Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[C:6]([C:10]1[C:15]2[CH:16]=[CH:17][O:18][C:14]=2[CH:13]=[CH:12][C:11]=1[OH:19])([CH3:9])([CH3:8])[CH3:7].[C:20](O)([CH3:23])([CH3:22])[CH3:21].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:20]([C:17]1[O:18][C:14]2[CH:13]=[C:12]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:11]([OH:19])=[C:10]([C:6]([CH3:9])([CH3:7])[CH3:8])[C:15]=2[CH:16]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1c(O)ccc2occc12
Reactant: CC(C)(C)O
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc2c(C(C)(C)C)c(O)c(C(C)(C)C)cc2o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 39.9 %

Procedure:
Methanesulfonic acid (140 ml) was added dropwise, under ice cooling, to a solution consisting of 4-tert-butyl-5-hydroxybenzofuran [J. Org. Chem., 53, 4135 (1988 ); 35 g, 0.18 mol], tert-butyl alcohol (70 g, 0.84 mol) and chloroform (50 ml). After stirring at 0° C. for 20 min, the mixture was poured into ice water. Subsequently, the mixture was neutralized with an aqueous solution of N sodium hydroxide and subjected to extraction with ethyl acetate. The extracted layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel chromatography (n-hexane) to afford 2,4,6-tri-tert-butyl-5-hydroxybenzofuran [10.87 g (yield, 20%)]. Also obtained, though in low yield, was 4,6-di-tert-butyl-5-hydroxybenzofuran.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][CH2:5][NH:6][C:7](=[O:40])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[C:16]([NH:18][C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH3:20])=[O:17])=[CH:10][CH:9]=1.[OH-].[Na+].Cl>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@@H:19]([NH:18][C:16](=[O:17])[N:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:41])=[O:2])=[O:40])=[CH:13][CH:12]=2)[C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)=[CH:30][CH:29]=2)[CH3:20])=[CH:22][CH:23]=1
Reactant: COC(=O)CCNC(=O)c1ccc(CN(C(=O)N[C@@H](C)c2ccc(Cl)cc2)c2ccc(C3CCCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(=O)N(Cc1ccc(C(=O)NCCC(=O)O)cc1)c1ccc(C2CCCCC2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-{4-[3-[1(S)-(4-Chlorophenyl)ethyl]1-(4-cyclohexylphenyl)ureidomethyl]benzoyl-amino}propionic acid methyl ester (1.1 g, 1.9 mmol) was dissolved in methanol (10 ml) and 1N aqueous sodium hydroxide (5.7 ml) was added. The reaction mixture was stirred at room temperature for 2 hours. Then 1N hydrochloric acid was added and the solvent was removed by rotary evaporation in vacuo. The residue was re-dissolved in ethyl acetate and diethyl ether and crystallised using sonication. Concentration in vacuo followed by re-suspension in a aqueous hydrochloric acid and sinication for 30 min afforded after filtration, washing with water and drying in vacuo 0.55 g (51%) of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1(C)C=CC=CC=1>[CH:20]1([CH2:26][CH2:27][CH2:28][CH2:29][N:30]2[C@@H:7]3[C@@H:8]([C:9]4[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=4[CH2:5][CH2:6]3)[CH2:13][C:14]2=[O:16])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCCCc1ccccc1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCCCC1CCCCC1
Reaction time: 10 h
Yield: 82.5 %

Procedure:
5.0 g (0.0191 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 100 ml of toluene, 3.0 ml (0.0191 mol) of 4-phenyl-butylamine were added thereto and the mixture was boiled for 16 hours on a water separator. After concentration the residue was hydrogenated with 2.0 g of Raney-nickel in 200 ml of ethanol at 120° and 140 bar for 10 hours. The product was chromatographed over silica gel with n-hexane/ethyl acetate 3:1. There were obtained 5.60 g (82.5%) of oily rac-cis-3-(4-cyclohexyl-butyl)-1,3,3a,4,5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[CH2:31]([NH2:33])[CH3:32]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][CH2:2][NH:33][CH2:31][CH3:32])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: ClCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CCN
Product: CCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12

