Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][CH:5]([CH2:20][CH2:21][N:22]1C(=O)C2=CC=CC=C2C1=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16](O)=[O:17])=[CH:9][CH:8]=1>C(O)C>[NH2:22][CH2:21][CH2:20][CH:5]([CH3:4])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][C:16](=[O:17])[NH:2][N:3]=2)=[CH:9][CH:8]=1
Reactant: CC(CCN1C(=O)c2ccccc2C1=O)Cc1ccc(C(=O)CCC(=O)O)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(CCN)Cc1ccc(C2=NNC(=O)CC2)cc1
Yield: 82 %

Procedure:
9.61 g of hydrazine monohydrate was added to an ethanol solution (500 ml) containing 15.06 g of 4-(2-methyl-4-phthalimidobutyl)-1-(3-hydroxycarbonylpropionyl)benzene, and the mixture was refluxed under heating for 2.5 hours. After cooling, precipitated crystal was collected by filtration and recrystallized from ethyl acetate to obtain 8.14 g of 6-[4-(4-amino-2-methylbutyl)phenyl]-4,5-dihydropyridazin-3 (2H)-one.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.[CH3:34][N:35]([CH2:37][CH2:38]Cl)[CH3:36]>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:38][CH2:37][N:35]([CH3:36])[CH3:34])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC
Reactant: CN(C)CCCl
Product: COc1cc(-c2nc3ccc(OCCN(C)C)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 104 with 2-(N,N-dimethylamino)ethyl chloride essentially as previously described. mp 151° C., NMR, IR, MS 529.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cccc(-c2cnc[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cncc1-c1cccc(Br)c1
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a stirred solution of 5-(3-bromophenyl)-1H-imidazole (1 g, 4.5 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added sodium hydride (60% in mineral oil, 160 mg, 4.7 mmol) at 0° C., and the mixture was stirred at this temperature for 0.5 h. A solution of (2-(chloromethoxy)ethyl)trimethylsilane (0.9 mL, 5.36 mmol) in N,N-dimethylformamide (5 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 4 h. When the starting material was consumed, the reaction was quenched with water. The mixture was extracted with ethyl acetate, and the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified on silica gel column (eluting with 5-10% ethyl acetate in petroleum ether) to give 5-(3-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1.1 mg, 69.6% yield) as a yellow solid. MS (ESI): m/z 353.0 [M+1]+.
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:45][O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:16][S:17][CH2:18][C@@H:19]([C:38]([O:40]C(C)(C)C)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CC(OC)(C)C>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:21]([NH:20][C@@H:19]([CH2:18][S:17][CH2:16][C@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:45][O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[C:38]([OH:40])=[O:39])=[O:37])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCC
Solvent: COC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC

Procedure:
A solution of ((5R,9R)-5-(tert-butoxycarbonyl)-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azatricosan-9-yl dodecanoate in 40% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of tert-butyl group (2 hours). The reaction mixture was diluted in MTBE, washed three times with 1M citric acid (adjusted to pH3), and once with 1:2 1N HCl/brine. The organic layer was dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting waxy solid was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:21]([O:22][CH3:23])=[CH:20][C:6]2[CH:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.C=[O:25].[CH:26]([OH:28])=[O:27]>O.C(=O)([O-])[O-].[Na+].[Na+]>[C:21]([OH:22])(=[O:25])/[CH:20]=[CH:6]\[C:26]([OH:28])=[O:27].[CH3:1][O:2][C:3]1[C:21]([O:22][CH3:23])=[CH:20][C:6]2[CH:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[CH2:8][N:9]([CH3:26])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)C(Oc1ccc(F)cc1)CNCC2
Reactant: O=CO
Reactant: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(cc1OC)C(Oc1ccc(F)cc1)CN(C)CC2
Product: O=C(O)/C=C\C(=O)O
Temperature: 75 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
7,8-Dimethoxy-1-(4-fluorophenoxy)-2,3,4,5-tetrahydro-3-benzazepine (3.5 g, 11 m mole) of Example 42 was dissolved in 9 ml 95% formic acid and to this was added 8 ml 37% formaldehyde solution. The mixture was stirred at 75° C. for one hour, then was cooled, diluted with water and basified with sodium carbonate. The oil which separated was extracted with ether then was washed with water, dried (saturated NaCl, anhydrous MgSO4), filtered and evaporated to an oil. The oil was converted as in Example 42 to the maleate salt (3.7 g, mp 124°-135° C.). This material was recrystallized twice from isopropanol to yield 2.7 g (55%) of 7,8-dimethoxy-1-(4-fluorophenoxy)-3-methyl-2,3,4,5-tetrahydro-3-benzazepine maleate d 152°-153° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].[CH2:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[I:37][C:38]1[CH:39]=[C:40]([CH:56]=[C:57]([C:61]([O:63][CH3:64])=[O:62])[C:58]=1[O:59][CH3:60])[C:41]([C:43]1[CH:48]=[C:47]([C:49]([O:51][CH3:52])=[O:50])[C:46]([O:53][CH3:54])=[C:45]([I:55])[CH:44]=1)=O>C1COCC1>[CH3:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[C:41]([C:43]1[CH:44]=[C:45]([I:55])[C:46]([O:53][CH3:54])=[C:47]([C:49]([O:51][CH3:52])=[O:50])[CH:48]=1)[C:40]1[CH:39]=[C:38]([I:37])[C:58]([O:59][CH3:60])=[C:57]([C:61]([O:63][CH3:64])=[O:62])[CH:56]=1
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(C(=O)c2cc(I)c(OC)c(C(=O)OC)c2)cc(I)c1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC=C(c1cc(I)c(OC)c(C(=O)OC)c1)c1cc(I)c(OC)c(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.8 %

