Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:20][O:21][C:22]1[C:23](=[O:49])[C:24]([CH3:48])=[C:25]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:36]([CH:40]=2)[C:37](O)=[O:38])[C:26](=[O:30])[C:27]=1[O:28][CH3:29]>C(Cl)Cl>[CH3:20][O:21][C:22]1[C:23](=[O:49])[C:24]([CH3:48])=[C:25]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:36]([CH:40]=2)[C:37]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])=[O:38])[C:26](=[O:30])[C:27]=1[O:28][CH3:29]
Reactant: CC1CCCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)N3CCCCC3C)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.9 %

Procedure:
2-Methylpiperidine (0.039 g, 0.391 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.112 g, 0.587 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenoxybenzoic acid (0.080 g, 0.196 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=9:1) to obtain the titled compound (0.045 g, 0.0919 mmol, 47%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][C:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:33][C:28]4([CH2:27][O:26][CH3:25])[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: COCC1(N)CCCC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCC1(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CCCC1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(methoxymethyl)cyclopentanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45-1.74 (m, 6H) 1.94-2.08 (m, 2 H) 2.37 (s, 3 H) 3.20 (s, 3 H) 3.54 (s, 2 H) 7.59 (dd, J=7.96, 1.39 Hz, 1H) 7.66 (s, 1 H) 7.70 (br. s., 1 H) 8.04 (s, 1 H) 8.06-8.18 (m, 1 H) 8.33 (d, J=6.57 Hz, 2 H) 8.75-8.86 (m, 1 H) 12.59-13.45 (m, 1 H). MS m/z [M+H]+ 432.2
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH:35][C:36]([CH2:40][OH:41])([CH3:39])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH:35][C:36]([CH2:40][OH:41])([CH3:39])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(CO)(CO)NS(=O)(=O)c1cccc(Br)c1
Product: CC(CO)(CO)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 3-Bromo-N-(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-benzenesulfonamide (example B.9) (294 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (240 mg, 41%). MS (ISP) 581.2 [(M+H)+]; mp 172-174° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH2:27][CH3:28]>>[CH2:27]([N:26]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1)[CH2:25][CH2:24][O:23][CH3:22])[CH3:28]
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Reactant: CCNCCOC
Product: CCN(CCCOc1ccc2c(-c3ccc(F)cc3)csc2c1)CCOC

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and N-(2-methoxyethyl)ethylamine were converted to yield Ethyl-{3-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-(2-methoxy-ethyl)-amine as colorless oil, MS: 388 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH2:11][O:12][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([CH2:11][O:12][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: CCCOCc1ccc(C(=O)O)c(F)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCOCc1ccc(C(=O)Cl)c(F)c1

Procedure:
2-Fluoro-4-(propoxymethyl)benzoic acid (1.5 g, 7.1 mmol) was mixed with thionyl chloride (1.3 g, 10.6 mmol), pyridine (0.1 ml) and toluene (3 ml), followed by reacting them at 80° C. for 2 hours, and distilling off superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 2-fluoro-4-(propoxymethyl)benzoyl chloride.
Reaction SMILES: CS([O:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][CH:28]=3)[NH:18][C:17](=[O:38])[NH:16]2)=[CH:8][C:7]=1[O:39][CH2:40][CH3:41])(=O)=O.[OH-].[Na+].Cl.O>C(O)C>[CH2:40]([O:39][C:7]1[CH:8]=[C:9]([CH:15]2[NH:16][C:17](=[O:38])[NH:18][C:19]([C:27]3[CH:28]=[CH:29][C:30]([NH:33][S:34]([CH3:37])(=[O:35])=[O:36])=[CH:31][CH:32]=3)=[C:20]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[OH:5])[CH3:41]
Reactant: CCOc1cc(C2NC(=O)NC(c3ccc(NS(C)(=O)=O)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1OS(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1cc(C2NC(=O)NC(c3ccc(NS(C)(=O)=O)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 80 °C
Yield: 68.6 %