Procedure:
5-(2-Chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (0.400 g) and ethylamine (1.2 g) were heated at 50° C. overnight and then the solution purified by chromatography using DCM to 10% 7N ammonia in methanol in DCM to give N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(ethylamino)ethoxy]quinazolin-4-amine; Mass spectrum MH+ 450.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][O:12][CH3:13])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>O1CCCC1.O>[OH:4][C@@H:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C@H:2]([NH:1][CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])[CH2:11][O:12][CH3:13]
Reactant: COC[C@H](N)[C@@H](O)c1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@H](NCCCS(=O)(=O)O)[C@@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of (1S,2S)-2-amino-3-methoxy-1-phenyl-1-propanol (1.0 g, 5.5 mmol) in tetrahydrofuran (10 mL) was slowly added 1,3-propane sultone (662 mg, 5.3 mmol). The mixture was stirred at reflux for 2.5 h. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL). The crude product was suspended 80% Acetone/EtOH. The suspension was stirred at reflux for 30 seconds. The solid product was collected by filtration and dried in a vacuum oven (50° C.), to afford compound EG (1.0 g, 63%). 1H NMR (D2O, 500 MHz) δ ppm 7.32 (m, 5H), 4.77 (d, 1H, J=9.8 Hz), 3.53 (m, 1H), 3.37 (m, 1H). 3.26 (m, 1H), 3.17 (m, 6H), 2.91 (t, 2H, J=7.3 Hz), 2.07 (m, 2H). 13C NMR (D2O, 125 MHz) δ ppm 139.09, 129.33, 129.27, 127.11, 70.85, 66.29, 62.62, 58.76, 48.14, 44.24, 21.47. [α]D=+42.6° (c=0.00091 in water), ES-MS 302 (M−1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1([C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOC(C)=O.C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:16]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Oc1cccc(-c2ccccc2)c1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Clc1cncc(Oc2cccc(-c3ccccc3)c2)n1
Yield: 98 %

Procedure:
Using Method DD (reaction time: 20 hours) with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 3-phenyl-phenol (268 mg, 1.49 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:2), the title compound was obtained (370 mg). Yield: 98%. 1H NMR (250 MHz, DMSO-d6) δ 7.35-7.72 (m, 9H, Harom), 8.53 (s, 1H, HPz 5), 8.59 (s, 1H, HPz 3). m/z: 283.1 [(M+H)+, calcd for C16H11ClN2O 282.1].
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14](C3CCN(C(OC(C)(C)C)=O)CC=3)=[CH:13][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].F[C:31](F)(F)[C:32](O)=O>C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>[N:4]1([C:14]2[CH:13]=[CH:12][C:11]([C:8]3[CH2:7][CH:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][N:9]=3)=[CH:16][CH:15]=2)[CH2:32][CH:31]=[CH:7][CH2:6][CH2:5]1
Reactant: CC(=O)NCC1CC(c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2)=NO1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)NCC1CC(c2ccc(N3CC=CCC3)cc2)=NO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a flame dried flask containing tert-Butyl 4-[4-[5-[(acetylamino)methyl]-4,5-dihydro-3-isoxazolyl]phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate (270 mg, 0.68 mmol) in methylene chloride (15 mL) at 0° C. is added trifluoroacetic acid (1.04 mL, 13.52 mmol). The reaction is stirred 1 hour at 0° C. and 2 hours at ambient temperature. The reaction is poured over a slurry of ice in saturated potassium carbonate (15 mL). The resulting aqueous phase is extracted with methylene chloride (5×25 mL). The extracts are dried over sodium sulfate concentrated in vacuo to give the title compound, MS (ESI+) for C17H21N3O2 m/z 300.2 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH2:6][CH2:5]1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][N:31]2[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]2)[CH2:5][CH2:6]1)=[O:26]
Reactant: OC1CCNCC1
Reactant: O=C(Nc1cc(Cl)ccc1N1CCC(CCBr)CC1)c1cccc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(Cl)ccc1N1CCC(CCN2CCC(O)CC2)CC1)c1cccc(Cl)c1
Temperature: 175 °C
Yield: 54.9 %

