Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[SH:6][C:7]1[C:8]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:9]=2[S:10][C:11]=1[C:12]([NH2:14])=[O:13].C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[NH2:14][C:12]([C:11]1[S:10][C:9]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:8]=2[C:7]=1[S:6][CH2:2][C:3]([OH:5])=[O:4])=[O:13]
Reactant: O=C(O)CBr
Reactant: COc1ccc2sc(C(N)=O)c(S)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2sc(C(N)=O)c(SCC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
Bromoacetic acid (72 mg, 0.52 mmol) is added to a room temperature solution of 3-mercapto-5-methoxybenzo[b]thiophene-2-carboxamide (50 mg, 0.21 mmol) in 3 mL of THF followed by NaHCO3 (219 mg, 2.60 mmol) and the reaction mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with ethyl acetate and washed with 1N HCl and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane provides [[2-(aminocarbonyl)-5-methoxybenzo[b]thien-3-yl]thio]acetic acid in 54% yield; mp=126°-127° C.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:22](Cl)(Cl)=[S:23].[OH-].[Na+]>O1CCCC1>[N:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:16][CH:17]=1)=[C:22]=[S:23]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(CN2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: S=C=Nc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Triethylamine (4.5 mL, 65.4 mmol) was added to a tetrahydrofuran (500 mL) solution of 4-morpholin-4-ylmethyl-phenylamine (F45-000, 5.16 g, 26.8 mmol). After cooling in ice cold, thiophosgene (2.45 mL, 32.1 mmol) was added. After stirring at room temperature overnight, aqueous sodium hydroxide was added until the reaction mixture became basic. The reaction mixture was extracted with ethyl acetate, washed with water and then washed with saturated sodium chloride. The extract solution was dried over anhydrous sodium sulfate, and then sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain a red syrup like substance. The syrup like substance was purified by silica gel column chromatography (hexane, ethyl acetate) to obtain 4-(4-isothiocyanatobenzyl)-morpholine (F45-00, brown oil, 5.72 g, 91%).
Reaction SMILES: Cl[CH:2](Cl)[C:3]([OH:5])=[O:4].[H-].[Na+].[CH:9]1([C:15]2[CH:16]=[CH:17][C:18]([OH:30])=[C:19]([C:21]([CH3:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[OH:22])[CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O1CCOCC1>[CH:9]1([C:15]2[CH:16]=[CH:17][C:18]3[O:30][CH:2]([C:3]([OH:5])=[O:4])[O:22][C:21]([CH3:29])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]=3[CH:20]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CC(O)(c1ccccc1)c1cc(C2CCCCC2)ccc1O
Reactant: O=C(O)C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(c2ccccc2)OC(C(=O)O)Oc2ccc(C3CCCCC3)cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
A solution of 14.18 g of dichloroacetic acid in 150 ml of dioxane was added with stirring at room temperature to a mixture of 11.8 g of sodium hydride as a 50% oil suspension, 120 ml of dioxane and 1.05 g of dibenzo-18-courone-6 and then a solution of 20.74 g of the product of Step B in 250 ml of dioxane was added dropwise thereto. The mixture was stirred at 80° C. for 2 hours and was cooled and poured into ice. The aqueous phase was washed with 300 ml of ether, was acidified with 30 ml of concentrated hydrochloric acid and was extracted 3 times with 250 ml of ether. The ether phase was washed twice with 100 ml of water and was extracted twice with 250 ml of aqueous 5% sodium bicarbonate solution. The aqueous phase was washed with 100 ml of ether, acidified with 60 ml of concentrated hydrochloric acid and was extracted 3 times with 250 ml of ether. The decanted organic phase was washed with water until the wash water was neutral, dried over magnesium sulfate and was evaporated to dryness under reduced pressure to obtain 18.7 g of raw 6-cyclohexyl-4-methyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of 2 diastereoisomeric racemates).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]([CH3:14])[CH3:13])=[N:7][N:6]=[CH:5]2.[CH2:15]([Sn](CCCC)(CCCC)C=C)[CH2:16]CC>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.C1(C)C=CC=CC=1>[CH3:13][N:12]([CH3:14])[C:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:15]=[CH2:16])=[CH:11][CH:10]=2)[CH:5]=[N:6][N:7]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CN(C)c1nncc2cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(N(C)C)nncc2c1
Temperature: 85 °C
Yield: 59.3 %

