Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[H-].[Na+].I[CH3:32]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][O:27][CH3:32])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CO)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Reaction time: 0.17 h

Procedure:
To a solution of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one (0.35 g, 0.00078 mol) in DMF at 0° C., was added NaH (0.022 g, 0.00092 mol) and stirred for 10 min. Iodomethane (0.05 mL) was added to the reaction and the mixture was stirred at 10° C. for 3 h. DMF was distilled in vacuo and the residue was partitioned between 5% citric acid and EtOAc (15.0 mL). The organic phase was washed with water, dried (Na2SO4) and concentrated to dryness. The residue was purified by flash chromatography (EtOAc), and the appropriate fractions were combined and concentrated to a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[C:5](=O)[N:6]=[CH:7][NH:8]2.O=P(Cl)(Cl)[Cl:20]>CN(C=O)C>[Cl:20][C:5]1[C:4]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:3]=2[O:2][CH3:1])[N:8]=[CH:7][N:6]=1
Reactant: COc1cc2[nH]cnc(=O)c2c(OC)c1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2c(OC)c1OC
Temperature: 100 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
5,6,7-tris(methyloxy)-4(1H)-quinazolinone (0.8 g, 3.39 mmol) was treated with POCl3 (10 ml, 107 mmol) and one drop of DMF, and stirred at 100° C. for 1 hour before being concentrated. The residue was treated with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic extracts were dried (sodium sulfate) and concentrated to give 4-chloro-5,6,7-tris(methyloxy)quinazoline (770 mg, 89%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (s, 1 H), 7.37 (s, 1 H), 4.04 (s, 3 H), 3.94 (s, 3 H), 3.91 (s, 3 H). MS (m/z) 255.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([CH3:19])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([O-:23])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCO>[CH3:19][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([C:2]3[CH:3]=[CH:4][CH:5]=[C:6]([CH:20]=[O:23])[CH:7]=3)[CH:7]=[CH:6][CH:5]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(Nc2cccc(Br)c2)c2ccccc2n1
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2cccc(-c3cccc(C=O)c3)c2)c2ccccc2n1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
To a suspension of 71 (294 mg, 0.94 mmol) in toluene (9.6 mL) under N2 were sequentially added saturated NaHCO3 (aq. 3.8 mL), a solution of 72 (199 mg, 1.33 mmol) in EtOH (6.7 mL), and PdCl2(Ph3P)3 (32 mg, 0.046 mmol). The reaction was heated at 80° C. for 21 hours before it was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate (40 mL) and washed with water (15 mL), brine (15 mL). The ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (dichloromethane to 20:1 dichloromethane/methanol) to give 73 as a yellow solid (219 mg, 68.9%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[NH:24]([C:26]([NH2:28])=[O:27])[NH2:25]>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18](/[C:21](=[N:25]/[NH:24][C:26]([NH2:28])=[O:27])/[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: CC(=O)c1ccc2ncc(Cc3ccc4c(cnn4C)c3)n2n1
Reactant: NNC(N)=O
Solvent: C1CCOC1
Product: C/C(=N\NC(N)=O)c1ccc2ncc(Cc3ccc4c(cnn4C)c3)n2n1
Yield: 88.9 %

Procedure:
A solution of 1-(3-((1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (40.0 mg, 0.09 mmol) and hydrazinecarboxamide (19.47 mg, 0.26 mmol) in 10 mL THF was stirred at 40° C. for overnight. Solvent was removed in vacuo. The crude product was purified on flash chromatography (DCM:MeOH=20:1) to give the title compound as a white solid (29.0 mg, 88%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 8.18 (d, 1H), 7.95 (m, 2H), 7.69 (s, 1H), 7.60 (s, 1H), 7.75 (d, 1H), 7.40 (dd, 1H), 6.76 (bs, 2H), 4.41 (s, 2H), 3.99 (s, 3H), 2.29 (s, 3H). LCMS (method A): [MH]+=363, tR=4.42 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CCOC(C)=O.[Pd]>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([F:1])=[C:3]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(N)c(F)cc1F
Reaction time: 12 h
Yield: 50 %

Procedure:
A mixture of ethyl 2-(2,4-difluoro-5-nitrophenyl)acetate (16 g, 130 mmol) and 10% Pd/C (1.6 g, 1.5 mmol) in EtOAc was hydrogenated at 30 psi at RT for 12 h. The catalyst was filtered off and the filtrate was evaporated. Then the residue was purified by column chromatography to give ethyl 2-(5-amino-2,4-difluorophenyl)acetate (14 g, 99% yield). 1H NMR (300 MHz, DMSO-d6): δ 6.98 (t, J=9.9 Hz, 1 H), 6.70 (t, J=7.8 Hz, 1 H), 4.50 (s, 2 H), 4.06 (m, 2 H), 3.53 (s, 2 H), 1.16 (t, 0.7=6.9 Hz, 3 H); MS (ESI) m/z: 216.2 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:20])=[C:7]([C:11]([I:19])=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[C:13]=1[I:14])[C:8](Cl)=[O:9])(=[O:3])[CH3:2].Cl.[CH2:22]([O:24][C:25](=[O:35])[C@H:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH2:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:35])[C@H:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:27][C:8](=[O:9])[C:7]1[C:6]([I:20])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:13]([I:14])=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[C:11]=1[I:19])[CH3:23]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)Cl)c1I
Agent: Cl
Product: CCOC(=O)CC[C@H](NC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I)C(=O)OCC

Procedure:
Following the procedure of example 13, 155 g (65%) of product is synthesized from 192 g (0.3 Mol) 3,5-diacetamido-2,4,6-triiodobenzoyl chloride and 108 g (0.45 Mol) L-glutamic acid diethyl ester hydrochloride.
Reaction SMILES: C(OC(=O)C)C.[ClH:7].C(OC(=O)[NH:14][CH2:15][CH2:16][C:17]1[CH:34]=[CH:33][C:20]2[N:21]([CH2:31][CH3:32])[C:22](=[O:30])[C:23]([CH3:29])([CH3:28])[C:24](=[O:27])[N:25]([CH3:26])[C:19]=2[CH:18]=1)(C)(C)C>C(OCC)(=O)C>[ClH:7].[NH2:14][CH2:15][CH2:16][C:17]1[CH:34]=[CH:33][C:20]2[N:21]([CH2:31][CH3:32])[C:22](=[O:30])[C:23]([CH3:28])([CH3:29])[C:24](=[O:27])[N:25]([CH3:26])[C:19]=2[CH:18]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCNC(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCN)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 4N-hydrogen chloride ethyl acetate solution (6 ml) was added to an ethyl acetate solution (20 ml) of [2-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl)ethyl]carbamic acid tert-butyl ester (0.38 g), and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure to give the title compound (0.26 g) as a pale orange amorphous solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:13]=1[C:14]([O:16]C)=O.[F:23][C:24]([F:31])([F:30])[CH2:25][CH2:26]C(O)=O>C1COCC1>[Br:11][C:12]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:13]=1[C:14](=[O:16])[CH2:26][CH2:25][C:24]([F:31])([F:30])[F:23]
Reactant: COC(=O)c1cc(Cl)ccc1Br
Reactant: O=C(O)CCC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CCC(F)(F)F)c1cc(Cl)ccc1Br
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A THF solution of sodium bis(trimethylsilyl)amide (1.0M, 194 mL, 194 mmol) was added dropwise to a −78° C. THF (400 mL) solution containing methyl 2-bromo-5-chlorobenzoate (16.10 g, 64.5 mmol) and 4,4,4-trifluorobutyric acid (9.17 g, 64.5 mmol). After stirring for 15 minutes at −78° C. the solution was warmed to 0° C. and stirred for an additional 2 hours. The reaction was quenched with an excess of aqueous 1N HCl (ca 400 mL) and stirred overnight at room temperature. The solution was concentrated to remove the majority of the THF. The solution was then diluted with EtOAc and washed with 1N NaHCO3 (twice) and brine. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound (solid). 1H NMR (500 MHz, CDCl3): δ 7.58 (d, J=8.4 Hz, 1H); 7.41 (d, J=2.5 Hz, 1H); 7.33 (dd, J=8.5, 2.5 Hz, 1H); 3.22 (t, J=7.8 Hz, 2H); 2.68-2.56 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH2:16]([O:18][C:19](=[O:49])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]Br)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:18][C:19](=[O:49])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15])[CH3:17]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCCOc2ccc(C(=O)c3cccc(C(=O)OCC)c3)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Yield: 80.2 %

Procedure:
A mixture of 0.144 g (0.70 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 0.371 g (0.70 mmol) of 2-[(6-bromohexyl)oxy]-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, 0.479 g (3.47 mmol) of anhydrous granular potassium carbonate and 13.1 mL of 2-butanone was stirred and refluxed for 18 hr. The resulting slurry was filtered with suction and the solids washed thoroughly with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo and the residue was purified by flash chromatography on 75 g of silica gel, eluting with 3:1 hexane-ethyl acetate, giving 0.37 g (80.6%) of 2-[6-[(2,3-dihydro-4-oxo-8-propyl-4H-1-benzopyran-7-yl)oxy]hexyloxy]-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester as a white solid, mp 58°-59.5° C. A mixture of 0.331 g (0.50 mmol) of this ester in 6 mL of THF and 6 mL of water was treated with 64.7 mg (1.54 mmol) of lithium hydroxide monohydrate and the resulting mixture was stirred for 25.5 hr at room temperature, before being acidified with 17 mL of 3N aqueous sulfuric acid. Work-up with ethyl acetate in the usual manner gave a crude product which was recrystallized from hexane-ethyl acetate affording 0.242 g (79.7%) of the title compound as a white solid, mp 169°-172° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]([F:20])([F:19])[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34]>Cl.CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([F:20])([F:19])[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Yield: 67.5 %

Procedure:
2-Chloro-9-cyclohexyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (2.77 g, 8.8 mmol), 4-amino-3-methoxy benzoic acid (1.61 g, 9.6 mmol), i-PrOH (30 mL) and conc. HCl (30 drops) were heated to 95° C. for 18 hours. A this time the reaction was cooled to room temperature and filtered to reveal the product as a tan solid (2.74 g, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=12.13 Hz, 1 H) 1.23-1.42 (m, 2 H) 1.53-1.78 (m, 5 H) 1.82 (d, J=12.63 Hz, 2 H) 3.32 (s, 3 H) 3.94 (s, 3 H) 4.26 (t, J=12.38 Hz, 2 H) 4.52 (t, J=11.62 Hz, 1 H) 7.47-7.65 (m, 2 H) 8.13 (d, J=8.08 Hz, 1 H) 8.28-8.45 (m, 1 H) 9.43 (br. s., 1 H). [M+H] calc'd for C22H25F2N5O4, 462; found 462.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12](=[O:18])[CH2:13][NH:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][C:3]=1[Cl:19].[BH4-].[Na+]>>[NH2:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]([CH:12]([OH:18])[CH2:13][NH:14][CH:15]2[CH2:16][CH2:17]2)=[CH:4][C:3]=1[Cl:19]
Reactant: Nc1c(Cl)cc(C(=O)CNC2CC2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: Nc1c(Cl)cc(C(O)CNC2CC2)cc1C(F)(F)F

