Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]=O.[OH-].[K+]>C(O)=O>[CH3:12][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Product: CN1C(C)(C)CC(O)CC1(C)C
Yield: 91 %

Procedure:
1,2,2,6,6-pentamethyl-4-piperidinol was synthesized upon reductive-amination of 2,2,6,6-tetramethy-4-piperidinol. A mixture of 2,2,6,6-tetranmethyl-4-piperidinol (3.55 g, 0.02 M), 37% formalin (3.3 mL) and 1 mL formic acid was heated under a reflux condenser on the steam bath for 5 h. The reaction mixture was made basic with (1.0 M) potassium hydroxide solution and the product was extracted with ether (5×50 mL). The combined extract was washed with saturated solution of potassium carbonate (2×20 mL) and dried over anhydrous magnesium sulfate and finally the solvent was evaporated under vacuum. The residue was then sublimed at 0.05 mm, bath temperature 85° C. The white sublimate weighed 3.5 g to give 91% yield, mp=72-74° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
4-Hydroxycinnamic acid (700 mg, 4.26 mmol) was dissolved in EtOAc (15 mL) and 10% Pd/C (51 mg, 0.479 mmol) was added. The reaction mixture was stirred under an atmosphere of H2 overnight at room temperature before it was filtered through diatomaceous earth and concentrated in vacuo. No further purification was needed to yield 3-(4-hydroxyphenyl)propanoic acid (700 mg, 99%). A solution of 3-(4-hydroxyphenyl)propanoic acid (700 mg, 4.21 mmol) in anhydrous DMF (16 mL) at 0° C. was treated with a solution of 60% NaH (450 mg, 18.75 mmol) in DMF dropwise. The reaction mixture was stirred for 10 min before benzyl bromide (0.675 mL, 5.68 mmol) was added. The reaction mixture was stirred overnight at room temperature, quenched with aqueous 1 N HCl and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NH4Cl, saturated aqueous NaCl and dried over Na2SO4. Column chromatography (SiO2, 4×9 cm, 20-40% EtOAc-hexanes gradient) afforded 3-(4-(benzyloxy)phenyl)propanoic acid (780 mg, 72%) as a white solid: 1H NMR (CDCl3, 500 MHz) 7.44 (d, 2H, J=7.4 Hz), 7.40 (t, 2H, J=7.4 Hz), 7.35-7.32 (m, 1H), 7.14 (d, 2H, J=8.8 Hz), 6.92 (d, 2H, J=8.4 Hz), 5.06 (s, 2H), 2.92 (t, 2H, J=7.7 Hz), 2.66 (t, 2H, J=7.7 Hz); 13C NMR (CDCl3, 125 MHz) 179.0, 157.3, 137.0, 132.5, 129.2, 128.5, 127.9, 127.4, 114.9, 70.0, 35.8, 29.7. (See: Xue, C.-B.; He, X.; et al. J. Med. Chem. 2001, 44, 3351-3354)
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:13])[CH:10]1[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([CH2:24][Mg]Cl)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[CH2:1]([O:8][C@H:9]([CH:10]([OH:12])[CH2:11][CH2:24][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1cccc2ccccc12
Reactant: C[C@H](OCc1ccccc1)C1CO1
Product: C[C@H](OCc1ccccc1)C(O)CCc1cccc2ccccc12

Procedure:
(2S)-2-benzyloxy-5-(1-naphthyl)pentan-3-ol was prepared from (3S)-3-benzyloxy-1,2-epoxybutane (obtained in Preparation 9) and 1-naphthylmethylmagnesium chloride (J. Am. Chem. Soc. 1943, 65, 295).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+]([O-])=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-4-nitro-benzonitrile (11.2 g, 68 mmole) was dissolved in DMF (200 ml). Potassium carbonate (11 g, 80 mmole) and benzyl bromide (9 ml, 75 mmole) were added. The reaction was stirred at room temperature overnight. The DMF was removed in vacuo and the residue taken up in ethyl acetate and water. The organic layer was separated, washed with 1 N NaOH, then with water, and dried over sodium sulfate. The crude product (5 g) was dissolved in ethyl acetate (75 ml) and added to a flask containing 5% Pt/C (500 mg). The reaction was placed under a hydrogen atmosphere (balloon) and stirred vigorously for several hours until the reaction was done (TLC). The catalyst was filtered off and the solvent removed. The product was purified by flash chromatography to yield 4.12 g of 4-amino, 2-benzyloxybenzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][C:9]=1Br)=[O:4].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(NC(C)C)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCOCC>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][C:9]=1[C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[O:4]
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1C#C[Si](C)(C)C
Yield: 57.3 %

