Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH:5][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([N+](=O)[O-])cc1N
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1NC(C)=O

Procedure:
2-Methoxy-5-nitroaniline 23 (13.17 gm, 0.078 moles) was dissolved in 60 ml tetrahydrofuran (THF) at room temperature under argon. Acetic anhydride (11.1 ml, 0.118 moles) was added. An orange solution was formed. The mixture was evaporated under reduced pressure, and kept under vacuum overnight to give N-(2-Methoxy-5-nitrophenyl)acetamide 24 (1H NMR (CDCl3) δ 9.20, 1H, br s; 7.99, 1H, d; 6.95, 1H, d; 4.02, 3H, s; 3.12, 1H, s; 2.26, 3H, s), which was suspended in 115 ml ethanol. 5% Palladium on carbon (8.05 gm) was added, followed by the slow addition of 8.05 ml hydrazine hydrate (1 ml/5 minutes). After 90 minutes of heating, TLC indicated the reduction was complete. The mixture was filtered and the cake was washed with six 100 ml portions of methanol. The combined filtrate was concentrated under reduced pressure, taken up in 100 ml methanol and filtered again through Celite. The filtrate was concentrated to an oil and triturated with DCM and methanol to give crystals of N-(3-amino-6-methoxyphenyl)acetamide 25 (12.8 gm, 91% from 23) in two crops. 1H NMR (CDCl3) δ 7.85, 1H, m; 7.80, 1H, br s; 6.67, 1H, d; 6.37, 1H, dd; 3.79, 3H, s; 3.5, 2H, br; 2.17, 3H, s.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([Cl:10])=[CH:8][N:9]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:13][O:14][CH2:15][CH2:16]Br>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[Cl:10][C:7]1[S:6][C:5](=[N:4][C:1](=[O:3])[CH3:2])[N:9]([CH2:16][CH2:15][O:14][CH3:13])[CH:8]=1
Reactant: COCCBr
Reactant: CC(=O)Nc1ncc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCn1cc(Cl)sc1=NC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
A flask was charged with 2-acetamido-5-chlorothiazole (Lancaster, 19.3 g, 110 mmol) in 200 mL of 2:1 THF/DMF. To the solution was added sodium hydride (60% dispersion in mineral oil, 5.44 g, 142 mmol). The mixture was stirred at room temperature for 15 minutes and then 2-bromoethyl methyl ether (18.3 g, 131 mmol) was added. The mixture was warmed to 85° C. and stirred overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on SiO2 using a gradient of 0% to 100% ethyl acetate:hexane to provide 10.3 g (42%) of the title compound as the more polar regioisomer: 1H NMR (300 MHz, CDCl3) δ 2.28 (s, 3H) 3.35 (s, 3H) 3.65-3.71 (m, 2H) 4.28-4.36 (m, 2H) 7.00 (s, 1H); MS (ESI+) m/z 235 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([SH:22])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br[CH2:24][CH2:25][CH2:26][S:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([OH:37])[C:29]=1[CH2:38][CH2:39][CH3:40].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([S:22][CH2:24][CH2:25][CH2:26][S:27][C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([OH:37])[C:29]=2[CH2:38][CH2:39][CH3:40])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(SCCCBr)ccc(C(C)=O)c1O
Reactant: CCCc1c(S)ccc(C(C)=O)c1OCCCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(SCCCSc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Reaction time: 9 h
Yield: 51.9 %

Procedure:
A mixture of ethyl 4-(6-acetyl-3-mercapto-2-propylphenoxy)butyrate (2.0 g), (4-(3-bromopropylthio)-2-hydroxy-3-propylphenyl)ethanone (2.0 g), potassium iodide (0.5 g) and potassium carbonate (1.7 g) in acetone (40 ml) was heated with refluxing and stirring for 9 hours. After cooled, inorganic materials were separated by filtration and the filtrate was concentrated. The resultant residue was separated, and was purified through silicagel column chromatography (eluting with benzene:ethyl acetate=9:1) to give the title compound (1.8 g, 50.8%) as yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:18][C:19]2[C:20]3[NH:27][CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[C:39](Cl)=[O:40]>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([NH:18][C:19]2[C:20]3[N:27]([C:39](=[O:40])[C:38]4[CH:42]=[CH:43][C:44]([O:45][CH3:46])=[C:36]([O:35][CH3:34])[CH:37]=4)[CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4cc[nH]c34)cc2Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)n2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1OC
Yield: 52.7 %

