Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[C:11]([C:14]2[N:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=2)([F:13])[F:12])=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.O=P(Cl)(Cl)Cl>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([C:14]3[N:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([F:13])[F:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: O=C(NNc1ccc(Br)cn1)C(F)(F)c1ccc(Cl)nn1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(c1ccc(Cl)nn1)c1nnc2ccc(Br)cn12
Temperature: 140 °C
Yield: 83.7 %

Procedure:
A mixture of N′-(5-bromopyridin-2-yl)-2-(6-chloropyridazin-3-yl)-2,2-difluoroacetohydrazide (1.0 g, 2.64 mmol) and PCl5 (1.2 g, 8 mmol) in POCl3 (40.5 g, 264 mmol) was heated at 140° C. in a sealed tube for 18 hrs. Solvent was removed via rotary evaporation, and the resulting residue was reconstituted in EtOAc. The organic solution was washed with saturated NaHCO3, dried with MgSO4, filtered, and concentrated to dryness. The resulting material was purified via MPLC (Hex:EtOAc, 50-100% gradient) to provide the title compound, 6-bromo-3-((6-chloropyridazin-3-yl)difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine 45F (0.8 g, 2.21 mmol, 84%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (dd, J=9.85, 1.77 Hz, 1 H) 8.01 (dd, J=9.85, 1.01 Hz, 1 H) 8.31 (d, J=9.09 Hz, 1 H) 8.42-8.51 (m, 1 H) 8.93 (s, 1 H). ESI-MS:m/z 359.9 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1.CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:11][O:10][C:8]([C:6]1[S:7][C:3]([C:2]([OH:20])=[O:1])=[CH:4][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: COC(=O)c1sc(CO)cc1-c1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1sc(C(=O)O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of 169 (1.20 g, 4.83 mmol) in 30 mL of acetone was added dropwise Jones reagent (5 mL, 1.3M, 6.5 mmol) and stirred at room temperature for 1 hour. The reaction mixture was quenched with 10 mL of IPA, stirred for 10 min, filtered over a pad of Celite®. The filtrate was concentrated under vacuum, diluted in ether, washed with brine, dried over sodium sulfate, filtered, concentrated under vacuum to yield compound 174 (1.156 g, 91%) as yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.C([O-])(=O)[C@H:9]([C:11]1C=CC=C[CH:12]=1)[OH:10].BrCCCO.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)[C@H](C1C=CC=CC=1)O.C[C@H]1CCCNC1>O1CCCC1>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:12][CH2:11][CH2:9][OH:10])[CH2:3]1
Reactant: C[C@H]1CCCNC1
Reactant: O=C([O-])[C@@H](O)c1ccccc1
Agent: O=C(O)[C@@H](O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OCCCBr
Solvent: C1CCOC1
Product: C[C@H]1CCCN(CCCO)C1

Procedure:
(3S)-3-methyl-piperidine/(S)-(+)-mandelate (19.9 g, 79.1 mmol), 3-bromo-1-propanol (10 g, 71.9 mmol) and potassium carbonate (14.9 g, 108 mmol) were mixed in tetrahydrofuran (200 mL), and heated under reflux for 30 hours. The insoluble matter was filtered off, the filtrate was concentrated, and ethyl acetate and hexane were added to the residue. The insoluble matter produced was filtered off, the filtrate was concentrated and the target substance (9.6 g, 85%) was obtained as a colorless oily material by distillation under reduced pressure. (3S)-3-methyl-piperidine (S)-(+)-mandelate was manufactured by the method described in the literature (J. Org. Chem., 1987, Vol. 52, p. 5466).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)=[O:3].Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]([CH3:33])=[C:23]([CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[CH3:32])[N:24]=2)=[CH:16][CH:15]=1>>[CH3:33][C:22]1[O:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:7]3[CH:8]=[CH:9][C:4]([C:2]([NH2:1])=[O:3])=[CH:5][CH:6]=3)=[CH:15][CH:16]=2)=[N:24][C:23]=1[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[CH3:32]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Product: Cc1oc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 4-aminocarbonyl phenyl boronic acid (236 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 17 mg (15%). MS (m/e) 390.3 (M+1)
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[C:15]([O:24][CH3:25])[CH:16]=[CH:17][C:18]=3[F:23])[CH:13]([C:26]([CH3:30])([CH3:29])[CH:27]=[CH2:28])[C:12]=2[CH:11]=1)(C)C)(C)(C)C.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[CH3:30][C:26]([CH:13]1[C:12]2[CH:11]=[C:10]([CH2:9][OH:8])[CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[C:15]([O:24][CH3:25])[CH:16]=[CH:17][C:18]=2[F:23])([CH3:29])[CH:27]=[CH2:28]
Reactant: C=CC(C)(C)C1c2cc(CO[Si](C)(C)C(C)(C)C)ccc2-c2c(F)ccc(OC)c21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: C=CC(C)(C)C1c2cc(CO)ccc2-c2c(F)ccc(OC)c21
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 21.7 (100 mg, 234 μmol) in MeOH, was added PPTS (12 mg, 47 μmol). The resulting mixture was stirred overnight. Solvent was then removed in vacuo to give a residue which was purified by CombiFlash® chromatography to give the product as an oil (70 mg, 96%). MS ESI m/e: 330.2 (M+18)+.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:45][CH2:46][CH2:47][N:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>C1COCC1.O.C(N(CC)CC)C.C(#N)C>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:45][CH2:46][CH2:47][N:48]3[CH2:52][CH2:51][CH2:50][CH2:49]3)=[O:14])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reactant: NCCN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(NCCN1CCCC1)c1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 29 h
Yield: 67.4 %