Procedure:
React 3-bromo-5-(4-chloro-phenyl)-thiophene-2-carboxylic acid methyl ester (0.66 g, 2.0 mmol) with (trimethylsilyl)acetylene (216 mg, 2.2 mmol), Pd(PPh3)2Cl2 (140 mg, 0.20 mmol), CuI (38.2 mg, 0.20 mmol), PPh3 (210 mg, 0.80 mmol) and diisopropyl amine (3.3 mL, 30 mmol) in DMF (1.0 mL) at 120° C. for 30 min in a microwave reactor. Treat the mixture with Et2O (15 mL), filter, pour into 0.1 M HCl (15 mL), and extract with Et2O (3×10 mL). Wash the combined organic layers with saturated NaHCO3 (20 mL) and water (20 mL). Purify the crude material by chromatography, eluting with 30% CH2Cl2/hexane to give 400 mg (57%) of the title compound. LC-MS/ES m/z (35Cl) 349.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][N:3]=1.[CH2:27]1[C:31]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:30][CH:29]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:28]1[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:34]3[CH2:33][CH2:32][C:31]4([CH2:27][N:28]([C:42]([O:44][CH2:45][C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)=[O:43])[CH:29]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:30]4)[CH2:36][CH2:35]3)[CH:7]=2)[C:10]([F:13])([F:11])[F:12])=[C:15]([N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[CH:16]=1
Reactant: CCOC(=O)C1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2ccnc(Cl)c2)C(F)(F)F)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)C1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)ccn3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of (R)-2-chloro-4-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridine (227 mg, 0.57 mmol) in 1,4-dioxane (5 mL) was added 2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (237 mg, 0.68 mmol), Cs2CO3 (557 mg, 1.71 mmol), BINAP (142 mg, 0.23 mmol), and Pd2(dba)3. The reaction was heated to 60° C. for 3 d, then cooled to RT, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided 2-benzyl 3-ethyl 8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH2:15])[N:14]=[C:10]2[CH:9]=[C:8]([Br:16])[CH:7]=1)=[O:5])[CH3:2].[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:20]([NH:19][CH2:17][CH3:18])=[O:21])[N:14]=[C:10]2[CH:9]=[C:8]([Br:16])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)cc2nc(N)nn12
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)OCC)n2n1
Temperature: 100 °C

Procedure:
2-Amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (7) (760 mg, 2.66 mmol) was dissolved in THF/toluene (1:1, 40 mL), then ethyl isocyanate (1.89 g, 26.6 mmol) and a catalytic quantity of dibutyltindiacetate (10 drops) were added to the mixture. The reaction was then heated in a sealed tube at 100° C. for 15 h. This mixture was allowed to cool, then the solvents removed under reduced pressure to afford a solid which was purified by flash chromatography on silica 2% MeOH/CH2Cl2 as eluant) to give 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (8) LCMS (APCI+) 356, 358.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N#N.[CH3:17][O:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][O:18][C:19]1[N:24]=[CH:23][C:22]([C:2]2[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Product: COc1ccc(-c2cc(NC(C)=O)cc([N+](=O)[O-])c2)cn1
Yield: 81 %

Procedure:
A solution of N-(3-bromo-5-nitrophenyl)acetamide (1 g, 3.86 mmol) in 1,2-dimethoxyethane (20 ml) was degassed by N2 bubbling for 5 min. (6-Methoxypyridin-3-yl)boronic acid (0.77 g, 5.0 mmol, 1.3 eq.) was added and the mixture was degassed for 5 min. Pd(dppf)Cl2 (0.630 g, 0.77 mmol, 0.2 eq.) and aqueous sodium carbonate (1.23 g, 11.58 mmol, 3.0 eq.) were added and the procedure of Example 1(d) was followed. The crude residue of the product was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the product in 81% yield (0.9 g).
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:26].[CH3:27][CH:28]([CH3:33])[CH2:29][CH2:30][CH2:31]N.S>C(O)C>[ClH:26].[CH3:27][CH:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[S:25]
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CC(C)CCCN
Agent: Cl
Agent: S
Solvent: CCO
Product: CC(C)CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reaction time: 16 h
Yield: 64.1 %

Procedure:
A solution of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2 g) and 4-methylpentylamine hydrochloride (7.4 g) is absolute ethanol (30 cc) is saturated with hydrogen sulphide. The reaction mixture is then brought for 16 hours to a temperature in the region of 105° C. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The pasty residue (5 g) is purified by chromatography on a column (height: 35 cm; diameter: 3 cm) of silica gel (0.2-0.063 mm), eluting successively with methylene chloride (500 cc) and then with a mixture (95:5 by volume) (500 cc) of methylene chloride and methanol, collecting 30-cc fractions. Fractions 25 to 28 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil (2.16 g) is dissolved in ethyl acetate (10 cc), and a 3.3N solution (1.5 cc) of hydrochloric acid in isopropyl ether is added with stirring, followed by ethyl ether until a persistent cloudiness has formed. After 1 hour at a temperature in the region of 5° C., the solid formed is drained, washed with ethyl ether (3×10 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. N-(4-Methylpentyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide hydrochloride (1.7 g) is thereby obtained in the form of a yellow solid, m.p. 186° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:27])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35]/[CH:36]=[CH:37]/[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[I-].[K+]>C(OCC)(=O)C.O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:27])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][N:19]([CH2:35]/[CH:36]=[CH:37]/[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCNCC1
Reactant: ClC/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(C/C=C/c2ccccc2)CC1
Reaction time: 4.5 h

Procedure:
To 3 mL of an N,N-dimethylformamide solution containing 0.10 g of ethyl 4-(3-(7-methoxy-2-oxo-1,2-dihydroquinolin-1-yl)propyl)piperidine-4-carboxylate, 0.11 g of potassium carbonate, 41 μL of ((1E)-3-chloro-1-propenyl)benzene and 45 mg of potassium iodide were added at room temperature and stirred for 4.5 hours. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=35:1], to give 0.11 g of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-((2E)-3-phenyl-2-propen-1-yl)piperidine-4-carboxylate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[O:24][CH3:25])[C:13](=[O:14])[C:4]=2[CH:3]=1)=[C:9]([C:26]([NH2:28])=O)[N:8]=[CH:7]3.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[O:24][CH3:25])[C:13](=[O:14])[C:4]=2[CH:3]=1)=[C:9]([C:26]#[N:28])[N:8]=[CH:7]3
Reactant: COc1ccc(CN2Cc3c(C(N)=O)ncn3-c3ccc(Cl)cc3C2=O)c(OC)c1
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(CN2Cc3c(C#N)ncn3-c3ccc(Cl)cc3C2=O)c(OC)c1
Yield: 62 %

Procedure:
8-Chloro-5-(2,4-dimethoxy-benzyl)-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid amide (5.9 g, 13.8 mmol) and phosphorous oxychloride (1.4 mL, 15.2 mmol) were mixed in dioxane (55 mL) and refluxed overnight. The resulting yellow solution was evaporated and the residue purified by chromatography on silica gel in CH2Cl2/acetone 20:1. One obtained a white foam (3.5 g, 61%). m/z 408 (MH+)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6](=O)[C:5](=[CH:8][NH:9][CH2:10][CH3:11])[C:4]([CH3:13])([CH3:12])[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>COCCOC>[CH3:1][C:2]1([CH3:14])[C:6](=[S:24])[C:5](=[CH:8][NH:9][CH2:10][CH3:11])[C:4]([CH3:13])([CH3:12])[O:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCNC=C1C(=O)C(C)(C)OC1(C)C
Solvent: COCCOC
Product: CCNC=C1C(=S)C(C)(C)OC1(C)C

Procedure:
A mixture of dihydro-2,2,5,5-tetramethyl-4-ethylaminomethylene-3(2H)furanone (1.0 g, 5.1 mmol) and Lawesson's Reagent (1.1 g, 2.7 mmol) was stirred in 20 mL of DME for 20 min. at room temperature. The solvent was evaporated and the residue was dissolved in methylene chloride and eluted through a plug of silica gel/basic alumina 1/1 (CH2Cl2). The eluant was evaporated to leave dihydro-2,2,5,5-tetramethyl-4-ethylaminomethylene-3(2H)furanthione as an orange solid.
Reaction SMILES: [F:1][CH:2]([F:15])[C:3]1([C:9]([O:11]C(C)C)=[O:10])[CH2:6][C:5]([F:8])([F:7])[CH2:4]1.[OH-].[Na+]>C(O)C.O>[F:15][CH:2]([F:1])[C:3]1([C:9]([OH:11])=[O:10])[CH2:6][C:5]([F:7])([F:8])[CH2:4]1
Reactant: CC(C)OC(=O)C1(C(F)F)CC(F)(F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1(C(F)F)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.6 %

Procedure:
To a solution of Intermediate 304D (500 mg, 2.191 mmol) in ethanol (10 mL) and water (2 mL) was added NaOH (2.191 mL, 10.96 mmol, 5 M in water) and the resulting solution was stirred at RT for 4 h. EtOH was removed under reduced pressure, and the aqueous solution was acidified with a 1.5 N aq. solution of HCl which was then extracted with DCM (3×30 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated to afford Intermediate 304E as a pale yellow liquid (300 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.87 (br. s., 1H), 6.21-6.63 (m, 1H), 2.77-3.11 (m, 4H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:9]=[C:10]([CH3:12])[N:11]=2)[C:7]=1[Cl:8].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:8][C:7]1[N:6]2[CH:9]=[C:10]([CH3:12])[N:11]=[C:5]2[CH:4]=[N:3][C:2]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: Cc1cn2c(Cl)c(Br)ncc2n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cn2c(Cl)c(C#C[Si](C)(C)C)ncc2n1
Temperature: 45 °C
Reaction time: 14 h
Yield: 51.3 %

Procedure:
A mixture of 6-bromo-5-chloro-2-methylimidazo[1,2-a]pyrazine (0.710 g, 2.88 mmol), bis(triphenylphosphine)palladium(II) chloride (0.1 g, 0.1 mmol), (trimethylsilyl)acetylene (0.90 mL, 6.3 mmol), copper(I) iodide (0.04 g, 0.2 mmol), and triethylamine (0.803 mL, 5.76 mmol) in N,N-dimethylformamide (8.5 mL) was heated in an oil bath at 45° C. and stirring for 14 h. The reaction was quenched with water (20 ml) and was extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with water (10 ml), saturated NaCl (10 ml), dried over Na2SO4 and the solvent removed in vacuo. The product was purified by silica gel chromatography eluting with 10-20% EtOAc in hexanes to give the desired product (0.39 g, 76%). LCMS calculated for C12H15ClN3Si (M+H)+: m/z=264.1. Found: 264.0.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].N1C=CC=CC=1.[Br:18]Br>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[S:7][C:8]([Br:18])=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1sccc1C
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1sc(Br)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 62.3 (0.61 g, 3.58 mmol) and pyridine (0.29 mL, 3.58 mmol) in DCM (24 mL) was added bromine (3.58 mL, 1.0 M solution in DCM) dropwise at 0° C. The mixture was stirred for 30 minutes at 0° C. and warmed to room temperature over 1 Hour. Upon completion, the reaction was diluted with DCM, washed with saturated Na2S2O3 and brine, dried (Na2SO4), and concentrated to afford 62.4. The crude product was used without further purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](O)=[O:10])(=[O:5])=[O:4].C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[F:1][C:2]([F:16])([F:15])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([Cl:20])=[O:10])(=[O:5])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(S(=O)(=O)C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(S(=O)(=O)C(F)(F)F)c1

Procedure:
A solution of the product of Example 6A (198 mg, 0.8 mmol) in dichloromethane (10 mL) was stirred with oxalyl dichloride (Aldrich, 2.0 mmol) and 1 drop of dimethylformamide at ambient temperature for 2 hours. The title compound was obtained by removing the solvent under vacuum as a yellow oil (250 mg) and the compound was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)cc1
Yield: 79.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 4-methoxyphenylboronic acid (119 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 1.5 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), followed by recrystallization from ethyl acetate to give 173 mg (79%) of the title compound as a white solid. mp 150°. FDMS: m/e=335. α[D]589 =+73.82 (c=1.01, methanol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]4[NH:33][C:32]5[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=5[N:30]=4)[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)(=O)C>C(O)(C)C>[NH:30]1[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=[C:29]1[C:24]1[CH:23]=[C:22]([N:19]2[CH2:20][CH2:21][CH:16]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[CH2:17][CH2:18]2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCN(c3ccc(Cl)c(-c4nc5ccccc5[nH]4)c3)CC2)CC1
Solvent: CC(C)O
Solvent: CC(=O)Cl
Product: O=C(C1CCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)CC1)N1CCNCC1
Temperature: 40 °C
Yield: 107.2 %

Procedure:
4-{1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-piperidine-4-carbonyl}-piperazine-1-carboxylic acid tert-butyl ester (0.05 g, 0.11 mmol) was suspended in isopropanol (4 mL). Acetyl chloride (55 μL, 0.77 mmol) was added dropwise and the reaction mixture was heated to 40° C. until no starting material remained. The reaction was concentrated under reduced pressure to afford 0.05 g of the title compound. (100%).