Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:11]([NH:14][C@@H:15]([CH2:19][NH:20][C:21](=[O:39])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)=[CH:24][CH:23]=2)[C:16]([OH:18])=[O:17])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:40](O)[CH3:41]>S(=O)(=O)(O)O>[CH2:40]([O:17][C:16](=[O:18])[C@@H:15]([NH:14][S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12])[CH2:19][NH:20][C:21](=[O:39])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]2[NH:37][CH2:36][CH2:35][CH2:34][N:33]=2)=[CH:24][CH:23]=1)[CH3:41]
Reactant: O=C(CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)O)cc1)NC1=NCCCN1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1cccc2ccccc12
Reaction time: 3 h

Procedure:
590 mg of (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid was dissolved in 80 ml of ethanol and 12 drops of concentrated sulfuric acid was added. The reaction solution was boiled for 3 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted once with dichloromethane and the combined organic phase was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was dissolved in 2N aqueous hydrochloric acid. The hydrochloric acid was removed in vacuo, the residue was dissolved in acetonitrile and added to water. This mixture was lyophilized. Yield 381 mg. MS (ES+): m/e=580.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[S:11][CH2:10][CH:9](C(O)=O)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.ClN1C(=[O:22])CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[S:11][CH2:10][C:9](=[O:22])[CH2:8]2
Reactant: COc1cccc2c1SCC(C(=O)O)C2
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COc1cccc2c1SCC(=O)C2
Reaction time: 0.25 h

Procedure:
To a solution 8-methoxy-3,4-dihydro-2H[1]-benzothiopyran-3-carboxylic acid (10 g) in 200 ml of methylene chloride is added 6.2 g of N-chlorosuccinimide in portions. After 10 minutes 60 g of silica gel is added. The reaction mixture is stirred for 15 minutes, filtered through 40 g of silica gel eluting with ether/methylene chloride (1:1). The solvent is concentrated to 100 ml, 5 ml of triethylamine and 5 g of ethyl chloroformate are added. After concentration 5 g of sodium azide in 60 ml of DMF are added and the reaction mixture is stirred for 1 hour. After dilution with water the products are extracted with ether, the ether extract is dried and evaporated to dryness; 150 ml of 10% aqueous sulfuric acid is added and the reaction mixture is heated under reflux for 2 hours. The reaction mixture is extracted with ether, the ether extract is washed with dilute sodium bicarbonate solution, dried and evaporated to dryness. Crystallization from methanol affords 8-methoxythiochroman-3-one, melting point 60°.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[C:2]1[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:13][C:12]([C:2]1[O:1][C:10]2[C:5]([C:4](=[O:11])[CH:3]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:14]
Reactant: O=C(O)c1cc(=O)c2ccccc2o1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(=O)c2ccccc2o1
Temperature: 0 °C

Procedure:
Combine chromone-2-carboxylic acid (2.0 g, 10.5 mmol) and methanol (25 mL). Add sulfuric acid (2.5 mL) and heat to reflux. After 2 hours pour the reaction mixture into ice water and filter. Rinse the filter cake with water and a cold dilute aqueous solution of sodium bicarbonate. Chromatograph on silica gel eluting with tetrahydrofuran to give a residue. Recrystallize the residue from methanol to give the title compound as a solid: mp; 120°-122° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:6])[CH3:5].[CH:7]12[O:13][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]2>[OH-].[Na+]>[OH:6][CH:4]([CH3:5])[CH2:3][O:2][CH2:1][O:13][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:7]1
Reactant: COCC(C)O
Reactant: C1CCC2OC2C1
Agent: [Na+]
Agent: [OH-]
Product: CC(O)COCOC1CCCCC1
Yield: 27.4 %

Procedure:
45 g (0.5 mole) of propylene glycol methyl ether (PM), 33 g (0.33 mole) of cyclohexene oxide and 0.3 g (0.007 mole) of sodium hydroxide were charged in a 100 ml eggplant type flask equipped with a reflux tube, and a reaction was allowed to proceed under reflux at a temperature for a reflux reaction for 10 hours. Results of the analysis of the resultant reaction mixture by GC showed that the conversion of PM was 20%. Then, the obtained reaction mixture was subjected to distillation, to thereby obtain 17 g of 2-hydroxycyclohexyloxymethoxypropane, i.e., propylene glycol methyl 2-hydroxycyclohexyl ether (hereinafter referred to as "PGMHCHE"). The IR spectrum of the product is shown in FIG. 3. Other properties of the product were measured and results are shown in Table 1.
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4](OCC)=[O:5].[CH3:13][C:14]1([CH3:31])[CH2:18][C:17]2[C:19]([CH3:30])=[C:20]([CH3:29])[C:21]([CH:24]=[CH:25][C:26](=[O:28])[CH3:27])=[C:22]([CH3:23])[C:16]=2[O:15]1.[OH-].[Na+]>CO>[CH3:13][C:14]1([CH3:31])[CH2:18][C:17]2[C:19]([CH3:30])=[C:20]([CH3:29])[C:21]([CH:24]3[CH2:3][C:4](=[O:5])[CH:27]=[C:26]([OH:28])[CH2:25]3)=[C:22]([CH3:23])[C:16]=2[O:15]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1c(C)c(C)c2c(c1C)OC(C)(C)C2
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C)c(C2CC(=O)C=C(O)C2)c(C)c2c1CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3.8 g of sodium 140 ml of absolute methanol was added 25 ml of diethyl malonate. After stirring for 20 minutes, the mixture was added 42.4 g of the 4-(2,3-dihydro-2,2,4,5,7-pentamethylbenzofuran-6-yl)-3-butene-2-one in 140 ml of absolute methanol, refluxed for 4 hours and 200 ml of 10% aqueous solution of sodium hydroxide. The reaction mixture was cooled to room temperature and washed with diethyl ether. 2N aqueous solution of hydrochloric acid was added dropwise into the aqueous layer until the bubble ceased. And then, solid was dissolved in ethyl acetate and washed with water. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford 38.8 g of 5-(2,3-dihydro-2,2,4,5,7-pentamethylbenzofuran-6-yl)-3-hydroxycyclohex-2-en-1-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:29]([O:31][CH3:32])=[O:30])([CH2:26][CH:27]=C)[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:34].[Na+].O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@:9]([C:29]([O:31][CH3:32])=[O:30])([CH2:26][CH:27]=[O:34])[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])=[O:18])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@@](CC1CCN(C(=O)OCC[Si](C)(C)C)CC1)(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@](CC=O)(CC1CCN(C(=O)OCC[Si](C)(C)C)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
750 mg of 2-trimethylsilanylethyl (S)-4-(2-tert-butoxycarbonylamino-2-methoxycarbonylpent-4-enyl)piperidine-1-carboxylate were dissolved in 30 ml of THF. 852 mg of sodium periodate and 10 ml of water were added. The mixture was then stirred at room temperature for 3 h and filtered through kieselguhr. The filter cake was washed twice with 10 ml of THF each time. The THF was removed in vacuo, and the residue was partitioned between 30 ml of water and 30 ml of ethyl acetate. The pH of the aqueous phase was adjusted to 2 with 1 N HCl solution. The phase were separated and the aqueous phase was extracted twice with 20 ml of ethyl acetate each time. The combined organic phases were dried with MgSO4. The solvents were removed in vacuo and the residue was chromatographed on silica gel.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl.C(O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(I)cc1
Reactant: C1CCNCC1
Solvent: CCO
Solvent: ClCCl
Product: Ic1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 1.1 c. from 4-iodobenzyl bromide and piperidine. Yield: 0.85 g (67% of theory); C12H16IN (M=301.17); calc.: molecular ion peak (M+H)+: 322; found: molecular ion peak (M+H)+: 302; Rf value: 0.55 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: [F:1][C:2]1[C:8]([OH:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[OH:4].[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O.O>CS(O)(=O)=O>[F:10][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([F:1])[C:8]=1[OH:9])[O:4][C:11](=[O:16])[CH:12]=[C:13]2[CH3:15]
Reactant: CCOC(=O)CC(C)=O
Reactant: Oc1ccc(F)c(O)c1F
Agent: CS(=O)(=O)O
Solvent: O
Product: Cc1cc(=O)oc2c(F)c(O)c(F)cc12
Yield: 49 %

Procedure:
A solution of 2,4-difluororesorcinol (Compound 4; 1.00 g, 8.76 mmol) and ethyl acetoacetate (1.14 g, 8.76 mmol) in 5 mL methanesulfonic acid is kept at room temperature for 24 hours, then poured into water (75 mL). The resulting precipitate is collected, rinsed with water and dried, giving 0.91 g of Compound 5 as a tan powder. An analytical sample is prepared by crystallization from light petroleum ether/methanol, giving the Compound 5 as colorless needles. UV-vis (pH 7 buffer): 358 nm, ε=17,700 cm-1M-1 ; ex/em 358/452 nm. 1H NMR (CDCl3) δ7.12 (dd, 1H), 6.27 (s, 1H), 2.38 (s, 3H). 19F NMR (CDCl3) Φ 136.5 (t, 1F), 152.8 (t, 1F).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][OH:11])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)CC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
In a round-bottom flask, (2S)-2-[(tert-butoxy)carbonylamino]-4-(methoxycarbonyl)butanoic acid (78 mmol, 20.36 g) was dissolved in THF (300 mL). The solution was cooled to −10° C. and N-methylmorpholine (78 mmol, 8.58 mL) and ethyl chloroformate (78 mmol, 7.48 mL) were added, followed by sodium borohydride (234 mmol, 8.85 g). The reaction was stirred for 30 min at this temperature and then quenched by slow addition of saturated solution of ammonium chloride until no further evolution of hydrogen was observed. The reaction mixture was then extracted with ethyl acetate and dried over magnesium sulfate. After filtration, solvent was evaporated and the crude material was purified by column chromatography (SiO2, 1:1 n-hexanes/ethyl acetate) to yield the title compound (11.68 g, 61% yield). ES-MS: 248 (M+1).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[CH:15]([Sn](CCCC)(CCCC)CCCC)=[CH2:16]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH:1]([NH:4][C:5](=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:15]=[CH2:16])=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)Cc1ccc(Br)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc(CC(=O)NC(C)C)cc1
Yield: 72.8 %

Procedure:
N-Isopropyl-4-bromophenylacetamide (1.0 g) and vinyltributyltin (1.4 ml) were dissolved in toluene (12 ml). After adding tetrakistriphenylphosphinepalladium (0.5 g) thereto, the resultant mixture was heated under reflux for 4 hr. Then it was allowed to cool and diluted with ethyl acetate. The resulting solid was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give colorless crystals (0.578 g) of the title compound (yield: 72.8%).
Reaction SMILES: [CH3:1][C:2]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH3:17])([CH3:11])[CH:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:18][C:19]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:18][C:19]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:2]([CH3:1])([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH3:17])[CH3:11])=[O:22]
Reactant: CC1CCCN1C(C)(C)C(N)c1ccccc1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1CCCN1C(C)(C)C(NC(=O)c1cccc(C(F)(F)F)c1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
A mixture of [2-methyl-2-(2-methyl-1-pyrrolidinyl)-1-phenylpropyl]amine D26 (0.150 g; 0.647 mmol), 2-chloro-3-(trifluoromethyl)benzoic acid (0.174 g; 0.775 mmol), EDC (0.149 g; 0.777 mmol) and HOBt (0.020 g; 0.148 mmol) in DCM (4 ml) was shaken at room temperature for 66 hours. Saturated sodium hydrogen carbonate (8 ml) was added and shaking continued for 0.5 hours. The organic layer was passed through a phase separation cartridge and applied to a 2 g SCX column. The column was washed with DCM and methanol and the product eluted with 1M ammonia in methanol. The crude product was purified by chromatography on silica gel (20 g) eluting with 0-100% ethyl acetate in pentane gradient to afford the title compound as two pairs of enantiomers.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=O)[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]([CH2:20][C:21]#[N:22])=[C:15]([C:18]#[N:19])[C:16]#[N:17].C(O)(=O)C.C([SiH](CC)CC)C>C(O)C>[NH2:17][C:16]1[N:22]=[C:21]2[O:12][C:7]3[C:8]([CH2:9][C:20]2=[C:14]([NH2:13])[C:15]=1[C:18]#[N:19])=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: N#CCC(N)=C(C#N)C#N
Agent: CC[SiH](CC)CC
Solvent: CC(=O)O
Solvent: CCO
Product: N#Cc1c(N)nc2c(c1N)Cc1cc([N+](=O)[O-])ccc1O2
Temperature: 66 °C
Yield: 60.1 %

