Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C:16]1[S:17][C:18]2[CH2:19][NH:20][CH2:21][CH2:22][C:23]=2[N:24]=1)=[O:15]>CN(C=O)C>[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C:16]1[S:17][C:18]2[CH2:19][N:20]([C:2]([O:4][CH3:5])=[O:3])[CH2:21][CH2:22][C:23]=2[N:24]=1)=[O:15]
Reactant: COC(=O)Cl
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Solvent: CN(C)C=O
Product: COC(=O)N1CCc2nc(C(=O)Nc3ccccc3N)sc2C1
Reaction time: 3 h

Procedure:
Methyl chloroformate (1.0 mmol) was added drop wise to N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained from step VIII of example 1 (1.0 mmol) solution in 10 mL of dry DMF at 0° C. Reaction mixture was stirred for additional 3 h Reaction mixture was concentrated, diluted with water, extracted with dichloromethane, washed with brine solution, and dried over anhydrous Na2SO4. Concentrated and purified by column chromatography to get the title compound.
Reaction SMILES: I[C:2]1[C:11]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.[CH3:22][N:23](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:22]([C:2]1[C:11]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1)#[N:23]
Reactant: CN(C)C=O
Reactant: CCC(CC)Nc1cc(C(=O)OC)c(C(F)(F)F)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCC(CC)Nc1cc(C(=O)OC)c(C(F)(F)F)cc1C#N
Temperature: 100 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
Methyl 4-iodo-5-(pentan-3-ylamino)-2-(trifluoromethyl)benzoate (401 mg, 0.966 mmol) was dissolved in DMF (9 mL) and the mixture was sparged with nitrogen for 15 minutes. Zinc cyanide (79 mg, 0.673 mmol) and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.086 mmol) were added and the mixture was stirred at 100° C. for 15 h. The reaction mixture was cooled to ambient temperature and was filtered through celite. The filter cake was washed with ethyl acetate and the filtrate was washed with 5% lithium chloride (2×). The combined aqueous wash was back-extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, then filtered and concentrated to afford a brown semi-solid which was purified by column chromatography (silica gel, 30-50% dichloromethane in hexanes) to afford methyl 4-cyano-5-(pentan-3-ylamino)-2-(trifluoromethyl)benzoate (262 mg, 0.834 mmol, 86% yield) as colorless crystals. 1H NMR (400 MHz, CDCl3): δ 7.71 (s, 1H), 6.96 (s, 1H), 4.76 (d, 1H), 3.94 (s, 3H), 3.49-3.38 (m, 1H), 1.75-1.63 (m, 2H), 1.61-1.49 (m, 2H), 0.96 (t, 6H); GCMS for C15H17F3N2O2: 314 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:28])=[C:4]([NH:10][C@H:11]([C:24]([OH:27])([CH3:26])[CH3:25])[C:12]([NH:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:28])=[C:4]([NH:10][C@@H:11]([C:12]2[O:13][C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:15][N:14]=2)[C:24]([OH:27])([CH3:26])[CH3:25])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)C(C)(C)O)ccc(C#N)c1Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)C(C)(C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 36.3 %

Procedure:
The crude material of (R)—N′-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)benzohydrazide (intermediate 14b) (218 mg, 0.54 mmol) was added to THF (50 mL) stirred at room temperature. PS-BEMP (742 mg, 1.63 mmol base) was added to the solution, followed by slow addition of p-TSCl (114 mg, 0.60 mmol). The reaction mixture was stirred for 1.5 h and the progress of the reaction was monitored by TLC. After the completion of the reaction, the BEMP reagent was filtered off and the solution concentrated to give the crude material. The crude material was chromatographed with hexanes:EtOAc (6:4) to give the title compound (75 mg, 28%): 1H NMR (500 MHz, CDCl3, δ in ppm) 7.94 (d, J=9 Hz, 2H), 7.54 (m, 1H), 7.46 (m, 2H), 7.34 (d, J=9 Hz, 1H), 6.56 (d, J=9 Hz, 1H), 5.45 (d, J=9 Hz, 1H), 4.71 (d, J=9 Hz, 1H), 3.12 (s, 1H), 2.37 (s, 3H), 1.50 (s, 3H), 1.37 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:18][CH3:19])[C:4]1[CH:5]=[C:6]([CH:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[OH:11])[CH:7]=[CH:8][CH:9]=1>[O-2].[Mn+4].[O-2].ClCCl>[CH3:1][O:2][CH:3]([O:18][CH3:19])[C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(OC)c1cccc(C(O)c2cccnc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(OC)c1cccc(C(=O)c2cccnc2)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 19 parts of α-[3-(dimethoxymethyl)phenyl]-3-pyridinemethanol, 36 parts of activated manganese(IV) oxide and 280 parts of dichloromethane was stirred over weekend at room temperature. The reaction mixture was filtered over silica gel and the filtrate was filtered again over diatomaceous earth and silica gel. The filtrate was evaporated and the residue was distilled in vacuo. The desired fraction was collected, yielding 15.7 parts (82%) of [3-(dimethoxymethyl)phenyl] (3-pyridinyl)methanone (intermediate 6).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([O:41][CH3:42])=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([NH:23][CH2:24][C:25](=[O:32])[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=O)=[CH:18][C:17]4[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([O:41][CH3:42])=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:32][C:25]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:24][N:23]=4)=[CH:18][C:17]4[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCC(=O)CNC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)CCc1cnc(C2=Cc3cc(OC)ccc3-c3c(C4CCCCC4)c4ccc(C(=O)OC)cc4n3C2)o1

