Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][C:13]2[N:14]=[N:15][C:16]([Cl:22])=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=2)=[C:7]([Cl:23])[CH:6]=1.[OH-].[Na+]>CO>[Cl:23][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:24])=[O:2])[CH:10]=[C:9]([CH3:11])[C:8]=1[O:12][C:13]1[N:14]=[N:15][C:16]([Cl:22])=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=1
Reactant: COC(=O)Cc1cc(C)c(Oc2cc(C(C)C)c(Cl)nn2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(CC(=O)O)cc(Cl)c1Oc1cc(C(C)C)c(Cl)nn1
Temperature: 25 °C
Reaction time: 96 h
Yield: 99.5 %

Procedure:
A solution of [3-chloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-5-methyl-phenyl]-acetic acid methyl ester (8b) (1.1 g, 2.97 mmol) in methanol (30 mL) at room temperature was treated dropwise with a 1N aqueous sodium hydroxide solution (5.9 mL, 5.9 mmol). The reaction was stirred at room temperature for 4 d. At this time, the reaction mixture was concentrated under vacuum. The resulting solid was diluted with water and ethyl acetate. The ethyl acetate layer was discarded. The water layer was acidified by the addition of a 1N aqueous hydrochloric acid solution and was extracted with ethyl acetate. The organic layers were washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum to afford [3-chloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-5-methyl-phenyl]-acetic acid (9b) (1.05 g, 100%) as a white solid. This material was used without further purification; EI(+)-HRMS m/z calcd for C16H16Cl2N2O3 (M+) 355.0611, found 355.0610. Molecular Weight=355.2235; Exact Mass=354.0538
Reaction SMILES: [C:1]([C:6]1[N:10]2[C:11]([CH2:15]Cl)=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)([O:3]CC)=O.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][N:31]2[CH2:15][C:11]3[N:10]4[C:6](=[CH:7][N:8]=[C:9]4[CH:14]=[CH:13][CH:12]=3)[C:1]2=[O:3])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)c1cnc2cccc(CCl)n12
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CN2Cc3cccc4ncc(n34)C2=O)CC1
Yield: 72.5 %

Procedure:
A solution prepared by dissolving 5.78 g (24.22 mM) of 3-carbethoxy-5-chloromethylimidazo[1,2-a]pyridine, 7.78 g (36.33 mM) of 1-tert-butoxycarbonyl-4-aminomethylpiperidine, and 6.75 ml (48.44 mM) of triethylamine in 100 ml of ethanol was refluxed under argon gas for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was extracted with 100 ml of chloroform. The organic layer was washed with saturated aqueous NaCl solution and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol=20:1) to provide 6.50 g (yield 72.4%) of the title compound as yellow liquid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]([C:19](=[O:22])[CH2:20][CH3:21])[CH2:14][C:13]3[CH:23]=[N:24][NH:25][C:12]=3[C:11]=2[CH:10]=1)=[O:6]>O.CO>[C:5]([CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]([C:19](=[O:22])[CH2:20][CH3:21])[CH2:14][C:13]3[CH:23]=[N:24][NH:25][C:12]=3[C:11]=2[CH:10]=1)([OH:6])=[O:4]
Reactant: CCC(=O)N1Cc2cn[nH]c2-c2cc(OCC(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(=O)N1Cc2cn[nH]c2-c2cc(OCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
A solution of sodium hydroxide (0.32 g) in water (4 ml) was added to a mixture of 4,5-dihydro-8-methoxycarbonylmethoxy-5-propionyl-1H-pyrazolo-[4,3-c]quinoline (1.26 g) in methanol (20 ml). After being stirred at room temperature for 1.5 hours, the solution was evaporated in vacuo and the residue was dissolved in an aqueous solution of sodium bicarbonate. The solution was washed with ethyl acetate and acidified with 10% hydrochloric acid under ice cooling and stirring. The resulting precipitates were collected by filtration, washed with water, and recrystallized for methanol to give 8-carboxymethoxy-4,5-dihydro-5-propionyl-1H-pyrazolo[4,3-c]quinoline (1.05 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH:47]([C:52]1[N:53]=[N+:54]([O-])[C:55]2[CH:61]=[C:60]([CH3:62])[CH:59]=[CH:58][C:56]=2[N:57]=1)[C:48]([O:50][CH3:51])=[O:49].[Cl-].[NH4+].CCOC(C)=O>O1CCOCC1.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[O:9]2)=[CH:4][C:3]=1[CH:47]([C:52]1[N:53]=[N:54][C:55]2[CH:61]=[C:60]([CH3:62])[CH:59]=[CH:58][C:56]=2[N:57]=1)[C:48]([O:50][CH3:51])=[O:49]
Reactant: COC(=O)C(c1nc2ccc(C)cc2[n+]([O-])n1)c1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)C(c1nnc2cc(C)ccc2n1)c1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Yield: 74.5 %

