Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](Cl)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)=[O:4].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1>>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:9][CH2:10][CH:5]([C:3]([NH:2][CH3:1])=[O:4])[CH2:6][CH2:7]4)=[CH:13][C:14]=3[N:15]=2)=[CH:37][CH:38]=1
Reactant: CNC(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: CNC(=O)C1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidine-4-carboxylic acid methylamide, prepared following General Procedure B-3, was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine by General Procedure A. Purification on silica yielded 124. NMR (CDCl3): 1.85-1.87 (m, 4H, 2×CH2), 2.10-2.18 (m, 3H, CH2+CH), 2.85 (d, 3H, Ch3, J=4.8 Hz), 3.03-3.06 (m, 2H, CH2), 3.82 (s, 2H, CH2), 3.89-3.92 (m, 4H, 2×CH2), 4.04-4.06 (m, 4H, 2×CH2), 4.63 (sbr, 2H, NH2), 5.46 (sbr, H, NH), 6.58 (d, H, ArH, J=8.59 Hz), 7.26 (s, H, ArH), 8.48 (dd, H, ArH, J=2.2 Hz, 8.58 Hz), 9.17 (d, H, ArH, J=2.03 Hz). MS: (ESI+): MH+=468.37
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])[CH3:11]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)c1ccccc1
Product: O=C(C=Cc1cccc(Cl)c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 3-chlorobenzaldehyde and acetophenone, 3-(3-chlorophenyl)-1-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[S:12]1[CH:16]=[CH:15][C:14]2[C:17]([NH:21][C:22]3[N:23]=[C:24](SC)[N:25]=[N:26][C:27]=3[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:18][CH:19]=[CH:20][C:13]1=2.[C:35]([O:39][C:40](=[O:49])[NH:41][C@H:42]1[CH2:47][CH2:46][CH2:45][CH2:44][C@H:43]1[NH2:48])([CH3:38])([CH3:37])[CH3:36].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[S:12]1[CH:16]=[CH:15][C:14]2[C:17]([NH:21][C:22]3[N:23]=[C:24]([NH:48][C@@H:43]4[CH2:44][CH2:45][CH2:46][CH2:47][C@@H:42]4[NH:41][C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:49])[N:25]=[N:26][C:27]=3[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:18][CH:19]=[CH:20][C:13]1=2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCOC(=O)c1nnc(SC)nc1Nc1cccc2sccc12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc2sccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of m-CPBA (65 mg) in chloroform (1.5 ml) was added to a solution of ethyl 5-(benzo[b]thiophen-4-ylamino)-3-(methylthio)-1,2,4-triazine-6-carboxylate obtained in the above-described Step 1 (33 mg) in chloroform (1.5 ml), the reaction solution was stirred at room temperature for 10 minutes. Thereafter, tert-butyl((1S,2R)-2-aminocyclohexyl)carbamate (60 mg) and diisopropylethylamine (0.10 ml) were added, and then the reaction solution was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate and then washed successively with an aqueous sodium bicarbonate solution and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum, and then the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain ethyl 5-(benzo[b]thiophen-4-ylamino)-3-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-1,2,4-triazine-6-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]O)[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=3)[C:21]([CH3:30])([CH3:29])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N-:50]=[N+:51]=[N-:52].[Na+]>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:50]=[N+:51]=[N-:52])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=3)[C:21]([CH3:30])([CH3:29])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ccc(Cl)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ccc(Cl)cc32)[C@@H](CN=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
(2R,5R)-4-[2-(6-Chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (175 mg, 0.39 mmol) was dissolved in anhydrous DCM (3.87 mL) and cooled in an ice bath. Triethylamine (0.27 mL, 1.94 mmol) was added followed by toluene-4-sulfonyl chloride (148 mg, 0.77 mmol). Reaction was stirred for 1 h at 0° C. (ice bath) and gently warmed to ambient temperature over 18 h. The solvent was removed in vacuo and residue purified by column chromatography on silica gel (0-50%, EtOAc/petrol). The product (117 mg, 0.25 mmol) was dissolved in DMF (2.5 mL) and sodium azide (24 mg, 0.37 mmol) added. The reaction was heated to 65° C. for 18 h, then cooled to ambient temperature and the solvent removed in vacuo. The residue was slurried in Et2O, filtered and the filtrate evaporated in vacuo. The resulting oil was purified by column chromatography on silica gel (gradient elution, 0-75%, EtOAc/petrol), to give the title compound (81 mg, 44%) as a colourless oil. 1H NMR (Me-d3-OD): 8.14 (1H, d), 7.21 (1H, d), 7.09 (1H, dd), 4.26-4.15 (1H, m), 4.10-3.97 (3H, m), 3.76-3.46 (3H, m), 3.46-3.36 (1H, m), 3.05-2.91 (1H, m), 2.85 (1H, dd), 2.70 (1H, dd), 1.50 (9H, s), 1.38 (6H, s), 1.24 (3H, d).