Procedure:
NaN(TMS)2 (1 mL, 1 mmol) was added to an ice cold suspension of hexyltriphenylphosphonium bromide (0.427 g, 1 mmol) in THF (20 mL) and the solution was stirred for 30 min at 0° C. A solution of the benzophenone 39 (0.2 g, 0.33 mmol) in THF (5 mL) was added to the preformed ylide and the solution was stirred at rt overnight. The mixture was partitioned between 1 N HCl (100 mL) and ethyl acetate (100 mL). The organic layer was evaporated and flash chromatographed on SiO2 (230-400 mesh, 50.0 g), eluting with hexanes-ethyl acetate (5:1). The fractions which contained the product were pooled, evaporated, and chromatographed on silica gel (230-400 mesh, 20 g), eluting with hexanes-ethyl acetate (5:1), to give the product 40 (0.022 g, 9%) as an oil: 1H NMR (CDCl3, 300 MHz) δ 7.69 (s, 2H), 7.54 (d, J=2.0 Hz, 1H), 7.52 (d, J=2 Hz, 1H), 6.01 (t, J=7.6 Hz, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 2.05 (q, J=7.3 Hz, 2H), 1.42 (m, 2H), 1.25 (m, 2H), 0.85 (t, J=6.7 Hz, 3H); IR (neat) 2953, 2929, 1742, 1738, 1731, 1713 cm−1; HRFABMS calcd for C25H28I2O6 m/z 677.9975 (M+). Found: m/z 677.9954. Anal. (C25H28I2O60.5EtOAc), C, H.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[C:15]([NH:19]C(=O)OCC)[NH:16]2)=[C:12]([NH:25][C@H:26]([CH3:29])[CH2:27][OH:28])[N:11]=1.O.[OH-].[Li+]>O1CCOCC1.O>[NH3:11].[NH2:19][C:15]1[NH:16][C:17]2[C:13]([N:14]=1)=[C:12]([NH:25][C@H:26]([CH3:29])[CH2:27][OH:28])[N:11]=[C:10]([S:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[N:18]=2
Reactant: CCOC(=O)Nc1nc2c(N[C@H](C)CO)nc(SCc3ccccc3F)nc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc2[nH]c(N)nc12
Product: N
Yield: 86.2 %