Procedure:
Under ice-cooling, to a suspension of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine hydrochloride (150 mg) and potassium carbonate (102 mg) in N,N-dimethylformamide (1.5 mL) was added 3,4-dimethoxybenzoyl chloride (82 mg), and the mixture was stirred under ice-cooling, for 1 hr. The mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The organic layer was washed with saturated brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→ethyl acetate:methanol=80:20), and crystallized from diisopropyl ether to give the title compound (104 mg).
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C@:30]([OH:34])([C:32]#[CH:33])[CH3:31])[N:26]=1>>[F:23][C:3]1[C:2]([C:33]#[C:32][C@@:30]([OH:34])([C:27]2[N:26]=[C:25]([CH3:24])[O:29][N:28]=2)[CH3:31])=[CH:22][C:6]2[C:7]3[N:8]([C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#C[C@@](C)(O)c3noc(C)n3)cc1-2

Procedure:
10-Bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide (0.08 g) was reacted with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol similar to as described in Procedure E to afford 8.6 mg of 9-fluoro-10-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 455 (M)+. 1H NMR (400 MHz, DMSO) δ 11.09 (q, J=4.4 Hz, 1H), 8.65 (d, J=8.3 Hz, 1H), 8.38 (s, 1H), 7.86 (s, 1H), 7.06 (d, J=10.5 Hz, 1H), 6.76 (s, 1H), 6.59 (s, 1H), 5.08-4.94 (m, 2H), 4.63-4.41 (m, 2H), 2.80 (d, J=4.5 Hz, 3H), 2.62 (s, 3H), 1.86 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([CH2:12][O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C:8]([O:10]C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].O>C1COCC1.O.CO>[C:1]1([CH:7]([CH2:12][O:13][Si:14]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:21]([CH3:22])[CH3:23])[C:8]([OH:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(CO[Si](C(C)C)(C(C)C)C(C)C)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)[Si](OCC(C(=O)O)c1ccccc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 2-phenyl-3-(triisopropylsilyloxy)propanoate (E399) in THF/H2O/MeOH was added LiOH*H2O and the solution was stir at room temperature overnight. The solution was poured into NH4Cl(sat)/HCl (1 N) (3:1) and extracted with EtOAc. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (0%-4% MeOH/CH2Cl2) gave pure 2-phenyl-3-(triisopropylsilyloxy)propanoic acid (E400).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][CH2:7][CH2:8][N:9]=[C:10]=[O:11]>C1COCC1>[Cl:6][CH2:7][CH2:8][NH:9][C:10]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:11]
Reactant: O=C=NCCCl
Reactant: COCCN
Solvent: C1CCOC1
Product: COCCNC(=O)NCCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of methoxyethylamine (0.40 mL, 4.60 mmol) in THF (15 mL) was treated with 2-chloroethylisocyanate (0.35 mL, 4.10 mmol), stirred at RT for 3 h and concentrated to dryness to afford 1-(2-chloroethyl)-3-(2-methoxyethyl)urea (100% yield assumed) as a white solid. MS (ESI) m/z: 181.1 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][C@H:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][O:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1.C(O[C:34]1(O[Si](C)(C)C)[CH2:36][CH2:35]1)C>>[ClH:2].[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][C@H:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][O:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([CH:34]4[CH2:36][CH2:35]4)[CH2:23][CH2:24]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: O=C(N[C@@H](COCC1CCNCC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: Cl
Product: O=C(N[C@@H](COCC1CCN(C2CC2)CC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1