Procedure:
Methyl 13-cyclohexyl-3-(methyloxy)-6-(((5-(methyloxy)-2,5-dioxopentyl)amino)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (1.60 g, 2.79 mMol) was suspended in 38 ml of toluene along with phosphorus oxychloride (0.58 mL, 6.34 mMol). The mixture was heated to reflux under nitrogen for 3 hrs, cooled and poured into a sepratory funnel containing ice and saturated aqueous sodium bicarbonate solution. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed sequentially with aqueous saturated bicarbonate, brine and dried over magnesium sulfate. Removal of volatiles and drying in vacuuo produced the title product in quantitative yield (1.55 g). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.27 (1 H, br. s.), 1.36-1.45 (2 H, m), 1.59 (2 H, br. s.), 1.78 (2 H, d, J=9.77 Hz), 1.96 (1 H, br. s.), 2.06 (2 H, br. s.), 2.71 (2 H, t, J=7.48 Hz), 2.81-2.90 (1 H, m), 3.04 (2 H, t, J=7.32 Hz), 3.70 (3 H, s), 3.95 (3 H, s), 3.98 (3 H, s), 4.37 (1 H, d, J=11.60 Hz), 5.93 (1 H, d, J=12.51 Hz), 6.91 (1 H, s), 7.02 (1 H, d, J=2.75 Hz), 7.07 (1 H, dd, J=8.70, 2.59 Hz), 7.53 (2 H, s), 7.74 (1 H, d, J=8.55 Hz), 7.85 (1 H, d, J=8.55 Hz), 8.38 (1 H, s). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% trifluoroacetic acid; % B=90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial % B=50; Final % B=100; Gradient=5 min; Runtime=6 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Phenomenex Luna 3.0 mm×50 mm S10; Retention Time=4.48 min, purity 96%. Flow injection Mass Spectrometry: MS m/z 555(MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1.[CH2:19]([OH:22])[CH2:20][OH:21]>C(Cl)(Cl)Cl>[OH:21][CH2:20][CH2:19][O:22][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1
Reactant: OCCO
Reactant: O=C1c2ccccc2C(=O)c2cc(CCl)ccc21
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)c2cc(COCCO)ccc21
Temperature: 160 °C
Reaction time: 14 h

Procedure:
A suspension of 10.14 g of 2-chloromethylanthraquinone in 50 ml of ethylene glycol is stirred for 14 hours at 160° C. It is taken up in chloroform and the resulting solution is washed with water and saturated sodium chloride solution. Crystallization of the residue of the organic phase (12 g) from toluene gives 9.0 g of 2-(2'-hydroxyethoxy)methylanthraquinone with an m.p. of 129°-130° C.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1Br>C(O)C>[CH2:11]([O:10][C:2](=[O:9])[CH:3]([CH:19]1[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Br[C@@H]1CCCC[C@H]1Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C1C=CCCC1
Reaction time: 2 h