Procedure:
A mixture of 0.040 g (0.088 mmol) of N-{2-[4-(2-bromo-ethyl)-piperidin-1-yl]-5-chloro-phenyl}-3-chloro-benzamide, 0.044 g (0.44 mmol) of 4-hydoxypiperidine, and 0.50 mL (2.9 mmol) of N,N-diisopropylethylamine in acetonitrile (1 mL) is heated to 175° C. in a microwave reactor for 30 minutes. The mixture is cooled to room temperature and purified by preparative reverse phase HPLC to provide 0.023 g (55%) of the title compound (100) as a colorless solid. [M+H]+=476.3.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2(O)[C:10]3[C:11]([CH3:31])=[C:12]([N:17]4[CH2:22][CH2:21][N:20]([C:23]5[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=5)[CH2:19][CH2:18]4)[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]=3[O:8][C:7]2([CH3:33])[CH3:32])=[CH:2]1>CO>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[C:10]3[C:11]([CH3:31])=[C:12]([N:17]4[CH2:18][CH2:19][N:20]([C:23]5[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=5)[CH2:21][CH2:22]4)[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]=3[O:8][C:7]2([CH3:33])[CH3:32])=[CH:2]1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccoc3)C(C)(C)O4)CC2)cc1
Solvent: CO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(c3ccoc3)C(C)(C)O4)CC2)cc1
Yield: 72 %

Procedure:
Using 1-(3-(3-furyl)-3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine obtained in Example 37, the title compound was synthesized in the same manner as in Example 46. Yield 72%. mp. 110–113° C. (methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:11])[C:12]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:18][C:19]=2[CH2:20][CH3:21])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C(Cc1cc(F)cc(F)c1)c1ccccc1O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccccc2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
Intermediate 70 (2.0 g, 8.08 mmoles) was taken in a RB flask and to this triethylamine (20 ml) and propionic anhydride (3.26 g, 25.2 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-colourless liquid (1.65 g, 72% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.05(dd, J=7.9,1.2Hz, 1H), 7.8 (dt, J=8.5,1.4Hz, 1H), 7.68(d, J=8.4Hz, 1H), 7.51(t, J=7.8Hz, 1H), 7.30(tt, J=7.2,2.2Hz, 1H), 7.07(d, J=6.1Hz, 2H), 2.58(q, J=7.5Hz, 1H), 1.21(t, J=7.6Hz, 3H).
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([CH2:32][O:33][C:34]2[C:42]([CH:43]3[CH2:45][CH2:44]3)=[CH:41][C:37]([C:38]([OH:40])=O)=[C:36]([F:46])[CH:35]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CS(N)(=O)=O.[N:52]1([S:56]([NH2:59])(=[O:58])=[O:57])[CH2:55][CH2:54][CH2:53]1>>[N:52]1([S:56]([NH:59][C:38](=[O:40])[C:37]2[CH:41]=[C:42]([CH:43]3[CH2:45][CH2:44]3)[C:34]([O:33][CH2:32][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:35][C:36]=2[F:46])(=[O:58])=[O:57])[CH2:55][CH2:54][CH2:53]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in preparation of Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoic acid with 4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained (0.13 g, 47%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.71-8.61 (m, 1H), 7.62-7.55 (m, 1H), 6.62-6.51 (m, 1H), 4.30-4.18 (m, 4H), 3.86-3.76 (m, 2H), 2.34-2.20 (m, 2H), 2.13-2.00 (m, 1H), 1.96-1.67 (m, 6H), 1.41-1.02 (m, 5H), 0.99-0.87 (m, 2H), 0.72-0.61 (m, 2H); MS (ES−) m/z 409.3 (M−1).
Reaction SMILES: [C:1]([C:5]1[CH:40]=[CH:39][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:14]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:13][C@@:12]2([CH2:35][CH:36]([CH3:38])[CH3:37])[C:28]([O:30]C(C)(C)C)=[O:29])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:40]=[CH:39][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:14]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:13][C@@:12]2([CH2:35][CH:36]([CH3:37])[CH3:38])[C:28]([OH:30])=[O:29])=[O:10])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)C[C@@]1(C(=O)OC(C)(C)C)C[C@H](c2cnccn2)[C@H](c2ccccc2)N1C(=O)c1ccc(C(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@]1(C(=O)O)C[C@H](c2cnccn2)[C@H](c2ccccc2)N1C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1, to afford the title compound as a solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCN(C(=O)[C@H](C)O)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f52) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][P:3]([CH3:7])(=[O:6])[O:4][CH3:5].O1CCCC1.C([Li])CCC.[CH3:18][C:19]([CH3:34])([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:20](=[O:26])CP(=O)([O-])[O-]>CCCCCC.C(O)(=O)C>[CH3:18][C:19]([CH3:34])([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:20](=[O:26])[CH2:7][P:3](=[O:6])([O:4][CH3:5])[O:2][CH3:1]
Reactant: CC(C)(Cc1ccccc1)C(=O)CP(=O)([O-])[O-]
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)C(C)(C)Cc1ccccc1)OC