Procedure:
m.p. 138°-139° C., was prepared from 4'-amino-3'-chloro-2-cyclopropylamino-5'-trifluoromethyl-acetophenone and sodium borohydride analogous to Example 1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[CH3:9][NH:10][O:11][CH3:12]>C(N(CC)CC)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([N:10]([O:11][CH3:12])[CH3:9])=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CCCCl
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
To a solution of 4-chlorobutyryl chloride (10.0 g in 200 mL of dry methylene chloride) was added 10.4 g of N,O-dimethylhydroxylamine hydrochloride. The mixture was stirred under nitrogen and maintained below 25° C. by cooling in an ice bath as necessary while triethylamine (29.1 mL) was added dropwise over about 20 minutes, resulting in precipitation. After 1.5 hours at room temperature, the mixture was concentrated in vacuo. The residue was partitioned between 100 mL of diethyl ether and 100 mL of saturated aqueous sodium bicarbonate solution. The organic layer was washed with an additional 100 mL of saturated sodium bicarbonate, and the aqueous fractions were back-extracted with ether. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo to give 10.5 g (90%) of an oil, which had satisfactory purity by 1H NMR (CDCl3). Mass spectrum (PB-NH3 /CI): m/e=166 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)=[O:8])=[CH:5][C:4]([CH3:19])=[N:3]1.O.NN>C(O)C.[Pd]>[NH2:16][C:12]1[CH:11]=[C:10]([NH:9][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:19])[CH:5]=2)=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(C(=O)Nc2cccc([N+](=O)[O-])c2)n(C)n1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)Nc2cccc(N)c2)n(C)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a solution of 3-nitroaniline (1.0 g, 7.2 mmol) in N,N-dimethylacetamide (6 mL) was added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonylchloride (1260 mg, 8.0 mmol) in N,N-dimethylacetamide (2 mL), and the mixture was stirred at room temperature for 30 min. Water (200 mL) was added to the mixture under ice-cooling, and the mixture was filtrated. The obtained solid was washed with water and diethyl ether to give 1,3-dimethyl-N-(3-nitrophenyl)-1H-pyrazole-5-carboxamide (1850 mg, 7.1 mmol). To a solution of the obtained 1,3-dimethyl-N-(3-nitrophenyl)-1H-pyrazole-5-carboxamide (1850 mg, 7.1 mmol) in ethanol (50 mL) was added 10% palladium/carbon (190 mg). Hydrazine monohydrate (1090 mg, 22 mmol) was slowly added to the mixture at room temperature and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was filtrated, and the filtrate was evaporated under reduced pressure. To the residue were added ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (1650 mg, 99%) as a pale-yellow solid.
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][C@@H:7]1[CH2:11][O:10][C@H:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C@@H:8]1/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[Si:5]([O:6][C@@H:7]1[CH2:11][O:10][C@H:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C@@H:8]1[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:25])[CH3:24]
Reactant: COC(=O)/C=C/[C@H]1[C@@H](c2cccnc2)OC[C@H]1O[Si](C)(C)C(C)(C)C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CC[C@H]1[C@@H](c2cccnc2)OC[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.93 g (0.0053 mol) of methyl (E)-(2S,3S,4S)-3-[4-(t-butyldimethyl-silyloxy)-2-(3-pyridyl)tetrahydrofuran-3-yl]-2-propenoate and 67 mg (0.28 mmol) of nickel dichloride hexahydrate in 17 ml of methanol is cooled to 0° C. and 0.21 g (0.0054 mol) of sodium borohydride is added in portions over a period of 20 min. The mixture is stirred at 0° C. for another 15 min and at room temperature for 1 h, evaporated to dryness, the residue is triturated with water and ethyl acetate and filtered through a celite bed. The aqueous layer of the filtrate is separated and extracted with ethyl acetate. The combined ethyl acetate extracts are washed with brine, dried (MgSO4) and evaporated to give methyl (2S,3S,4S)-3-[4-(-t-butyldimethylsilyloxy)-2-(3-pyridyl)tetrahydrofurane-3-yl]propanoate as an oil. Flash chromatography of the crude product gave 0.8 g of analytically pure material.
Reaction SMILES: O[C:2]1[C:3]2[C:8]([C:9]3C=CC=C[C:14]=3[CH:15]=1)=CC=CC=2.[C:16]([OH:20])(=[O:19])[CH:17]=[O:18]>ClCCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:18][CH:17]1[C:15]2[CH:14]=[CH:9][CH:8]=[CH:3][C:2]=2[O:19][C:16]1=[O:20]
Reactant: O=CC(=O)O
Reactant: Oc1cc2ccccc2c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Product: O=C1Oc2ccccc2C1O
Yield: 79.2 %