Procedure:
To a mixture of 2-ethoxy-4-(6-(4-(methylsulfonamido)phenyl)-2-oxo-5-phenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-6-nitrophenyl methanesulfonate (60 mg, 0.10 mmol) in ethanol (2 mL) was added sodium hydroxide aqueous solution (2 mL, 1.25 mol/L) at 0° C. The mixture was heated at 80° C. for 5 h, cooled down to room temperature, adjusted to pH=5 with diluted hydrochloric acid, poured into water (20 mL), and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and evaporated. The residue was purified by preparative HPLC to give Compound 101 (36.0 mg, yield 68.9%). HNMR (DMSO-d6 300 MHz): δ 10.34 (s, 1H), 9.91 (s, 1H), 8.73 (s, 1H), 7.59 (s, 1H), 7.49 (s, 1H), 7.23 (d, J=9.0 Hz, 3H), 7.12-7.06 (m, 5H), 6.90 (d, J=6.9 Hz, 2H), 5.24 (d, J=2.7 Hz, 1H), 4.12-4.08 (m, 2H), 3.04 (s, 3H), 1.42-1.37 (m, 3H); MS (ESI): m/z 525.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([N:14]([CH2:16][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:18][CH:19]=C)[CH3:15])=[O:13])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.FC1C=CC([C@H](CC=C)CN(C)C(=[O:53])C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]([N:14]([CH2:16][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:18][CH:19]=[O:53])[CH3:15])=[O:13])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(F)cc2c1CCCC2)c1ccc(F)cc1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(F)cc1
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(F)cc2c1CCCC2

Procedure:
The compound was synthesized in an analogous way to that of Method 20b but using 3-fluoro-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide rather than N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide (yield, 68%). 1H NMR (500 MHz, CDCl3): 1.6-4.2 (cm, 16H), 6.2-7.8 (cm, 6H), 9.8 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[OH:10].[Br:11][CH2:12][CH2:13]Br>>[Br:11][CH2:12][CH2:13][O:10][C:3]1[C:2]([Cl:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[F:9]
Reactant: Oc1c(F)ccc(F)c1Cl
Reactant: BrCCBr
Product: Fc1ccc(F)c(OCCBr)c1Cl
Yield: 31 %

Procedure:
2-Chloro-3,6-difluorophenol was reacted with 1,2-dibromoethane according to the procedure described in Step 2A to yield 2C (2.1 g, 31%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.65 (t, J=6.57 Hz, 2H), 4.43 (t, J=6.57 Hz, 2H) 6.89 (m, 1H) 7.01 (m, 1H).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=O>CO.Cl.O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[CH2:9][CH2:8][CH2:7][Cl:6])=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=O)CCCCl)cc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(C(CCCCl)=NNC(N)=S)cc1
Reaction time: 72 h
Yield: 63 %

Procedure:
Thiosemicarbazide (6.4 g, 70 mmol) was added under nitrogen to a solution of 4-chloro-4'-methoxybutyrophenone (10.0 g, 47 mmol) in 150 mL of methanol plus 12.7 mL of 1 N HCl plus 11.8 mL of water and the reaction stirred for approximately three days (over the weekend). The solid formed was collected by filtration and dissolved in methylene chloride. The organic solution was washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give a white solid. Recrystallization of the solid from isopropyl alcohol gave 8.46 g (63%) of the title compound as a light yellow solid, mp 137-140° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][O:13][C:14]([C@@:16]12[CH2:24][N:23](CC3C=CC=CC=3)[CH2:22][C@@H:21]1[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15]>ClCCl>[CH3:12][O:13][C:14]([C@@:16]12[CH2:24][N:23]([C:2]([O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:3])[CH2:22][C@@H:21]1[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15]
Reactant: COC(=O)[C@]12CCCC[C@H]1CN(Cc1ccccc1)C2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@]12CCCC[C@H]1CN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.8 %

Procedure:
Benzyl chloroformate (33.4 mL, 234 mmol) was added to a solution of [(1R*,6R*)-8-benzyl-8-azabicyclo[4.3.0]nonan-1-yl]carboxylic acid methyl ester (21.3 g, 77.9 mmol) in dichloromethane (259 mL) in a nitrogen atmosphere, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Then, the residue (58.0 g) was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→80:20→75:25) to give 17.5 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:17][CH3:18].C(N(CC)CC)C>C1COCC1>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=2)=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCCc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)Nc2ccc(C(=O)c3ccccc3)cc2)cc1
Yield: 78.4 %

Procedure:
Reaction of 4-aminobenzophenone (99 mg, 0.51 mmol) in THF (6 mL) with 4-propylbenzoyl chloride (100 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-benzoyl-phenyl)-4-propyl-benzamide (136 mg, 0.40 mmol, 78% yield) as a white powder after purification by chromatography on silica gel (eluent EtOAc/DCM 0/100 to 5/95).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCNCC3)cnc21
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC(NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Piperidin-4-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride (0.073 g, 0.158 mmol) was suspended in DCM (1 mL) and pyridine (0.045 mL, 0.55 mmol) was added. Acetic anhydride (0.018 mL, 0.19 mmol) was added and the resulting solution stirred at RT overnight. The solvent was evaporated. The remaining oil was purified by SiO2 chromatography (12 g SiO2, DCM:MeOH 0 to 5% MeOH) to give 0.053 g of 1-(1-acetyl-piperidin-4-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as off-white foam (78% yield).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:22][CH2:21][C@@:12]34[C:13]5[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=5[CH2:19][C@@H:6]2[C@:7]3([OH:23])[CH2:8][CH2:9][O:10][CH2:11]4)[CH2:3][CH2:2]1.[C:24](Cl)(=[O:26])[CH3:25].N1C=CC=CC=1>C(Cl)Cl>[C:24]([O:20][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][C@H:6]3[N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:22][CH2:21][C@@:12]4([C:13]=2[CH:14]=1)[C@@:7]3([OH:23])[CH2:8][CH2:9][O:10][CH2:11]4)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Oc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@]1(O)CCOC3
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@]1(O)CCOC3

Procedure:
Equimolar quantities of 17-cyclopropylmethyl-3,14β-dihydroxy-6-oxamorphinan (XVI), acetyl chloride and pyridine are mixed together in dry methylene chloride and the resultant mixture is heated at reflux for several hours to produce the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:24]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1cccs1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cccs4)cc3c2C1
Yield: 62.1 %

Procedure:
Beginning with 10.6 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.8 μL (0.082 mMol) 2-thienoyl chloride, 9.7 mg (62%) of the title compound were recovered as a brown solid.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1Br.[F:17][C:18]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:22]=[CH:21][C:19]=1[NH2:20].C([O-])([O-])=O.[K+].[K+]>[Cu]I>[CH3:1][N:2]([CH3:16])[C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH:20][C:19]1[CH:21]=[CH:22][C:23]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[CH:24][C:18]=1[F:17]
Reactant: Nc1ccc(-c2ccc(F)cc2)cc1F
Reactant: CN(C)C(=O)Cc1cc(C2CC2)ccc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)C(=O)Cc1cc(C2CC2)ccc1Nc1ccc(-c2ccc(F)cc2)cc1F

Procedure:
A mixture of N,N-dimethyl-2-bromo-5-cyclopropylphenylacetamide (1.0 g), 2-fluoro-4-(4-fluorophenyl)aniline (1.5 g), K2CO3 (490 mg), KI (590 mg), Cu (113 mg), CuI (337 mg) in xylenes (10 mL) is heated to reflux for 48 hours. After cooling, the reaction is filtered through silica gel and the filtrate concentrated to a brown oil. The oil is purified by flash chromatography using 10%, then 20%, then 30%, then 40% EtOAc in hexane to give the title product as a foam.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH2:3][OH:4].[N:17]#[C:18]Br>>[F:16][C:13]1[CH:12]=[CH:11][C:10]([S:7]([CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:18]([NH2:17])=[N:1]2)(=[O:9])=[O:8])=[CH:15][CH:14]=1
Reactant: N[C@H](CO)CCS(=O)(=O)c1ccc(F)cc1
Reactant: N#CBr
Product: NC1=N[C@@H](CCS(=O)(=O)c2ccc(F)cc2)CO1

Procedure:
In analogy to example 1d (S)-2-amino-4-(4-fluoro-phenylsulfonyl)-butan-1-ol was reacted with cyanogen bromide to give (S)-4-[2-(4-fluoro-phenylsulfonyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine. Colourless oil. MS (ISP): 273.1 ([M+H]+).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClCCCl.O>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: COc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Anisole (70.0 g) and succinic anhydride (65.0 g) were dissolved in 1,2-dichloroethane (1 liter) and the mixture was cooled to 0° C. To the resulting suspension there was added, in portions, AlCl3 (172 g) and the resulting mixture was stirred with a mechanical stirrer for 1 hour. The mixture was then poured into a mixture of ice and water (about 1 liter) containing 50 ml of concentrated HCl. The resulting white solid was collected by filtration, washed with water and air dried to yield the title compound, mp 145°-147° C.
Reaction SMILES: [CH3:1][N:2]([CH:14](Cl)[C:15]([Cl:18])([Cl:17])[Cl:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:4].[S-:20][C:21]#[N:22].[NH4+]>C(COC)OC>[CH3:1][N:2]([CH:14]([N:22]=[C:21]=[S:20])[C:15]([Cl:18])([Cl:17])[Cl:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:4]
Reactant: N#C[S-]
Reactant: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)C(Cl)C(Cl)(Cl)Cl
Agent: [NH4+]
Solvent: COCCOC
Product: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)C(N=C=S)C(Cl)(Cl)Cl
Reaction time: 2 h

