Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:31]([C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1)([O-:33])=[O:32].C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][N:11]([O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[S:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=1)(=[O:41])=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
A mixture of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (200 mg, 0.474 mmol), 3-nitrophenylsulphonyl chloride (105 mg, 0.474 mmol), diisoproylethylamine (0.084 mL, 0.474 mmol) and dimethylaminopyridine (˜1 mg) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature over 16 hours under an Argon atmosphere. The reaction was evaporated in vacuo and the residue was partitioned between dichloromethane and aqueous hydrochloric acid (1N). After separating the phases, the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 1:1 ethyl acetate:hexane. Fractions containing the product were combined, evaporated in vacuo and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(3-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (246 mg, 86%). H1-NMR (chloroform-D3): 0.98 (m, 6H), 1.68 (m, 7H), 2.99 (m, 5H), 3.73 (m, 2H), 3.96 (m, 4H), 4.27 (m, 1H), 4.86 (d, 1H), 5.07 (m, 1H), 5.69 (d, 1H), 7.27 (m, 5H), 7.84 (m, 1H), 8.16 (d, 1H), 8.57 (d, 1H), 8.76 (s, 1H). MS(ESI): 630(M+Na).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:16]=[N:17][NH:18][N:19]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:26][C:27]1[N:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[C:20]([N:6]1[C:5]2[CH:24]=[CH:25][C:2]([C:30]3[CH:29]=[N:28][C:27]([NH2:26])=[N:32][CH:31]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[N:17][NH:18][N:19]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)n1c(-c2ccccc2-c2nn[nH]n2)nc2cc(Br)ccc21
Reactant: CC1(C)OB(c2cnc(N)nc2)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: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)n1c(-c2ccccc2-c2nn[nH]n2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 110 °C
Yield: 8.1 %

Procedure:
To a sealed vial is added 5-bromo-1-tert-butyl-2-[2-(2H-tetrazol-5-yl)-phenyl]-1H-benzimidazole (190 mg, 0.478 mmol) in DMF (5 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (126 mg, 0.57 mmol), tetrakis(triphenylphosphine)palladium(0) (55 mg, 0.048 mmol) and 2M aq. Na2CO3 (1 mL, 2 mmol). The reaction mixture is heated under Argon at 110° C. for 3 hours. The residue is diluted with EtOAc, washed with brine, dried with Na2SO4, filtered and concentrated. The residue is loaded onto a silica gel column. The column is eluted with 0-20% 7M NH3 in MeOH/CH2Cl2. The product fractions are collected and concentrated to afford the title compound (16 mg, 8%) as a light yellow solid. LCMS (ESMS): m/z 412.67 (M++1)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[N:9][CH2:10][CH2:11][N:12]([CH2:24][CH2:25][N:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34])[CH2:13][CH2:14][N:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].[BH4-].[Na+]>CO.C(Cl)Cl>[OH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][NH:15][CH2:14][CH2:13][N:12]([CH2:11][CH2:10][NH:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[CH2:24][CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34]
Reactant: Oc1ccccc1C=NCCN(CCN=Cc1ccccc1O)CCN=Cc1ccccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Oc1ccccc1CNCCN(CCNCc1ccccc1O)CCNCc1ccccc1O
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A solution of N, N, N-tris[[[(2-hydroxyphenyl)methylene]amino]ethyl]amine (40.0 g, 87 mmol) in 250 mL of methanol and 250 mL of methylene chloride was cooled in an ice bath. Sodium borohydride (10.0 g, 263 mmol) was added in several portions. Stirring was continued at room temperature for two hours. The solvents were evaporated and the residue was taken up in ether. This solution was washed with water and brine, dried over magnesium sulfate, filtered and evaporated to afford N, N, N-tris[[[(2-hydroxyphenyl)methyl]amino]ethyl]amine(30.0 g, 74%) as a colorless glass.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([CH2:12][OH:13])[CH:3]=1.CN([CH:17]=[O:18])C.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[C:17]([O:13][CH2:12][C:4]1[CH:3]=[C:2]([OH:1])[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=1)(=[O:18])[CH3:19]
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1nc2nc(CO)cc(O)n2n1
Solvent: CC(=O)O
Product: CC(=O)OCc1cc(O)n2nc(C)nc2n1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A mixture of 33.06 g of 7-hydroxy-5-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidine, 500 ml of DMF, 86 ml of anhydrous acetic acid and 1.5 g of p-toluenesulfonic acid was stirred in a bath at 50° C. for 6 hours. To an oily residue obtained by removing DMF was added 300 ml of isopropanol to dissolve therein, and the solution was added dropwise in 4 liters of ether. Precipitates were collected by filtration and dried to obtain 38.08 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=C[N:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2].[N:17]1C2NC=C(C(=O)C)C=2C=CN=1>>[C:1]([C:4]1[C:12]2[CH:11]=[CH:10][N:9]=[N:17][C:7]=2[N:6]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cn(CC(=O)O)c2cnccc12
Reactant: CC(=O)c1c[nH]c2nnccc12
Product: CC(=O)c1cn(CC(=O)O)c2nnccc12

