Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]([OH:18])=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([O:3][CH3:4])=[O:2].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]([O:18][C:19](=[O:21])[CH3:20])=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ncc(O)c2c1[nH]c1ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ncc(OC(C)=O)c2c1[nH]c1ccccc12
Reaction time: 8 h

Procedure:
Four grams of 1-carbomethoxy-4-hydroxy-9H-pyrido[3,4-b]-indole were dissolved in a mixture of 20 ml pyridine and 24 ml acetic anhydride and the solution was allowed to stand at room temperature overnight. The resultant crystals were collected by filtration and recrystallized from methanol to yield 2.9 g of the title compound. Yield 61.8% colorless prisms, m.p. 220°-221° C. Elemental analysis--found: C, 63.23%; H, 3.94%, N, 9.59%; calculated for C15H12N2O4 (mol. wt. 284): C, 63.38%; H, 4.26%; N, 9.86%. Mol. wt. (based on mass spectrum) 284. NMR (DMSO-d6): δ2.62 ppm, 3H (COCH3), 4.07 ppm, 3H (COOCH3), 8.37 ppm, 1H (3-H), 7.20-8.20 ppm, 4H, 11.85 ppm; 1H (NH). UV spectrum (methanol): 360, 300, 264, 243, 212 mμ. IR spectrum: 3380, 1760, 1675, 1242, 1222 cm-1.
Reaction SMILES: [Br-].[Br:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH:39]=O>C1COCC1>[Br:2]/[CH:3]=[CH:39]\[C:30]1[CH:31]=[CH:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:29]=1
Reactant: O=Cc1ccc2ccccc2n1
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: Br/C=C\c1ccc2ccccc2n1
Temperature: -70 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A suspension of 24.97 g (57.3 mmol) of (bromomethyl)triphenylphosphonium bromide in 160 mL of THF was chilled to −70° C. under argon. Then, 6.43 g (57.3 mmol) of potassium tert-butoxide were added portionwise and the suspension was allowed to stir at this temperature for 1 h. A solution of 7.5 g of (47.7 mmol) quinoline-2-carbaldehyde in 40 mL of THF was slowly added dropwise. The mixture was allowed to stir at −75° C. for further 5 hours and then warmed to room temperature overnight. 160 mL of PE were added. The precipitate formed was sucked off. The mother liquid was evaporated and the residue was stirred with diisopropyl ether. The residue formed was sucked off. Purification by chromatography (heptane/EA 3/1) yielded 6.6 g (59.1%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][C:13]3=[O:20])=[CH:8]2)=[N:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:19][CH2:18][C:15]1[CH:16]=[CH:17][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=3)[CH:8]=2)[C:13](=[O:20])[CH:14]=1)(=[O:31])=[O:30]
Reactant: Cc1c2cc(-n3ccc(CO)cc3=O)ccc2nn1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c2cc(-n3ccc(COS(C)(=O)=O)cc3=O)ccc2nn1C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-(hydroxymethyl)pyridin-2(1H)-one (100 mg) in dichloromethane (5 ml) was added triethylamine (0.153 ml) at 0° C., and the mixture was stirred at the same temperature for 30 min. To the obtained reaction mixture was added methanesulfonyl chloride (0.057 ml) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[C:21]([CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[N:20][C:19]4[CH:31]=[CH:32][CH:33]=[N:34][C:18]3=4)[CH:14]=[CH:15][CH:16]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:43])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[C:21]([CH2:24][C:25]4[CH:26]=[N+:27]([O-:43])[CH:28]=[CH:29][CH:30]=4)=[N:20][C:19]4[CH:31]=[CH:32][CH:33]=[N:34][C:18]3=4)[CH:14]=[CH:15][CH:16]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=c1c(Cc2cccnc2)nc2cccnc2n1-c1cccc(/C=C/c2cc(Cl)cc(Cl)c2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c(Cc2ccc[n+]([O-])c2)nc2cccnc2n1-c1cccc(/C=C/c2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a solution of 4-[3-[(E)-2-(3,5-dichlorophenyl)vinyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (255 mg) in dichloromethane (10 ml) was added m-chloroperbenzoic acid (181 mg). The mixture was stirred at room temperature for 1 hour, then poured into aqueous sodium bicarbonate and extracted with chloroform. The organic solution was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was washed with diisopropyl ether to give 4-[3-[(E)-2-(3,5-dichlorophenyl) vinyl]phenyl]-2-[(1-oxido-3-pyridyl)methyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (167 mg).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][O:31][C:30]2[CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=[CH:37][C:29]1=2>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38]([C:35]5[CH:36]=[CH:37][C:29]6[O:28][CH2:33][CH2:32][O:31][C:30]=6[CH:34]=5)=[O:39])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)c1ccc2c(c1)OCCO2

