Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.[CH3:25][O:26][NH2:27]>>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:27][O:26][CH3:25])=[O:24])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reactant: CON
Product: CONC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Yield: 35 %

Procedure:
Prepared by the method as described in Example 1 using (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I) and O-methylhydroxylamine to yield the title compound as a white solid (15 mg, 35% yield). MS (apci) m/z=357.0 (M+H).
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:3].C(N(CC)CC)C.[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl)([O-:18])=[O:17]>C(O)C>[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][CH2:3][CH2:2][NH:4][CH2:5][C:6]([OH:8])=[O:7])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: CCNCC(=O)O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)CNCCCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a suspension of 55.9 g. (4.0 × 10-1 moles) of ethyl glycine hydrochloride in 300 ml. of absolute ethyl alcohol was slowly added (~5 minutes) under a nitrogen atmosphere a solution of 70 ml. (5.0 × 10-1 moles) of triethylamine in 200 ml. of absolute ethyl alcohol. The mixture was heated to reflux and a solution of 17.2 g. (1.0 × 10-1 moles)o-nitrobenzylchloride in 200 ml. of absolute ethyl alcohol was added over a 1.5 hour period. Upon complete addition, the mixture was allowed to reflux for 18 hours, cooled to room temperature and the solvent removed in vacuo. To the solid residue was added 500 ml. of water and enough 10% hydrochloric acid to make the solution acidic (pH~3). The acidic solution was washed with methylene chloride (2 × 150 ml.), made neutral (pH~7) by the addition of saturated sodium bicarbonate and the insoluble oil extracted with methylene chloride (2 × 250 ml). The methylene chloride extracts were combined, washed with water (250 ml.), dried (K2CO3) and the solvent removed in vacuo resulting in a yellow oil. Owing to the instability of the oil toward distillation, the compound was used as such in subsequent reaction.
Reaction SMILES: [H-].[Na+].Cl[C@@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C1OCCOCCOCCOCCOC1.O>O1CCCC1>[C:17]([O:16][C:14]([N:13]1[CH:5]2[CH2:6][C:7]3[C:12]([CH:4]12)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@H]1Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Temperature: 50 °C
Yield: 97.8 %

Procedure:
To a suspension of NaH (80% disp. in oil, 2.016 g, 67.2 mmol) in dry tetrahydrofuran (300 ml) was added (±)trans-1-chloro-2-tert-butoxycarbonylaminoindane (15 g, 56 mmol) and 15-crown-5 (50 μl). The mixture was then warmed at 50° C. under nitrogen for 18 h after which it was poured into water (700 ml) and extracted with diethyl ether (3×150 ml). The combined organic extracts were dried (Na2SO4) and solvents were removed in vacuo to afford the title compound as a brown solid (12.67 g).
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[C:18]([O:19][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1c(O)c2cccc(O)c2oc1=O
Reactant: CCOC(=O)CCBr
Product: CCCCCCOc1c(O)c2cccc(OCCC(=O)OCC)c2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-hexyloxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopropionate was used in place of ethyl bromoacetate in Reference Example 3, 3-hexyloxy-4-hydroxy-8-(2-ethoxycarbonylethoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[C:6]=12.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[C:6]=12
Reactant: Cn1cc(-c2cc(OCC3CCCN(C(=O)OC(C)(C)C)C3)c3c(Br)cnn3c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2cc(OCC3CCCNC3)c3c(Br)cnn3c2)cn1
Reaction time: 0.5 h

Procedure:
tert-butyl 3-({[3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxy}methyl)piperidine-1-carboxylate (55.0 mg, 0.112 mmol) was dissolved in dichloromethane (3 ml) at 0° C. Trifluoroacetic acid (1.0 ml) was added and the solution was allowed to stir for 30 minutes. The solution was concentrated to a colorless oil, which was dissolved in 2 ml of methanol and eluted through a bicarbonate resin cartridge (StratoSpheres SPE, PL-HCO3 MP SPE), flushing with 10 mL of methanol. The solution was concentrated and eluted through a second bicarbonate resin cartridge to afford 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)-4-(piperidin-3-ylmethoxy)pyrazolo[1,5-a]pyridine. 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H); 8.28 (s, 1H); 8.01 (s, 1H); 7.96 (s, 1H); 6.89 (s, 1H); 3.98-4.06 (m, 2H); 3.85 (s, 3H), 3.12-3.16 (m, 1H); 2.84-2.89 (m, 1H); 1.92-2.01 (m, 1H); 1.84-1.90 (m, 1H); 1.58-1.64 (m, 1H); 1.20-1.45 (m, 4H). LRMS (ESI) calculated for C17H2179BrN5O [M+H]+, 390.1; found 390.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH:17]([C:19]1[NH:20][C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=2[C:27]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=O.N1CCCC1.C(O)(=O)C>C(O)C>[O:16]=[C:10]1[C:9](=[CH:17][C:19]2[NH:20][C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=3[C:27]=2[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11]1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Solvent: C1CCNC1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)CCc1c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)[nH]c2c1CCCC2
Reaction time: 0.17 h