Procedure:
A solution of the product from example 4, step (f) (0.042 g) and lithium hydroxide monohydrate (16 mg) in dioxan (4 ml) and water (2 ml) was heated under reflux for 5 hr. The reaction mixture was concentrated in vacuo and the residue purified by silica gel column chromatography, eluting with 4:1 DCM:ethanol containing 0.5% 880 ammonia, to afford the titled compound as a white solid (0.015 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[OH:12][C:13]1[CH:18]=[C:17](O)[CH:16]=[C:15]([OH:20])[CH:14]=1>CC(C)=O>[Cl:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[NH:1][C:17]1[CH:16]=[C:15]([OH:20])[CH:14]=[C:13]([OH:12])[C:18]=1[C:4]2=[O:6]
Reactant: Oc1cc(O)cc(O)c1
Reactant: Nc1c(Cl)cccc1C(=O)O
Solvent: CC(C)=O
Product: O=c1c2cccc(Cl)c2[nH]c2cc(O)cc(O)c12
Temperature: 230 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
A 250-mL sealed reactor was charged with 2-amino-3-chlorobenzoic acid (8.58 g, 50 mmol, and 1,3,5-trihydroxybenzene (110 mg, 1.0 mmol). The mixture was then heated to 230° C. for 40 min. The solids melted after ˜10 minutes and stayed as liquid for ˜1 minute before solidifying again. The mixture was cooled to room temperature and acetone (600 mL) was used to break the solids and transferred to a 1-L Erlenmeyer flask. The slurry was stirred for 30 minutes with periodic breaking of the solid with a spatula2. The solid was filtered and washed with acetone (200 mL), affording a dark yellow to brown powder. The powder was then triturated in hot methanol (1.5 L) at 60° C. for 30 minutes and filtered after the slurry cooled to ˜30° C. and washed with methanol (200 mL) to afford the product 3 (4.87 g, 37%) as yellow solid. 1H NMR (DMSO-d6): 6.06 (1H, d, J=2.3), 6.81 (1H, d, J=2.0), 7.23 (1H, t, J=8.1), 7.87 (1H, d, J=7.3), 8.11 (1H, d, J=7.3), 10.64 (1H, s), 10.97 (1H, s): LC-MS: m/z+1=262.1.
Reaction SMILES: C(O[C:6](=[O:17])[NH:7][CH:8]1[CH2:15][CH:14]2[NH:16][CH:10]([CH2:11][O:12][CH2:13]2)[CH2:9]1)(C)(C)C.[CH3:18][O:19][C:20]([C:22]1[C@H:23]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[Cl:42])[N:24]=[C:25]([C:30]2[S:31][CH:32]=[CH:33][N:34]=2)[NH:26][C:27]=1[CH2:28]Br)=[O:21].[CH3:43]CN(C(C)C)C(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.CCOC(C)=O>[CH3:18][O:19][C:20]([C:22]1[C@H:23]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[Cl:42])[N:24]=[C:25]([C:30]2[S:31][CH:32]=[CH:33][N:34]=2)[NH:26][C:27]=1[CH2:28][N:16]1[CH:14]2[CH2:15][CH:8]([NH:7][C:6](=[O:17])[CH3:43])[CH2:9][CH:10]1[CH2:11][O:12][CH2:13]2)=[O:21]
Reactant: CC(C)(C)OC(=O)NC1CC2COCC(C1)N2
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(CN2C3COCC2CC(NC(C)=O)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of (3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-carbamic acid tert-butyl ester (PharmaBlock (Nanjing) R&D Co. Ltd, catalog number: PB05636) (106 mg, 0.44 mmol) and Compound C (100 mg, 0.22 mmol) in CH2Cl2 (5 mL) was added DIPEA (0.14 mL, 0.44 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature, then diluted with EtOAc (60 mL). The organic layer was washed with sat. NH4Cl, sat. NaHCO3 and brine (20 mL) respectively. The organic layer was dried over Na2SO4, and then concentrated under reduced pressure to give the crude product which was dissolved in CH2Cl2 (5 mL). To the solution was added trifluoroacetic acid (2 mL) at 0° C. The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give the crude (R)-6-(7-amino-3-oxa-9-aza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound AP) which was directly used for next step.
Reaction SMILES: [CH:1]1([C:5]([OH:15])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:8])[CH3:7])[CH2:4][CH2:3][CH2:2]1.C1CNC(=O)C1.[Br:22][Br-]Br>O1CCCC1>[Br:22][CH2:7][C:6](=[O:8])[C:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)([OH:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)C(O)(c1ccccc1)C1CCC1
Agent: O=C1CCCN1
Solvent: C1CCOC1
Product: O=C(CBr)C(O)(c1ccccc1)C1CCC1
Temperature: 25 °C