Procedure:
Using alkylation method A with addition of 3A molecular sieves, 3-chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)-ethyl]-1H-indole-6-carboxamide hydrochloride (200 mg, 0.44 mmol) and [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.53 mL, 2.7 mmol) afforded, after purification (SiO2: 0 to 5% isopropylamine in 10:2:2:DCM:EtOAc:hexane) and after conversion to the HCl salt by general method B, 80 mg (40%) of the title compound.
Reaction SMILES: [C:1]([NH:20][C@@H:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg]I.O>CCOCC>[CH3:23][C:22]([OH:24])([C@@H:21]([NH:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:25][CH3:26])[CH3:27]
Reactant: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Reactant: C[Mg]I
Solvent: CCOCC
Solvent: O
Product: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)(C)O

Procedure:
To a stirred solution of (3S)-3-(trityl-amino)-pentan-2-one (0.59 g, 1 eq, 1.72 mmol) in Et2O (100 mL) under an argon atmosphere at room temperature, was added methylmagnesium iodide (3 M in Et20, 1.72 mL, 3 eq, 5.16 mmol) dropwise. The solution was placed in a preheated oil bath at 45° C. and refluxed at this temperature for 16 h. The mixture was recooled to 0° C., H2O (100 mL) added, the solution filtered through Celite, and the Celite washed with more Et2O (50 mL). The combined organic phase was separated, the aqueous phase was extracted with Et2O (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane: Et2O (100:0→90:10) to afford the title compound as a light yellow oil. Yield: 0.10 g (16%). 1H-NMR (d6-DMSO, 250 MHz): δ0.27 (t, J=7.10 Hz, —NHCH(CH2CH3)CH(CH3)OH), 0.99 & 1.25 (2×s, 6H, —NHCH(CH2CH3)C(CH3)2OH), 0.75-1.42 (m, 2H, —NHCH(CH2CH3)C(CH3)2OH), 1.88 (m, 1H, —NHCH(CH2CH3)C(CH3)2OH), 2.92 (m, 1H, —NHCH(CH2CH3)C(CH3)2OH), 4.32 (s, 1H, —NHCH(CH2CH3)C(CH3)2OH), 7.18-7.46 (m, 15H, 3×Ph).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:28]=[CH:27][CH:26]=[CH:25][C:9]=3[S:10][C:11]=2[CH:12]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>CCO>[C:1]1([C:7]2[C:8]3[CH:28]=[CH:27][CH:26]=[CH:25][C:9]=3[S:10][C:11]=2[CH:12]([NH2:14])[CH3:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(c1sc2ccccc2c1-c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(N)c1sc2ccccc2c1-c1ccccc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(1-(3-phenylbenzo[b]thiophen-2-yl)ethyl)isoindoline-1,3-dione (170 mg, 0.443 mmol) and hydrazine, monohydrate (0.215 mL, 4.43 mmol) in EtOH (5 mL) was heated to 50° C. overnight. After 18 h, a precipitate had developed. The precipitate was removed by filtration, rinsed with EtOH, and concentrated under reduced pressure. The concentrate was dissolved in DCM, adsorbed onto silica gel and purified by column chromatography using 10% of MeOH in DCM as eluent to give 1-(3-phenylbenzo[b]thiophen-2-yl)ethanamine as a colorless, crystalline solid: 1H NMR (400 MHz, CDCl3) δ 1.51 (d, J=6.5 Hz, 3H), 1.74 (br. s., 2H), 4.55 (q, J=6.5 Hz, 1H), 7.30-7.38 (m, 2H), 7.41-7.57 (m, 6H), 7.87-7.91 (m, 1H); LC-MS (ESI)] m/z 237.1 [M-16]−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9]1.[NH2:23][C:24]1([C:27]([O-:29])=[O:28])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:27]([C:24]1([NH:23][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH2:26][CH2:25]1)([OH:29])=[O:28]
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1Br
Reactant: NC1(C(=O)[O-])CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1NC1(C(=O)O)CC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
A mixture of 2-(2-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.42 mmol), copper(I) iodide (24 mg, 0.13 mmol), 1-amino-cyclopropane-1-carboxylate (170 mg, 1.7 mmol) and potassium carbonate (174 mg, 1.26 mmol) in dimethyl sulfoxide (3 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-(1-carboxy-cyclopropylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (128 mg, 80%) as a white solid: LC/MS m/e calcd for C22H24N2O4 (M+H)+: 381.46, observed: 381.1.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[C:11]1([N:17]([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)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>O>[C:24]1([N:17]([C:11]2[CH:12]=[CH:13][C:14]([CH:8]=[O:9])=[CH:15][CH:16]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(C)C=O
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
Phosphorus oxychloride (MW 153, 0.129M, 19.7 g) was added dropwise to dimethylformamide ("DMF") (MW 73, 0.774M, 56.5 g) maintaining the temperature at <10° C. with external cooling. Triphenylamine (MW 245, 0.129M, 31.5 g) was added and the reaction mixture stirred at 100° C. for 1 hour. After cooling to room temperature and pouring into water (500 ml), the suspension was neutralised to pH 6 with saturated sodium acetate solution. The suspension was filtered off and washed with water, then redissolved in dichloromethane and dried over MgSO4 before screening through Silica gel (MERCK 60H Art 7736) and solvent removed under reduced pressure to give 27.5 g of 4-(N,N-diphenylamino) benzaldehyde (78% yield) as a yellow solid, m.p. 132°-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:10]=3[C:11]3[C:21]([CH3:22])=[N:20][O:19][C:12]=3[C@H:13]([CH2:15][C:16]([NH2:18])=O)[N:14]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:10]=3[C:11]3[C:21]([CH3:22])=[N:20][O:19][C:12]=3[C@H:13]([CH2:15][C:16](=[S:37])[NH2:18])[N:14]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1noc2c1-c1sc(C)c(C)c1C(c1ccc(Cl)cc1)=N[C@H]2CC(N)=O
Solvent: C1CCOC1
Product: Cc1noc2c1-c1sc(C)c(C)c1C(c1ccc(Cl)cc1)=N[C@H]2CC(N)=S
Yield: 64.1 %