Procedure:
Within 2 hours, 1.1 l of ethanol was added dropwise to 69 g of finely chopped sodium in a 2-liter three-necked flask equipped with dropping funnel, reflux condenser, and agitator. The hot alcoholate solution was combined dropwise--again within 2 hours--with 196 g of diethyl malonate. After allowing the reaction mixture to cool, 296 g of trans-1,2-dibromocyclohexane was added--within 2 hours--to the reaction solution, which latter was then boiled under reflux overnight. After concentration of the reaction solution on a forced circulation evaporator, the residue was combined with ether and dilute hydrochloric acid, the organic phase then washed with saturated sodium chloride solution, concentrated, and distilled under vacuum, thus obtaining 197 g, bp1 119°-121° C.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[CH3:7][CH:8]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][C:10](O)=[O:11]>C(CC(C)(C)C)(C)C>[CH3:7][CH:8]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][C:10]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11]
Reactant: CC(CC(=O)O)CC(C)(C)C
Reactant: CC(C)(C)OO
Solvent: CC(C)CC(C)(C)C
Product: CC(CC(=O)OOC(C)(C)C)CC(C)(C)C

Procedure:
To a reaction vial with a TEFLON fluoropolymer magnetic stirring rod, 3 ml containing 0.2 M tert-butyl hydroperoxide and 0.2 M 3,5,5-trimethylhexanoic acid in isooctane was added. The reaction was started by addition of 200 mg of Candida antartica enzyme and about 10 mg of molsieves (3 grains). After twenty-fourand one-half hours, 11.2% conversion to tert-butyl peroxy-3,5,5-trimethylhexanoate was obtained as measured with GC.
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:11])=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[O:12]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl-]>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.CN(C=O)C>[O:12]([C:19]1[CH:20]=[CH:21][C:22]([C:2]2[C:6]3[C:7]([NH2:11])=[N:8][CH:9]=[CH:10][C:5]=3[S:4][CH:3]=2)=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nccc2scc(Br)c12
Reactant: OB(O)c1ccc(Oc2ccccc2)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: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nccc2scc(-c3ccc(Oc4ccccc4)cc3)c12
Yield: 74.3 %

Procedure:
A mixture of Example 219A (5.43 g, 23.7 mmol), 4-phenoxyphenylboronic acid (6 g, 28.03 mmol), Na2CO3 (3.7 g, 34.9 mmol), Pd(PPh3)4 (5.4 g, 4.7 mmol), DMF (96 mL), and water (24 mL) was stirred for 18 hours at 80° C. under nitrogen, poured into 10% aqueous NaCl (400 mL), and extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was dissolved in 300 mL of dichloromethane. Silica gel (90 g) was added to the solution and the mixture was concentrated under vacuum. The residual silica gel with the absorbed crude product was transferred to a silica gel column (600 g) and chromatographed (eluent 40% ethyl acetate/heptane) to provide 5.61 g (75%) of the desired product. 1H NMR (DMSO-d6, 400MHz) δ 7.85 (d, 1H), 7.49-7.44 (m, 5H), 7.29 (d, 1H), 7.22 (t, 1H), 7.16-7.12 (m, 4H), 5.44 (br s, 2H); 13C NMR (DMSO-d6, 100 MHz) δ 156.9, 156.1, 154.5, 148.3, 141.8, 136.1, 130.9, 130.1, 123.9, 123.0, 119.2, 118.4, 118.1, 107.8.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[K+].Cl>C(O)C.O>[OH:1][C:2]1[C:3]([C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1csc(-c2ncccc2O)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1csc(-c2ncccc2O)n1
Yield: 92.4 %

Procedure:
To a solution of ethyl 2-(3-hydroxy-2-pyridyl)-4-thiazolecarboxylate (350 mg) dissolved in ethanol (7 ml) at 80° C. was added a solution of potassium hydroxide (436 mg) in water (5.5 ml) and the mixture was allowed to react at the same condition for 30 minutes. Then the reaction mixture was nuetralized with 1N--HCl under ice-cooling. The resulting solids were sucked off and dried to give yellowish crystals of 2-(3-hydroxy-2-pyridyl)-4-thiazolecarboxylic acid (287 mg, 92%), m.p. above 300° C.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18]1[CH:23]=[C:22](F)[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Sc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2ccccc2)cc1OCc1ccccc1
Reaction time: 1 h