Procedure:
To a solution of 4-(4-biphenylylmethoxy)benzoic acid (1.005 g) in THF(30 ml)/acetonitrile (30 ml) were added, WSC (0.772 g), HOBt (0.516 g), 1-(2-aminoethyl)pyrrolidine (0.453 g), and triethylamine (1.2 ml). The reaction mixture was stirred at room temperature for 29 hr, diluted with water, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate and saturated aqueous sodium chloride sequentially, dried, and concentrated. The residue was recrystallized from ethanol/diisopropyl ether to obtain the titled compound (0.891 g).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[I:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[I:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: BrCc1ccccc1I
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccccc1I

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-iodobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: O=S(Cl)Cl.[C:5]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=2[C:21]([OH:23])=[O:22])([CH3:8])([CH3:7])[CH3:6].[CH3:24]O>>[C:5]([C:9]1[CH:17]=[C:16]2[C:11](=[C:12]([C:21]([O:23][CH3:24])=[O:22])[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[CH2:15]2)[N:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CO
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(C(=O)O)c2[nH]1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1=C2N=C(C(C)(C)C)C=C2CC([N+](=O)[O-])=C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
SOCl2 (3.6 g, 30 mol) was added dropwise to a solution of 2-tert-butyl-5-nitro-1H-indole-7-carboxylic acid (4.0 g, 15 mol) and methanol (30 mL) at 0° C. The mixture was stirred at 80° C. for 12 h. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (5% EtOAc in petroleum ether) to afford methyl 2-tert-butyl-5-nitro-4H-indole-7-carboxylate (2.95 g, 70%). 1H NMR (CDCl3, 300 MHz) δ 9.99 (brs, 1H), 8.70 (d, J=2.1 Hz, 1H), 8.65 (d, J=2.1 Hz, 1H), 6.50 (d, J=2.4 Hz, 1H), 4.04 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH2:30]([NH:37][C@@H:38]([CH3:48])[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([N:37]([C@@H:38]([CH3:48])[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([C:8]2[C:7]3[CH:26]=[C:27]([O:28][CH3:29])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]3)[N:9]=2)=[CH:18][CH:19]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: C[C@@H](COCc1ccccc1)NCc1ccccc1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(Cc3ccccc3)[C@@H](C)COCc3ccccc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and N-benzyl-N-((S)-2-benzyloxy-1-methyl-ethyl)-amine as described for example 1.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][O:15][C:16]([NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][C:21]([OH:23])=O)=[O:17]>C(OCC)(=O)C>[CH3:14][O:15][C:16]([NH:18][C@@H:19]1[C:24](=[O:25])[O:26][C:21](=[O:23])[CH2:20]1)=[O:17]
Reactant: COC(=O)N[C@@H](CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)N[C@H]1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
110.52 g of trifluoroacetic anhydride are added dropwise to a solution of 76.29 g of DL-N-(methoxycarbonyl)aspartic acid in ethyl acetate under cooling. After the mixturte is stirred at room temperature for 2 hours, a part of solvent is distilled off. n-hexane is added to the solution slowly under cooling, and the precipitated crystals are collected by filteration to give 65.54 g of DL-N-(methoxycarbonyl)aspartic anhydride as colorless prism.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:6]([CH3:16])[N:5]=1)[NH2:3].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:26])=O)=[CH:20][CH:19]=1>C(O)C>[CH3:1][N:2]([C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]=[C:6]([CH3:16])[N:5]=1)[N:3]=[C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=1)[CH3:26]
Reactant: Cc1nc(-c2ccccc2)cc(N(C)N)n1
Reactant: CC(=O)c1ccc(C)cc1
Solvent: CCO
Product: CC(=NN(C)c1cc(-c2ccccc2)nc(C)n1)c1ccc(C)cc1

