Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:19])[C:17]#[CH:18].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:19][CH2:16][C:17]#[CH:18])[N:3]=[CH:4][N:5]=1
Reactant: C#CCO
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
In 6 ml of N,N-dimethylformamide were dissolved 96 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 26 mg of 2-propyn-1-ol, to which 19 mg of sodium hydride. (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 42 mg of 4-(2,3-difluorophenyl)-6-(2-propynyloxy)pyrimidine (the present compound (82)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([O:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:6].[CH:24](O)=[O:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([O:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:6])=[O:25]
Reactant: Nc1cccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c1
Reactant: O=CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=CNc1cccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c1
Yield: 91.7 %

Procedure:
0.26 g (0.000838 mol) of 1-benzyl-piperidin-4-yl 3-amino-benzoate was dissolved in 8.5 ml of toluene, treated with 0.84 ml (0.0222 mol) of formic acid and boiled at reflux for 12 hrs. The mixture was freed from solvent and the residue was taken up in ethyl acetate and washed with sat. carbonate solution and sodium chloride solution. It was dried over sodium sulfate. 0.26 g (92%) of 1-benzyl-piperidin-4-yl 3-formamido-benzoate was obtained as a brownish oil. MS: me/e=339 (C20H23N2 O3 +).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8]([C:10]1[S:11][C:12]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=2[N:14]=1)#N>>[CH2:3]1[S:4]/[C:8](=[C:10]2/[N:14]=[C:13]3[C:12]([S:11]/2)=[CH:18][C:17](=[O:19])[CH:16]=[CH:15]3)/[NH:1][C@H:2]1[C:5]([OH:7])=[O:6]
Reactant: N[C@H](CS)C(=O)O
Reactant: N#Cc1nc2ccc(O)cc2s1
Product: O=C1C=Cc2n/c(=C3\N[C@@H](C(=O)O)CS3)sc2=C1

Procedure:
First, in Step 1, a reagent for quantitating D-cysteine is added to a sample. If D-cysteine is present in the sample, it reacts with 2-cyano-6-hydroxybenzothiazole to produce D-luciferin. Then, in Step 2, a bioluminescent reagent is added to the sample to measure the generated luminescent level with a luminometer. Finally, the D-cysteine level in the sample is calculated from the luminescent level based on the calibration curve prepared beforehand.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH:14]=[CH:13][NH:12][CH2:11][C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:16][C:17]1[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH:13]=[CH:14][C:15]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=[N:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: C1=Cc2c(ncn2-c2ccccc2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1C=Cc2c(ncn2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of the product of Example 49, Step A (5.5 mg, 0.028 mmol) in DCM (3 mL) was added TEA (11 μL, 0.084 mmol), 2-chloro-3-(trifluoromethyl)benzoic acid (7 mg, 0.031 mmol) and HATU (13 mg, 0.033 mmol). The reaction was stirred at room temperature overnight. The crude reaction mixture was concentrated and purified on 4 g SiO2 column with 0-3% NH3/MeOH CH2Cl2 to give the desired compound (9.9 mg, 87%). MS (ESI): mass calcd. for C20H13ClF3N3O, 403.1. m/z found, 404.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.09 (m 1H), 7.94-7.84 (m, 1H), 7.76-7.53 (m, 2H), 7.53-7.39 (m, 2H), 7.39-7.22 (m, 4H), 6.96-6.86 (m, 1H), 6.73 (s, 1H), 5.95 (q, J=7.0 Hz, 1H), 5.54 (s, 1H), 3.22 (q, J=7.3 Hz, 2H), 1.37 (t, J=7.3 Hz, 3H).
Reaction SMILES: BrN1C(=[O:7])CCC1=O.[BrH:9].[C:10]([CH:18]([CH2:24][C:25](Br)=[CH2:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O.C(OCC)C>[C:10]([C:18](=[CH:24][C:25](=[O:7])[CH2:26][Br:9])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(Br)CC(C(=O)OCC)C(=O)c1ccccc1
Reactant: Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)C(=CC(=O)CBr)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 58 %