Reaction SMILES: F[C:2]1[C:24]([O:25][CH:26]([F:28])[F:27])=[C:23]([F:29])[C:22]([F:30])=[CH:21][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(=O)([O-])O.[Na+].O>CN(C)C=O>[F:30][C:22]1[CH:21]=[C:3]2[C:2](=[C:24]([O:25][CH:26]([F:28])[F:27])[C:23]=1[F:29])[N:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]2=[O:5]
Reactant: CCOC(=O)C(=CNCc1ccccn1)C(=O)c1cc(F)c(F)c(OC(F)F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccn2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
In 50 ml of N,N-dimethylformamide was dissolved 5.6 g (0.013 mole) of ethyl 2-(2,4,5-trifluoro-3-difluoromethoxybenzoyl)-3-(2-pyridylmethylamino)acrylate, and 2.2 g (0.026 mole) of sodium hydrogen carbonate was added thereto. The mixture was stirred at 120° C. for 30 minutes. Then, the reaction mixture was poured into 200 ml of water, and crystals precipitated were collected by filtration. The collected crystals were washed with water and ethanol and dried to obtain 2.6 g of ethyl 6,7-difluoro-8-difluoromethoxy-1-(2-pyridylmethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate as yellow crystals.
Reaction SMILES: [CH2:1]1[O:21][C:4]([CH2:19][CH3:20])([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:7]=2[N+:16]([O-])=O)[O:3][CH2:2]1>C(O)C.[Pd]>[CH2:2]1[O:3][C:4]([CH2:19][CH3:20])([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:7]=2[NH2:16])[O:21][CH2:1]1
Reactant: CCC1(Cc2cccc(C(=O)OC)c2[N+](=O)[O-])OCCO1
Agent: [Pd]
Solvent: CCO
Product: CCC1(Cc2cccc(C(=O)OC)c2N)OCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.4 %

Procedure:
To a solution of 1-(3-methoxycarbonyl-2-nitrophenyl)butan-2-one ethylene ketal (S) (1.12 g) (prepared, e.g., as described in Preparation 13), in absolute ethanol (50 ml) was added palladium on carbon (150 mg, 10%), and the mixture stirred under hydrogen at atmospheric pressure and room temperature for 6 hours. The reaction mixture was passed through a Celite pad to remove catalyst, and the pad was washed with methylene chloride. The combined filtrate and washings were concentrated under reduced pressure to give 1-(2-amino-3-methoxycarbonylphenyl)butan-2-one ethylene ketal (0.98 g), a compound of Formula (T), as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:31]=[N+:32]=[N-:33])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][N:31]=[N+:32]=[N-:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1cccc(OCc2ccccc2)c1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-benzyloxybenzyl alcohol (5.0 g, 23.3 mmol) and diphenylphosphoryl azide (7.7 g, 28.0 mmol) in dry toluene (40 mL) at 0° C., was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.9 g, 25.6 mmol). The resulting mixture was allowed to warm to ambient temperature, and stirred under argon for 18 hrs, then washed with water (2×15 mL), then 5% hydrochloric acid (15 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with hexane −4% ethyl acetate to yield the product as a colorless oil.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[N:21]([C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH3:35])=[C:22]=[O:23]>CO>[CH3:35][C:25]1[N:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:28][C:24]=1[NH:21][C:22](=[O:23])[NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9]
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Reactant: Cc1nc(-c2ccccc2)sc1N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1nc(-c2ccccc2)sc1NC(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C
Reaction time: 18 h

Procedure:
To a solution of (R)-aminocarnitine (21 mg, 0.13 mmol) and diisopropylethylamine (68 uL, 0.39 mmol) in MeOH (2 mL) was added 5-isocyanato-4-methyl-2-phenylthiazole (57 mg, 0.26 mmol) and the reaction stirred for 18 hrs. The MeOH was removed in vacuo and the residue stirred with 1:1 ether/EtOAc. Impurities dissolved into the ether/EtOAc which were discarded and the remaining material taken up into 90:10 CH2Cl2/MeOH and then loaded onto a short SiOH plug. The title compound was eluted by increasing MeOH content in 10% steps to 60%. The compound was then taken up into 90:10 CH2Cl2/MeOH and filtered through a plug of celite which gave after drying the title compound as a yellow powder (6 mg, 12%). 1H NMR (400 MHz, CD3OD) δ 7.85-7.82 (m, 2H), 7.47-7.41 (m, 3H), 4.73-4.71 (m, 1H), 3.82-3.57 (m, 2H), 3.26 (s, 9H), 2.79-2.75 (m, 2H), 2.37 (s, 3H); MS ESI 377.1 [M+H]+, calcd for [C18H24N4O3S+H]+ 377.47.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.II.C(N(CC)CC)C.[S:18](=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]12[S:18][CH:3]1[CH:4]1[S:8][CH:5]1[CH:6]=[CH:7]2
Reactant: Sc1ccc(Br)cc1
Reactant: O=S([O-])O
Agent: II
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: BrC12C=CC3SC3C1S2
Reaction time: 1 h

Procedure:
To a solution of 4-bromothiophenol (16 g, 85 mmol) in CH2Cl2 (85 mL) was added iodine (10.7 g, 42 mmol, in CH2Cl2) and triethylamine (11.8 mL, 85 mmol). After 3 h the resulting reaction mixture was diluted with a sodium bisulfite solution and ethyl acetate. The organic extracts were washed (1N NaOH, brine), dried (MgSO4), filtered and concentrated. The resulting residue was stirred vigorously in hexane/ether for 1 h then filtered to afford the 4-bromobenzene disulfide compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12](O)=[O:13])[CH2:8][CH2:7]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH:9]([CH2:12][OH:13])[CH2:10][CH2:11]1
Reactant: O=C(O)C1CCC(Cc2cccc(Cl)c2)CC1
Solvent: C1CCOC1
Product: OCC1CCC(Cc2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 32.9 %

Procedure:
4-(3-Chlorobenzyl)cyclohexanecarboxylic acid (550 mg; 2.2 mmol) was cooled to 0° C. in 5 mL of anhydrous tetrahydrofuran under nitrogen flow, and BH3 THF was added over 5 minutes. Mixture was warmed to room temperature. After 3.5 hours, mixture was cooled to 0° C. and quenched with slow additions of sat. NH4Cl. Mixture was stirred for 20 minutes and water was added to dissolve precipitates. Mixture was extracted 3×20 mL with ethyl acetate, and combined organics were washed with brine and dried over MgSO4. Material was purified via flash chromatography using 1-5% methanol in dichloromethane gradient to obtained 173 mgs of title compound. (33% yield)
Reaction SMILES: [OH-].[Li+].[NH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[CH3:11])[N:7]=[C:6]([C:14]([O:16]C)=[O:15])[C:5]=1[Cl:18]>O.O1CCCC1>[NH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[CH3:11])[N:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]=1[Cl:18]
Reactant: COC(=O)c1nc(C(C)(F)F)cc(N)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(F)(F)c1cc(N)c(Cl)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A solution of lithium hydroxide (159 mg, 1.27 mmol) in water (6 mL) was added to a solution of methyl 4-amino-3-chloro-6-(1,1-difluroethyl)-pyridine-2-carboxylate (159 mg, 0.63 mmol) in tetrahydrofuran (6 mL). The mixture was vigorously stirred at room temperature overnight and was then concentrated to near dryness. After adding water, the reaction mixture was washed once with ethyl acetate to remove unreacted starting material. The aqueous layer was then acidified to pH<3 with 1N HCl and extracted with ethyl acetate. The organic layer was dried (MgSO4), concentrated and the residue triturated with cold hexane to provide 4-amino-3-chloro-6-(1,1-difluoroethyl)-pyridine-2-carboxylic acid (105 mg, 0.44 mmol) as a white solid; 1H NMR (DMSO-d6): δ 7.02 (s, 1H), 6.94 (br.s, 2H), 1.90 (t, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](B3OC(C)(C)C(C)(C)O3)[C:8]=2[O:12][CH2:13][CH2:14][CH3:15])[N:3]1[C:25](=[O:27])[CH3:26].I[C:29]1[N:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+].O1CCOCC1.O>[C:25]([N:3]1[C:4]2[C:9](=[C:8]([O:12][CH2:13][CH2:14][CH3:15])[C:7]([C:29]3[N:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])=[CH:31][CH:30]=3)=[CH:6][CH:5]=2)[CH2:10][CH2:11][C@@H:2]1[CH3:1])(=[O:27])[CH3:26]
Reactant: CCCOc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1CC[C@H](C)N2C(C)=O
Reactant: CS(=O)(=O)Nc1ccc(I)nc1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: C1COCCO1
Solvent: O
Product: CCCOc1c(-c2ccc(NS(C)(=O)=O)cn2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 100 °C
Yield: 11.4 %

Procedure:
A mixture of (S)-1-(2-methyl-5-propoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.055 g, 0.147 mmol), N-(6-iodopyridin-3-yl)methanesulfonamide (0.046 g, 0.155 mmol), XPhos Precatalyst 2nd Generation (0.012 g, 0.015 mmol), and cesium carbonate (0.144 g, 0.442 mmol) in 1,4-dioxane (2.0 mL) and water (0.40 mL) was heated in the microwave at 100° C. for 1.5 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 25-100% ethyl acetate-hexane) to afford (S)—N-(6-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)methanesulfonamide (0.007 g, 11%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ ppm 0.79-0.85 (m, 3H), 1.08 (d, J=6.45 Hz, 3H), 1.17-1.55 (m, 3H), 2.12 (s, 3H), 2.20-2.41 (m, 2H), 2.82-3.01 (m, 1H), 3.04 (s, 3H), 3.28-3.59 (m, 2H), 4.76 (br s, 1H), 6.64-6.86 (m, 1H), 6.98 (br s, 1H), 7.52 (d, J=8.21 Hz, 1H), 7.68 (dd, J=8.79, 2.64 Hz, 1H), 7.87 (d, J=8.50 Hz, 1H), 8.47 (d, J=2.64 Hz, 1H). MS (ESI, pos. ion) m/z 418 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:29])=[C:10]([CH3:28])[C:11]=2[C:12]([C:14]2[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17]([O:23]C)=[C:16]([CH:25]([CH3:27])[CH3:26])[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:29])=[C:10]([CH3:28])[C:11]=2[C:12]([C:14]2[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17]([OH:23])=[C:16]([CH:25]([CH3:26])[CH3:27])[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccc(Br)cc3)oc(C)c2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1oc(Cc2ccc(Br)cc2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Yield: 87.9 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using [2-(4-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-methoxy-phenyl)-methanone (1.61 g, 3.32 mmol) and 1M boron tribromide/CH2Cl2 (6.97 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 1.37 g (88%) of the title compound. 1H NMR (DMSO-d6) δ1.12 (d, 12H), 1.78 (s, 3H), 2.17 (s, 3H), 3.30 (septet, 2H), 3.81 (s, 2H), 7.01 (dd, 2H), 7.40 (s, 2H), 7.42 (d, 2H), 9.10 (s, 1H). IR (KBr) 3400, 2950, 1640, 1580 and 1310 cm−1. mass spectrum (EI) m/z 468 (M+). Anal. Calcd. for C26H29BrO3: C, 66.53; H, 6.23; N, 0.00. Found: C, 66.57; H, 6.39; N, 0.05.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([CH2:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=3[F:36])[CH:20]=2)=[N:15][CH:14]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[N:38]([CH:41]([CH3:43])[CH3:42])=[C:39]=[O:40].CC(=O)OCC.CCCCCC>CO.CC(=O)OCC>[C:1]([O:5][C:6](=[O:37])[N:7]([CH2:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:39]([NH:38][CH:41]([CH3:43])[CH3:42])=[O:40])=[CH:31][C:30]=3[F:36])[CH:20]=2)=[N:15][CH:14]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N=C=O
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(C)C)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 64.6 %

Procedure:
The reaction mixture of aniline 46 (200 mg, 0.379 mmol) and 2-isocyanatopropane (64.5 mg, 0.758 mmol) was heated to 100° C. for 15 min in a microwave reactor. The reaction mixture was loaded directly into Biotage (Silicycle, HR, 12 g column, 50-100% EA/Hexane, then MeOH/EA, 0-20%). The collected fractions afforded the desired product 314 (150 mg, 0.245 mmol, 64.6% yield) as a white solid. MS: 613(MH)+, very weak signal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[CH3:11][N:12]([CH3:18])[CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:15]1[CH2:16][CH2:17][CH:13]([N:12]([CH3:18])[CH3:11])[CH2:14]1)[C:5]#[N:6]
Reactant: CN(C)C1CCNC1
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2ccc(C#N)cc2Cl)C1

Procedure:
0.75 g (4.82 mmol) 3-chloro-4-fluoro-benzonitrile together with 0.65 ml (0.58 g, 5.06 mmol) 3-dimethylamino-pyrrolidine in 12 ml DMF are combined with 231 mg (5.30 mmol) 55% sodium hydride dispersion at ambient temperature with stirring and under an argon atmosphere. After stirring at ambient temperature for 3.5 h the reaction mixture is poured into water and extracted with ethyl acetate after thorough mixing. The combined organic phases are washed with sat. sodium chloride solution, dried over magnesium sulphate and evaporated down completely i. vac.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[C:9]([CH:17]3[CH2:19][CH2:18]3)[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][C:6]=2[O:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][CH2:35][CH2:36][S:37]([NH2:40])(=[O:39])=[O:38].[I-].[Na+]>CS(C)=O.C(OCC)(=O)C>[C:1]([C:3]1[C:7]2[CH:8]=[C:9]([CH:17]3[CH2:18][CH2:19]3)[C:10]([N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:34][CH2:35][CH2:36][S:37]([NH2:40])(=[O:39])=[O:38])=[CH:11][C:6]=2[O:5][C:4]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)#[N:2]
Reactant: NS(=O)(=O)CCCCl
Reactant: CS(=O)(=O)Nc1cc2oc(-c3ccc(F)cc3)c(C#N)c2cc1C1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(CCCS(N)(=O)=O)c1cc2oc(-c3ccc(F)cc3)c(C#N)c2cc1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
A solution of Example 11A (0.150 g, 0.405 mmol) in dry dimethyl sulfoxide (1.3 mL) under a nitrogen atmosphere was treated with potassium carbonate (0.090 g, 0.648 mmol), and the bright yellow mixture was stirred at room temperature for 30 minutes. Then 3-chloropropane-1-sulfonamide (0.096 g, 0.607 mmol) and sodium iodide (0.091 g, 0.607 mmol) were added, and the resultant mixture was heated at 50° C. for 22 hours. Additional potassium carbonate (0.090 g, 0.648 mmol), 3-chloropropane-1-sulfonamide (0.096 g, 0.607 mmol) and sodium iodide (0.091 g, 0.607 mmol) were added and stirring was continued at 50° C. for 23 hours. The reaction was incomplete by LCMS, so additional potassium carbonate (0.090 g, 0.648 mmol), 3-chloropropane-1-sulfonamide (0.096 g, 0.607 mmol) and sodium iodide (0.091 g, 0.607 mmol) were added followed by continued stirring at 50° C. for 22 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with water (3×25 mL) and brine (10 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel flash chromatography (10 g) eluting with 3% methanol/dichloromethane followed by trituration with diethyl ether (3×5 mL) afforded the title compound as white solid (0.128 g, 64%). MS (ESI+) m/z 509 (M+NH4)+, (ESI−) m/z 490 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[C:22](OC(=O)C)(=O)[CH3:23].C(=O)([O-])[O-].[K+].[K+].[CH3:35][S:36]([OH:39])(=[O:38])=[O:37]>O.CC(C)=O>[CH3:35][S:36]([OH:39])(=[O:38])=[O:37].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)C(=C1CCNCC1)c1ccccc1O2
Reactant: CC(=O)OC(C)=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCN1CCC(=C2c3ccccc3Oc3ccc(Cl)cc32)CC1
Reaction time: 1 h

Procedure:
A solution of 4-(2-chloro-9-xanthenylidene)piperidine (2.0 g., 6.75 mmol) in 5 ml. of acetic anhydride is heated on a steam bath for 2.5 hours. Acetone (30 ml.) and 50 ml. and 20% aqueous potassium carbonate is added to the cooled solution and the mixture stirred for one hour. Additional water is added and the mixture is extracted with ether. The extract is washed with 1N hydrochloric acid, water and dried. The solvent is evaporated to give the crude amide, 2.2 g. (recrystallized amide m.p. 165°-166° C.). The amide is dissolved in 500 ml. of ether and added to a stirred suspension of 2.0 g. of lithium aluminum hydride in 200 ml. of ether. After two hours at 23° C. excess hydride is decomposed with water (4 ml.) and 10% sodium hydrixode (3.2 ml.). The mixture is filtered and the filtrate is evaporated. The residue is dissolved in a mixture of methanol and ether and treated with one equivalent of methanesulfonic acid. The precipitated salt is filtered and recrystallized from methanol/ether to give 4-(2-chloro-9-xanthenylidene)-1-ethylpiperidine methanesulfonate, m.p. 249°-252° C.