Procedure:
In a 5-L round bottomed flask equipped with a reflux condenser and an overhead stirrer was placed a solution of 276 3 g (1.35 mole) of 1-cyclobutyl-1-hydroxy-1-phenyl-2-propanone in 3 L of tetrahydrofuran. To this solution was added 903 g (1.82 mole) of pyrrolidone hydrotribromide. The mixture was refluxed for 24 hours and allowed to cool to room temperature. It was partitioned between 4 L of water and 4 L of ether. The organic layer was separated, washed three times with a saturated solution of sodium bicarbonate and once with brine. It was dried over anhydrous magnesium sulfate and the solvent removed. Crystallization of the residue from hexane gave 195 g of 3-bromo-1-cyclobutyl-1-hydroxy-1-phenyl -2-propanone, mp 79°-80° C. NMR (CDCl3) 1.8-2.2 (m, 6 H), 3.4-3.6 (m, 1 H), 3.9-4.1 (m, 2 H), 7.2-7.7 (m, 5 H); IR (KBr) 3471, 2946, 1725, 627 cm-1.
Reaction SMILES: C(O)C.Br[C:5]1[CH:6]=[CH:7][C:8]2[N:14]([C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[O:16])[CH2:13][CH2:12][C:11]([C:22]([O:24][CH3:25])=[O:23])=[CH:10][C:9]=2[CH:26]=1.B([O-])([O-])O[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:39]([O:38][CH2:37][CH2:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([C:5]2[CH:6]=[CH:7][C:8]3[N:14]([C:15]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:16])[CH2:13][CH2:12][C:11]([C:22]([O:24][CH3:25])=[O:23])=[CH:10][C:9]=3[CH:26]=2)=[CH:34][CH:33]=1)[CH2:40][CH2:41][CH3:42]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C(=O)c2cccs2)CC1
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(=O)c2cccs2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
In toluene (10 ml), ethanol (1.0 ml) and water (1.0 ml) were suspended methyl 7-bromo-1-(2-thienylcarbonyl)-2,3-dihydro-1-benzazepine-4-carboxylate (210 mg), 4-butoxyethoxyphenyl borate (166 mg) and potassium carbonate (192 mg), and the mixture was stirred for 30 minutes under argon atmosphere. Then, to the suspension was added tetrakistriphenylphosphinepalladium (43 mg), and the mixture was heated at 100° C. for 5 hours under argon atmosphere. After allowing to cool, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(2-thienylcarbonyl)-2,3-dihydro-1-benzazepine-4-carboxylate (201 mg) as colorless oil.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].Cl[Al](C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]CC)=O)=[CH:13][CH:12]=1>C(Cl)Cl>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([N:3]([O:4][CH3:5])[CH3:2])=[O:20])=[CH:15][CH:16]=1
Reactant: CNOC
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: C[Al](C)Cl
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To a round bottom flask containing N-methyl-N-methoxy amine hydrochloride (878 mg, 9 mmol) in CH2Cl2 (6 mL), a solution of ClAlMe2 (9 mL, 1M, 9 mmol) was added at 0° C. dropwise. The solution was stirred at rt for 30 min. A solution of ethyl 4-bromophenylacetate (1.09 g, 4.05 mmol) was added dropwise at 0° C. The solution was stirred at rt for 1 h, quenched with sat. NH4Cl, and extracted with EtOAc (3×20 mL). The organic layer washed with brine, dried (Na2SO4) and concentrated. Purification via flash chromatography (0-50% EtOAc/hexanes) afforded 70A (1.03 g, 80%). MS (ESI) m/z 258.1 (M+H)+.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[C:13]([C:15]1[C:16]([O:45][C@H:46]([CH3:50])[CH2:47][O:48][CH3:49])=[CH:17][C:18]([NH:21][C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([CH2:39][NH:40][C@@H:41]([CH3:44])[CH2:42][OH:43])=[C:31]([CH:34]([O:37][CH3:38])[O:35][CH3:36])[N:32]=3)[CH2:27][CH2:26][CH2:25]2)=[O:23])=[N:19][CH:20]=1)#[N:14]>C(Cl)Cl>[C:13]([C:15]1[C:16]([O:45][C@H:46]([CH3:50])[CH2:47][O:48][CH3:49])=[CH:17][C:18]([NH:21][C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([CH2:39][N:40]4[C@@H:41]([CH3:44])[CH2:42][O:43][C:1]4=[O:2])=[C:31]([CH:34]([O:35][CH3:36])[O:37][CH3:38])[N:32]=3)[CH2:27][CH2:26][CH2:25]2)=[O:23])=[N:19][CH:20]=1)#[N:14]
Reactant: COC[C@@H](C)Oc1cc(NC(=O)N2CCCc3cc(CN[C@@H](C)CO)c(C(OC)OC)nc32)ncc1C#N
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: COC[C@@H](C)Oc1cc(NC(=O)N2CCCc3cc(CN4C(=O)OC[C@@H]4C)c(C(OC)OC)nc32)ncc1C#N