Procedure:
To a solution of 2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetamide (Compound 110, 0.120 g, 0.30 mmol) in THF (5 mL) was added Lawesson reagent (0.248 g, 0.60 mmol). The mixture was refluxed overnight. The reaction mixture was concentrated in vacuo and the residue was recrystallized by petroleum and ethyl acetate to give 2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)ethanethioamide (0.080 g, 64% yield).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[CH:8]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[O:20])[N:7]=1)([CH3:5])[CH3:4].Br[CH2:30][C:31]([N:33]1[CH2:39][CH:38]2[CH2:40][CH2:41][CH:35]([CH2:36][CH2:37]2)[CH2:34]1)=[O:32]>CN(C)C=O>[CH:38]12[CH2:40][CH2:41][CH:35]([CH2:36][CH2:37]1)[CH2:34][N:33]([C:31]([CH2:30][N:10]1[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]([CH:3]([CH3:5])[CH3:4])=[N:7][CH:8]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)=[O:20])[C:9]1=[O:17])=[O:32])[CH2:39]2
Reactant: O=C(CBr)N1CC2CCC(CC2)C1
Reactant: Cc1cccc(NC(=O)NC2N=C(C(C)C)c3ccccc3NC2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)NC2N=C(C(C)C)c3ccccc3N(CC(=O)N3CC4CCC(CC4)C3)C2=O)c1
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a suspension of sodium hydride (0.030 g of a 65% dispersion in mineral oil) in dry N,N-dimethylformamide (5 ml) was added gradually N-[(3RS)-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (0.250 g) at 5˜10° C. in an ice-bath for 30 minutes. The mixture was stirred at the same temperature for 1 hour and then at room temperature for 2 hours. To the above mixture was added dropwise a solution of N-bromomethylcarbonyl-3-azabicyclo[3.2.2]nonane (0.200 g) in dry N,N-dimethylformamide (5 ml) for 10 minutes and stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo and the residue was taken up with ethyl acetate (100 ml) and a saturated aqueous sodium hydrogen carbonate (50 ml). The organic layer was separated, washed with a brine (50 ml), dried over anhydrous magnesium sulfate and evaporated in vacuo to give a crude product. The product was purified by column chromatography on silica gel with a mixture of chloroform and ethyl acetate (10:1) as an eluent. The fractions containing the desired compound were combined and evaporated in vacuo to afford N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (0.160 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12](O)[CH2:13][CH2:14][OH:15].C(OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>>[CH2:1]([O:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCO
Reactant: O=CCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(OCC)OCC
Solvent: O
Product: c1ccc(COCC2OCCCO2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 58 %