Procedure:
5-nitrosalicylaldehyde (132 mmol, 22.00 g), 2-amino-1-propene-1,1,3-tricarbonitrile (132 mmol, 17.39 g), acetic acid (31 mL), and ethanol (500 mL) were combined and heated to reflux overnight. The resulting slurry was concentrated in vacuo and then dissolved in trifluoroacetic acid (350 mL) at 0° C. Triethylsilane (1.40 mol, 162 g, 225 mL) was added. The mixture was heated overnight at 66° C. The mixture was cooled and concentrated in vacuo. Triturating with methanol gave 2,4-diamino-7-nitro-5H-chromeno[2,3-b]pyridine-3-carbonitrile as a yellow solid (22.48 g, 60% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.13 (d, J=9.0 Hz, 1H), 8.00 (s, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.70 (br s, 2H), 6.50 (bs, 2H), 3.82 (s, 2H); m/z 284 (M+H); Anal. Calcd for C13H9N5O3-0.5H2O: C, 53.43; H, 3.45; N, 23.96, found: C, 53.41; H, 3.17; N, 23.71.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH2:4][CH2:3]1.[CH2:14](OC(=N)C(Cl)(Cl)Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)S(O)(=O)=O>C1CCCCC1.C(Cl)Cl>[CH2:14]([O:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH2:4][CH2:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CON(C)C(=O)[C@H]1CC[C@@H](O)CC1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CON(C)C(=O)[C@H]1CC[C@@H](OCc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To a mixture of cis-4-hydroxy-N-methoxy-N-methylcyclohexanecarboxamide (3.556 g, 0.0190 mol) and benzyl-2,2,2-trichloroacetimidate (4.0 mL, 0.021 mol, 1.1 eq) in cyclohexane/DCM (20 mL/10 mL) at 0° C. was added trifluoromethanesulfonic acid dropwise with stirring under nitrogen atmosphere over 30 min. There was an immediate precipitate. The mixture was stirred at room temperature for 15 h, filtered, and the filtrate washed with sodium bicarbonate solution and brine. The organic layer was concentrated and purified by silica gel column chromatography using petroleum ether/ethyl acetate (5/1) as eluent to give product as a colorless oil (5.079 g, 77%). 1H NMR (400 MHz, CDCl3) δ 7.38-7.23 (m, 5H), 4.50 (s, 2H), 3.71 (s, 3H), 3.70-3.66 (m, 1H), 3.18 (s, 3H), 2.78-2.62 (m, 1H), 2.07-1.89 (m, 4H), 1.59-1.25 (m, 4H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:20])[CH2:9][C:10]([C:12]1[CH:17]=[C:16](OC)[CH:15]=[CH:14][N:13]=1)=[O:11].C[C:22](O)=[O:23]>Cl.O>[CH3:22][O:23][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:11][C:2]3[C:3]([C:8](=[O:20])[CH:9]=2)=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:13][CH:14]=1
Reactant: CC(=O)O
Reactant: COc1ccnc(C(=O)CC(=O)c2ccccc2O)c1
Agent: Cl
Solvent: O
Product: COc1ccc(-c2cc(=O)c3ccccc3o2)nc1
Temperature: 100 °C
Yield: 98 %

Procedure:
1-(2-Hydroxy-phenyl)-3-(4-methoxy-pyridin-2-yl )-propane-1,3-dione (870 mg, 3.21 mmol) was dissolved in a mixture of 48% HCl (1 mL) and AcOH (10 mL) and heated at 100° C. for 1 h. The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried and concentrated to give 2-(5-methoxy-pyridin-2-yl)-chromen-4-one (794 mg, 98%).
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].O=O>[Pd].CO>[CH3:1][CH:2]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:13][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)/C(C)=C/c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=O
Solvent: CO
Product: CCOC(=O)C(C)Cc1ccc(C(F)(F)F)cc1
Reaction time: 16 h
Yield: 91.8 %

Procedure:
Dissolve ethyl(E)-2-methyl-3-[4-(trifluoromethyl)phenyl]prop-2-enoate (2.58 g, 10 mmol) in a suspension of 10 wt % Pd—C (258 mg)/MeOH (20 mL) in an RBF under nitrogen, as exposure of Pd—C to oxygen can lead to fire. Carefully purge the flask with hydrogen and stir the resulting mixture under hydrogen (1 Atm) for 16 h. Purge the flask nitrogen and degas the solvent to remove all hydrogen before exposing to air. Filter the suspension through a pad of celite. Concentrate the filtrate to give the title compound (2.39 g).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[OH:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:40][C:41]([NH2:43])=[O:42]>CC(C)=O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH2:40][C:41](=[O:42])[NH2:43])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1)c1ccccc1O
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)COc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1
Yield: 95.4 %

