ice-water. After extraction with n-hexane followed by washing with water and concentration, the resulting reaction mixture was treated by alumina column chromatography to obtain 6 g (33%) of the title compound as a colorless oil.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[NH2:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12]>C(O)C>[OH:13][CH:10]([CH2:11][OH:12])[CH2:9][NH:8][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: NCC(O)CO
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: O=C1N=C(NCC(O)CO)CS1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (2.0 g) in ethanol (20 mL) was added 3-aminopropane-1,2-diol (1.00 g), and the mixture was stirred at room temperature for 3 hr. The precipitate was collected by filtration and washed with ethanol to give the title compound (1.56 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>O1CCCC1.C(N(CC)CC)C>[CH3:8][S:9]([O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:11])=[O:10]
Reactant: OC1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCOCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tetrahydro-2H-pyran-4-ol (20 g) in tetrahydrofuran (150 mL) and triethylamine (28.5 mL) is slowly added methanesulfonyl chloride (15.5 mL), while keeping the temperature below 30° C. The mixture is stirred for 12 hours at room temperature. The precipitate is filtered off and washed twice with tetrahydrofuran. The combined organic phases are concentrated and partitioned between ethyl acetate and water. The organic phase is dried (Na2SO4) and concentrated to give the title compound. Yield: 29.4 g; TLC: rf=0.36 (silicagel, petrole ether/ethyl acetate 1:1); Mass spectrum (ESI+): m/z=198 [M+NH4]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1>>[Br:10][C:4]1[CH:3]=[C:2]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: COc1cc(Br)cc(Br)c1
Reactant: C1CSCCN1
Product: COc1cc(Br)cc(N2CCSCC2)c1

Procedure:
This material was prepared starting from 1,3-dibromo-5-methoxy-benzene following general procedures described in these Examples, but using thiomorpholine instead of pyrrolidine.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([NH:10][C:11](=[O:21])[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[N:8][CH:9]=1)=O.[OH-].[NH4+:23]>>[CH2:14]([O:13][CH2:12][C:11]([NH:10][N:6]1[C:5]([C:3]([NH2:23])=[O:2])=[CH:9][N:8]=[CH:7]1)=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cncn1NC(=O)COCc1ccccc1
Agent: [OH-]
Product: NC(=O)c1cncn1NC(=O)COCc1ccccc1
Temperature: 70 °C
Yield: 88 %

Procedure:
Compound 2 (8.7 g, 30.1 mmol) and ammonium hydroxide (15 ml) were combined in a sealed tube and heated to 70° C. under microwave irradiation for 2 hours. The mixture was concentrated in vacuo to afford compound 3 (7.3 g, 88% yield) as a white solid. LC-MS: m/z 275.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[O:12])=[N:8][C:6]=2[N:7]=1.B(O)(O)[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH:32]=[N:33][NH:34]2.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>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.O>[NH:34]1[C:35]2[C:31](=[C:30]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[S:10][C:9]([C:11]([N:13]5[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]5)=[O:12])=[N:8][C:6]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: CS(=O)(=O)N1CCN(C(=O)c2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: OB(O)c1cccc2[nH]ncc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)N1CCN(C(=O)c2nc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
(5-Chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)(4-methylsulfonylpiperazin-1-yl)methanone, 1H-indazol-4-yl-4-boronic acid (2.5 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was microwaved at 140° C. for 10 minutes. Water was added and the solution was filtered. The resulting precipitate was washed with methylene chloride and the organic layer was purified by silica gel chromatography followed by reverse phase silica gel chromatography to give the product 141.
Reaction SMILES: C(C1C([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=NC(CC)=CN=1)C.Cl[C:23]1[C:24]([CH:32]2[CH2:34][CH2:33]2)=[N:25][CH:26]=[C:27]([CH:29]2[CH2:31][CH2:30]2)[N:28]=1>>[CH:32]1([C:24]2[C:23]([NH:11][C@@H:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][C@@H:13]3[OH:21])=[N:28][C:27]([CH:29]3[CH2:31][CH2:30]3)=[CH:26][N:25]=2)[CH2:34][CH2:33]1
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: Clc1nc(C2CC2)cnc1C1CC1
Product: O[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)cnc1C1CC1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3-chloro-2,5-dicyclopropylpyrazine and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.86–0.89, 2.00, 2.89, 3.11, 4.54, 5.17, 5.42, 6.22–6.24, 7.17–7.25, 7.64; MS (ESI+) for C19H21N3O m/z 308 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[N:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[N:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: c1cn(-c2nccc(N3CCCCC3CCNCc3ccc4c(c3)OCO4)n2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)N(CCC1CCCCN1c1ccnc(-n2ccnc2)n1)Cc1ccc2c(c1)OCO2
Reaction time: 16 h
Yield: 48.2 %