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol), 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (57 mg, 0.23 mmol) and pyrrolidine (0.3 mL) in ethanol (0.5 mL) was heated to reflux for 2 hours. Acetic acid (0.05 mL) was added to the reaction and heating was continued for another 10 minutes. The reaction was cooled and the precipitate which formed was collected by vacuum filtration, washed with ethanol and dried to give the title compound.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2.O>N1C=CC=CC=1>[C:1]12([C:11]([O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[O:12])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Oc1ccc2ncccc2c1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Oc1ccc2ncccc2c1)C12CC3CC(CC(C3)C1)C2
Reaction time: 16 h

Procedure:
1-Adamantanecarbonyl chloride (1.37 g, 6.90 mmol) in pyridine (5 mL) was added to a solution of 6-hydroxyquinoline (1.00 g, 6.89 mmol) in pyridine (15 mL). The reaction was stirred for 16 h. To the stirring reaction mixture was added water (200 mL) which caused the product to precipitate. This precipitate was filtered, washed with water (3×50 mL), and dried under high vacuum. This provided 1.56 g (73.7%) of (41) as a light-brown powder:
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH:28]4[O:33][CH2:32][CH2:31][NH:30][CH2:29]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH:28]4[O:33][CH2:32][CH2:31][N:30]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:29]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnn2c(CC3CNCCO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCOC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 21.2 %

Procedure:
To a solution 5-(2-benzyl-2H-indazol-6-yl)-7-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0182 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (15 μL, 0.20 mmol) and N,N-diisopropylethylamine (95 μL, 0.55 mmol). The reaction was stirred at rt for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 20 mg (21%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.91 (s, 1 H), 7.80 (d, 1 H), 7.59 (s, 1 H), 7.26-7.41 (m, 5 H), 7.14 (d, 1 H), 6.68 (s, 1 H), 5.74 (s, 1 H), 5.65 (s, 2 H), 3.86-3.95 (m, 2 H), 3.51 (t, 1 H), 3.40 (d, 1 H), 3.04-3.17 (m, 2 H), 2.88 (s, 3H), 2.78-2.88 (m, 1 H), 2.62-2.71 (m, 1 H); ES-MS m/z 518.40 [M+H]+, HPLC RT (min) 2.51.
Reaction SMILES: [Br:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]>N1C=CC=CC=1.ClCCl.Cl>[Br:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: BrC1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC(Br)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Bromopiperidine (5.75 g, 23.5 mmol) was dissolved in pyridine (50 mL) and treated with tosyl chloride (5.8 g, 30.5 mmol). The reaction mixture was stirred for 12 h at r.t. and then diluted with dichloromethane (150 mL) and HCl (1 M aqueous solution, 50 mL). The organic layer was washed with brine (80 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (40% EtOAc/hexane) to give 4-bromo-1-tosylpiperidine as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 4.27-4.24 (m, 1H), 3.20-3.17 (m, 2H), 3.13-3.11 (m, 2H), 2.46 (s, 3H), 2.23-2.17 (m, 2H), 2.08-2.05 (m, 2H); MS (ESI) 318.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]([C:44]([O:46]CC)=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:32][CH:31]=2)[C:8]2=[N:9][C:10]([CH3:27])=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]3=[O:26])[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:28]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH:37]([C:44]([OH:46])=[O:45])[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:34][CH:35]=2)[C:8]2=[N:9][C:10]([CH3:27])=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]3=[O:26])[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(N3CCCN(Cc4ccccc4)C3=O)c(C)nc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2cc(N3CCCN(Cc4ccccc4)C3=O)c(C)nc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-3-[4-[(α-ethoxycarbonyl)benzyloxy]benzyl]-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-imidazo[4,5-b]pyridine and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH2:15]([O:17][C:18]([CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[CH3:16].C(N(CC)CC)C>O1CCCC1>[C:23]1([N:22]([CH2:21][CH2:20][C:18]([O:17][CH2:15][CH3:16])=[O:19])[C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([NH:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CCNc1ccccc1
Reactant: CNc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(C(=O)c1ccc(NC)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 24.7 g (0.115 mol) of 4-methylamino-3-nitrobenzoic acid chloride and 22.3 g (0.115 mol) of N-(2-ethoxycarbonylethyl)aniline in 300 mL of tetrahydrofuran, 13.1 g (0.13 mol) of triethylamine were added dropwise in 15 minutes, with stirring, at room temperature. After 2 hours stirring, the solvent was distilled off in a water-jet vacuum and the residue was mixed with 700 mL of water with stirring. The mixture was extracted 3 times with 200 mL of dichloromethane, the organic extract was washed twice with 200 mL of 2N hydrochloric acid and twice with 300 mL of water and dried over sodium sulfate. The solvent was then distilled off and the oily product thus obtained was purified by column chromatography (1 kg silica gel; eluant: petroleum ether/ethyl acetate=2:1). Yield: 35.0 g (82% of theory); Rf value: 0.28 (silica gel; dichloromethane/ethanol=50:1).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[N:14]3[C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N+:18]([O-])=[CH:17][C:16]=4[N:26]=[C:13]3[CH2:12][O:11][CH2:10]2)=[CH:4][CH:3]=1.[NH4+:29].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[N:14]3[C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=[C:17]([NH2:29])[C:16]=4[N:26]=[C:13]3[CH2:12][O:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: [O-][n+]1cc2nc3n(c2c2ccccc21)[C@@H](COCc1ccc(F)cc1)COC3
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc2ccccc2c2c1nc1n2[C@@H](COCc2ccc(F)cc2)COC1