Procedure:
To a solution of 5-oxo-1-[4-(2-hydroxybenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (400 mg) in acetone (20 ml) are added potassium carbonate (210 mg), potassium iodide (250 mg) and 2-chloroacetamide (120 mg), and the mixture is refluxed for 2 hours. The insoluble materials are removed by filtration, and the filtrate is distilled off. Dichloromethane is added to the resulting residue, and the mixture is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is recrystallized from ethyl acetate/n-hexane to give 5-oxo-1-[4-(2-carbamoylmethoxybenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (436 mg) as white powder, m.p. 226°-228° C.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:10]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=2[CH:12]=O)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:22][N:23]1[N:27]=[N:26][C:25]([NH2:28])=[N:24]1.C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1([C:10]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=2[CH2:12][NH:28][C:25]2[N:26]=[N:27][N:23]([CH3:22])[N:24]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cn1nnc(N)n1
Reactant: COC1(c2ccc(C(F)(F)F)cc2C=O)CCCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC1(c2ccc(C(F)(F)F)cc2CNc2nnn(C)n2)CCCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.1 %

Procedure:
A mixture of 2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzaldehyde (118 mg, 0.393 mmol) and 2-methyl-2H-tetrazol-5-amine (148 mg, 1.49 mmol) in toluene (3 mL) was heated at reflux for 16 hours, after which solvent was removed to give a gummy solid. Ethanol (3 mL) and sodium borohydride (25 mg; 0.660 mmol) were added to the residue. The resulting mixture was stirred at room temperature for 16 hours. Solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate and washed twice with water and dried over sodium sulfate and concentrated under reduced pressure. The crude was purified over 4 g RediSep (eluted with 20-60% ethyl acetate in heptane) to give 83 mg (55% yield) of title compound. MS (ES+): Calc: 383.4, Found: 352.3 (M-OMe). 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (s, 1H), 7.48 (dd, J=8.77 Hz, 1H), 7.42 (d, J=8.30 Hz, 1H), 4.92 (d, J=6.22 Hz, 2H), 4.75 (t, J=6.22 Hz, 1H), 4.16 (s, 3H), 3.03 (s, 3H), 2.26 (m, 2H), 2.07 (m, 2H), 1.88-1.77 (m, 2H), 1.75-1.65 (m, 2H), 1.64-1.52 (m, 4H).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:12][CH:13]([OH:16])[C:14]#[CH:15]>CN(C=O)C.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.[Cu]I>[OH:16][CH:13]([CH3:12])[C:14]#[C:15][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C#CC(C)O
Reactant: COC(=O)c1ccccc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1C#CC(C)O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Pd(PPh3)4 (1.9 g, 0.006 eq) and CuI (2.6 g, 0.05 eq) were suspended in DMF (350 ml). Methyl 2-iodobenzoate (70.8 g, 1 eq), but-3-yn-2-ol (32 ml, 1.5 eq), TEA (75 ml, 2 eq) were added under nitrogen atmosphere and the mixture was stirred at 60° C. for 6 hrs and at RT. overnight. The precipitated solid was filtered off, the mother liquors was diluted with a saturated solution of NaClaqueous and extracted with EtOAc (twice). The collected organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound, as a brownish thick oil (47.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:24])=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2.[CH:25]([N:28]=[C:29]=[O:30])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:29]([NH:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([NH:12][CH:10]1[C:11]3[C:7](=[C:6]([CH3:24])[CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[CH2:8][CH2:9]1)[CH:22]=[CH:21]2)=[O:30])([CH3:27])[CH3:26]
Reactant: COc1ccc(C)c2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: CC(C)N=C=O
Product: COc1ccc(C)c2c1C(Nc1ccc3cc(NC(=O)NC(C)C)ccc3n1)CC2

Procedure:
Rac-N2-(7-methoxy-4-methyl-indan-1-yl)-quinoline-2,6-diamine was obtained from (7-methoxy-4-methyl-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine according to the general procedure described in step B of example 2; MS: m/e=320.6 (M+H+). Step E: The title compound was prepared in accordance with the general method described in example 3 from rac-N2-(7-methoxy-4-methyl-indan-1-yl)-quinoline-2,6-diamine and isopropyl isocyanate; MS: m/e=405.6 (M+H+).