Procedure:
A 60% suspension of sodium hydride in mineral oil (490 mg, 12.2 mmol) is stirred in 15 mL of DMF. To this mixture is carefully added benzenethiol (1.25 mL, 1.34 g, 12.2 mmol) and the mixture stirred for 1 h. To this solution is added portionwise 2-benzyloxy-4-fluoronitrobenzene (3.00 g, 12.1 mmol), giving initially a dark solution that eventually changed to pale yellow. When LC shows disappearance of starting material, the mixture is poured into ethyl acetate and extracted with water, 1N sodium hydroxide, and four times with brine. This solution is dried, filtered, and solvent removed under reduced pressure to leave a heterogeneous mixture that is triturated with hexane, filtered, and the solids washed with hexane to afford 2-benzyloxy-1-nitro-4-phenylsulfanylbenzene, mp 77-79° C.: NMR (CDCl3) δ 7.79 (d, 1H, J=8.6 Hz), 7.46 (m, 5H), 7.33 (m, 5H), 6.77 (d, 1H, J=1.8 Hz), 6.72 (dd, 1H, J=8.6, 1.8 Hz), 5.08 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:3]=1[O:4][CH2:5][C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7](O)=[O:8].CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[O:8]=[C:7]1[C@@H:6]([NH:10][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5][O:4][C:3]2[C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=[CH:21][C:2]=2[NH:1]1
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1c(N)cccc1C(F)(F)F)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1COc2c(cccc2C(F)(F)F)NC1=O
Yield: 88.9 %

Procedure:
A solution of (S)-3-(2-amino-6-(trifluoromethyl)phenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (1.23 g, 3.38 mmol) and EDCI (803 mg, 4.19 mmol) in DMF (25 mL) was stirred at RT for 6 h, diluted with EtOAc and washed with H2O. The combined aqueous washes were extracted with EtOAc and the combined organic solutions were dried over MgSO4, filtered. The filtrate was concentrated to give a residue that was purified by silica gel chromatography to afford the title compound (1.04 g, 89%) as a light brown oil. MS m/z 369 (M+Na)+
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(#N)C>[Br:13][CH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccc(=O)oc2c1
Solvent: CC#N
Product: O=c1ccc2ccc(CBr)cc2o1
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
To a solution of 7-methylcoumarin (50 g) in acetonitrile (1.2 L), N-bromosuccinimide (56 g) and α,α′-azobisisobutylonitrile (510 mg) were added, and the mixture was stirred for 30 minutes at 78° C. of inside temperature. The reaction mixture was concentrated, and water was added. The crystal was collected by filtration to give the title compound (76 g) having the following physical data.
Reaction SMILES: [CH2:1]([CH:3]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7]([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)(O)[C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[CH2:4]1)[CH3:2].Cl>C(O)(C)C>[CH2:1]([CH:3]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7](=[C:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCC1Cc2ccccc2C(O)(C2CCN(C)CC2)c2ccsc21
Agent: Cl
Solvent: CC(C)O
Product: CCC1Cc2ccccc2C(=C2CCN(C)CC2)c2ccsc21

Procedure:
A solution of 15.0 g of 10-ethyl-9,10-dihydro-4-(1-methyl-4-piperidyl)-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen-4-ol in 450 cc of a 3.5 N solution of hydrogen chloride in isopropanol is heated to the boil for 4 hours, and the title compound obtained after working up the reaction mixture is converted into the hydrogen fumarate form thereof. M.P. 220°-221° (from methanol/ethanol).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]1[CH2:17][CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.[CH3:30]I>CC(C)=O>[CH3:30][N:11]1[CH2:10][CH2:9][C:8]2[C:2](=[O:1])[N:3]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=3)[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[O:6][C:7]=2[CH2:12]1
Reactant: COC(=O)c1ccc(OCCN2C(=O)c3ccncc3Oc3ccccc32)cc1
Reactant: CI
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCN2C(=O)C3=C(CN(C)CC3)Oc3ccccc32)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
Title compound 448 (0.249 g, 0.638 mmol) was solubilized in acetone (15.0 mL) and the methyl iodide (2.0 mL) was added. The reaction mixture was stirred in a sealed tube at 60° C. for 18 hours. The mixture was cooled down and evaporated. The residue was dissolved in methanol (15 mL) and Pt black (55 mg) was added. The reaction mixture was stirred over 55PSI of hydrogen for 3 hours. The catalyst was filtered and the filtrate was evaporated. The crude was purified by flash chromatography (75-100% ethyl acetate in hexanes with 1.5% of ammonium hydroxide) to afford title compound 452 (133 mg, 51%). 1H NMR (DMSO-d6) δ (ppm): 7.89 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.0 Hz, 1H), 7.26 (t, J=7.7 Hz, 1H), 7.19 (t, J=7.7 Hz, 1H), 7.07 (dd, J=7.4, 1.2 Hz, 1H), 6.88 (d, J=8.2 Hz, 2H), 4.38 (t, J=4.9 Hz, 2H), 4.31 (t, J=4.9 Hz, 2H), 3.84 (s, 3H), 3.17 (s, 2H), 2.52-2.51 (m, 2H), 2.44 (m, 2H), 2.36 (s, 3H). MS (m/z): 409.4 (M+H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.[CH3:14][C:15]1[C:23]2[C:22]([N:24]3[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]3)=[N:21][CH:20]=[N:19][C:18]=2[S:17][CH:16]=1>CC(O)C.CS(C)=O>[OH:13][CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH:2]([OH:1])[CH2:3][NH:30][CH:27]1[CH2:26][CH2:25][N:24]([C:22]2[C:23]3[C:15]([CH3:14])=[CH:16][S:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:29][CH2:28]1
Reactant: OCc1cccc(OCC2CO2)c1
Reactant: Cc1csc2ncnc(N3CCC(N)CC3)c12
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Cc1csc2ncnc(N3CCC(NCC(O)COc4cccc(CO)c4)CC3)c12
Yield: 26 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 30 h at 80° C. and 20 h at 100° C.), using 220 μmol (3-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give the title compound with 26% yield upon purification by prep. HPLC (reversed phase) and subsequent by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1).
Reaction SMILES: [CH2:1]([NH:7][C:8]1[S:9][C:10](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[C:11](=[O:13])[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:28][CH2:29][C@H:30]([OH:39])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([NH:7][C:8]1[S:9][C:10](=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([NH:28][CH2:29][C@H:30]([OH:39])[CH2:31][O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:23][CH2:22]3)=[CH:19][CH:20]=2)[C:11](=[O:13])[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Reactant: NC[C@H](O)COc1ccccc1
Product: CCCCCCNC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)S1