Procedure:
The title compound was prepared from N-methyl-N-(2-methyl-6-phenyl-pyrimidin-4-yl)-hydrazine (196 mg, 0.91 mmol) and 4-methylacetophenone (122 μL, 0.91 mmol) in 10 mL of ethanol by a procedure similar to example 8, step 4 yielding 180 mg (60%) of a cream solid. HPLC Purity: 97%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=2)=[N:5][N:4]=[N:3]1.N1C(C)=CC=CC=1C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].Cl>ClCCl.C1(C)C=CC=CC=1>[C:26]1([O:25][C:23](=[O:24])[NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[CH:8]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cn1nnnc1-c1cccc(N)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
1-Methyl-5-(3-aminophenyl)-tetrazole (24.0 g, 137 mmol) was dissolved in dichloromethane (1.4 L) and 2,6-lutidine (44.1 g, 411 mmol) was added. Phenyl chloroformate (21.2 g, 136 mmol) was added in 4 portions over 15 minutes, and the mixture was stirred for 1.5 hours. The mixture was poured into 1N aqueous hydrochloric acid (200 mL) and the mixture was extracted three times with dichloromethane (200 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under vacuum to give a crude brown material. The crude brown material was dissolved in hot toluene, filtered, and allowed to precipitate at 0° C. to give a white solid (34.1 g). The filtrate was concentrated and recrystallized again from toluene to give an additional crop of off-white crystals (3.44 g, 93% total). 1H NMR (300 MHz, CDCl3), δ10.51 (bs, 1H), 8.01 (s, 1H), 7.71 (dt, J=7, 2 Hz, 1H), 7.55 (m, 2H), 7.41 (m, 2H), 7.24 (m, 2H), 4.14 (s, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1>>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)([O-:14])=[O:13]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: c1nc[nH]n1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cncn3)cc2c1=O
Yield: 83 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (20 mg, 0.0628 mmol) is reacted with 1H-[1,2,4]triazole according to the GPB affording 19 mg (83%) of a yellowish powder. Rt=2.87 min.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[C:14]1([CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][SH:21].CC(C)([O-])C.[K+]>O1CCCC1>[CH3:11][N:7]1[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=[C:2]([S:21][CH2:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH3:22])[CH:12]=[C:6]12
Reactant: Cc1ccccc1CS
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1CSc1cc2n(c(=O)n1)CCCN2C
Temperature: 25 °C
Yield: 15.8 %

Procedure:
To a suspension of 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (200 mg, 1.002 mmol) and o-tolylmethanethiol (166 mg, 1.202 mmol) in tetrahydrofuran (THF) (5 mL) stirred in air at room temperature was added potassium tert-butoxide (112 mg, 1.002 mmol) in one charge. The reaction mixture was stirred at rt for 3 hr. The resulting mixture was concentrated and purified by prep-HPLC to give 50 mg 1-methyl-8-((2-methylbenzyl)thio)-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (50 mg, 0.158 mmol, 15.73% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16]OC)=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:21].[NH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[NH2:23]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[ClH:21].[CH3:20][O:19][C:10]1[CH:11]=[C:12]([CH2:15][CH:16]=[N:23][NH:22][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC=Cc1ccc(OCc2ccccc2)c(OC)c1
Reactant: NNc1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: COc1cc(CC=NNc2ccncc2)ccc1OCc1ccccc1
Yield: 60.7 %