Procedure:
To a solution of 63 g. of dimethylmethylphosphonate in 600 ml. of tetrahydrofuran under nitrogen at -75° C. is added with stirring 312 ml. of 1.6 molar n-butyllithium in hexane. The addition rate is adjusted so that the reaction temperature remains below 55° C. Ten minutes after the addition is complete, 48.2 g. of the reaction product of part B of this example and 50 ml. of tetrahydrofuran are added dropwise at such rate as to maintain the reaction temperature below -60° C. The resulting mixture is then stirred at -75° C. for 2 hr. and then ambient temperature overnight. Acetic acid (20 ml.) is thereafter added and the resulting mixture distilled under vacuum, thereby removing most of the tetrahydrofuran. The residue is then shaken with diethyl ether in methylene chloride (3:1 by volume) and a cold dilute sodium bicarbonate solution. The organic layer is then washed with brine, dried, and concentrated. The residue was crystallized from diethyl ether, yielding 54 g. of dimethyl, 3,3-dimethyl-2-oxo-4-phenylbutylphosphonate, the title compound. The melting point is 48°-50° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-])=O)=[C:4]([F:12])[CH:3]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([F:12])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(F)c(Cl)cc1F

Procedure:
1-Chloro-2,5-difluoro-4-nitrobenzene (XXXVIII) (17.5 g) was dissolved in acetic acid (150 ml) in a 1 L 3-neck round bottom flask equipped with cooling condenser. To it iron powder (35.0 g) was added slowly while the solution was stirred by an overhead stirrer. The reaction was exothermic which occurred in less than 30 min and generated much heat that was absorbed by a cooling bath. After that, ethyl acetate (300 ml) was added and the mixture filtered. The solution was washed with water and dried over sodium sulfate. The product was purified by column chromatography (silica gel, hexane:ethyl acetate, 4:1) (14.3 g). 1H NMR (CDCl3, 300 MHz) 3.89 (2H, br), 6.56 (1H, m), 7.02 (1H, m) ppm.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9](=[O:30])[CH2:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:6]([C:31]([N:33]2[CH2:37][CH2:36][CH2:35][C@@H:34]2[C:38]([NH:40][CH2:41][C@H:42]2[CH2:47][CH2:46][CH2:45][N:44]([CH2:48][CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)[CH2:43]2)=[O:39])=[O:32])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(Cl)(Cl)Cl>[NH2:1][C@@H:4]1[CH2:8][N:7]([C:9](=[O:30])[CH2:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]([C:31]([N:33]2[CH2:37][CH2:36][CH2:35][C@@H:34]2[C:38]([NH:40][CH2:41][C@H:42]2[CH2:47][CH2:46][CH2:45][N:44]([CH2:48][CH:49]3[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]3)[CH2:43]2)=[O:39])=[O:32])[CH2:5]1
Reactant: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: N[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 3 h
Yield: 69.1 %