Procedure:
A mixture of (6-bromo-phthalazin-1-yl)-dimethyl-amine (0.32 g, 1.27 mmol) and toluene (8 mL) was purged with N2. Pd(PPh3)4 (0.4 g, 0.346 mmol) and tributyl vinyl stannane (1.11 mL, 3.80 mmol) were added and the reaction heated to 85° C. for 4 h. The reaction was cooled, filtered through celite and rinsed with CH2Cl2. The organic layers were washed with water, brine, dried (Na2SO4) and concentrated. Column chromatography (Hexanes/EtOAc) afforded the desired product (0.15 g, 59.3%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([SH:11])[NH:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25]Br)=[CH:22][C:21]=1[F:30])#[N:19]>C(#N)C>[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25][S:11][C:8]2[NH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:10][N:9]=2)=[CH:22][C:21]=1[F:30])#[N:19]
Reactant: CCOC(=O)c1c[nH]c(S)n1
Reactant: N#Cc1ccc(C(=O)CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cnc(SCC(=O)c2ccc(C#N)c(F)c2)[nH]1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a solution 4-ethoxycarbonylimidazole-2-thiol (8.47 g, 49.2 mmol) and potassium carbonate (20.4 g, 148 mmol) in dry acetonitrile (200 mL) at room temperature was added bromide from Step G (11.9 g, 49.2 mmol). The reaction mixture was stirred for 20 hours, during which time a white precipitate formed. To the solution was added 100 mL ice water. The resulting solid was filtered and washed with water (2×25 mL) to provide the title product as an off-white solid which was sufficiently pure for use in the next step.
Reaction SMILES: OC1C=CC(S[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([NH2:18])[CH:10]=2)=CC=1.[H-].[Na+].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([SH:31])[C:26]([O:29][CH3:30])=[CH:27][CH:28]=1>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([S:31][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([NH2:18])[CH:10]=2)[C:26]([O:29][CH3:30])=[CH:27][CH:28]=1
Reactant: COc1ccc(OC)c(S)c1
Reactant: Nc1cc(Sc2ccc(O)cc2)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(OC)c(Sc2ccc([N+](=O)[O-])c(N)c2)c1

Procedure:
Using the general method described for 4-(4-hydroxyphenylsulphanyl)-2-amino-nitrobenzene in Example 2, except that one equivalent of NaH was used, 4-(3,6-dimethoxyphenylsulphanyl)-2-amino-nitrobenzene (4.19 g) was prepared from 3,6-dimethoxybenzenethiol (2.55 g; 15 mmol).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:16]2[O:15][CH:14]=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[CH3:17][S:18]SC.O>O1CCCC1>[CH3:6][O:7][C:8]1[C:16]2[O:15][C:14]([S:18][CH3:17])=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CSSC
Reactant: COc1cccc2ccoc12
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2cc(SC)oc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.6M in hexanes, 10.2 ml) was added dropwise to a cooled (-78° C.) solution of 7-methoxybenzofuran (2.0 g) in tetrahydrofuran (40 ml) under an inert atmosphere. Methyl disulfide (1.46 ml) was added and the reaction mixture was stirred at -78° C. for 30 minutes, then at room temperature for 1 h. Water was added and the tetrahydrofuran was removed in vacuo. The aqueous residue was extracted with ether (3×100 ml) and the combined organic phases were washed with water (100 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford the title compound as a yellow oil (2.73 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Li+].[CH3:33]C([N-]C(C)C)C.CI>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)([CH3:33])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a mixture of tert-butyl 4-(5-(1-(4-fluorophenyl)-2-methoxy-2-oxoethyl)pyrimidin-2-yl)piperazine-1-carboxylate (1.0 g, 2.33 mmol) in THF (20 mL) at −78° C. was added LDA (2 M, 2.33 mL, 4.65 mmol) dropwise, After stirred at −78° C. for 30 min, CH3I (0.66 g, 4.65 mmol) was added. After stirred at RT for another 1 h, the reaction was quenched by water and extracted with EA. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was passed a column (silica gel, PE:EA=6:1) to afford the title compound (0.8 g, 77%) as a yellow solid. MS (ES+) C23H29FN4O4 requires: 444. found: 445 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:21])=[O:20])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:22]1([NH2:25])[CH2:24][CH2:23]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:22]1([NH:25][CH:1]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:21])=[O:20])[C:12]=4[N:11]=3)=[CH:6][CH:5]=2)[CH3:2])[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: CC(=O)c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(NC1CC1)c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of EXAMPLE 1A (0.07 g, 0.3 mmol) and cyclopropylamine (0.33 mL, 4.8 mmol) in methanol (1 mL) was treated with sodium cyanoborohydride (0.016 g, 0.3 mmol) and acetic acid (0.2 mL). The mixture was stirred at ambient temperature for 48 hours and concentrated. The residue was purified by chromatography on silica gel column with 0-10% dichloromethane/methanol/0.1% ammonium hydroxide to provide the title compound. 1H NMR (DMSO-d6) δ 9.12 (s, 2H), 8.33 (d, J=8.3 Hz, 2H), 7.88 (d, J=7.4 Hz, 1H), 7.71-7.78 (m, 4H), 7.37 (t, J=7.8 Hz, 1H), 4.59 (m, 1H), 2.57 (s, 1Hz), 1.64 (d, J=6.6 Hz, 3H), 0.81-0.87 (m, 1H), 0.75-0.79 (m, 1H), 0.66-0.72 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8].[C-:16]#[N:17].[K+].ClCCl>C(O)C>[C:16]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8])#[N:17]
Reactant: CCOC(=O)CNC(=O)CCCCCBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CCCCCC#N
Yield: 99 %

Procedure:
23.73 g (84.7·10-3 mol) of N-(6-bromohexanoyl)-glycine, ethyl ester are dissolved in 200 ml of ethanol, and 6.5 g (0.1 mol) of powdered potassium cyanide are added. The reaction mixture is brought to the reflux point and stirred under reflux for 15 hours. After concentration of the mixture under reduced pressure, the residue is taken up with dichloromethane and the organic phase is washed with aqueous sodium chloride solution. The organic phase is dried and concentrated under reduced pressure to give 19 g of the expected product (yield=99%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]([O:11]C)=O)[CH:2]=1.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.C1CCN2C(=NCCC2)CC1>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:22][CH:23]=2)=[O:11])[CH:2]=1
Reactant: COC(=O)COc1cccnc1
Reactant: NCc1ccc(C(=O)O)cc1
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(COc1cccnc1)NCc1ccc(C(=O)O)cc1
Reaction time: 24 h
Yield: 89.3 %

Procedure:
32 g (0.19 mole) of methyl 2-(pyridin-3-yloxy)-acetate, 27 g (0.18 mole) of 4-aminomethylbezoic acid and 59 g (0.39 mole) of DBU were added to ethanol (350 ml), and reaction was then carried out at room temperature for 24 hours. After the reaction mixture had been concentrated, partition was carried out between toluene and water. Concentrated hydrochloric acid was added to the resultant aqueous layer to accomplish neutralization, and a deposited solid was collected by filtration, washed with water and methanol, and then dried to obtain 46 g (yield: 89%) of 4-[N-(pyridin-3-yl)oxyacetylaminomethyl]benzoic acid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[C:7]=2[CH:27]=1.[C:28](Cl)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:21][CH2:22]3)[C:7]=2[CH:27]=1
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CSc1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccccc1S2
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCC(=O)OCCCN1CCN(C2Cc3ccccc3Sc3ccc(SC)cc32)CC1

Procedure:
In accordance with the general procedure described in the foregoing Examples, 14.0 grams of 8-methylthio-10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was reacted with 15.3 grams of lauroyl chloride (dodecanoyl chloride) in a mixture of benzene and chloroform. In this manner, 8-methylthio-10-[4-(3-dodecanoyloxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was obtained. The pure base was a viscous oil which formed a crystalline di(hydrogen maleate) that had a melting point of 121°-122°C, after recrystallization from acetone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]2[CH3:25])=[C:4]([F:27])[CH:3]=1.[N:28]([C:31]1[C:32]([CH3:37])=[N:33][O:34][C:35]=1[CH3:36])=[C:29]=[O:30]>ClCCl>[CH3:37][C:32]1[C:31]([NH:28][C:29]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][N:10]3[C:14](=[O:15])[C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]3[CH3:25])=[C:4]([F:27])[CH:3]=2)=[O:30])=[C:35]([CH3:36])[O:34][N:33]=1
Reactant: Cc1noc(C)c1N=C=O
Reactant: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc(N)cc2F)C1=O
Solvent: ClCCl
Product: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc(NC(=O)Nc3c(C)noc3C)cc2F)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.8 %

Procedure:
A mixture of (+/−)-3-[2-(4-amino-2-fluoro-phenyl)-2-oxo-ethyl]-2-methyl-5-phenyl-5-propyl-3,5-dihydro-imidazol-4-one (116 mg, 0.25 mmol) and 4-isocyanato3,5-dimethyl-isoxazole (34.5 mg, 0.25 mmol) in 3 mL dichloromethane is stirred at room temperature for 18 hours. Subsequently the solvent is evaporated and the residue is dissolved in acetonitrile, the solution filtrated and subjected to preparative HPLC purification (Method 3) to yield (+/−)-1-(3,5-dimethyl-isoxazol-4-yl)-3-{3-fluoro-4-[2-(2-methyl-5-oxo-4-phenyl-4-propyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-urea (44 mg, 35%), LC/MS at 254 nm; [M+H] 506; Rt 2.754 min.
Reaction SMILES: I[CH2:2][CH3:3].[OH:4][CH2:5][C@H:6]1[C@H:10]([CH3:11])[O:9][C:8]([CH3:13])([CH3:12])[N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[H-].[Na+]>CN(C=O)C>[CH2:2]([O:4][CH2:5][C@H:6]1[C@H:10]([CH3:11])[O:9][C:8]([CH3:12])([CH3:13])[N:7]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH3:3]
Reactant: C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CO
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC[C@H]1[C@H](C)OC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Iodoethane (0.80 mL) was added to a solution of (4S,5S)-tert-butyl 4-(hydroxymethyl)-2,2,5-trimethyloxazolidine-3-carboxylate (1.23 g), which can be synthesized by a method described in Bioorganic Chemistry 36 (2008) 4-15, in DMF (10 mL). Sodium hydride (60% in oil, 300 mg) was added under ice-cooling. Thereafter, the ice bath was removed, and the reaction solution was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution. After separation, the organic layer was washed with water twice. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain (4S,5S)-tert-butyl 4-(ethoxymethyl)-2,2,5-trimethyloxazolidine-3-carboxylate as light yellow amorphous.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31](Cl)([Cl:33])=[O:32]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:31]([Cl:33])=[O:32]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(Cl)Oc1ccc2ccccc2c1
Reaction time: 1 h
Yield: 75 %

Procedure:
433 g (3.0 mols) of 2-naphthol and 15.7 g of triphenylphosphine are initially introduced into an apparatus as described in Example 1. The mixture is heated to 120° to 125° C. and 325 g of COCl2 are introduced in the course of 12 hours. The reaction mixture is stirred for a further 1 hour, excess phosgene is drawn off in vacuo and crude chloroformic acid 2-naphthyl ester is obtained in a yield of 75% of the theoretical yield.
Reaction SMILES: C(O)C.[N+:4]([C:7]1[CH:8]=[C:9]([OH:20])[CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-])=O.Cl>[Fe].O>[NH2:4][C:7]1[CH:8]=[C:9]([OH:20])[CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Oc1ccccc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(O)ccc1Oc1ccccc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 82.1 %

Procedure:
120 ml of ethanol and 120 ml of water were added to 23.1 g of 3-nitro-4-phenoxyphenol, and the mixture was made into a solution by heating at 60° C. 2.3 ml of 4N hydrochloric acid was added thereto. While maintaining the reaction temperature at 65°-70° C., 16.8 g of an iron powder was added thereto in portions in 20 minutes. Stirring was conducted for 30 minutes at the same temperature. The reaction mixture was hot-filtered. 50 ml of water was added to the filtrate and the mixture was allowed to stand. The resulting crystal was collected by filtration to obtain 16.5 g (yield: 82.1%) of 3-amino-4-phenoxyphenol having a melting point of 156°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:20]=[C:21]([C:29](OC)=[O:30])[CH:22]=[C:23]([C:25](OC)=[O:26])[CH:24]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1COCC1>[OH:26][CH2:25][C:23]1[CH:24]=[C:19]([NH:18][C:16]([C:13]2[N:12]=[N:11][N:10]([CH2:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:14]=2[CH3:15])=[O:17])[CH:20]=[C:21]([CH2:29][OH:30])[CH:22]=1
Reactant: COC(=O)c1cc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)cc(C(=O)OC)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)Nc2cc(CO)cc(CO)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of dimethyl 5-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-benzenedicarboxylate (Intermediate 14) (0.65 g, 1.3 mmol) in THF (40 mL), was added a 1M solution of DIBAL-H in toluene (10 mL, 7 eq) and the reaction was stirred to room temperature for 2 hours. Solid NH4Cl was added and the reaction mixture was stirred at RT for 30 min. The aqueous phase was extracted with ether and AcOEt, dried over sodium sulphate and evaporated. After recrystallisation from acetonitrile, the title compound was obtained as a white solid (240 mg, 44%). HRMS calculated for C19H18Cl2N4O3 (M+H)+421.0834, found: 421.0833, Rt: 2.51 min. MP: 194.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]1[CH2:14][C:13](/[CH:15]=[N:16]/[OH:17])=[N:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][N:9]1[CH2:14][C:13](/[C:15](/[Cl:26])=[N:16]/[OH:17])=[N:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)NN1CC(/C=N/O)=NN(C(=O)OC(C)(C)C)C1=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NN1CC(/C(Cl)=N/O)=NN(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl 4-(tert-butoxycarbonylamino)-6-[(E)-hydroxyiminomethyl]-3-oxo-5H-1,2,4-triazine-2-carboxylate (3.20 g, 8.00 mmol) in DMF (11 mL) at room temperature was slowly added N-chlorosuccinimide (“NCS”)) (1.39 g, 10.4 mmol) and the obtained solution was stirred for 20 h at room temperature. After addition of ice water, the mixture was extracted with diethyl ether and the combined organic layers were washed with brine. Drying (Na2SO4) and evaporation under reduced pressure furnished the desired product as a viscous oil which was used as obtained. 1H NMR (400 MHz, CDCl3) 1.48 (s, 9H), 1.62 (s, 9H), 4.60 (s, 2H), 8.05 (s, 1H).
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=2[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:10]2=[O:20])[N:3]=[CH:4][CH:5]=1.C(N(C(C)C)CC)(C)C.Cl[C:35]1[CH:44]=[N:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1>C(#N)C>[N:1]1[N:2]([C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=2[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([CH2:15][CH2:16][N:17]([C:35]4[CH:44]=[N:43][C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=4)[CH2:18][CH2:19]3)[C:10]2=[O:20])[N:3]=[CH:4][CH:5]=1
Reactant: Clc1cnc2ccccc2n1
Reactant: O=C1N(Cc2ccccc2-n2nccn2)CCCC12CCNCC2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N(Cc2ccccc2-n2nccn2)CCCC12CCN(c1cnc3ccccc3n1)CC2
Temperature: 120 °C
Yield: 66 %

Procedure:
To a stirred solution of 2-(2-(2H-1,2,3-triazol-2-yl)benzyl)-2,9-diazaspiro[5.5]undecan-1-one (TFA salt) (200 mg, 0.354 mmol, contains 2.0 moleq. TFA) and diisopropylethylamine (0.64 mL, 3.61 mmol) in acetonitrile (1 mL) was added 2-chloroquinoxaline [1448-87-9] (121 mg, 0.72 mmol). The mixture was heated at 120° C. for 40 min under microwave conditions. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude mixture was purified by flash-column chromatography over silicagel (eluent: gradient 10%-100% ethyl acetate/heptane) to yield the title compound (106 mg, 65%). [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.81 (s, 1H), 8.11 (s, 2H), 7.80 (d, 1H), 7.59-7.63 (m, 1H), 7.56-7.59 (m, 2H), 7.44-7.55 (m, 2H), 7.33-7.40 (m, 1H), 7.24-7.29 (m, 1H), 4.54 (br. s, 2H), 4.19-4.29 (m, 2H), 3.39-3.49 (m, 2H), 3.13 (t, 2H), 1.99-2.10 (m, 2H), 1.84-1.92 (m, 2H), 1.73-1.83 (m, 2H), 1.54-1.65 (m, 2H); LCMS RtA=1.16, [M+H]+=454.4].