Procedure:
The title compound was prepared from 1-[4-(2-hexylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Intermediate 32) and (2S)-1-amino-3-phenoxy-propan-2-ol(which was obtained in Intermediate 3) according to the procedure of Example 1 as a yellowish solid; mp 182-184° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 0.87(t, J=6.5 Hz, 3 H), 1.20-1.40 (m, 10 H), 1.50-1.65 (m, 2 H), 1.80-1.95 (m, 2 H), 2.60-4.00(m, 10 H), 6.85-6.95(m, 3 H), 7.02 (d, J=9.0 Hz, 2 H), 7.20-7.35 (m, 2 H), 7.40 (d, J=9.0 Hz, 2 H), 7.45 (s, 1 H), 9.62 (brs, 1 H); MS (ES) m/z: 269.1 ((M+2H)2+, 100%), 537.1(MH+, 20%); HRMS Calcd. for C30H41N4O3S (MH+): 537.2899. Found: 537.2875.
Reaction SMILES: [C:1]([Cl:5])(=O)[CH2:2][CH3:3].[ClH:6].Cl.[CH:8]1[CH:17]=[CH:16][C:15]2[CH2:18][CH2:19][CH2:20][N:13]3[C:14]=2[C:9]=1[C@H:10]1[CH2:23][NH:22][CH2:21][C@H:11]1[CH2:12]3>>[ClH:5].[ClH:6].[CH2:1]([N:22]1[CH2:23][C@H:10]2[C@H:11]([CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C:15]4[CH:16]=[CH:17][CH:8]=[C:9]2[C:14]3=4)[CH2:21]1)[CH2:2][CH3:3]
Reactant: c1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CCC2
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCCN1C[C@H]2CN3CCCc4cccc(c43)[C@H]2C1

Procedure:
Using propionyl chloride and following the procedures described in EXAMPLE 102, (±)-cis-5,6,8,8a,9,10,11,11a-octahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline free base from EXAMPLE 11 was converted into the title compound of EXAMPLE 103 as an off-white powder. 1H NMR (dmso-D6) δ: 11.10 (broad s, 1H), 6.90-6.77 (m, 2H), 6.63-6.55 (m, 1H), 3.99-3.90 (m, 1H), 3.85-3.75 (m, 1H), 3.67-3.58 (m, 1H), 3.50-3.35 (m, 2H), 3.15-2.93 (m, 4H), 2.90-2.75 (m, 3H), 2.70-2.63 (m, 2H), 1.95-1.85 (m, 2H), 1.70-1.59 (m, 2H), 0.91-0.82 (m, 3H). LRMS (ES)+: 257.1 (M+H)+.