Procedure:
A mixture of benzyloxyacetaldehyde (3.6 g, 24 mmol), 1,3-propanediol (5.2 ml, 72 mmol), triethyl orthoformate (4 ml, 24 mmol), and p-toluenesulfonic acid monohydrate (414 mg, 2.45 mmol) was stirred at room temperature for 17 hours. To the reaction mixture, triethylamine (669 μl, 4.8 mmol) was added, which was concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to obtain the title compound (2.9 g, yield: 58%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=O.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:28])([F:27])/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl>CN(C=O)C>[Cl:1][C:2]1[C:3]([F:11])=[C:4]2[C:7](=[CH:8][CH:9]=1)[O:10][CH:20]([C:19]([F:18])([F:28])[F:27])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2
Reactant: O=Cc1c(O)ccc(Cl)c1F
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2c(ccc(Cl)c2F)OC1C(F)(F)F
Temperature: 70 °C

Procedure:
To 1.1 g (6.7 mmole) of 3-chloro-2-fluoro-6-hydroxybenzaldehyde in 2 mL DMF was added 1.0 g (7.2 mmole) of potassium carbonate and 3A molecular sieves. The stirred mixture was heated to 70° C. and treated with 1.5 mL (1.69 g, 10.0 mmole) of ethyl 4,4,4-trifluorocrotonate. After lh the mixture was treated with an additional 1.5 mL of ethyl 4,4,4-trifluorocrotonate and allowed to react overnight. To the cooled mixture was added 1N HCl, the mixture extracted three times with methylene chloride and the combined organic fractions dried and concd. The resultant oil was dissolved in ether, washed three times with water and concd to give an oil. Chromatographic purification (silica, 5-10% EtOAc/hex) gave 0.76 g (35%) of a clear, yellow oil: 1H NMR (CDCl3/400 MHz) 1.37 (t, 3H, J=7.2 Hz), 4.34 (m, 2H), 5.72 (q, 1H, J=6.8 Hz), 6.77 (d, 1H, J=8.8 Hz), 7.32 (t, 1H, J=8.5 Hz), 7.92 (s, 1H); 19F NMR (CDCl3/400 MHz) −78.7 (d, 3F, J=6.8 Hz), −119.6 (d, 1F, J=7.7 Hz); 13C NMR (CDCl3/100 MHz) 14.2, 61.9, 70.8 (q, J=33.4 Hz), 110.0 (d, J=18.1 Hz), 112.6 (d, J=4.0 Hz), 114.4 (d, J=17.3 Hz), 118.2 (J=2.3 Hz), 123.2 (q, J=287.3 Hz), 129.2 (d, J=4.6 Hz), 133.2 (d, J=1.3 Hz), 152.2 (d, J=4.4 Hz), 154.9 (d, J=256.4 Hz), 163.3; MS (ESI+) 325 (M+l, 100); MS (EI) 324 (M+, 21), 255 (100), 227 (83); HRMS (EI) m/z calcd for (C13H9O3ClF4) 324.0176, found 324.0171.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[O:15])[CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(F)c[nH]1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(F)cn1CC(=O)c1ccc(Br)cc1
Temperature: 35 °C
Reaction time: 72 h

Procedure:
To a solution of 15.7 g (100 mmol) 4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester and 27.8 g (100 mmol) 2,4′-dibromoacetophenone in 150 ml acetone is added 16.6 g (120 mmol) cesium carbonate. The resulting suspension is stirred at 35° C. for 3 days. The reaction mixture is added to 600 ml water under stirring. The resulting precipitate is filtered off, washed with water and dried under vacuum to afford 1-[2-(4-bromo-phenyl)-2-oxo-ethyl]-4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester as light yellow solid; HPLC/MS 3.14 (B), [M+H] 354/356;