Procedure:
Alternatively, to THF (3 mL) was added N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl)piperidine-2-ethanamine (8 mg, 0.03 mmol), Hünig's base (8 mg, 0.06 mmol), and methanesulfonyl chloride (4.5 mg, 0.04 mmol). After stirring for 16 hours, the solvent was removed in vacuo and the residue was chromatographed (CH2Cl2/MeOH. 19/1) to give 7 mg (51%) of N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-N-(methylsulfonyl)piperidine-2-ethanamine (the compound of formula (Iff)); 1H NMR (CDCl3) δ 8.10 (s, 1), 7.78 (d, 1), 7.13 (s, 1), 6.82 (s, 1), 6.72 (s, 2), 6.30 (d, 1), 5.94 (s, 2), 4.23 (m, 3), 3.20 (m, 2), 2.80 (s, 3), 1.14 (m); MS: 485.7 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:16][C@@H:15]2[C@@:10]([CH3:23])([C@@H:11]([CH3:22])[CH2:12][C:13]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)C1C=CC=CC=1.CC(Cl)OC(Cl)=O>C1(C)C=CC=CC=1.Cl.CO>[ClH:21].[Cl:21][C:20]1[C:13]2[CH2:12][C@H:11]([CH3:22])[C@:10]3([CH3:23])[C@@H:15]([CH2:16][NH:8][CH2:9]3)[C:14]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C[C@H]1Cc2c(Cl)cccc2[C@@H]2CN(Cc3ccccc3)C[C@]12C
Agent: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: C[C@H]1Cc2c(Cl)cccc2[C@@H]2CNC[C@]12C
Temperature: 160 °C
Yield: 132.1 %

Procedure:
(3aR*,4S*,9bS*)-2-Benzyl-6-chloro-3a,4-dimethyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.153 mmol, 49.8 mg) was dissolved in toluene (1 ml). ACE-Cl (1.070 mmol, 0.118 ml, 153 mg) was added and the reaction mixture was heated in a microwave reactor at 160° C. for 15 minutes. Methanol (1 ml) was added and the reaction mixture was again heated in a microwave reactor at 160° C. for 5 minutes. The resulting solution was passed through an SCX cartridge and concentrated in vacuo to give a residue that was dissolved in 2 M HCl in MeOH and concentrated in vacuo to afford (3aR*,4S*,9bS*)-6-chloro-3a,4-dimethyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole hydrochloride (27.5 mg). m/z: 236.1 [M+H]+.
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:2]([C:12]([NH:14][C@H:15]([C:25](OC)=[O:26])[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[NH2:37][NH2:38]>CN(C=O)C>[NH:1]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[C@H:2]([C:12]([NH:14][C@H:15]([C:25]([NH:37][NH2:38])=[O:26])[CH2:16][O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)NN
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
The substance [28] (191 g, 0.393 M) was dissolved in DMF (500 ml). Hydrazine hydrate (100%) (200 ml) was added dropwise and stirred at room temperature for three hours. The DMF was removed in vacuo and water was added thereto. The thus-formed precipitate was filtered, dried, and recrystallized twice from ethyl acetate-hexane to obtain the substance [29] (183.6 g, yield: 96.0%).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:12]C(=O)CCC.CC([O-])(C)C.[K+].O>CN(C=O)C>[C:2]([C:3]1[NH:12][C:6]2[C:5]([CH:4]=1)=[C:10]([F:11])[CH:9]=[CH:8][CH:7]=2)([CH3:19])([CH3:18])[CH3:1]
Reactant: CCCC(=O)Nc1cccc(F)c1C#CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2c(F)cccc2[nH]1
Temperature: 90 °C
Yield: 151.6 %

Procedure:
To a solution of N-(2-(3,3-dimethylbut-1-ynyl)-3-fluorophenyl)butyramide (6.0 g, 20 mmol) in DMF (100 mL) was added t-BuOK (5.0 g, 50 mmol) at room temperature. The mixture was heated at 90° C. overnight before it was poured into water and extracted with EtOAc (100 mL×3). The organic layers were washed with sat. NaCl and water, dried over anhydrous Na2SO4, and evaporated under vacuum to give 2-tert-butyl-4-fluoro-1H-indole (5.8 g, 97%). 1H NMR (400 MHz, CDCl3) δ 8.17 (br s, 1 H), 7.11 (d, J=7.2 Hz, 1 H), 7.05-6.99 (m, 1 H), 6.76-6.71 (m, 1 H), 6.34 (m, 1 H), 1.41 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:11])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(Cl)ccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Cl)ccc1CBr
Yield: 67.4 %