Procedure:
The title compound, white solid (19 mg, 47.2%), MS (ISP) m/z=494.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:36]=2)O1>>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][N:35]1[CH:36]=[C:32]([C:2]2[CH:23]=[CH:22][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:33]=[N:34]1)[CH3:42]
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CCOC(=O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)cn1

Procedure:
Similarly to as described in General Procedure C, 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 27 was reacted with ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate to give {4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-acetic acid ethyl ester as a colorless solid. LCMS: 466.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:23]=1[O:24][CH2:25][C:26]#[N:27].[Br:33]N1C(=O)CCC1=O>C1COCC1>[Br:33][CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:23]=1[O:24][CH2:25][C:26]#[N:27]
Reactant: Cc1cccc(CO)c1OCC#N
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(CBr)c1OCC#N
Temperature: 0 °C

Procedure:
Triphenylphosphine (15.2 g, 57.8 mmoles) is added to (2-Hydroxymethyl-6-methyl-phenoxy)-acetonitrile (9.3 g, 52.5 mmoles) in THF (175 mL). The mixture is stirred until homogeneous and cooled to 0° C., followed by addition, in three portions, of N-bromosuccinimide (10.3 g, 57.8 mmoles). After 90 minutes the reaction is concentrated and the residue purified by column chromatography (silica, 5:1 hex:EtOAc) to yield the title compound as a pale yellow crystalline solid. MS (EI) 239, 241 (M)+, Br pattern.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([OH:15])[CH:14]=1)OCCC)#[N:2].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][NH2:25]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([OH:15])[CH:14]=1)=[N:25][CH2:24][CH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[Cl:16])#[N:2]
Reactant: NCCc1ccccc1Cl
Reactant: CCCOC(=NC#N)c1cncc(O)c1
Solvent: CO
Product: N#CNC(=NCCc1ccccc1Cl)c1cncc(O)c1
Reaction time: 4 h
Yield: 41.8 %

Procedure:
To a solution of propyl N-cyano-5-hydroxy-3-pyridinecarboximidate (0.26 g) in methanol (5 ml) was added 2-(2-chlorophenyl)ethylamine (0.22 g, 1.4 mmol), and the mixture was stirred for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with chloroform (50 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 30 g; eluted with chloroform:methanol=50:1) and further crystallized from diethyl ether to give the title compound (0.16 g, 0.53 mmol) as colorless crystals. (Yield starting from 3-cyano-5-hydroxypyridine 15%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27](OC)[O:28]C)[CH:8]=[C:9]2[C:17]=1[C:16](=[O:18])[C:15]1([O:20][C:21](=[O:23])[CH3:22])[O:19][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2C(=O)C)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)(Cl)Cl>CC(C)=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[O:28])[CH:8]=[C:9]2[C:17]=1[C:16](=[O:18])[C:15]1([O:20][C:21](=[O:23])[CH3:22])[O:19][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2]
Reactant: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3C(N3C(C)=O)C(OC(C)=O)(O1)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc(C=O)cc2c1C(=O)C1(OC(C)=O)ON2CC2NC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
To a solution of A-isomer of 11-acetyl-4-dimethoxymethyl-8-oxo-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (6 mg) in acetone (0.5 ml) was added p-toluene sulfonic acid (1 mg). The mixture was stirred for 1 hour at ambient temperature, and then subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and acetone (5:1, v/v) to afford A-isomer of 4-formyl-8-oxo-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (1 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:31])[C@H:22]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[NH2:23]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:23][C@@H:22]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:21]([O:20][CH3:19])=[O:31])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)CCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](CCCCN(C)C)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and Nε,Nε-dimethyl-L-lysine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=123-126° C.). The reaction was monitored by tlc (Rf=0.22 in 10% MeOH/DCM+1% TEA) and the product was purified by silica gel column chromatography.
Reaction SMILES: [OH-].[K+].[N:3]1([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[C:17]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=4)=[N:18][C:19]4[C:24]([C:25]=3[C:26]([O:28]C)=[O:27])=[CH:23][C:22]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])=[C:21]([O:35][CH3:36])[CH:20]=4)[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[K]>CO.O>[N:3]1([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[C:17]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:46])[F:45])[CH:38]=4)=[N:18][C:19]4[C:24]([C:25]=3[C:26]([OH:28])=[O:27])=[CH:23][C:22]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])=[C:21]([O:35][CH3:36])[CH:20]=4)[CH2:13][CH2:14]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCS(=O)(=O)c1cc2c(C(=O)OC)c(CN3CCC(N4CCCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)c1cc2c(C(=O)O)c(CN3CCC(N4CCCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Potassium hydroxide (1.86 g, 33.1 mmol) was added to a solution of methyl 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.1 g, 3.31 mmol) in methanol (60 mL) and water (20 mL). The mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and diluted with water. The methanol was removed in vacuo. The solid precipitate was collected by filtration, washed with cold water, and air dried to afford 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.0 g, 92% yield) as the potassium salt. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.11 (s, 1H), 7.91 (d, J=7.78 Hz, 1H), 7.79 (d, J=7.78 Hz, 1H), 7.67 (t, J=7.78 Hz, 1H), 7.55 (s, 1H), 4.04 (s, 3H), 3.42-3.52 (m, 4H), 2.33 (br. s., 4H), 2.03 (t, J=11.80 Hz, 1H), 1.82 (t, J=11.29 Hz, 2H), 1.39-1.48 (m, 6H), 1.30-1.39 (m, 2H), 1.12 (t, J=7.40 Hz, 3H), 0.97-1.09 (m, 2H); MS (m/z) 620.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12]O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11].N1C=CC=CC=1.S(Cl)([Cl:22])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][Cl:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: O=S(Cl)Cl
Reactant: COCOc1ccc(CO)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCOc1ccc(CCl)cc1Br
Reaction time: 1 h