Procedure:
A mixture of carbonyl diimidazole (49 mg, 0.301 mmol) and N-(5-cyano-4-(((R)-1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-(dimethoxymethyl)-6-((((S)-1-hydroxypropan-2-yl)amino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 148, 118 mg, 0.223 mmol) in DCM (10 ml) was heated in a septum sealed vial at 45° C. for 2.5 h. The cooled reaction mixture was partitioned between DCM and aqueous citric acid solution (5% w/w), extracted 2× with DCM, the DCM layers dried over Na2SO4 and evaporated to give the title compound as a yellow-white solid. (UPLC-MS 6) tR 1.14; ESI-MS 555.3 [M+H]+.
Reaction SMILES: [C:1]([N:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:1]([N:5]1[CH2:6][CH2:7][O:8][C:20](=[O:22])[O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)N(CCO)CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)N1CCOC(=O)OCC1

Procedure:
The procedure of Example 1 was followed using N-tert-butyl diethanolamine (16.4 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry THF (600 mL) and triphosgene (8.3 g, 28.8 mmol). The filtrate was concentrated yielding a clear oil containing a non-isolable amount of product within a mixture of oligomeric diethanolamines.
Reaction SMILES: [N:1]1([C:7](=[S:11])[CH2:8][C:9]#[N:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=O.CCN(C(C)C)C(C)C.I[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(#N)C>[C:9]([C:8]1[C:15]([C:14]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=2[Cl:12])=[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[S:11][C:7]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)#[N:10]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CI
Reactant: N#CCC(=S)N1CCOCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(Cl)cc1Cl
Reaction time: 0.17 h
Yield: 27.6 %

Procedure:
A solution of 3-morpholin-4-yl-3-thioxopropanenitrile (0.150 g, 0.88 mmol) in anhydrous ACN (1.2 mL) was cooled to 0° C. To this cooled solution was added of 2,4-dichlorobenzoyl chloride (0.149 mL, 1.06 mmol) and DIPEA (0.161 mL, 0.93 mmol). The mixture was allowed to stir at rt under nitrogen for 15 min before ethyl iodoacetate (0.110 mL, 0.93 mmol) and DIPEA (0.161 mL, 0.93 mmol) were added. The reaction mixture was subjected to MWI at 140° C. for 10 min. The mixture was allowed to cool and was concentrated. The residue was purified by column chromatography to give ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylate (0.1 g, 28%). LCMS: (AA) ES+ 411. 1H NMR (400 MHz, d1-chloroform) δ: 7.49 (d, 1H), 7.33 (dd, 1H), 7.20 (d, 1H), 4.16-4.08 (m, 2H), 3.89-3.85 (m, 4H), 3.66-3.63 (m, 4H) and 1.12 (t, 3H).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:15][CH:14]([C:16]([O:18]C)=[O:17])[CH2:13][CH2:12][N:11]2[C:20]([O:22][CH3:23])=[O:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[Br-].[Li+].CC(OC)(C)C>C(#N)C>[C:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:15][CH:14]([C:16]([OH:18])=[O:17])[CH2:13][CH2:12][N:11]2[C:20]([O:22][CH3:23])=[O:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(C)(C)C)s2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(C(C)(C)C)s1
Reaction time: 0.08 h
Yield: 47.1 %

Procedure:
Dimethyl 2-(5-tert-butylthiophen-2-yl)piperidine-1,4-dicarboxylate (2.49 g, 7.34 mmol) was dissolved in acetonitrile (20 mL). Water (0.400 mL) and lithium bromide (5.10 g, 58.68 mmol) were added. After 5 min, TEA (4.09 mL, 29.34 mmol) was added and the reaction heated at reflux for 1 h. MTBE (150 mL) and water (150 mL) were added, shaken and the phases separated. The organic phase was extracted with water (150 mL). The combined aqueous phases were acidified with 3 M HCl to pH 1 and extracted with MTBE (2×300 mL). The combined organic phases were dried with Na2SO4, filtered and evaporated in vacuo yielding 2-(5-tert-butylthiophen-2-yl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (1.125 g, 47.1%) as a white foam. MS m/z 326 (M+H)+
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36]COCC[Si](C)(C)C)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:45]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([OH:36])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3ccccc3)cc2)C(OCc2cc(O)c3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate with benzyl bromide there was obtained tert-butyl (3RS,4RS)-4-[4-(2-benzyloxy-ethoxy)-phenyl]-3-(4-hydroxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate.