Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:18]CC=O)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[CH3:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29]([C:33]([OH:35])=O)=[N:30]2)=[CH:25][CH:24]=1.ON1C2C=CC=CC=2N=N1.C(O)C(N)(CO)CO>ClCCl>[CH3:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29]([C:33]([NH2:18])=[O:35])=[N:30]2)=[CH:25][CH:24]=1
Reactant: O=CCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1ccc2ccc(C(=O)O)nc2c1
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1ccc2ccc(C(N)=O)nc2c1
Reaction time: 0.08 h
Yield: 339.2 %

Procedure:
A solution of the amine 4 (1.0 mg, 1.9 μmol, 1.0 equiv) in dichloromethane (0.1 mL) was added to 7-methylquinoline-2-carboxylic acid (2.8 μmol, 1.5 equiv) and 1-hydroxybenzotriazole (0.44 mg, 3.2 μmol, 1.7 equiv) in a vial at 23° C. The solution was stirred for 5 min, then N-cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene (Argonaut Technologies, 1.13 mmol/g, 3.4 mg, 3.8 μmol, 2.0 equiv) was added in one portion at 23° C. The reaction mixture was stirred gently at 23° C. under an argon atmosphere for 16 h. PS-Trisamine (Argonaut Technologies, 4.71 mmol/g, 2.0 mg, 9.5 μmol, 5.0 equiv) was then added in one portion and the reaction mixture was stirred for a further 2 h. The mixture was filtered through Celite (0.5 cm) and concentrated in vacuo to give the 7-methylquinoline-2-carboxylic acid amide derivative (1.2 mg, 95%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[C:4]([Cl:21])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=1)=[CH:7][C:6]=2[Cl:20].B(Br)(Br)Br>>[Br:1][C:2]1[C:3]([OH:22])=[C:4]([Cl:21])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)=[CH:7][C:6]=2[Cl:20]
Reactant: COc1ccc(-c2cc(Cl)c3c(Cl)c(O)c(Br)cc3c2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2cc(Cl)c3c(Cl)c(O)c(Br)cc3c2)cc1

Procedure:
The title compound was prepared by reacting 3-bromo-1,8-dichloro-6-(4-methoxyphenyl)-2-naphthol (0.18 g, 0.45 mmol) with boron tribromide (0.9 mL of 1N solution, 0.9 mmol) according to method D to yield 0.12 g (69%) of a light brown solid. The product was further purified by reverse phase preparative HPLC to yield the title compound as a white solid: mp 184-188° C.; 1H NMR (DMSO-d6): δ 6.89 (2H, d, J=8.59 Hz), 7.65 (2H, d, J=8.61 Hz), 7.95 (1H, d, J=1.78 Hz), 8.13 (1H, d, J=1.75 Hz), 8.37 (1H, s), 9.74 (1H, s), 10.50 (1H, s); MS (ESI) m/z 381/383/385 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:16]1([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH2:28][CH2:29]2)=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: O=C(N1CCCCC1)N1CCNCC1
Product: COc1cc2ncnc(N3CCN(C(=O)N4CCCCC4)CC3)c2cc1OC

Procedure:
In like manner, 1-chloro-6,7-diethoxyisoquinoline and 1-(piperidinocarbonyl)piperazine react to afford 1-(4-piperidinocarbonyl-1-piperazinyl)-6,7-diethoxyisoquinoline, while 4-chloro-6,7-dimethoxyquinazoline and 1-(piperidinocarbonyl)piperazine react to afford 4-(4-piperidinocarbonyl-1-piperazinyl)-6,7-dimethoxyquinazoline respectively. The latter compound is, of course, identical in every respect with the product of Example V.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([NH:5][C:6]([CH3:14])([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[NH3:16]>C(O)C>[CH3:13][C:6]([NH:5][C:3](=[O:4])[C@H:2]([CH3:15])[NH2:16])([CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N
Reactant: CC(Br)C(=O)NC(C)(C)c1ccccc1
Solvent: CCO
Product: C[C@H](N)C(=O)NC(C)(C)c1ccccc1
Reaction time: 168 h

Procedure:
A solution of 2-bromo-N-(α,α-dimethylbenzyl)propionamide (24.0 g; 0.088 mole) in ethanol (500 ml) was cooled to 0°C. The solution was saturated with ammonia (5 hours). Stirring was continued at room temperature for about 7 days. The solvent was removed under vacuum. The oily residue was taken up in benzene. The benzene phase was extracted with 5N HCl. The aqueous phase was washed with ether, made alkaline with 5N NaOH, saturated with NaCl and extracted several times with benzene. The benzene solution was dried over anhydrous Na1SO4 and the solvent was evaporated. The N1 -(α,α-dimethylbenzyl)alanineamide was obtained as an almost colourless oil. Yield: 14.6 g (79.8 %).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[N:12]=[C:11](Cl)[C:10]([N+:14]([O-:16])=[O:15])=[C:9]([Cl:17])[N:8]=1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:6][C:7]1[N:12]=[C:11]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[C:10]([N+:14]([O-:16])=[O:15])=[C:9]([Cl:17])[N:8]=1
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1Cl
Reactant: NC1CCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1c(Cl)nc(Cl)nc1NC1CCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cyclobutanamine (0.485 mL, 5.68 mmol) in iPrOH (20 mL) was added to a solution of 2,4,6-trichloro-5-nitropyrimidine (1.29 g, 5.65 mmol) in iPrOH (40 mL) at −78° C. dropwise via addition funnel. After complete addition, the mixture was allowed to warm to rt over 30 min, then DIEA (0.940 mL, 5.66 mmol) was added and the mixture stirred at rt for 10 min. The solvent was removed under reduced pressure and dried to give the title compound as a pale yellow oil which was used without purification.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH2:11][CH2:10][N:9]([C:14]4[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=4)[C:17]([OH:19])=O)[CH2:8][C:7]=3[CH:6]=[N:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.CCCP(=O)=O.[CH2:38]([C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43])[CH3:39]>CN(C1C=CN=CC=1)C.ClCCCl>[S:1]1[C:13]2[C:12]3[CH2:11][CH2:10][N:9]([C:14]4[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=4)[C:17]([NH:43][C:42]4[CH:44]=[CH:45][CH:46]=[C:40]([CH2:38][CH3:39])[CH:41]=4)=[O:19])[CH2:8][C:7]=3[CH:6]=[N:5][C:4]=2[CH:3]=[CH:2]1
Reactant: CCc1cccc(N)c1
Reactant: O=C(O)c1cccc(N2CCc3c(cnc4ccsc34)C2)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCc1cccc(NC(=O)c2cccc(N3CCc4c(cnc5ccsc45)C3)c2)c1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 68.5 %

Procedure:
To a mixture of 3-(8,9-dihydrothieno[3,2-c]-2,7-naphthyridin-7(6H)-yl)benzoic acid (0.113 mmol, 35 mg), N, N-diisopropylethylamine (0.339 mmol, 0.059 mL), and catalytic DMAP in 1.2 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.136 mmol, 0.081 mL). After 7 min at rt, 3-ethylaniline (0.17 mmol, 0.021 mL) was added and the reaction stirred at rt for 5 hours. The reaction was quenched into dilute aqueous NaHCO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, dilute aqueous NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting oil was chromatographed eluting with EtOAc/CDCl3 to give the title compound as a light yellow solid (32 mg, 69%).
Reaction SMILES: [C:1]1([C:7]2C=C[N:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[N:15][N:16]3[C:21]([N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]([CH:39]4[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]4)=[N:18][C:17]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N(Br)C(=O)C1>C(#N)C>[N:10]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:7]=[C:8]([C:13]2[CH:14]=[N:15][N:16]3[C:21]([N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:30])[CH3:28])[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])=[CH:20][C:19]([CH:39]4[CH2:40][CH2:41][S:42](=[O:46])(=[O:45])[CH2:43][CH2:44]4)=[N:18][C:17]=23)[CH:9]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCS(=O)(=O)CC2)nc2c(-c3cnccc3-c3ccccc3)cnn12
Agent: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCS(=O)(=O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.7 %

Procedure:
To a solution of 3-(4-phenyl-3-pyridyl)-5-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (Int-3a, 190 mg, 0.29 mmol) in acetonitrile (5 mL) was added NBS (51 mg, 0.29 eq). The mixture was stirred at rt for 2 h and concentrated. The residue was purified by Biotage (CH2Cl2/EtOAc, 20:1 to 4:1) to give 210 mg (99%) of the title compound as a light brown solid (Int-3b). LC/MS tR=2.55 (5 min method). Mass calculated for, M+H 757.20, observed 757.20 & 759.20 (doublet for Br).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:11]([O-])([O-:13])=[O:12].[K+].[K+].Cl>C(OCC)(=O)C>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=1[C:11]([OH:13])=[O:12]
Reactant: CC(C)c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(O)c(C(=O)O)c1

Procedure:
4-Isopropylphenol (2.7 g, 19.83 mmol) and K2CO3 (5.48 g, 39.7 mmol) were heated to 150° C. under an atmosphere of carbon dioxide. The cooled residue was suspended in ethyl acetate and acidified with 2N hydrochloric acid. The organic layer was separated and the combined extracts were dried (MgSO4) and evaporated under reduced pressure to yield the title compound which was used in the next step without further purification. 2.0 g.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[O:19][CH2:18][CH2:17][N:16]([C:20]3[N:25]([CH3:26])[C:24](=[O:27])[CH:23]=[C:22]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[N:21]=3)[CH2:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][N:2]([CH3:6])[C:3]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[O:19][CH2:18][CH2:17][N:16]([C:20]3[N:25]([CH3:26])[C:24](=[O:27])[CH:23]=[C:22]([C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)[N:21]=3)[CH2:15]2)=[CH:12][CH:13]=1)=[O:4]
Reactant: Cn1c(N2CCO[C@@H](c3ccc(N)cc3)C2)nc(-c2ccncc2)cc1=O
Reactant: CN(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Nc1ccc(C2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCO2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 29.3 %

Procedure:
N,N-Dimethylcarbamoyl chloride (0.24 g, 2.23 mmol) was added to a solution of 2-[(2S)-2-(4-aminophenyl)morpholin-4-yl]-3-methyl-6-(pyridin-4-yl)-pyrimidin-4(3H)-one (0.40 g, 1.10 mmol) and triethylamine (1.1 g, 10.9 mmol) in tetrahydrofuran (20 ml) and the solution was stirred at 50° C. for 48 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 1,1-Dimethyl-3-{4-[4-(1-methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidin-2-yl) morpholin-2-yl]-phenyl}-urea (0.14 g, 30%) as white crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7])[CH3:4].Br[CH2:19][C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:30][CH3:31]>CN(C)C=O.O>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]([CH3:27])([CH3:29])[CH3:28])[CH:23]=[CH:22][C:21]=2[O:30][CH3:31])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COc1ccc(C(C)(C)C)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1cc(C(C)(C)C)ccc1OC
Yield: 93.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.154 g, 3.85 mmol) was added to a solution of 5-chloro-1H indole-2-carboxylic acid ethyl ester (0.70 g, 3.14 mmol) in dimethyl formamide (8 ml) with stirring under nitrogen, followed after 1 h by 2-bromomethyl-4-tert-butyl-1-methoxybenzene (1.00 g, 3.89 mmol). After stirring for 17 h, the reaction was diluted with water (15 ml), extracted into ethyl acetate (2×30 ml), washed with water (2×30 ml), dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification was achieved by chromatography on silica using DCM as eluent to yield 1-(5-tert-butyl-2-methoxybenzyl)-5-chloro-1H-indole-2-carboxylic acid ethyl ester as an off-white solid (1.18 g, 2.95 mmol, 94%).
Reaction SMILES: [Cl-].[NH4+].Cl[C:4]1(Cl)[C:17](=[O:18])[CH2:16][C:5]21[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]2>CO.O.[Zn]>[O:18]=[C:17]1[CH2:4][C:5]2([CH2:6][N:7]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:8]2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(=O)C2(Cl)Cl)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2(CC(=O)C2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.9 %

Procedure:
15.13 g (0.283 mmol) of ammonium chloride are added to a solution containing 13.21 g (47.15 mmol) of tert-butyl 5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, obtained in the preceding step, in 250 mL of methanol. The reaction medium is cooled with the aid of an ice/water bath, and 30.83 g (0.471 mmol) of zinc are added. After stirring at room temperature for 12 hours, the Celite is filtered off and rinsed with methanol. The filtrate is evaporated to dryness. The residue obtained is taken up in water and extracted several times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure. After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 90/10 mixture of cyclohexane and ethyl acetate. 1.78 g of pure product are thus obtained in the form of a white powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[CH3:13][O:14][NH2:15].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH:15][O:14][CH3:13])=[O:5]
Reactant: CON
Reactant: O=C(Cl)c1cc(F)ccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CONC(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a mixture of 2,5-difluorobenzoyl chloride (1.77 g, 10 mmol) and O-methylhydroxylamine hydrochloride (830 mg, 10 mmol) in methylene chloride (25 mL) at 0° C. was added dropwise triethylamine (2.8 mL, 20 mmol) and the mixture was stirred at room temperature for 8 h. The mixture was then washed with water, brine, dried with MgSO4 and concentrated under reduced pressure. The residue was chromatographed (hexane-EtOAc 2:1) to afford 1.4 g of the title compound. 1H NMR (300 MHz-DMSO-d6) δ 3.70 (s, 3H), 7.42 (m, 3H), 11.64 (s, 1H); MS (DCI/NH3) m/z 188 (M+H)+, 205 (M+NH4)+.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[OH:6][C@H:7]1[O:14][C@@H:13]2[CH2:15][O:16][C@@H:10]([C@H:11]2[OH:12])[C@H:8]1O>>[S:1]([O:5][C@H:8]([C@H:10]1[O:16][CH2:15][C@@H:13]([OH:14])[C@@H:11]1[OH:12])[CH:7]=[O:6])([OH:4])(=[O:3])=[O:2]
Reactant: O[C@@H]1[C@H]2OC[C@@H](O[C@@H]1O)[C@@H]2O
Reactant: O=S(=O)([O-])[O-]
Product: O=C[C@H](OS(=O)(=O)O)[C@H]1OC[C@@H](O)[C@@H]1O

Procedure:
Carrageenans having a moleculr weight of from 100.000 to 800.000 Dalton are known; approximately 25% sulfate-content; various types: kappa-carrageenan: comprised of alternating 1,3 or 1,6, respectively, linked 3,6-anhydro-α-D-galactose and D-galactose-4-sulfate; gel-forming; only partially oxidizable lambda carrageenan: α-1,3-glycosidically linked D-galactose-2(4)-sulfate residues and 1,4-linked D-galactose-2,6-disulfate residues and 1,4-linked-D-galactose-2,6-disulfate residues; does not gel; and still partially oxidizable at C-6: i-carrageenan: from D-galactose-4-sulfate formed in 1,3-linkage and 3,6-anhydro-D-galactose-2-sulfate formed in 1,4-linkage; forms gel with Ca2+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=O.Cl.C(O[C:17](=O)[C@H:18](C)[NH2:19])C>N1C=CC=CC=1>[CH3:17][C@@H:18]1[NH:19][C:2](=[O:4])[C:1]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]1=[O:12]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: c1ccncc1
Product: C[C@@H]1NC(=O)c2ccccc2NC1=O
Yield: 48.5 %

Procedure:
Following the method of Example 5 isatoic anhydride (61.3 mmol) was allowed to react with L-alanine ethyl ester HCl (73.6 mmol) in pyridine (200 mL) to give 29.7 mmol of (3S)-3-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione as a light, brown solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][OH:14].[CH3:15][O:16][C:17]([C:19]1[S:23][N:22]=[C:21](O)[CH:20]=1)=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:15][O:16][C:17]([C:19]1[S:23][N:22]=[C:21]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[CH:20]=1)=[O:18]
Reactant: Cc1onc(-c2ccccn2)c1CO
Reactant: COC(=O)c1cc(O)ns1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)ns1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a solution of (5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-methanol (360 mg, 1.9 mmol) in THF (10 mL) was added 3-hydroxy-isothiazole-5-carboxylic acid methyl ester (300 mg, 1.9 mmol) and triphenylphosphine (594 mg, 1.9 mmol) at 0° C. under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 0.95 mL, 1.9 mmol) was added and the reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (silica, heptane:ethyl acetate=4:1 to 1:4) afforded the title compound (350 mg, 56%) as a white solid. MS: m/e=332.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:11]1([OH:33])[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1.[O:34]1CCC[CH2:35]1>O>[F:31][C:29]([F:32])([F:30])[C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=1)[C:17]([N:14]1[CH2:15][CH2:16][C:11]2([O:33][C:35](=[O:34])[NH:1][CH2:2][CH:3]2[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=2)[CH2:12][CH2:13]1)=[O:18]
Reactant: NCC(c1cccc(Cl)c1)C1(O)CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: C1CCOC1
Solvent: O
Product: O=C1NCC(c2cccc(Cl)c2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)O1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
To a solution of 1.48 g (3 mmol) {4-[2-amino-1-(3-chloro-phenyl)-ethyl]-4-hydroxy-piperidin-1-yl}-(3,5-bis-trifluoromethyl-phenyl)-methanone in 30 ml of tetrahydrofuran 1.46 g (9 mmol)1,1′-carbonyl-diimidazole was added and the mixture was stirred over night at room temperature under argon. Water (15 ml) was added, the organic layer was separated, washed twice with a solution of hydrochloric acid (1 M), dried and evaporated. The residue was purified by flash column chromatography (SiO2, ethyl acetate) to yield 1.08 g (69%) of the title compound.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([Cl:20])(=[O:19])=[O:18])=[CH:14][CH:15]=2)[C:10](=O)[NH:9][CH:8]=1.CCOCC>CC#N>[Cl:20][S:17]([C:13]1[CH:12]=[C:11]2[C:16]([C:7]([Cl:6])=[CH:8][N:9]=[C:10]2[Cl:3])=[CH:15][CH:14]=1)(=[O:19])=[O:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cc(Cl)c2ccc(S(=O)(=O)Cl)cc12
Solvent: CCOCC
Solvent: CC#N
Product: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Yield: 84.2 %

Procedure:
Phosphorus oxychloride (POCl3) (9.65 mL, 103.5 mmol) was added to a stirred suspension of 4-chloro-7-chlorosulphonyl-1-(2H)-isoquinolone (22.1 g, 79.6 mmol) in MeCN (500 mL) at room temperature and the mixture was then heated at reflux for 15 h. On cooling, the MeCN solution was decanted from the insoluble sludge and evaporated in vacuo. The residue was extracted with hot EtOAc and evaporated to leave a solid which was stirred with Et2O (1.2 L) at room temperature overnight. The ethereal solution was decanted from the insoluble material and evaporated in vacuo to give 7-chlorosulphonyl-1,4-dichloroisoquinoline (20 g, 67 mmol) as a pale yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].N1CCCCC1.[Br-:13].[NH2:14][C:15]1[CH:40]=[CH:39][CH:38]=[CH:37][C:16]=1[CH2:17][P+:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCl>[Br-:13].[Cl:1][CH2:2][CH2:3][C:4]([NH:14][C:15]1[CH:40]=[CH:39][CH:38]=[CH:37][C:16]=1[CH2:17][P+:18]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:5]
Reactant: Nc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: [Br-]
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C(CCCl)Nc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 48 %

Procedure:
3-Chioropropionyl chloride (3.0 ml, 32 mmol) and piperidine (3.5 ml, 43.5 mmol) were added to a suspension of 2-aminobenzyltriphenylphosphonium bromide (13.0 g, 29 mmol) (synthesised using the procedure of Capuano et al, Chem. Ber., 1986, 119, 2069-2074) in dichloromethane (60 ml) under a nitrogen atmosphere. The mixture was heated at reflux for 30 min. and then cooled to room temperature. Dichloromethane (60 ml) and hydrochloric acid (1N, 50 ml) were added and the precipitated solid was collected by filtration, washed with dichloromethane and dried in vacuo to give 2-(3-chloropropionylamino)benzyltriphenylphosphonium bromide (7.5 g, 48%). The filtrate was diluted with dichloromethane (300 ml) and washed with sodium carbonate (satd., 150 ml). Evaporation of the dichloromethane gave a residue which was triturated with ether (200 ml) and the white solid collected to afford a second crop of product (5.0 g, 32%).
Reaction SMILES: [C:1](C1[N-]C=CN=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:24][CH2:25][CH2:26][N:27]=1>C1(C)C=CC=CC=1>[C:1]([N:27]1[CH2:26][CH2:25][N:24]=[C:23]1[NH:22][C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(c1cccnc1)c1ncc[n-]1
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Solvent: Cc1ccccc1
Product: O=C(c1cccnc1)N1CCN=C1Nc1c(Cl)cccc1Cl
Yield: 43.3 %

Procedure:
4.15 g (24 millimoles) of nicotinoylimidazolide and 4.6 g (20 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 100 ml of absolute toluene are refluxed for 3 hours. The mixture is then concentrated to dryness on a rotary evaporator and the residue is worked up as described in Example 41. 2.9 g of pure 1-nicotinoyl-2-(2',6'-dichlorophenylamino)-2-imidazoline of melting point 172.5°-173.5° C. are obtained; the material is identical with the product obtained according to Example 1.