Procedure:
N-bromosuccinimide (0.95 g, 5.3 mmol) and a drop of hydrobromic acid were added to a solution of ethyl 2-benzoyl-4-bromo-4-pentenoate (1.5 g, 4.82 mmol) in acetonitrile (16 ml) and water (4 ml), followed by stirring at room temperature for 3 hours and 40 minutes. The reaction mixture was diluted with diethyl ether, and a 5% aqueous sodium thiosulfate solution was added to separate the mixture into layers. The organic layer was washed twice with a saturated aqueous sodium hydrogencarbonate solution, washed with a saturated salt solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1). The solvent was distilled off under reduced pressure, to thereby obtain 0.91 g (yield: 58%) of ethyl 2-benzoyl-5-bromo-4-oxopentenoate as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[CH:22]=[CH:23][O:24][CH2:25][CH3:26])CCC>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>[Cl:8][C:5]1[N:4]=[C:3]([NH2:9])[C:2]([CH:22]=[CH:23][O:24][CH2:25][CH3:26])=[CH:7][N:6]=1
Reactant: Nc1nc(Cl)ncc1Br
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC=Cc1cnc(Cl)nc1N
Temperature: 110 °C
Reaction time: 15 h
Yield: 45.9 %

Procedure:
A 500 mL round bottomed flask is charged with 5-bromo-2-chloropyrimidin-4-ylamine (1) (10 g, 48 mmol), tetrakis(triphenylphosphine)palladium(0) (2.8g, 2.5 mmol), and toluene (200 mL). Tributyl-(2-ethoxyvinyl)-stannane (22 g, 60 mmol) is added and the reaction heated to 110° C. with stirring for approximately 15 hours. After cooling to room temperature, the solution is diluted with 100 mL ethyl acetate and washed with water and brine. The organic extract is dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, Hexane:Ethyl acetate/5:1) provides 2 (4.4 g, 46%) as a yellow solid.
Reaction SMILES: N#N.[NH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>C(OCC)C.C1COCC1>[CH3:17][C:18]([CH3:23])([CH3:22])[C:19]([NH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:20]
Reactant: Nc1cccnc1
Reactant: CC(C)(C)C(=O)Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1cccnc1
Temperature: 0 °C
Yield: 76.1 %

Procedure:
Equip a 250-mL round bottom flask with an ice bath, a magnetic stirrer, and a N2 atmosphere. Add 3-aminopyridine (15 g, 159 mmol), THF (60 mL), diethylether (60 mL), triethylamine (17.7 g, 24.4 mL, 175 mmol). Cool the mixture to 0° C. and add trimethylacetyl chloride (21.0 g, 14.9 mL, 175 mmol) slowly via syringe. Mix overnight while warming to RT. Add water (100 mL), transfer to a separatory funnel, and extract and discard the lower aqueous layer. Dry the organic layer over Na2SO4, filter, and concentrate via a rotovap to a colorless oil that solidifies on cooling. Dry under high vacuum for 2.5 h to give the title compound as a tan solid 21.56 g (76%). MS (ES) m/z 179 [M+1]+.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:7]=1[NH2:8].[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19][C:20]([CH3:22])=[O:21].C([O-])(=O)C.[Na+]>S(=O)(=O)(O)O.C(O)(=O)C.C(O)C>[Cl:5][C:6]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:7]=1[NH:8][N:1]=[C:19]([C:20](=[O:21])[CH3:22])[C:18]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(=NNc1c(Cl)cc(C(F)(F)F)cc1Cl)C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of sodium nitrite (45 g) in concentrated sulphuric acid (340 ml) was added to a solution of 2,6-dichloro-4-trifluoromethylaniline (140 g) in glacial acetic acid (550 ml) while maintaining the temperature below 25°. The mixture was stirred at room temperature for one hour, and was added quite rapidly to a stirred mixture of ethyl acetoacetate (80 g), sodium acetate (180 g), ethanol (300 ml) and ice-water (3 1). After 1 hour, the brown solid was filtered and dried to give ethyl 2-(2,6-dichloro-4-trifluoromethylphenylhydrazono)-3-oxobutyrate.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)([OH:13])N.Cl([O-])=O.[Na+].C(OCC)(=O)C>O1CCOCC1.O>[N+:1]([C:4]1[S:8][C:7]([C:9]([OH:13])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NS(=O)(=O)O
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc([N+](=O)[O-])s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 193.9 %

Procedure:
A mixture of 5-nitrothiophene-2-carbaldehyde (1.685 g, 10.72 mmol) and sulfamic acid (1.249 g, 12.87 mmol) in dioxane (30 ml) was cooled to 0° C., and a solution of sodium chlorite (1.940 g, 21.44 mmol) in water (14 ml) was added drop-wise. The mixture was allowed to warm to RT and stirred for 2 hours. A second batch of 5-nitrothiophene-2-carbaldehyde (1.966 g, 12.51 mmol) was reacted under the same conditions using the molar ratios described above. The two reaction mixtures were combined and portioned between ethyl acetate and water. The organic layer was extracted twice with 5% NaHCO3 and the organic phase was discarded. The basic aqueous phase was acidified with 2N HCl (pH=2) and extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate; the solvent was removed affording 5-nitrothiophene-2-carboxylic acid (Int. 53) (3.6 g, 20.79 mmol, MS/ESI+173.9 [MH]+).
Reaction SMILES: C(N=C=NC(C)C)(C)C.[Cl:10][C:11]1[C:12]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[C:30]#[N:31])=[CH:13][C:14](=[O:22])[N:15]([CH:17]([CH3:21])[C:18]([OH:20])=O)[CH:16]=1.[NH2:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([F:42])[CH:34]=1>ClC(Cl)C>[Cl:10][C:11]1[C:12]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[C:30]#[N:31])=[CH:13][C:14](=[O:22])[N:15]([CH:17]([CH3:21])[C:18]([NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([F:42])[CH:34]=2)=[O:20])[CH:16]=1
Reactant: CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc(C(=O)O)c(F)c1
Agent: CC(C)N=C=NC(C)C
Solvent: CC(Cl)Cl
Product: CC(C(=O)Nc1ccc(C(=O)O)c(F)c1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Reaction time: 0.17 h

Procedure:
Under argon and at RT, 37 mg (0.30 mmol, 1.0 eq.) of N,N′-diisopropylcarbodiimide were added to a solution of 100 mg (0.30 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 12.1D) in 2 ml of dichloroethane, the mixture was stirred for 10 min, 46 mg (0.30 mmol) of 4-amino-2-fluorobenzoic acid were added and the mixture was stirred under reflux overnight. Subsequently, the reaction mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (Reprosil C18, water/methanol gradient). Yield: 41 mg (29% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=3[F:27])[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:28].[I-].N.CCO>>[NH2:28][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=3[F:27])[CH2:10]2)[N:12]=1
Reactant: [NH4+]
Reactant: CSC1=NC2(CC(c3cccc(F)c3F)Oc3ccc(Br)cc32)C(=O)N1C
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(c3cccc(F)c3F)Oc3ccc(Br)cc32)N=C1N
Yield: 59.2 %

Procedure:
A solution of 6-bromo-2-(2,3-difluorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (63 mg, 0.14 mmol), NH4I (60.6 mg, 0.42 mmol) in a solution of NH3/EtOH (3 mL, 1.5 N) was heated at 110° C. in a tube under microwave reactor for 3 hrs. After cooling, the mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(2,3-difluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (35 mg, 60%). 1H-NMR (CDCl3): 2.31 (d, 1H), 2.45 (t, 1H), 3.27 (s, 3H), 6.12 (d, 1H), 6.87 (m, 1H), 7.09 (m, 3H), 7.34 (m, 2H), 7.45 (m, 1H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH2:12][CH2:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6](=[CH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:41][OH:42]>[Cl-].[Na+].O.CN(C=O)C>[CH:1]1[C:11]2[C:10]3[CH2:12][CH2:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6](=[CH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:41][OH:42])=[O:27])=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(O)CCCCCNC(=O)C=C1C=CC2=C(CCC=C2)c2ccccc21
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(C=C1C=CC2=C(CCC=C2)c2ccccc21)NCCCCCC(=O)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
6-(2-(10,11-dihydro-5H-dibenzocyclohepten-5-ylidene)acetamido)hexanoic acid (363 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (178 mg, 47%) as a yellow solid. LC-MS (m/z) 379 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][N:35]([CH3:54])[CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:41]=[N:42][C:43]([C:46]2[CH:47]=[C:48]([CH2:52]O)[CH:49]=[CH:50][CH:51]=2)=[N:44][CH:45]=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[CH3:54][N:35]([CH3:34])[CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[N:44][C:43]([C:46]2[CH:47]=[C:48]([CH:49]=[CH:50][CH:51]=2)[CH2:52][N:6]2[C:5]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=3[O:3][C:2]2=[O:1])=[N:42][CH:41]=1
Reactant: COC(=O)c1ccc2oc(=O)[nH]c2c1
Reactant: CN(C)CCCOc1cnc(-c2cccc(CO)c2)nc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2oc(=O)n(Cc3cccc(-c4ncc(OCCCN(C)C)cn4)c3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.84 g (9.5 mmol) of methyl 2-oxo-2,3-dihydrobenzoxazole-5-carboxylate and 4.75 g (14.25 mmol) of polymer-bound triphenylphosphine (3 mmol/g) are added to a solution of 3.03 g (10.45 mmol) of {3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]phenyl}methanol in 40 ml of THF. The suspension is shaken at room temperature for 30 min. The suspension is cooled in an ice bath, and 3.35 g (14.25 mmol) of di-tert-butyl-azodicarboxylate are added in portions. After the mixture has been stirred at room temperature for 24 h, a further 4.75 g (14.25 mmol) of polymer-bound triphenylphosphine (3 mmol/g) and 3.35 g (14.25 mmol) of di-tert-butyl azodicarboxylate are added, and the mixture is shaken at room temperature for a further 24 h. The reaction mixture is filtered, the filtrate is evaporated to dryness, and the residue is purified by column chromatography on silica gel, giving 947 mg of “A64”; m.p. 125° C., ESI: 463 (M+H); Rt=3.07 min (method C);
Reaction SMILES: [O:1]1[CH:5]([CH2:6][NH2:7])[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[C:2]1=2.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].CC1C=CC(S(OC)(=O)=O)=CC=1>>[O:1]1[CH:5]([CH2:6][NH:7][C:26](=[O:27])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[C:2]1=2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2ccc3c(c2O1)CCCC3
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2ccc3c(c2O1)CCCC3)OCc1ccccc1
Yield: 79.1 %

Procedure:
Treatment of (±)-1-(2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-yl)methanamine (0.846 g, 4.16 mmol) with diisopropylethylamine (0.592 g, 4.58 mmol) followed by benzyl chloroformate (0.745 g, 4.37 mmol) generally according to the procedure described for Intermediate 7 provided 1.11 g (79%) of (±)-benzyl 2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-ylmethylcarbamate as a white solid. Rf=0.39 (silica, ethyl acetate:hexanes 1:4); mp 88-90° C.; 1H NMR (DMSO-d6) δH 7.49 (t, 1H); 7.33 (m, 4H); 6.87 (d, 1H); 6.50 (d, 1H); 5.02 (s, 2H); 4.76 (m, 1H); 3.20 (m, 3H); 2.83 (dd, 1H); 2.62 (s, 2H); 2.49 (m, 2H); 1.67 (m, 4H). Chiral HPLC separation of (±)-benzyl 2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-ylmethylcarbamate (Chiralcel OJ, isopropanol:hexane 9:1) provided two fractions. Fraction 1 (Rt=11.576 min, Chiralcel OD, isopropanol:hexanes 1:9); Fraction 2 (Rt=14.729 min, Chiralcel OD, isopropanol:hexanes 1:9).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7]([OH:9])=[O:8].[C:15]([OH:24])(=[O:23])[C:16]1C(=CC=[CH:21][CH:22]=1)N>>[C:7]([C:6]1[CH:10]=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[NH:14][CH:16]1[CH2:22][CH2:21][O:24][C:15]1=[O:23])([OH:9])=[O:8]
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: Nc1ccccc1C(=O)O
Product: COc1cc(NC2CCOC2=O)c(C(=O)O)cc1OC

Procedure:
In the method of the Reference Example 1, 4,5-dimethoxyanthranilic acid was reacted in the place of anthranilic acid to obtain α-[(2-carboxy-4,5-dimethoxyphenyl)-amino]-γ-butyrolactone, melting point: 214° C.(decomp.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][CH2:24][O:25][CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+].O>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N)cc2)CC1
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N3CCOCC3)cc2)CC1
Yield: 69.9 %

Procedure:
1-tert-Butoxycarbonyl-4-(4-aminobenzyl)piperidine (1 g, 3.45 mmol) was dissolved in 1-butanol (20 mL). To the solution were added bis(2-chloroethyl) ether (490 mg, 3.45 mmol) and potassium carbonate (1 g, 7.23 mmol), and the mixture was heated for 30 hours under reflux. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give 1-tert-butoxycarbonyl-4-(4-morpholinobenzyl)piperidine (869 mg) as a colorless oily substance. This compound (859 mg, 2.39 mmol) was dissolved in ethyl acetate (10 mL). To the solution was added 4N-hydrogen chloride in ethyl acetate (5 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure to give the titled compound (562 mg) as colorless powders.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.[OH:36][CH:37]([CH:40]1[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]1)[CH2:38][NH2:39]>C(OCC)(=O)C>[OH:36][CH:37]([CH:40]1[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]1)[CH2:38][NH:39][C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:21]([F:22])([F:23])[F:24])=[CH:20][CH:19]=1
Reactant: CC1(C)OCC(C(O)CN)O1
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC1(C)OCC(C(O)CNC(=O)c2ccc(S(=O)(=O)Nc3ccc(F)cc3C(F)(F)F)cc2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.63 g (10 mmol) of 4-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]-benzoic acid is suspended in 36 ml of ethyl acetate, 2.38 g (20 mmol) of thionylchloride is added and the suspension is heated to boiling temperature. After 15 minutes a clear solution is present, after 1 hour the formation of the acid chloride is complete. The solution is evaporated to dryness under reduced pressure, the residue is concentrated by evaporation in a vacuum twice with 50 ml of dichloromethane each and the dissolved in 36 ml of dioxane. 1.21 g (12 mmol) of triethylamine and 1.93 g (12 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamine are added to this solution and it is stirred for 5 hours at room temperature. The reaction solution is then evaporated to dryness in a vacuum, the residue is extracted with ethyl acetate, the ethyl acetate extract is concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. 3.19 g (6.3 mmol) =63% of the theoretical yield of the product is obtained as an amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[O:34][CH:33]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.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:34]1[C:33]2=[CH:32][CH:36]=[CH:37][C:38]2=[CH:39][C:40]([C:14]2[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([N:16]3[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]3)[CH:11]=[CH:12][CH:13]=2)=[CH:35]1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: CC1(C)OB(c2coc3ccccc23)OC1(C)C
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: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CN(c2cccc(-c3coc4cccc-4c3)c2OCc2ccccc2)S(=O)(=O)N1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (80 mg, 0.18 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzofuran (44 mg, 0.18 mmol), Cs2CO3 (235 mg, 0.72 mmol) and Pd(PPh3)4 (8 mg) in DMF (5 mL) is stirred at 80° C. for 7 h. The mixture is cooled to RT and is diluted with EtOAc, washed with water and bride and dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound.