Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[NH:4][CH2:5][C:6]1[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][O:23]C3CCCCO3)[CH:16]=2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1.C(N(CC)CC)C.[C:41](Cl)(Cl)=[O:42].[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[N:4]1[CH2:5][C:6]2[C:7](=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=2)[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][OH:23])[CH:16]=2)[C:41]1=[O:42]
Reactant: CSc1ncc(CNc2ccccc2Br)c(Nc2cccc(CCOC3CCCCO3)c2)n1
Reactant: O=C(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(c1cccc(CCO)c1)C(=O)N(c1ccccc1Br)C2
Temperature: 0 °C
Yield: 78 %

Procedure:
A solution of 2.6 g (4.9 mmol) of 5-(2-bromoanilino)methyl-4-[3-(2-(tetrahydropyranyloxy)ethyl)phenyl]amino-2-methylthiopyrimidine in 40 ml of tetrahydrofuran was treated with 2 ml (14.4 mmol) of triethylamine and the resulting solution added dropwise to an ice-cooled solution of phosgene (3 ml of a 20% solution in toluene, 5.8 mmol) in 40 ml of tetrahydrofuran. After 1 hour 50 ml of a saturated solution of ammonium chloride was added. The mixture was separated and the organic phase dried over magnesium sulfate and filtered. To the solution was added 20 ml of a saturated solution of hydrogen chloride in ethyl acetate. After 10 minutes the solution was evaporated to afford 1.8 g (78%) of 3-(2-bromophenyl)-3,4-dihydro-1-[3-(2-hydroxyethyl)phenyl]-7-methylthio-pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid. [Mass spectrum (ESI) MH+ =471].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].[Cl:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F.Cl>CS(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9]
Reactant: COc1ccc[nH]c1=O
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cccn(-c2ccc([N+](=O)[O-])cc2Cl)c1=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
15 g (120 mmol) of 3-methoxypyridone are dissolved in 120 ml of anhydrous dimethyl sulfoxide and admixed with 16.1 g (144 mmol) of potassium tert-butoxide with stirring. After 30 min, 21.0 g (120 mmol) of 3-chloro-4-fluoronitrobenzene are added and the mixture is heated to 80° C. After 16 h, the mixture is allowed to cool, admixed with 1N hydrochloric acid and extracted repeatedly with dichloromethane. The combined dichloromethane phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The resulting residue is stirred with tert-butyl methyl ether and filtered. The solid is dried under reduced pressure. 22.8 g (60% of theory) of the desired compound are obtained.
Reaction SMILES: CC#N.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH3:14])=[CH:7][C:6]=1[OH:22].[CH2:23]1[O:26][CH:24]1[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH3:14])=[CH:7][C:6]=1[O:22][CH2:23][CH:24]([OH:26])[CH3:25]
Reactant: C[C@@H](NCc1ccc(Cl)c(O)c1)c1cccc(Cl)c1
Reactant: CC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(O)COc1cc(CN[C@H](C)c2cccc(Cl)c2)ccc1Cl
Yield: 61.8 %

Procedure:
A microwave compatible vial was charged with 2 mL of CH3CN, (R)-2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenol 96 (115 mg, 388 μmol), propylene oxide (33 μL, 466 μmol), and cesium carbonate (139 mg, 427 μmol). The vial was sealed and was subjected to microwave irradiation at 140° C. for 30 min. The reaction was checked for completion by TLC. The reaction solution was diluted with EtOAc and it was washed with water (2×) and then brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a 10% to 70% gradient of EtOAc in hexanes as the eluant. The desired fractions were combined and concentrated to give 1-(2-chloro-5-(((R)-1-(3-chlorophenyl)ethylamino)methyl)phenoxy)propan-2-ol 97 (85 mg, 62% yield), as a colorless oil and as a mixture of diastereomers. 1H NMR (400 MHz, d4-methanol) δ ppm 1.32 (d, J=6.46 Hz, 3H) 1.73 (d, J=6.85 Hz, 3H) 3.92-4.02 (m, 3H) 4.13-4.21 (m, 2H) 4.49 (q, J=6.78 Hz, 1H) 6.98 (dd, J=8.12, 1.66 Hz, 1H) 7.43-7.49 (m, 2H) 7.49-7.53 (m, 2H) 7.58 (s, 1H). Mass spectrum: calculated for C18H21Cl2NO2 354.3. found 355.4 (M++1).
Reaction SMILES: C(O[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:22][CH3:23])=[C:10]([CH:21]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(=O)C.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O>C(Cl)Cl>[CH2:14]([O:13][C:11]([C:10]1[CH:21]=[C:6]([CH2:5][C:10]([CH3:21])([CH3:9])[C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][C:9]=1[O:22][CH3:23])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(COC(C)=O)cc1C(=O)OCc1ccccc1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1ccc(OC)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 36.8 %

Procedure:
Benzyl 5-acetoxymethyl-2-methoxybenzoate (630 mg, 2.00 mmol), methyl trimethylsilyldimethylketeneacetal (730 mg, 4.02 mmol) and 25 ml of dehydrated methylene chloride were mixed and magnesium perchlorate (45 mg, 0.202 mmol) was added under an atmosphere of argon, which was stirred for 6 hours at room temperature. The reaction mixture was washed with water and with brine, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=8:1 v/v) to obtain 131 mg (18%) of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]([NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([O:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:27][CH2:26]2)=[O:21])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]([NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([O:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:27][CH2:26]2)=[O:21])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[OH:9]
Reactant: COCCOCOc1c(OC)cc(C=CC(=O)NCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C=CC(=O)NCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc(OC)c1O
Yield: 65.6 %

Procedure:
To a solution of 276 mg (0.456 mmol) of the amide compound in methanol (6 ml) was added 79 mg (0.415 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 20 minutes. Water was added to the reaction mixture, which was adjusted to a pH value of 11 by the addition of an aqueous solution of sodium carbonate and then extracted with ethyl acetate. The organic layer was washed with water and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (20:1), to give 162 mg (0.299 mmol) of 1-[2-[3-(3,5-dimethoxy-4-hydroxyphenyl)-2-propenoyl]aminoethyl]-4-benzhydroxypiperidine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([CH3:31])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Na].[CH2:33]([OH:38])[CH2:34][CH2:35][CH2:36][OH:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:37][CH2:36][CH2:35][CH2:34][CH2:33][OH:38])[N:18]=[C:17]([CH3:31])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OCCCCO
Agent: [Na]
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OCCCCO

Procedure:
By reacting p-tert-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzenesulfonamide with the monosodium salt of 1,4-butanediol, there was obtained p-tert-butyl-N-[6-(4-hydroxybutoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzenesulfonamide as a white foam.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[NH2:10][C:11]1[CH:26]=[C:25]([C:27](=O)[NH2:28])[C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)=[O:16])=[CH:13][CH:12]=1.[NH4+].[OH-].CC(C)=O>C(O)C>[NH2:10][C:11]1[CH:26]=[C:25]([C:27]#[N:28])[C:14]([C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[O:16])=[CH:13][CH:12]=1
Reactant: NC(=O)c1cc(N)ccc1C(=O)Nc1ccc(N)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CCO
Product: N#Cc1cc(N)ccc1C(=O)Nc1ccc(N)cc1

Procedure:
350 ml of oleum (30% by weight) was cooled down below 0° C. using an ice bath, 99.6 g (0.368 mol) of 4,4'-diamino-6-carbamoyl benzanilide in a powder form was added below 5° C. with stirring. The stirring was continued to the next day, and the solution was neutralized by adding 1100 ml of NH4OH (28% by weight) already cooled down to -5° to 0° C. The solution was sufficiently washed to remove salt by filtering and washed with a small amount of warm ethanol and then dried in a vacuum oven at 80° C. The dried reactant which was mixed with by-products was extracted by soxlet and treated with the activated carbon and then ethanol was added to recrystallize in the mixture solvent (acetone:ethanol=1:1). The light yellow-scalelike crystal was filtered and dried in a vacuum oven at 80° C. The light yellow-scalelike crystal was extracted again by soxlet with acetone and treated with the activated carbon. And then the white-scalelike crystal obtained by recrystalling in the mixture solvent (acetone:ethanol=1:1) was dried in a vacuum oven at 80° C. (40 g of the raw material was obtained and the boiling point thereof was 250° to 251° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.CCO>[Pd].O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:6]([C:7]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH3:15])=[O:8])[CH:5]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCCN(CCC)C(=O)c1cc(N)cc(C(=O)OC)c1
Temperature: 50 °C
Yield: 88 %

Procedure:
A mixture of 5-nitro-N,N-dipropyl-isophthalamic acid methyl ester (D87) (1.5 g, 4.9 mmol, 1 equiv), NH4COOH (3.0 g, 49 mmol, 10 equiv), 10% Pd on charcoal (50% wet, 250 mg, 0.082 equiv w/w), EtOH (20 ml) and H2O (10 ml) was heated at 50° C. for 90 min. The mixture was cooled to room temperature, filtered through a pad of celite and concentrated in vacuo. The residue was dissolved in AcOEt (200 ml) and the resulting solution was washed with saturated NaHCO3 solution (100 ml), dried over MgSO4 and concentrated in vacuo to give 5-amino-N,N-dipropyl-isophthalamic acid methyl ester (D88) (1.2 g, 88%) as a white waxy solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Br[CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:9](=[O:11])[CH3:10])[C:2]=2[O:1][CH2:14][CH2:13]1
Reactant: CC(=O)c1cccc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cccc2c1OCCO2

Procedure:
Prepared by reacting 1-(2,3-dihydroxy-phenyl)-ethanone with 1,2-dibromoethane in the presence of potassium carbonate in N,N-dimethylformamide at 100° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=C[C:46]([O:49]C)=CC=3)C=2N=1)(C)(C)C.Cl.OC[C@H]1[C@@H](O)CCN1>>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:24][CH2:25][C@H:27]([OH:26])[C@@H:28]2[CH2:46][OH:49])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cn2nnc3c(N4CCOCC4)nc(C(C)(C)C)nc32)cc1
Reactant: COc1ccc(Cn2nnc3c(Cl)nc(C(C)(C)C)nc32)cc1
Agent: Cl
Agent: OC[C@@H]1NCC[C@@H]1O
Product: COc1ccc(Cn2nnc3c(N4CC[C@H](O)[C@@H]4CO)nc(C(C)(C)C)nc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of 4-(5-tert-butyl-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)morpholine (example 58, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2S,3S)-2-(hydroxymethyl)pyrrolidin-3-ol hydrochloride and isolated as light-yellow gum. MS (m/e): 413.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[OH:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:32]([CH:29]3[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]3)=[O:33])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCC(O)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-Chloro-phenyl)-1-(4-hydroxy-cyclohexanecarbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using trans-4-hydroxycyclohexanecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 475.2 [M+H]+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.[F:22][C:23]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=1[C:25]([OH:27])=O.[CH3:34][CH:35]([S:38]([NH2:41])(=[O:40])=[O:39])[CH2:36][CH3:37]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:35]([S:38]([NH:41][C:25](=[O:27])[C:24]1[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:23]=1[F:22])(=[O:40])=[O:39])([CH2:36][CH3:37])[CH3:34]
Reactant: CCC(C)S(N)(=O)=O
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)S(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Reaction time: 18 h
Yield: 46 %

Procedure:
N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.41 g, 2.1 mmol), 4-dimethylaminopyridine (0.26 g, 2.1 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.9 mL, 4.2 mmol) were added to a solution of 2,4,5-trifluorobenzoic acid (0.25 g, 1.4 mmol) in DCM. After 10 minutes butane-2-sulfonamide (Preparation 29, 0.29 g, 2.1 mmol) was added and the reaction was left at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC to yield the title compound as a white solid (0.19 g, 31% yield):
Reaction SMILES: [OH-].[Na+].[CH2:3]([P:5]([CH3:12])(=[O:11])[O:6]CCCC)[CH3:4].O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Al+3:36].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Al+3]>O>[CH2:3]([P:5]([CH3:12])(=[O:6])[O-:11])[CH3:4].[Al+3:36].[CH2:3]([P:5]([CH3:12])(=[O:6])[O-:11])[CH3:4].[CH2:3]([P:5]([CH3:12])(=[O:6])[O-:11])[CH3:4]
Reactant: CCCCOP(C)(=O)CC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Na+]
Solvent: O
Product: CCP(C)(=O)[O-]
Yield: 190.5 %

Procedure:
Under an atmosphere of argon, 312.5 g (2.5 mol) of 32% strength aqueous sodium hydroxide and 156 ml of water are added at 25° C., without interruption and with stirring, to 330.3 g (2.5 mol) of n-butyl ethylmethylphosphinate. The n-butanol/water mixture is distilled off azeotropically at 140° C. (boiling range: from 93 to 96° C.), the reflux ratio being adjusted so that after 2 h 15 min only pure water distils over. The resultant yellowish solution of sodium methylphosphinate is mixed with a further 936 ml of water. 277.7 g (0.42 mol) of aluminum sulfate octadecahydrate in 270 ml of water are added dropwise at 23° C. within a period of 2 hours, with stirring, and the product precipitates immediately. The resultant solution is filtered, and the residue is washed a number of times with water. Drying under reduced pressure at 150° C. gives 278.6 g of aluminum ethylmethylphosphinate (96% of theory) as a white powder (m.p. >380° C.).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14].[Cl:15][CH2:16][C:17](Cl)=[O:18].Cl>C(Cl)Cl>[Cl:15][CH2:16][C:17]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[NH:5][C:6](=[O:14])[CH2:7]2)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1Cc2cc(C(=O)CCl)ccc2N1
Temperature: 45 °C

Procedure:
Under ice-cooling, aluminum chloride (anhydride) (3.5 equivalents) was suspended in methylene chloride, and oxindole (1 equivalent) was added to this solution while stirring. To this solution, chioroacetyl chloride (2 equivalents) was gradually added dropwise, and after generation of hydrogen chloride gas was stopped, the resulting mixture was stirred for about 10 minutes. Thereafter, the reaction mixture was warmed to 40 to 50° C. and stirred for 2 hours. After cooling, the reaction mixture was poured into ice water and the resulting precipitate was collected by filtration, washed with water and dried, whereby 5-chloroacetylindolin-2-one was obtained. 5-chloroacetylindolin-2-one was dissolved in pyridine and the resulting mixture was heated and stirred at 80 to 90° C. for 3 hours. After cooling, the resulting precipitate was collected by filtration, washed with ethanol several times and dissolved in 2.5 N sodium hydroxide, and the resulting solution was stirred at 70 to 75° C. After cooling, the reaction mixture was acidified with hydrochloric acid and the resulting precipitate was collected by filtration, washed with water and dried, whereby 5-carboxyindolin-2-one was obtained. From the thus obtained 5-carboxyindolin-2-one and diformylfuran, a target compound was obtained in the same manner as in Example 1.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:15](I)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN(C)C=O>[CH2:15]([N:9]1[CH2:10][CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:12])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCI
Reactant: O=C1NCCN1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCN1CCN(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 47 %

Procedure:
To a 0° C. suspension of 5.00 g (30.8 mmol) 1-phenylimidazolidin-2-one in 50 mL of dimethylformamide was added 1.48 g (37.0 mmol, 1.2 equiv) of sodium hydride (60% oil dispersion). After 45 minutes, 6.7 mL (8.88 g, 37.0 mmol, 1.2 equiv) of octyl iodide was added. The mixture was allowed to stir overnight with gradual warming to room temperature. TLC analysis indicated the presence of starting material. An additional 830 mg portion of sodium hydride was added. After 5 hours, TLC analysis again indicated the presence of starting material, so 0.5 g more sodium hydride and 6 mL of octyl iodide were added. After 2 hours, the reaction was complete as judged by TLC analysis. The mixture was concentrated in vacuo, and partitioned between 200 mL of ethyl acetate and 50 mL of water. The organic phase was washed sequentially with three 50-mL portions of water and one portion of brine, dried over magnesium sulfate, and concentrated in vacuo. Purification by flash chromatography (silica gel, 10-25% ethyl acetate/hexane) provided 3.97 g (47%) of 3-octyl-1-phenylimidazolidin-2-one. A 3.93 g portion of this material was added over 45 min to 6 mL of chlorosulfonic acid in a salt/ice bath. Stirring was continued at -5° C. until gas evolution ceased (~3 hours). The reaction mixture was poured into 50 mL of ice and extracted with 3 150-mL portions of ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (25% ethyl acetate/hexane) provided 2.49 g of the title compound: 1H NMR (500 MHz, CDCl3) δ7.94 (d, 2H), 7.76 (d, 2H), 3.87 (dd, 2H), 3.55 (dd, 2H), 3.31 (t, 2H), 1.56 (m, 2H), 1.36-1.21 (m, 10H), 0.85 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]2[CH2:11][O:10][CH2:9][C@@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[F-].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:20]=[CH:19][C:5]([O:6][C@@H:7]2[CH2:11][O:10][CH2:9][C@@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)N[C@H]1COC[C@H]1Oc1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: CC(C)S(=O)(=O)N[C@H]1COC[C@H]1Oc1ccc(-c2ccccc2)cc1

Procedure:
To a microwave vial was added N-[(3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide (124 mg, 0.340 mmol), phenylboronic acid (63.5 mg, 0.521 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos, 16.2 mg, 0.034 mmol), palladium(II) acetate (5.2 mg, 0.023 mmol) and potassium fluoride (99.6 mg, 1.71 mmol). The vial was capped, and purged three times with nitrogen/vacuum. A 1:1 mixture of degassed methanol/toluene (1.5 mL) was added and the reaction was subjected to microwave irradiation at 130° C. for 30 minutes. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 10% to 25% ethyl acetate in heptane), to afford the title compound as a solid. Yield: 90 mg, 0.25 mmol, 73%. 1H NMR (400 MHz, CDCl3) δ 1.37 (d, J=6.8 Hz, 3H), 1.40 (d, J=6.8 Hz, 3H), 3.17 (septet, J=6.8 Hz, 1H), 3.76 (dd, J=8.6, 8.6 Hz, 1H), 4.01 (dd, J=10.6, 1.6 Hz, 1H), 4.16-4.30 (m, 3H), 4.84 (m, 1H), 5.09 (d, J=9.4 Hz, 1H), 6.97 (d, J=8.7 Hz, 2H), 7.34 (t, J=7.4 Hz, 1H), 7.44 (dd, J=7.6, 7.6 Hz, 2H), 7.55 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 16.48, 16.55, 54.27, 55.35, 70.29, 71.96, 75.87, 115.85, 126.65, 126.88, 128.34, 128.68, 135.11, 140.25, 155.93.