Procedure:
(3-Bromo-4-methoxymethoxy-phenyl)-methanol (250 mg) was dissolved in DCM (20 mL), pyridine (0.15 mL) was added followed by thionyl chloride (0.15 mL), and the mixture was stirred for 1 hour. The mixture was partitioned with water and ethyl acetate. The solvent removal gave 2-bromo-4-chloromethyl-1-methoxymethoxy-benzene as a clear oil, which was used directly in next step. The oil was dissolved in acetone, and sodium iodide (300 mg) was added. The mixture was stirred overnight and a yellow precipitate was formed. Extraction with ethyl acetate and water gave 2-iodo-4-chloromethyl-1-methoxymethoxy-benzene as a brown oil that turned into solid after standing. 1HNMR (CDCl3, 300 MHz): 7.58 (d, J=2.0 Hz, 1H), 7.25 (dd, J=2.0, 8.5 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 5.25 (s, 2H), 4.39(s, 2H), 3.51 (s, 3H) ppm. The iodide (170 mg) and trimethylphosphate (0.1 mL) were mixed and stirred at 120° C. for 1 hour. After cooling to room temperature, the reaction mixture was directly applied to silica gel column eluting with 5% MeOH in DCM to yield 150 mg of the corresponding phosphonate.
Reaction SMILES: [C:1]([C:5]1[CH:53]=[CH:52][C:8]2[NH:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:20][C@@H:21]3[C@H:25]4[O:26]C(C)(C)[O:28][C@H:24]4[C@H:23]([N:31]4[C:35]5[N:36]=[CH:37][N:38]=[C:39]([NH:40]CC6C=CC(OC)=CC=6OC)[C:34]=5[CH:33]=[CH:32]4)[O:22]3)[CH:17]([CH3:19])[CH3:18])=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(O)=O.O>[NH2:40][C:39]1[C:34]2[CH:33]=[CH:32][N:31]([C@H:23]3[C@H:24]([OH:28])[C@H:25]([OH:26])[C@@H:21]([CH2:20][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][C:10]4[NH:9][C:8]5[CH:52]=[CH:53][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][C:7]=5[N:11]=4)[CH:17]([CH3:19])[CH3:18])[O:22]3)[C:35]=2[N:36]=[CH:37][N:38]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCCc3nc4cc(C(C)(C)C)ccc4[nH]3)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)N(CCCCc1nc2cc(C(C)(C)C)ccc2[nH]1)C[C@H]1O[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
7-((3aR,4R,6R,6aR)-6-(((4-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)butyl)(isopropyl)amino)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (120 mg, 0.16 mmol) was dissolved in a mixture of trifluoroacetic acid (5.0 mL) and water (0.5 mL) which had been precooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, and then warmed to room temperature. After 4.5 h at room temperature, the reaction was found to be complete by HPLC and the now pink reaction mixture was concentrated. The residue was taken up in 10 mL MeOH and concentrated. This procedure was repeated twice and the residue placed on high vac for 1 h. The material was taken up in 6 mL MeOH and was treated with 100 mg K2CO3 and five drops of water. The mixture was stirred for 30 minutes during which time the mixture was found to be basic. The mixture was filtered through a fine frit, the solids were washed with 10 mL MeOH and the filtrate was concentrated to yield a nearly colorless solid. The crude material was purified by flash chromatography (20 g silica gel; 8% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (60 mg, 68%) as a colorless glass: MS (ESI+) for C29H41N7O3 m/z 536.5 (M+H)+; MS (ESI−) for C27H41N7O3 m/z 534.5 (M−H)−; HPLC purity>95% (ret. time, 2.53 min); 1H NMR (400 MHz, d4-MeOH) δ 8.07 (s, 1H), 7.48 (br. s., 1H), 7.38 (d, J=8.50 Hz, 1H), 7.27 (dd, J=8.50, 1.87 Hz, 1H), 7.22 (d, J=3.73 Hz, 1H), 6.61 (d, J=3.73 Hz, 1H), 6.11 (d, J=4.77 Hz, 1H), 4.43 (t, J=5.08 Hz, 1H), 4.14 (t, J=5.49 Hz, 1H), 4.04 (m, 1H), 3.00 (m, 1H), 2.83 (m, 3H), 2.67 (dd, J=14.10, 6.84 Hz, 1H), 2.53 (m, 2H), 1.80 (m, 2H), 1.52 (m, 2H), 1.36 (s, 9H), 1.01 (d, J=6.63 Hz, 3H), 0.97 (d, J=6.63 Hz, 3H).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][S:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[ClH:17]>>[Cl:17][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][S:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2
Reactant: Cl
Reactant: OC1c2ccccc2CSc2ccccc21
Product: ClC1c2ccccc2CSc2ccccc21
Reaction time: 72 h

Procedure:
A solution of 33 g of 11-hydroxy-6,11-dihydrodibenz[b,e]thiepin in 400 ml of absolute alcohol is saturated with hydrogen chloride gas at 5° C. for 1/2 hour. The resulting solution is dried with CaCl2, filtered and concentrated in vacuo to an oil which crystallizes upon standing in a refrigerator (10° C.) after 3 days. Recrystallization from cyclohexane provides 27 g of 11-chloro-6,11-dihydrodibenz[b,e]thiepin m.p. 79°-82° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2[nH]cnc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Brc1cccc2c1ncn2C1CCCCO1
Yield: 81.3 %

Procedure:
A mixture of 4-bromo-1H-benzo[d]imidazole (1.5 g, 7 mmol), TsOH.H2O (0.1 g, 0.7 mmol), and 3,4-dihydro-2H-pyran (2.9 g, 35 mmol) in THF (10 mL) was heated at reflux overnight. The reaction mixture was concentrated in vacuo. To the residue was added water and the mixture was extracted with EtOAc. The combined extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography using a petroleum ether/EtOAc gradient (10:1 to 3:1) to afford 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole as a gray solid (1.6 g, 75%). MS (ESI): m/z=281 [M+1]+.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Cl[CH2:53][CH2:54][O:55][CH:56]1[CH2:58][CH2:57]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:53][CH2:54][O:55][CH:56]3[CH2:58][CH2:57]3)[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Reactant: ClCCOC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCOC2CC2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]-amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.1 M) was added (2-chloroethoxy)cyclopropane (3 eq.) and cesium carbonate (2 eq.). The reaction was heated to 100° C. and stirred for 3 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 35% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C[Al](C)C.[O:10]1[CH:14]=[C:13]([C:15]([O:17]C)=O)[N:12]=[CH:11]1.Cl.C(Cl)Cl>ClC(Cl)C>[O:10]1[CH:14]=[C:13]([C:15]([N:4]([CH3:5])[O:3][CH3:2])=[O:17])[N:12]=[CH:11]1
Reactant: COC(=O)c1cocn1
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1cocn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81.1 %

Procedure:
To a suspension of methoxy-methylamine hydrochloride (2.3 g, 23.6 mmol) in 30 ml of dichloroethane at 0° C. was added dropwise 11.8 ml (23.6 mmol) of trimethylaluminum. The mixture was stirred at 0° C. for 20 min, methyl 4-oxazolecarboxylate (1 g, 7.9 mmol) in 20 ml of dichloroethane was added in one portion. The mixture was poured into an ice-cold solution of 0.5N HCl/methylene chloride (2:1) and stirred for 10 min. The aqueous layer was extracted with methylene chloride (2×50 ml), and the combined organic layer was washed with saturated ammonium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by chromatography on silica (methylene chloride/ethyl acetate/methanol 6:3:1) to afford 1.0 g (81.9%) of 4-oxazolyl-N-methyl-N-methoxy-carboxamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:18](OC)=[O:19])=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:17]2[NH:16][CH:15]=[CH:14][C:13]=2[C:12]([CH2:18][OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)c2[nH]ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(OCc2ccccc2)c2[nH]ccc12
Temperature: 50 °C

Procedure:
A solution of 7-benzyloxy-4-(methoxycarbonyl)indole (Example 4a) (2.08 g, 7.4 mmol) was added to a stirred suspension of lithium aluminium hydride (0.38 g, 10 mmol) in tetrahydrofuran (15 ml). The mixture was heated at 50° C. for 1 hour, poured onto ice-hydrochloric acid and extracted with dichloromethane. The extract was dried and evaporated and the residue was chromatographed on silica in ethyl acetate-hexane (1:2 then 1:1) to give a pale oil.