Procedure:
4.9 g of 9-hydroxyphenanthrene, 4.1 g of 50% aqueous glyoxylic acid and 0.05 g of p-toluenesulfonic acid are heated for 2 h in 70 ml of 1,2-dichloroethane under a water separator. The precipitated solid is then cooled down, filtered off, washed with cold 1,2-dichloroethane and dried to leave 3.0 g of hydroxybenzofuranone, which is introduced in 20 ml of toluene as initial charge together with 1.5 ml of thionyl chloride and 3 drops of DMF and then gradually heated to 100° C. so that the evolution of HCl and SO2 remains lively, but still controllable. The reaction mixture is subsequently stirred at 100° C. for 1 h. About 20 ml of liquid are then distilled off to remove excess thionyl chloride. The residue is diluted with 10 ml of toluene and admixed at room temperature with 1.7 ml of triethylamine added dropwise. The thick blue reaction mixture is then refluxed for 2 h. The precipitated isoxindigo is filtered off after cooling down to room temperature, freed of the triethylamine hydrochloride by washing with water, dried and recrystallized from dichloromethane/ethanol to leave 1.3 g (47% of theory) of [3,3′]bi[1-oxacyclopenta[l]phenanthrenylidene]-2,2′dione of the formula:
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=[O:6].[C:12]1([N:18]2[C:22]3([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:21](=[O:28])[NH:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[I-].[K+]>CN(C)C=O>[O:28]=[C:21]1[C:22]2([CH2:23][CH2:24][N:25]([CH2:2][CH2:3][NH:4][C:5]([C:7]3[O:8][CH:9]=[CH:10][CH:11]=3)=[O:6])[CH2:26][CH2:27]2)[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19][NH:20]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C(NCCCl)c1ccco1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccccc1)c1ccco1
Temperature: 25 °C

Procedure:
A member of 6.9 parts of N-(2-chloroethyl)-2-furancarboxamide, 9.2 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 6.6 parts of potassium iodide and 135 parts of N,N-dimethylformamide is stirred first for 3 hours at reflux and further overnight at room temperature. The reaction mixture is evaporated and the residue is taken up in water. The whole is alkalized and the product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 2-propanone. The product is filtered off and dried, yielding 1.9 parts of N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro [4,5]dec-8-yl)ethyl]-2-furancarboxamide; mp. 196.3° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].O.[C:12](O)(=O)[CH:13]=[O:14]>Cl>[O:14]=[C:13]1[CH:12]=[N:1][C:2]2[C:9](=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)[NH:10]1
Reactant: O=CC(=O)O
Reactant: N#Cc1ccc(N)c(N)c1
Agent: Cl
Solvent: O
Product: N#Cc1ccc2[nH]c(=O)cnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3,4-diaminobenzonitrile (5.00 g, 37.6 mmol) in 5% aq HCl (20 mL) was added glyoxilic acid monohydrate (4.32 g, 46.9 mmol). The mixture was stirred overnight at rt and filtered. The filter cake was washed with water and MeOH to afford 2-oxo-1,2-dihydroquinoxaline-6-carbonitrile as a grey solid which was used directly in the next step.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([S:6]([O-:9])(=O)=[O:7])=[CH:2]1.[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:12]>C(OCC)C>[NH:1]1[CH:5]=[CH:4][C:3]([S:6]([Cl:12])(=[O:9])=[O:7])=[CH:2]1
Reactant: O=S(=O)([O-])c1cc[nH]c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(Cl)c1cc[nH]c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
A suspension of 16.9 g (100 mmol) of Compound 1 and 22.9 g (110 mmol) of phosphorus pentachloride in 750 ml of diethyl ether was stirred at room temperature for 2 hours, and was then refluxed for 4 hours. After the reaction mixture was allowed to cooled down, it was filtered. The filtrate was washed successively with ice water (twice), a chilled, saturated aqueous solution of sodium hydrogencarbonate, ice water and a chilled, saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, whereby 11.2 g of 3-pyrrolesulfonyl chloride were obtained as crude crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1.O1CCOCC1.CS(O)(=O)=O>C(OCC)(=O)C>[CH3:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:10]=2)[N:23]=1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: Cc1ccnc(Cl)n1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccnc(Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)n1
Temperature: 100 °C
Yield: 57.7 %

Procedure:
To a flask containing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.50 g, 6.85 mmol) and 2-chloro-4-methylpyrimidine (1.01 g, 7.87 mmol) were added dioxane (69 mL) and methanesulfonic acid (0.51 mL, 7.87 mmol). The reaction was heated at 100° C. overnight. The reaction was then cooled to room temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield 4-methyl-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (1.23 g, 3.95 mmol, 58% yield).