Procedure:
To a stirred solution of 1-benzyloxy-2-methoxy-4-(2-methoxyvinyl)benzene (11.0 g), 4-hydrazinopyridine hydrochloride (6.6 g), and ethanol (150 ml) was added p-toluene sulfonic acid (0.39 g). The reaction mixture was stirred under reflux for 2 hrs and concentrated in vacuo. Recrystallization of the residue from methanol/ether gave 9.48 g (61%) of product, mp 154-155° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:35]([O:36][CH3:37])=[CH:34][C:24]2[CH2:25][CH2:26][N:27]([CH2:30][C@H:31]([OH:33])[CH3:32])[CH2:28][CH2:29][C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[C:35]([O:36][CH3:37])=[CH:34][C:24]3[CH2:25][CH2:26][N:27]([CH2:30][C@H:31]([OH:33])[CH3:32])[CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(C[C@@H](C)O)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(C[C@@H](C)O)CC2
Yield: 63 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and (R)-1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol. Product was isolated as an off-white foam (65 mg, 63%). MS (ESI+): 513 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.22 (s, 1H), 7.91 (s, 1H), 7.42 (s, 1H), 6.66 (s, 1H), 6.57 (s, 1H), 6.51 (s, 1H), 6.33 (s, 2H), 5.60 (s, 1H), 5.35 (s, 1H), 5.32 (s, 1H), 4.47 (t, J=8 Hz, 1H), 3.88 (s, 4H), 3.08 (s, 1H), 2.88 (m, 8H), 2.62 (br s, 2H), 2.53 (m, 2H), 2.27 (m, 2H), 1.66 (d, J=8.5 Hz, 1H), 1.16 (d, J=6 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:18])[CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:2]1.[H-].[Na+].[F:21][C:22]1[CH:41]=[CH:40][C:25]([CH2:26][NH:27][C:28]([C:30]2[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[O:29])=[CH:24][CH:23]=1>CN(C=O)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][NH:27][C:28](=[O:29])[C:30]2[CH:35]=[CH:34][C:33]([S:36]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]([C:10](=[O:18])[CH2:11][N:12]4[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]4)=[CH:2]3)(=[O:37])=[O:38])=[CH:32][CH:31]=2)=[CH:40][CH:41]=1
Reactant: O=C(CN1CCCCC1)c1c[nH]c2ccccc12
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(C(=O)CN3CCCCC3)c3ccccc32)cc1
Reaction time: 0.08 h
Yield: 56.8 %

Procedure:
Slowly add 1-(1H-Indol-3-yl)-2-piperidin-1-yl-ethanone (199 mg, 0.821 mmol, 1.0 eq) as a 2 ml DMF solution to a flask under N2 containing sodium hydride (36 mg, 60 wt % on oil, 0.903 mmol, 1.1 eq) in 2 ml DMF solution. Stir solution for 5 minutes. Slowly add 4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (296 mg, 0.903 mmol, 1.1 eq) as a 3 ml DMF solution. Stir reaction for 18 hours at room temperature. Strip reaction of solvent and purify on silica gel chromatography to give N-(4-Fluoro-benzyl)-4-[3-(2-piperidin-1-yl-acetyl)-indole-1-sulfonyl]-benzamide (249 mg, 57% yield). Mass Spectrum (m/e): 534 (MH+).
Reaction SMILES: [F:1][C:2]1[C:14]2[NH:13][C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Li+].[Li+].[Br-].[Li+]>[Cu].C(OCC)(=O)C>[F:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[C:8]([OH:15])[CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCc2[nH]c3c(F)cccc3c21
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Product: Oc1cccc2[nH]c3c(F)cccc3c12
Temperature: 25 °C
Yield: 28.9 %