Procedure:
303 g of 4-chloro-2-methoxytoluene are dissolved in 1665 ml of carbon tetrachloride and, together with 355 g of N-bromosuccinimide, heated at reflux for 2 h while 4.0 g of AIBN are added. The solid is filtered off and wasted with a small amount of carbon tetrachloride, the filtrate is concentrated, and the residue which remains is fractionated. 307 g of colorless oil are obtained (b.p. 103° C./1.5 mbar, m.p. 42-45° C.).
Reaction SMILES: [SH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].Cl[CH2:12][C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[CH2:2]([S:1][CH2:12][C:13]#[N:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: N#CCCl
Reactant: O=C(CS)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCSCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Part A. A mixture of 2-mercaptoacetophenone (6.96 g, 45.7 mmol), chloroacetonitrile (3.00 mL, 47.4 mmol), and potassium carbonate (7.21 g, 52.2 mmol) in tetrahydrofuran (100 mL) was stirred at ambient temperature for 12 hours. The mixture was poured into water (400 mL), and this was extracted with ethyl acetate (400 mL), then methylene chloride (400 mL). The extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual oil was separated by flash chromatography (1:4 ethyl acetate-hexane) to afford the product, phenacylthio-acetonitrile, as a pale pink oil (7.51 g, 39.3 mmol, 86%). 1H NMR (CDCl3): δ 7.96 (2H, dd, J=8.0, 1.1 Hz); 7.65-7.56(1H, m); 7.50 (2H, t, J=7.7 Hz); 4.13 (2H, s); 3.45 (2H, s). Mass spectrum (NH3 -CI/DDIP): m/z 210 (21%); 209 (100%); 192 (2%); 170 (1%); 139 (1%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.Cl.[NH2:15][OH:16].C([O-])(O)=O.[Na+]>CO>[OH:16]/[N:15]=[C:10](\[NH2:11])/[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:8][CH:7]=1
Reactant: NO
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N/C(Cc1ccc(C(F)(F)F)cc1)=N\O
Yield: 84.9 %

Procedure:
A suspension of [4-(trifluoromethyl)phenyl]acetonitrile (1.0 g, 5.4 mmoles), hydroxylamine hydrochloride (0.41 g, 5.9 mmoles) and NaHCO3 (0.50 g, 5.9 mmoles) in MeOH (15 ml) was refluxed for 4 hours. The reaction mixture was then concentrated to remove the solvent methanol. The residue was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4 and concentrated to afford the desired product (1.0 g, 84.9%) as white solid. LCMS calculated for C9H10F3N2O (M+H): 219.1. Found: 219.1.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:28]=[C:27]([C:26]2[CH:29]=[CH:30][C:31]([N+:33]([O-:35])=[O:34])=[CH:32][C:25]=2[Cl:24])[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1Cl
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc([N+](=O)[O-])cc1Cl
Temperature: 140 °C
Reaction time: 1 h
Yield: 118.3 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.90 g), 2-chloro-4-nitrobenzonitrile (1.80 g), anhydrous iron (III) chloride (1.60 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 1 hour. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 2.20 g of desired compound (melting point: 144.0°-148.0° C.).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C@@H:14]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH2:31][O:32][C:33](=[O:51])[C:34]3[CH:39]=[CH:38][C:37]([NH:40]C(OCC4C=CC=CC=4)=O)=[CH:36][CH:35]=3)=[O:28])[C:15]([O:17]CC3C=CC=CC=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(C)C>[Pd].C1COCC1>[NH2:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]([O:32][CH2:31][CH2:30][O:29][C:27](=[O:28])[CH2:26][CH2:25][C@H:14]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:15]([OH:17])=[O:16])=[O:51])=[CH:39][CH:38]=1
Reactant: O=C(CC[C@@H](C(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21)OCCOC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)OCCOC(=O)CC[C@@H](C(=O)O)n2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
10% Palladium on charcoal (0.140 g) was added in one portion to a stirred solution of 24 (0.70 g, 1.02 mmol) in 1:1 mixture of isopropanol (10 mL) and THF (10 mL) under nitrogen atmosphere. The suspension was then stirred under hydrogen atmosphere at room temperature for 4 h. The solution was filtered through celite and concentrated under reduced pressure to obtain (S)-5-(2-(4-aminobenzoyloxy)ethoxy)-2-(9H-carbazol-9-yl)-5-oxopentanoic acid 25 (0.45 g, 96%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.S(O[CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C.[K]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:22][CH:23]2[CH2:26][CH2:25][CH2:24]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OCC1CCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 117.1 %

Procedure:
5-Chlorosalicylaldehyde (7.7 g, 49.4 mmol) was dissolved in DMF (20 ml) with potassium carbonte (7.5 g, 54.1 mmol) and the cyclobutanemethanol tosylate (1 3 g, 54.1 mmol). The mixture was stirred at 50° C. under argon for 16 hours. Poured into water (500 ml). extracted with ethyl acetate (4×100 ml)and the combined organic fractions washed with 1M sodium hydroxide solution (100 ml), water (100 ml), saturated brine (100 ml) dried (MgSO4) and concentrated in vacuo to give 5-chloro-2-(cyclobutylmethoxy)benzaldehyde as a brown oil (13 g) which was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.C(NC(C)C)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)(=[O:23])=[O:22]
Reactant: OCCCCc1cccc(I)c1
Reactant: CS(=O)(=O)Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCc1cccc(I)c1

Procedure:
4-(3-Iodophenyl)butan-1-ol (1.7 g) was stirred with diisopropylamine (1.74 ml) and methanesulfonyl chloride (0.66 ml) in dichloromethane (50 ml) at 21° for 2 h. The solution was washed successively with sodium bicarbonate solution, water, water acidified with a few drops of 2M HCl and water, each time back extracting with dichloromethane. The combined organic layers were dried (MgSO4) and evaporated to give the title compound (2.23 g), tlc Rf=0.28 (1:3 ethyl acetate in cyclohexane)