Procedure:
1-methyl-1-(1,2,2,2-tetrachloroethyl)-3-(3,4-dichlorophenyl) urea (7.7 g, 0.02 mol) was dissolved in 200 ml dimethoxyethane, followed by addition of 1.5 g (0.02 mol) of ammonium thiocyanate. The mixture was stirred for 2 hours, filtered and stripped of solvent. Ether was added to the residue, which was again filtered to remove a small amount of solid. The remaining solvent was then removed, leaving a dark oil which solidified upon standing. This material had a melting point of 142°-146° C. The infrared spectrum of the material showed a broad absorption band at 4.9 micron (for the --N=C=S group). Elemental analysis showed: %Cl, calc., 43.6, found 36.7; %S, calc. 7.9, found 6.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[C:14](O)([CH3:17])([CH3:16])[CH3:15].Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[C:14]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:12]([CH3:13])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 3-nitro-4-methylbenzoic acid (17.3 g 96 mmol) in dichloromethane (250 ml) and tert-butanol (35.8 g 470 mmol) at 0° C. under nitrogen was added 4-dimethylaminopyridine (6 g 50 mmol) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25.8 g 140 mmol) and the solution allowed to come to room temperature over 1 hour. then stirred overnight. The solution was poured into 1:1 ethyl acetate:water (800 ml) and the organic layer washed with aqueous bicarbonate and saturated aqueous sodium chloride. then dried (MgSO4) and evaporated. to give the product as a clear oil (22.6 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11]O)[C:4]=2[O:3]1.[ClH:14]>O>[Cl:14][CH2:11][C:10]1[C:4]2[O:3][C:2]([CH3:13])([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC1(C)Cc2cccc(CO)c2O1
Reactant: Cl
Solvent: O
Product: CC1(C)Cc2cccc(CCl)c2O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethanol (6.3 grams, 0.035 mole) and concentrated hydrochloric acid (38%) was stirred at ambient temperature for 0.75 hour. The reaction mixture was diluted with water (50 ml) and extracted with diethyl ether. The extract was washed successively with a 10% aqueous solution of sodium hydroxide and a saturated aqueous sodium chloride solution. The dried (sodium sulfate) extract was concentrated under reduced pressure, yielding 7-chloromethyl-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].OC=[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:6]([C:16]3[CH2:15][CH2:14][CH2:13][C:12](=[O:17])[C:11]=3[NH:5]2)=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C1CCCCC1=CO
Product: O=C1CCCc2c1[nH]c1cc(Br)ccc21

Procedure:
7-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one was prepared 3-bromoaniline (7.6 g, 44 mmol) and 2-(hydroxymethylene)cyclohexanone (4.3 g, 34 mmol) in a similar manner as described above and recrystallization from methanol to isolate 7-bromo isomer to give 280 mg (1%). of a light brown solid. 1H-NMR (DMSO-d6): δ 8.94 (s, 1H), 7.60 (d, 1H), 7.52 (d, 1H), 7.27-7.25 (m, 1H), 3.01-2.98 (m, 2H), 2.68-2.65 (m, 2H), 2.31-2.24 (m, 2H); MS m/z 263, 265 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][S:10]2(=[O:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][C:21](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:22]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][S:10]2(=[O:19])=[O:18])=[CH:4][CH:3]=1)(=[O:22])[CH3:20]
Reactant: O=S1(=O)Nc2ccccc2C1=Cc1ccc(O)cc1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=C2c3ccccc3NS2(=O)=O)cc1
Yield: 80 %

Procedure:
To a cooled solution of 3-(4'-hydroxyphenyl)methylene-2,1-benzisothiazoline-2,2-dioxide (273 mg, 1 mmol) in dry pyridine (0.5 ml) is added acetic arthydride (204 mg, 2 mmol) and the mixture maintained at 0°-5° C. overnight. Thereupon the mixture is concentrated under vacuum, the residue dissolved in dichloromethane, the organic layer washed with water and then evaporated under reduced pressure. The crude product is crystallized from chloroformmethanol to yield pure 3-(4'-acetoxyphenyl)methylene-2,1-benzisothiazoline-2,2-dioxide (80% yield).