Procedure:
To a solution of 24 mg of (2R)-1-{(2S,4S)-4-azido-1-(3,3,3-triphenyl-propanoyl)pyrrolidin-2-yl}carbonyl-N-{((3R)-1-cyclohexylmethyl-3-piperidyl)methyl}pyrrolidine-2-carboxamide in 0.5 ml of 20% hydrous tetrahydrofuran, 13 mg of triphenylphosphine was added at room temperature, followed by 3 hours' refluxing under heating. The reaction liquid was diluted with chloroform, washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resultant residue was purified by means of a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=90/10/1) to provide 16 mg of the title compound in the form of a white solid.
Reaction SMILES: COC1C=CC(C2C(C)(C)C3C(CC=2)=CC(OC)=CC=3)=C(N)C=1.BrC1C=CC(OCCN2CCCCC2)=C(F)C=1.[F:41][C:42]1[CH:43]=[C:44]([NH:57][C:58]2[CH:63]=[C:62]([O:64]C)[CH:61]=[CH:60][C:59]=2[C:66]2[C:67](C)(C)[C:68]3[C:73]([CH2:74][CH:75]=2)=[CH:72][C:71]([O:76]C)=[CH:70][CH:69]=3)[CH:45]=[CH:46][C:47]=1[O:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1>>[F:41][C:42]1[CH:43]=[C:44]([NH:57][C:58]2[CH:63]=[C:62]([OH:64])[CH:61]=[CH:60][C:59]=2[C:66]2[CH2:67][C:68]3[CH:69]=[CH:70][C:71]([OH:76])=[CH:72][C:73]=3[CH2:74][CH:75]=2)[CH:45]=[CH:46][C:47]=1[O:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: COc1ccc2c(c1)CC=C(c1ccc(OC)cc1Nc1ccc(OCCN3CCCCC3)c(F)c1)C2(C)C
Agent: COc1ccc(C2=CCc3cc(OC)ccc3C2(C)C)c(N)c1
Agent: Fc1cc(Br)ccc1OCCN1CCCCC1
Product: Oc1ccc2c(c1)CC=C(c1ccc(O)cc1Nc1ccc(OCCN3CCCCC3)c(F)c1)C2
Yield: 77.2 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,1-dimethyl-1,4-dihydronaphthalen-2-yl)phenylamine and 1-[2-(4-bromo-2-fluorophenoxy)ethyl]piperidine according to an analogous synthetic method to Example 116, [3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl][5-methoxy-2-(6-methoxy-1,1-dimethyl-1,4-dihydronaphthalen-2-yl)phenyl]amine (439 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (303 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](=[O:37])[O:29][C:28]=1[CH2:38]O.[Br:40]C(Br)(Br)Br.C(Cl)Cl>CO>[Br:40][CH2:38][C:28]1[O:29][C:30](=[O:37])[C:31]2[C:36]([C:27]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[F:20])=[CH:35][CH:34]=[CH:33][CH:32]=2
Reactant: BrC(Br)(Br)Br
Reactant: O=c1oc(CO)c(-c2ccccc2F)c2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=c1oc(CBr)c(-c2ccccc2F)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
Triphenylphosphine (0.127 g, 0.488 mmol)) was added to a solution of 4-(2-fluorophenyl)-3-(hydroxymethyl)-1H-isochromen-1-one (intermediate B4, 40 mg, 0.148 mmol) and perbromomethane (0.161 g, 0.488 mmol) in DCM (0.7 ml, 57.5 mmol), and the resulting mixture was stirred at RT for 24 hrs. The reaction was taken up with MeOH then concentrated under reduced pressure. The crude was purified over a Biotage Silica 10 g SNAP cartridge with a gradient of hexane and EtOAc to give the title compound (37 mg, 75%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[CH2:25][N:26]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[O:33]=[S:29]1(=[O:32])[CH2:30][CH2:31][N:26]([CH2:25][C:24]2[CH:23]=[C:22]([NH:20][C:18]3[N:19]=[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[N:16]4[N:17]=3)[CH:36]=[CH:35][CH:34]=2)[CH2:27][CH2:28]1
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Reactant: O=S1(=O)CCN(Cc2cccc(Br)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccc3nc(Nc4cccc(CN5CCS(=O)(=O)CC5)c4)nn23)cc1

Procedure:
N-{3-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-5-[4-(methylsulfonyl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(3-bromo-benzyl)-thiomorpholine 1,1-dioxide (90.0 mg, 0.296 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.042 g, 32%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.26 (d, J=8.5 Hz, 2H), 8.14 (d, J=8.5 Hz, 2H), 7.45 (dd, J=8.2, 1.8 Hz, 1H), 7.30 (t, J=7.7 Hz, 1H), 7.07 (t, J=4.3 Hz, 1H), 6.96-6.91 (m, 2H), 3.65 (s, 2H), 3.16 (s, 3H), 3.07-2.97 (m, 8H). MS=512 (MH)+.