Procedure:
was prepared using similar procedures as described for the synthesis of (3-acetyl-pyrrolo[2,3-c]pyridin-1-yl)-acetic acid in Scheme A15 from 1-(7H-pyrrolo[2,3-c]pyridazin-5-yl)-ethanone (prepared according to J. Org. Chem. 2002, 67, 6226). MS (UPLC/MS): 220.1 [M+H]+, 178.0 [MH-CH3CO]+, 218.1 [M−H]−, 437.2 [2M−H]−.
Reaction SMILES: Cl[C:2]1([CH2:7][C:8]([Cl:11])([Cl:10])Cl)[O:5][C:4](=[O:6])[CH2:3]1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(OC)(C)C>[Cl:11][C:8]([Cl:10])=[CH:7][C:2](=[O:5])[CH2:3][C:4]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:6]
Reactant: O=C1CC(Cl)(CC(Cl)(Cl)Cl)O1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: O=C(C=C(Cl)Cl)CC(=O)N1CCOCC1
Temperature: 15 °C
Yield: 72927.5 %

Procedure:
Two separate solutions of 1 (62.5 g, 0.26 mmol) and morpholine (24.0 g, 0.28 mol) in DCM (120 ml) were added simultaneously to a mixture of NaHCO3 (44.0 g, 0.52 mol) in dry DCM (300 ml). The reaction was maintained at 15° C. over 140 minutes with stirring. The reaction was filtered, washed with DCM (3×100 ml) and the combined organic layers were concentrated in vacuo to a slurry which was then passed through a short silica pad, and further washed with DCM (4×100 ml). The combined organic layers were concentrated in vacuo, suspended in hexane (400 ml) and stirred for 1 hour, filtered and dried to give a cream solid. The solid was suspended in TBME (100 ml), stirred for 15 minutes, filtered, washed with TBME and dried to give 2 as a white powder (47.8 g, 72%). m/z (LC-MS, ESP): 252 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.Br[C:11]1[S:12][CH:13]=[CH:14][N:15]=1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[C:13]2[S:12][CH:11]=[N:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CNc1ccc(F)cc1
Reactant: Brc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc(F)cc1)c1cncs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.0 g (40 mmol) of 4-fluoro-N-methylaniline and 3.6 mL (40 mmol) of 2-bromothiazole were added to a suspension of 1.9 g (81 mmol) of NaH in 100 mL of DMF, and the suspension was stirred overnight at rt. The reaction mixture was concentrated onto 20 g of silica in vacuo and the residue purified by flash chromatography eluting with a linear gradient of 20% EtOAc in hexane to 100% EtOAc to deliver the desired compound. MS (M+H)+ 209.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([Sn](C)(C)C)=[CH:14][CH:13]=1.O>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3](=[O:4])[CH3:2])=[CH:14][CH:13]=1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: 150 °C
Yield: 71.2 %

Procedure:
A vigorously stirred solution of 13.25 g (66 mmol) of 2-bromoacetophenone and 22.8 g (89 mmol) of 4-methylphenyltrimethylstannane in 190 mL of dimethylformamide under a nitrogen atmosphere was treated with 8.64 g (12 mmol) of bis(triphenylphosphine) palladium(II) chloride and the resulting mixture heated at 150° C. for 6 hours. The reaction mixture was cooled, poured into water (1000 mL) and the resultant suspension extracted with ethyl ether. The combined extracts were washed with water (4×), dried over magnesium sulfate and evaporated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (10:1), to give 9.8 g (47 mmol, 71%) of the product as an oil. EI-MS: calculated for C15H14O 210: found 210 (M+). 1H NMR (200 MHz, CDCl3): 1.98 (s, 3H), 2.37 (s, 3H), 7.20 (s, 4H), 7.3-7.5 (m, 4H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CS(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[C:15]([C:22]4[NH:30][C:29]5[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=5[CH:23]=4)[CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5ccc(Cl)cc5)nc34)cc21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
NaH (60% in mineral oil; 0.071 g, 1.763 mmol) was suspended in 1 mL DMF and p-chlorophenol (Aldrich; 0.174 ml, 1.763 mmol) was added. After 10 min, 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added, and the reaction was sealed and heated at 70° C. for 2 h, then at 90° C. for 1 h. The reaction mixture was then treated with TFA (0.136 ml, 1.763 mmol) and 1 mL DMSO, filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 20-100% ACN/H2O with 0.1% TFA); product-containing fractions were concentrated in vacuo to give 2-(2-(4-chlorophenoxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.044 g, 0.113 mmol, 45% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.07 (1H, br. s), 8.50 (1H, d, J=9.0 Hz), 8.11 (1H, dt, J=7.6, 0.7 Hz), 7.80 (1H, dt, J=7.9, 0.7 Hz), 7.60-7.71 (2H, m), 7.31-7.55 (4H, m), 6.94 (2H, dd, J=2.0, 0.4 Hz), 3.31-3.42 (2H, m), 2.47-2.51 (2H, m). m/z (ESI, +ve) 389.9 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C1COCC1.C([Li])CCC.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CCCCCC.O>[CH2:17]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCBr
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCCCCCCc1cccs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 107.1 %

Procedure:
Thiophene (59.9 g, 0.713 mol) and dehydrated tetrahydrofran (hereinafter referred to as “THF”) (200 ml) were placed in a 1000-ml three-necked flask equipped with a 200-ml dropping funnel and a reflux tube. The solution was cooled to −78° C., and a solution (200 ml) of n-butyllithium (2.6 M) in n-hexane was added dropwise to the cooled solution over a period of about one hr. After the completion of the dropwise addition, the mixture was stirred at −78° C. for about one hr. Thereafter, the reaction temperature was raised to room temperature. At that temperature, the mixture was again stirred for one hr, and 1-bromooctane (91.8 g, 0.475 mol) was added dropwise thereto at 0° C. over a period of about one hr. After the completion of the dropwise addition, the reaction temperature was raised to room temperature, and, at that temperature, the mixture was stirred overnight. After the completion of the reaction, water (200 ml) was added, and the organic layer was extracted with diethyl ether, was dried over sodium sulfate, and was applied to column chromatography (n-hexane) to give an objective compound 2-octylthiophene as a yellow liquid (99.9 g, yield 97.8%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (CDCl3, TMS/ppm): 0.88 (t, 3H, J=6.83 Hz), 1.28 (m, 10H), 1.67 (m, 2H), 2.81 (t, 2H, J=7.32 Hz), 6.77 (dd, 1H, J=0.976 Hz, J=3.90 Hz), 6.91 (dd, 1H, J=3.90 Hz, J=4.88 Hz), 7.10 (dd, 1H, J=0.976 Hz, J=4.88 Hz).
Reaction SMILES: [CH:1]1([NH2+:7]C2CCCCC2)CC[CH2:4][CH2:3][CH2:2]1.[CH2:14]([C@H:18]1[O:20][C@@H:19]1[C:21]([O-:23])=O)[CH2:15][CH2:16][CH3:17].C(Cl)(=O)C(C)(C)C.C(N)CCC>O1CCCC1>[CH2:1]([NH:7][C:21]([C@@H:19]1[C@@H:18]([CH2:14][CH2:15][CH2:16][CH3:17])[O:20]1)=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: C1CCC([NH2+]C2CCCCC2)CC1
Reactant: CCCC[C@H]1O[C@@H]1C(=O)[O-]
Agent: CC(C)(C)C(=O)Cl
Solvent: CCCCN
Solvent: C1CCOC1
Product: CCCCNC(=O)[C@H]1O[C@@H]1CCCC
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
Under ice-cooling, to 10 ml of an anhydrous tetrahydrofuran solution containing 299 mg (1.84 mmol) of (2S-trans)-3-butyl-oxiranecarboxylic acid-dicyclohexylammonium salt was added 2 ml of an anhydrous tetrahydrofuran solution containing 222 mg (1.84 mmol) of pivaloyl chloride, and the resulting mixture was stirred at the same temperature for 15 minutes. Moreover, the temperature of the reaction mixture was returned to room temperature, and the mixture was stirred for 2 hours. After filtering off insoluble materials in the reaction mixture, the filtrate was added to 10 ml of an anhydrous tetrahydrofuran solution containing 135 mg (1.84 mmol) of n-butylamine under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. Under reduced pressure, the reaction mixture was concentrated and ethyl acetate was added to the concentrate, and the resulting mixture was washed successively with a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and then a saturated NaCl solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 366 mg (Yield: 100%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:45])[C:5]2[S:10][C:9](=[S:11])[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][O:36]C(=O)C4C=CC=CC=4)[C@@H:23]([O:24]C(=O)C4C=CC=CC=4)[C@H:13]3[O:14]C(=O)C3C=CC=CC=3)[C:6]=2[N:7]=1.C[O-].[Na+]>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:45])[C:5]2[S:10][C:9](=[S:11])[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:23]([OH:24])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: Nc1nc2c(sc(=S)n2[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc2c(sc(=S)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reaction time: 8 h

Procedure:
To a solution of 15 (1.25 g, 1.94 mmol) in dry methanol (100 mL) was added sodium methoxide powder until the pH reached 10. The solution was stirred overnight and then neutralized with Dowex H+ resin and filtered. After evaporation of the filtrate, the residue was washed with ether to remove methyl benzoate and the crude material was crystallized from water: yield 520 mg, 81%: mp 220° C. dec.: UV λmax 1H NMR (DMSO-d6) δ 6.48 (d, J=3.00 Hz, 1H, C1,H), 6.99 (s, 2H, NH2), 11.47 (s, 1H, NH), and other sugar protons. Anal. Calcd. for C10H12N4O5S2.H2O: C, z34.28: H, 4.03: N, 15.99: S, 18.30. Found: C, 33.99: H, 3.92: N, 15.68: S, 18.22.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH2:23])[CH:17]=[CH:18][C:19]=1[Cl:20].[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:16]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.227 ml 2-(3,4-dichloro-phenyl)-ethylamine (1.5 mmol) were dissolved in 4.5 ml methanol at RT, and after stirring for 30 min at RT, were refluxed for 2 h. After cooling down to RT, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at RT, the reaction mixture was then refluxed for 2 h. After cooling down to RT, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 515 mg colorless viscous oil (97%). MS (ISP) 336.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#[N:10])=[CH:4][C:3]=1[N+:11]([O-])=O.Cl>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#[N:10])=[CH:4][C:3]=1[NH2:11]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Product: N#CSc1ccc(N)c(N)c1
Temperature: 25 °C

Procedure:
4 G. of 1-amino-2-nitro-4-thiocyanatobenzene is suspended in 12 ml. concentrated hydrochloric acid and cooled to about -40° C. A solution of 24 g. stannous chloride in 12 ml. concentrated hydrochloric acid is added. The mixture is allowed to warm slowly to room temperature and after 20 minutes the product is filtered off and washed with 24 ml. 6N hydrochloric acid. The salt is dissolved in water, treated with potassium bicarbonte, and the mixture extracted with chloroform. Evaporation of the chloroform extracts followed by crystallization of the crude product from benzene yields pure 1,2-diamino-4-thiocyanatobenzene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH2:8][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:2]=1.[CH2:15]([O:17][C:18]1[C:19]([OH:29])=[C:20]([CH:24]=[C:25]([CH:27]=O)[CH:26]=1)[C:21]([OH:23])=[O:22])[CH3:16].[NH2:30][C:31]([NH2:33])=[O:32].Cl>CCO>[CH2:15]([O:17][C:18]1[C:19]([OH:29])=[C:20]([CH:24]=[C:25]([CH:27]2[C:8]([C:9]3[CH:13]=[CH:12][S:11][CH:10]=3)=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:26]=1)[C:21]([OH:23])=[O:22])[CH3:16]
Reactant: CCOc1cc(C=O)cc(C(=O)O)c1O
Reactant: NC(N)=O
Reactant: O=C(Cc1ccsc1)c1cccnc1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3cccnc3)=C2c2ccsc2)cc(C(=O)O)c1O
Yield: 32.9 %

Procedure:
A mixture of 1-(pyridin-3-yl)-2-(thiophen-3-yl)ethanone (Intermediate 56) (372 mg, 1.83 mmol), 3-ethoxy-5-formyl-2-hydroxybenzoic acid (Intermediate 62) (350 mg, 1.67 mmol), urea (300 mg, 5.00 mmol) and HCl (12 M, 0.14 mL, 1.67 mmol) in EtOH (10 mL) was refluxed overnight. The mixture was concentrated in vacuo and purified by preparative HPLC to give Compound 126 (240 mg, yield 33%) as a yellow solid. 1H NMR (DMSO-d6 400 MHz): δ 11.35 (br, 1H), 8.87 (d, J=1.6 Hz, 1H), 8.56 (dd, J=1.6 Hz, J=5.2 Hz, 1H), 8.45 (d, J=1.6 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.51-7.48 (m, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.24-7.22 (m, 1H), 7.15 (d, J=2.0 Hz, 1H), 6.87 (dd, J=1.2 Hz, J=3.2 Hz, 1H), 6.33 (dd, J=1.2 Hz, J=4.8 Hz, 1H), 5.16 (d, J=2.4 Hz, 1H), 4.03-3.95 (m, 2H), 1.31 (t, J=6.8 Hz, 3H); MS (ESI): m/z 438.0 [M+1]+;
Reaction SMILES: C(O)C.[NH2:4][C:5]1[CH:14]=[CH:13][C:8]2=[N:9][C:10](=[O:12])[N:11]=[C:7]2[CH:6]=1.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1>O>[C:18]([NH:4][C:5]1[CH:14]=[CH:13][C:8]2=[N:9][C:10](=[O:12])[N:11]=[C:7]2[CH:6]=1)(=[O:19])[CH2:17][C:16]([CH3:15])=[O:20]
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Reactant: C=C1CC(=O)O1
Solvent: CCO
Solvent: O
Product: CC(=O)CC(=O)Nc1ccc2c(c1)=NC(=O)N=2
Yield: 95 %

Procedure:
The mother liquor obtained is re-used in four further reaction cycles by using it at 80° C. to replace fresh ethanol containing 50% by weight of water for dissolving 2.86 kg per hour of 5-amino-2-benzimidazolone at such a rate that 26.86 kg per hour of amine solution can be reacted as described above with 2.06 kg per hour of diketene. Workup gives 4.25 to 4.34 kg per hour of 5-acetoacetylamino-2-benzimidazolone of consistent quality, corresponding to a yield of 95 to 97% based on amine.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C.[ClH:27].[OH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[OH:38])[CH2:32][CH2:33][NH2:34].C(O)CCC>O>[ClH:27].[CH2:17]([O:16][C:14]([N:6]([CH2:5][CH:4]1[C:35]2[C:31](=[CH:30][C:29]([OH:28])=[C:37]([OH:38])[CH:36]=2)[CH2:32][CH2:33][NH:34]1)[C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)c1ccc(F)cc1)OCC
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: O=C(OCc1ccccc1)N(CC1NCCc2cc(O)c(O)cc21)c1ccc(F)cc1
Yield: 44.6 %

Procedure:
N-benzyloxycarbonyl-p-fluoroanilinoacetaldehyde diethyl acetal (6 g) and 3,4-dihydroxyphenethylamine hydrochloride (2.5 g) were added to a mixture of n-butyl alcohol (60 ml) and water (8.5 ml). The mixture was then refluxed for 11 hours in a stream of nitrogen. In the course of the reaction, amounts of the above-mentioned acetal (0.6 g and 1.2 g) were added to the mixture after 4.5 hours and 6 hours, respectively, from the beginning of the reaction. The reaction mixture was concentrated to dryness and the residue was washed with ether and dissolved in water. The solution was washed with ether and concentrated to dryness to give amorphous 1-(N-benzyloxycarbonyl-p-fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.7 g), mp 122° C. (dec.).