Procedure:
A mixture of 1-fluoro-5-oxo-5,6,7,8-tetrahydrocarbazole (111 mg, 0.55 mmol), copper II bromide (244 mg, 1.09 mmol), and 5 mL of ethyl acetate was heated to reflux for about 12 hours. The reaction was cooled to room temperature, treated with celite, and then filtered. The reaction was partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in 5 mL of dimethylformamide and lithium carbonate (52 mg, 0.7 mmol) and lithium bromide (61 mg, 0.7 mmol) were added. The resulting mixture was heated to reflux for 1.5 hours. The reaction was concentrated in vacuo and the crude product was purified via flash silica gel chromatography eluting with 15% ethyl acetate/hexanes to give 32 mg of the title compound. Yield: 18%. 1H NMR. MS(FD).
Reaction SMILES: [CH2:1]([Si:5]([CH3:22])([C:12]1([CH2:18][CH:19]([CH3:21])[CH3:20])SCCCS1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[OH2:23]>CC#N.Cl[Hg]Cl>[CH2:1]([Si:5]([CH3:22])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12](=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC[Si](C)(c1ccccc1)C1(CC(C)C)SCCCS1
Reactant: O
Agent: Cl[Hg]Cl
Solvent: CC#N
Product: C=CCC[Si](C)(C(=O)CC(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 44 (6.19 g, 17.7 mmol) in CH3CN (200 ml) was added water (10 mL) and HgCl2 (24 g, 88 mmol). After stirring overnight at rt, the mixture was concentrated and partitioned between water (100 mL) and hexane (200 mL). The organic layer was isolated and the aqueous layer extracted twice with 50-mL portions of hexane. The combined organic extracts were washed with saturated aqueous NaCl and dried over Na2SO4. Concentration to dryness in vacuo at rt gave quantitatively crude ketone 45 as a yellow oil. This ketone was used in the next reaction without further purification: Rf=0.75 (1/19 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.54-7.51 (m, 2H), 7.41-7.35 (m, 3H), 5.91-5.78 (m, 1H), 4.99 (dd, J=17.0, 1.7 Hz, 1H), 4.90 (dd, J=10.0, 1.7 Hz, 1H), 2.44 (d, J=6.7 Hz, 2H), 2.16-2.06 (m, 3H), 1.16-1.07 (m, 2H), 0.78 (pd, J=6.7 Hz, 6H), 0.51 (s, 3H).
Reaction SMILES: C(=O)=O.[CH2:4]([O:6][C:7](=[O:10])[CH2:8][SH:9])[CH3:5].[Cl:11][C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:4]([O:6][C:7](=[O:10])[CH2:8][S:9][C:12]([Cl:11])=[O:14])[CH3:5]
Reactant: CCOC(=O)CS
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C=O
Agent: [Cl-]
Product: CCOC(=O)CSC(=O)Cl
Temperature: 80 °C

Procedure:
A flask equipped with a refrigerant cooled with dry ice was charged with thioglycolic acid ethyl ester (1.202 g, 10.0 mmol) and triphosgene (2.000 g, 6.7 mmol). A catalytical amount of tetrabutylammonium chloride was added and the mixture was heated to a temperature of 80° C. for fifteen hours. The exhaust gases were treated with 4N sodium hydroxide aqueous solution. The resulting light brown liquid was flushed with a stream of nitrogen, then distilled under vacuum (110° C./4 mbar) to yield the desired compound as a colorless oil. 1H-NMR (400 MHz, CDCl3, reference TMS); δ (ppm): 4.22 (q, 2H), 3.76 (s, 2H), 1.30 (t, 3H). 13C-NMR (100 MHz, CDCl3, reference TMS); δ (ppm): 166.63, 165.05, 62.44, 35.43, 14.02.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:8]=[C:9]([CH:17]=[C:18]([F:27])[C:19]=1[C:20]([CH3:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])[O:10][CH2:11][C:12]([O:14]CC)=[O:13].[OH-].[Na+].Cl>CO>[F:6][C:7]1[CH:8]=[C:9]([CH:17]=[C:18]([F:27])[C:19]=1[C:20]([CH3:25])([CH3:26])[C:21]([F:22])([F:23])[F:24])[O:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)COc1cc(F)c(C(C)(C)C(F)(F)F)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(c1c(F)cc(OCC(=O)O)cc1F)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a tetrahydrofuran (1 ml) solution of ethyl [3,5-difluoro-4-(2,2,2-trifluoro-1,1-dimethylethyl)phenoxy]acetate (267 mg, 0.82 mmol) and methanol (1.5 ml) was added 2 N sodium hydroxide aqueous solution (1 ml) and the mixture was stirred at 60° C. for 30 minutes. After the reaction was complete, the basic mixture was acidified with 2 N hydrochloride aqueous solution and the product was extracted with ethyl acetate which was dried over sodium sulfate. The organic layer was filtered and concentrated to give 242 mg (99% yield) of the title compound as a brown solid.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5](C)C)[CH3:3].[CH2:8](Cl)[CH:9]=[C:10]([CH3:12])C>CC(C)=O>[CH3:5][CH2:4][C:2](=[O:1])[CH:3]=[CH:8][CH2:9][CH2:10][CH3:12]
Reactant: CC(C)=CCCl
Reactant: CC(=O)C=C(C)C
Solvent: CC(C)=O
Product: CCCC=CC(=O)CC

Procedure:
Acetone under the reaction conditions forms mesityl oxide, and this then reacts with the prenyl chloride to produce the above isomers; in the same manner, acetone reacts with prenyl chloride to produce methyl heptenone.