Procedure:
3-(1-(2-Chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)-2-methoxy-2-oxoethyl)-7-methylbenzo[e][1,2,4]triazine 1-oxide (compound 61, 310 mg, 0.36 mmol) was treated with Zn (500 mg, 7.6 mmol) and ammonium chloride (500 mg, 9.34 mmol) in aqueous dioxane at room temperature for 1 day. The reaction mixture was diluted and work-up with EtOAc. After evaporating the volatile solvent under reduced pressure, the residue was purified with silica gel column (Hx/EtOAc=⅓) to afford title compound (228 mg, 75% yield) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:32]([CH2:34][NH2:35])[OH:33]>C1COCC1>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][CH2:16][C:17]([NH:35][CH2:34][CH2:32][OH:33])=[O:19]
Reactant: COc1c(C)c(C)c(OC)c(CCCC(=O)O)c1C
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(CCCC(=O)NCCO)c1C
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 74.9 %

Procedure:
In 25 mL THF was dissolved 4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-butanoic acid (1.32 g, 4.96 mmol) prepared as described in Example 1. CDI (884 mg, 5.46 mmol, 1.1 equiv.) was added and the solution stirred for 1.75 h at room temperature. A small portion (2 mL) was removed for other studies. The remainder was treated with 370 μL ethanolamine (365 mg, 5.96 mmol, 1.3 equiv.) and let stir at room temperature overnight. The clear pale brown solution was concentrated and the residue dissolved into 100 mL isopropyl acetate and washed with 100 mL 1.25 M HCl, 1×100 mL saturated aqueous NaCl, 1×50 mL brine and dried over Na2SO4. The reaction mixture was concentrated yielding 1.15 g of a white powder. M++H at 310 m/z;
Reaction SMILES: [F-:1].[K+].CC(CC(O)CO)C.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].C1(C)C(C)=CC=CC=1>[Cl-].C[N+](C)(C)C>[F:1][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: CC(C)CC(O)CO
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccccc1F
Temperature: 150 °C
Reaction time: 28 h

Procedure:
In a 2 liter flange flask and fitted with a distillation bridge and impeller stirrer, 290.5 g (5.0 mol) of potassium fluoride, 71.1 g (0.1 mol) of trimethyl(ethoxypolyoxypropyl)ammonium chloride, 11.0 g (0.1 mol) of tetramethylammonium chloride and 17.7 g (0.035 mol) of polyethylene glycol dimethyl ether 500 were introduced at 120° C. into the melt of 630 g (4.0 mol) of 2-chloronitrobenzene. Subsequently, the mixture was azeotropically dried using 100 g (0.94 mol) of xylene and the reaction mixture was stirred for 28 hours at a temperature of 150° C. Amount of 2-fluoronitrobenzene formed: after 6 hours: 36 GC area-%. after 28 hours: 74 GC area-%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][C@H:10]([OH:13])[CH2:11]Cl)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:14])[N:7]([CH3:8])[CH2:9][C@H:10]1[CH2:11][O:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C[C@H](O)CCl)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C[C@H]1CO1)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
((S)-3-chloro-2-hydroxypropyl)-methylcarbamic acid tert-butyl ester (2.23 g, 10 mmol) was dissolved in THF (30 mL), and then an aqueous sodium hydroxide solution (0.48 g in 10 mL water) was added. The mixture was stirred for 2 h. The mixture was then concentrated under reduced pressure to remove most of the THF, and the remaining aqueous solution was extracted into ethyl acetate, washing with water. The product was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title intermediate as an oil (1.6 g). (m/z): [M+Na]+ calcd for C9H17NO3, 210.10. found 210.1. 1H-NMR (DMSO d6, 299.96 MHz): δ (ppm) 1.32-1.42 (s, 9H), 2.69-2.73 (m, 1H), 2.75-2.85 (s, 3H), 2.95-3.05 (br s, 1H), 3.10-3.15 (dm, 1H), 3.16-3.21 (d, 1H), 3.37-3.51 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH3:11])[CH:10]=2)[CH2:5][CH2:6][N:7]=1.[BH4-].[Na+].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>CO.O.C(O)C>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH3:11])[CH:10]=[C:3]12
Reactant: CC1=NCCn2c1cc(C)c2-c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: Cc1cc2n(c1-c1ccccc1)CCNC2C
Yield: 63 %

Procedure:
3,4-Dihydro-1,7-dimethyl-6-phenylpyrrolo[1,2-a]pyrazine (0.6 g) was dissolved in a mixture of 40 ml of methanol and 4 ml of water under argon. The solution was treated portionwise with 0.3 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 50 ml of methylene chloride and washed with 50 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 30 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 0.6 g of yellow, amorphous solid, was dissolved in a 25-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.5 g (63%) of 1,2,3,4-tetrahydro-1,7-dimethyl-6-phenylpyrrolo[1,2-a]pyrazine fumarate (2:1); m.pt.: 152°-154° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[OH-].[NH4+:15]>C1COCC1>[CH3:1][C:2]1[S:6][C:5]([S:7]([NH2:15])(=[O:9])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: [NH4+]
Reactant: Cc1sc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(S(N)(=O)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a stirred solution of 5-methyl-4-nitrothiophene-2-sulfonyl chloride [CAS No. 61714-77-0] (1.0 g, 4.14 mmol) in THF (20 ml) was added at 0° C. (ice water bath) ammonium hydroxide solution (25%, 5 ml). The reaction mixture was stirred at room temperature for 1 h, evaporated, poured into water (30 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (2×30 ml), dried (MgSO4) and evaporated. The crude product was further purified by crystallization from ethyl acetate/hexane to yield 5-methyl-4-nitro-thiophene-2-sulfonamide (0.75 g, 82%) as a brown solid. MS (ISP) 221.0 [(M−H)−], mp 120° C.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.C[Si](Cl)(C)C.[CH2:15]([O:17][C:18](=[O:50])[CH2:19][CH2:20][N:21]([C:39]1([C:47](Cl)=[O:48])[CH2:45][CH:44]2[O:46][CH:41]([CH2:42][CH2:43]2)[CH2:40]1)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:16].Cl>ClCCl>[CH2:15]([O:17][C:18](=[O:50])[CH2:19][CH2:20][N:21]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)=[CH:29][CH:30]=1)(=[O:24])=[O:23])[C:39]1([C:47](=[O:48])[NH:2][OH:3])[CH2:45][CH:44]2[CH2:40][CH:41]([CH2:42][CH2:43]2)[O:46]1)[CH3:16]
Reactant: CCOC(=O)CCN(C1(C(=O)Cl)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: NO
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCN(C1(C(=O)NO)CC2CCC(C2)O1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 mL (114 mmol, 7.5 equivalents) of dry pyridine at 0 ° C. is treated with 5.8 mL (45 mmol, 3.0 equivalents) of trimethylsilyl chloride, causing white solids to precipitate. The mixture is allowed to warm to ambient temperature overnight. This mixture is then cooled to 0° C. and treated with a solution of (15.1 mmol) of the product from Step F in 73 mL of dichloromethane causing an exotherm to about 8° C. This mixture is stirred at 0° C. for 30 minutes and at ambient temperature for about one hour. The reaction is then treated with 50 mL of 2N aqueous hydrochloric acid and was stirred at ambient temperature for one hour. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with 2N aqueous hydrochloric acid (2×50 mL) and water (50 mL). This solution of the title compound in dichloromethane is used in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=C(C)C)=[N:5][C:4]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:3]1.I([O-])(=O)(=O)=[O:18].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[CH3:1][N:2]1[C:6]([CH:7]=[O:18])=[N:5][C:4]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)=Cc1nc(N2CCCCC2)nn1C
Agent: O=[Os](=O)(=O)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(N2CCCCC2)nc1C=O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
A mixture of 1-(1-methyl-5-(2-methylprop-1-enyl)-1H-1,2,4-triazol-3-yl)piperidine (376 mg, 1.71 mmol, Eq: 1.00), sodium periodate (1.46 g, 6.83 mmol, Eq: 4), osmium tetroxide 4% aq. (325 mg, 325 μl, 51.2 μmol, Eq: 0.03) and benzyltriethylammonium chloride (155 mg, 683 μmol, Eq: 0.4) in dioxane (17.9 ml) and water (4.12 ml) was stirred for 1.5 hours at 70° C. The mixture was diluted with ethyl acetate and washed 2× with water and brine. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording 2-methyl-5-piperidin-1-yl-2H-[1,2,4]triazole-3-carbaldehyde (331 mg, 99.9%) as a brown waxy solid. MS: m/z=195.4 (M+H+)
Reaction SMILES: [C:1]([O:6][CH2:7]Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Na+].[I-].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([F:47])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:41][C@@H:42]([OH:46])[C:43]([OH:45])=[O:44])[NH:26][C:27]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[F:40])[CH:30]=3)=[O:28])=[CH:20][CH:19]=2)[CH:17]=1.CCN(CC)CC>CC(C)=O.CC(O)=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([F:47])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:41][C@@H:42]([OH:46])[C:43]([O:45][CH2:7][O:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[O:44])[NH:26][C:27]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[F:40])[CH:30]=3)=[O:28])=[CH:20][CH:19]=2)[CH:17]=1
Reactant: CCCC(=O)OCCl
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cc(-c2ccccc2F)no1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(-c2ccccc2F)no1
Temperature: 65 °C
Reaction time: 0.42 h
Yield: 30.3 %

Procedure:
Chloromethyl butyrate (11.4 μL, 0.1 mmol) and NaI (13.6 mg, 0.1 mmol) were combined in acetone (0.7 mL, 10 mmol) and heated at 65° C. for 1 hour. The mixture was then cooled to room temperature. A mixture of (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (16.0 mg, 30 μmol) dissolved in acetone (0.2 mL) and treated with Et3N (8.5 μL, 61 μmol) was added and the resulting mixture was stirred at room temperature for 25 minutes. The mixture was concentrated and the residue was dissolved in AcOH (2.0 mL), filtered and purified by reverse phase preparative HPLC. The desired fractions were combined and freeze dried to yield a yellowish solid. This solid was dissolved in AcOH (1.5 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and freeze dried to yield the title compound (5.7 mg, purity 100%) as a TFA salt white solid. MS m/z [M+H]+ calc'd for C31H28ClF2N3O2, 628.16. found 628.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[C:18]([OH:23])=[N:19][CH:20]=[CH:21][CH:22]=1>>[OH:23][C:18]1[C:17]([NH:16][C:12]2[C:7]3[C:6]([CH3:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:14][C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1cccnc1O
Product: COC(=O)c1sc2ncnc(Nc3cccnc3O)c2c1C

Procedure:
Prepared analogously to example III using 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and 3-amino-2-hydroxypyridine
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[N:15][N:7]3[C:6](=[O:19])[C:5]=2[CH:4]=1.[OH-].[Na+].I([O-])(=O)(=O)=[O:23].[Na+].Cl>O>[CH3:1][S:2]([C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[N:15][N:7]3[C:6](=[O:19])[C:5]=2[CH:4]=1)=[O:23]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc2[nH]c3cc(C(=O)O)nn3c(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)c1ccc2[nH]c3cc(C(=O)O)nn3c(=O)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4,9-dihydro-7-methylthio-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (5.5 g; 0.02 mole) and 1(N) sodium hydroxide solution (25 ml) in water (500 ml) is chilled to 12° and a solution of sodium metaperiodate (4.28 g, 0.02 mole) in water (150 ml) is added. The reaction mixture is stirred at room temperature for 4 hrs and the resulting solution is cooled and treated with 1(N) HCl (30 ml). The greenish precipitate is filtered, washed and recrystallized from DMF-methanol. Yield 4.4 g; mp 285°-90° (d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].CN(C(O[N:33]1N=[N:40][C:35]2[CH:36]=[CH:37][CH:38]=C[C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(OC(NCC1CCCN1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCl>CN(C=O)C>[NH2:33][CH2:34][CH:35]1[CH2:36][CH2:37][CH2:38][N:40]1[C:22]([C:21]1[CH:20]=[CH:19][C:4]([C:5]([NH:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=3[N:10]=2)=[O:6])=[CH:3][C:2]=1[Cl:1])=[O:24]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CC(C)(C)OC(=O)NCC1CCCN1
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NCC1CCCN1C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 47 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, TBTU, diisopropylethylamine, and rac.-2-tert-butoxycarbonylaminomethylpyrrolidine in DMF followed by treatment with trifluoroacetic acid analogously to Example 17. Yield: 47%; C21H21Cl2N5O2 (446.34); mass spectrum: (M+H)+=446/448/450 (chlorine isotope).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][NH:12][C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[C:6]=2[CH:21]=1.[CH:22]([Sn](CCCC)(CCCC)CCCC)=[CH2:23]>CN1CCCC1=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>[CH:22]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][NH:12][C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[C:6]=2[CH:21]=1)=[CH2:23]
Reactant: O=C(NCCc1csc2ccc(I)cc12)C1CCCCC1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: C=Cc1ccc2scc(CCNC(=O)C3CCCCC3)c2c1

Procedure:
15 mmol of the product obtained in Step C, 16 mmol of vinyl tributyltin and 0.43 mmol of tetrakis(triphenylphosphine)palladium, are heated at 110° C., with stirring, for 3 hours in 30 ml of N-methylpyrrolidinone. After removal of the solvent by evaporation, the residue is taken up in 20 ml of dichloromethane and treated with an aqueous 10% potassium fluoride solution. Extraction, concentration under reduced pressure and chromatography over silica gel yield the pure title product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]=[C:13]=[O:14])=[C:4]([F:15])[CH:3]=1.[NH2:16][C:17]([CH2:25][CH3:26])=[C:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(OCC)C>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([NH:12][C:13](=[O:14])[NH:16][C:17]([CH2:25][CH3:26])=[C:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:4]([F:15])[CH:3]=1
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)C(C)=C(N)CC
Solvent: CCOCC
Product: CCOC(=O)C(C)=C(CC)NC(=O)Nc1cc(OC(C)C)c(Cl)cc1F

Procedure:
using 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate in diethyl ether with ethyl 3-amino-2-methyl-2-pentenoate there is obtained ethyl 3-[3-(4-chloro-2-fluoro-5-isopropoxyphenyl)ureido]-2-methyl-2-pentenoate, m.p. 104°-106° C., and from this intermediate with sodium hydride in dimethylformamide there is obtained 6-ethyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5 -methyl-2,4(1H,3H)-pyrimidinedione, m.p. 196°-198° C.:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:15][C:16]3[CH:23]4[CH2:24][N:19]([CH2:20][CH2:21][CH2:22]4)[CH2:18][CH:17]=3)=[C:10](Br)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([N:4]1[C:12]2[CH:11]=[C:10]3[C:16]4([CH2:15][O:14][C:9]3=[CH:8][C:7]=2[CH2:6][CH2:5]1)[CH:23]1[CH2:24][N:19]([CH2:20][CH2:21][CH2:22]1)[CH2:18][CH2:17]4)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(OCC3=CCN4CCCC3C4)c(Br)cc21
Solvent: Cc1ccccc1
Product: CC(=O)N1CCc2cc3c(cc21)C1(CCN2CCCC1C2)CO3

Procedure:
The title compound was prepared from 1-acetyl-5-(1-azabicyclo[3.3.1]non-3-en-4-yl)methoxy-6-bromo-2,3-dihydro-1H-indole (D9) by a similar procedure to Description 4 using toluene as solvent. The two isomers (2:1 ratio) formed around the spirocyclic junction were separated by column chromatography on silica gel eluting with 0-15% methanol/chloroform.