Procedure:
(11S)-11-{[(4-Fluorobenzyl)oxy]methyl}-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (732 mg, 1.93 mmol) was dissolved in 50 mL of CH2Cl2 and treated with 5 mL of concentrated NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (370 mg, 1.93 mmol) was carefully added. Rapid stirring continued overnight. The reaction mixture was treated with 5 mL of H2O, and the layers were separated. The organic portion was washed with saturated NaHCO3 (2×50 mL) followed by brine (50 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude orange solid. Chromatography (SiO2, 10-30% CMA/CHCl3) gave 236 mg of (11S)-11-{[(4-fluorobenzyl)oxy]methyl}-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as a tan solid, mp 134-137° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][CH:13]([CH3:15])[CH3:14])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CC(C)N
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Product: CSc1nc(Cl)c(C=O)c(NC(C)C)n1

Procedure:
Prepared as described above in Example 2 starting from 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and isopropylamine to give the title compound 4-chloro-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 1.31 (d, 6H, J=5.7 Hz), 2.60 (s, 3H), 4.47 (m, 1H), 9.16 (br s, 1H), 10.25 (s, 1H). LC MS (m/e)=246 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].BrC1C=C(F)C=CC=1S(NC1C(C(OC)=O)=C2C(C3C=COC=3CO2)=CC=1)(=O)=O.C([Sn](CCCC)(CCCC)/C=C\CN1CCCC1)CCC>>[N:3]1([CH2:4]/[CH:5]=[CH:6]\[C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[S:14]([NH:17][C:18]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]3[C:21]([C:22]4[CH:34]=[CH:33][O:32][C:23]=4[CH2:24][O:25]3)=[CH:20][CH:19]=2)(=[O:16])=[O:15])[CH2:1][CH2:2][CH2:36][CH2:35]1
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Agent: CCCC[Sn](/C=C\CN1CCCC1)(CCCC)CCCC
Agent: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occc1-2
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CCCC2)ccc2c1OCc1occc1-2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 9, starting from methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 10) and 1-((Z)-3-tributylstannanylallyl)pyrrolidine (Intermediate 16).
Reaction SMILES: C1O[C:4]2([CH2:13][CH2:12][C@H:11]3[C@@H:6]([CH2:7][CH2:8][C:9](=[O:14])[CH2:10]3)[CH2:5]2)[O:3]C1.C(O)=O.O>C1(C)C=CC=CC=1>[CH2:5]1[C@H:6]2[C@@H:11]([CH2:10][C:9](=[O:14])[CH2:8][CH2:7]2)[CH2:12][CH2:13][C:4]1=[O:3]
Reactant: O=C1CC[C@H]2CC3(CC[C@@H]2C1)OCCO3
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=CO
Product: O=C1CC[C@H]2CC(=O)CC[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
21 g of trans-decahydronaphthalen-2,6-dione monoethyleneacetal was dissolved in 110 ml of toluene. 50 ml of formic acid was added to the solution, and the mixture was stirred for 1 hour at room temperature. Water was added to the mixture, and the organic phase was separated, rinsed with water, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated saline solution, in sequence, and dried on anhydrous sodium sulfate. Then, the solvent was evaporated to obtain 16 g of pale yellow solid trans-decahydronaphthalen-2,6-dione.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:15]2[C:35]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][C:18]3[C:19]([C:29]([O:31]CC)=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][C:5]=1[Cl:39].CCOC(C)=O.Cl>C1COCC1.CO>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:15]2[C:35]([CH:36]3[CH2:37][CH2:38]3)=[CH:34][C:18]3[C:19]([C:29]([OH:31])=[O:30])=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:12])=[O:13])=[CH:6][C:5]=1[Cl:39]
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(Br)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)N(c1ccc(Br)c(Cl)c1)c1cc2oc(-c3ccc(Cl)cc3)c(C(=O)O)c2cc1C1CC1
Temperature: 60 °C
Yield: 93.6 %

Procedure:
A 1M solution of NaOH (1.877 mL, 1.877 mmol) was added to a solution of ethyl 6-(N-(4-bromo-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate (234 mg, 0.375 mmol) in THF (2 mL) and MeOH (1 mL) at RT. After 1 h a white precipitate formed but starting material is still evident by LCMS. THF (3 mL) and a 4N solution of NaOH (1 mL) were added and the mixture was heated to 60° C. for 4 h. EtOAc was added and the aqueous layer was made acidic with the addition of 1N HCl. The organic layer was separated, washed with water, brine, dried over Na2SO4, filtered and concentrated to give 6-(N-(4-bromo-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylic acid (220 mg, 0.351 mmol, 94% yield) as a white solid. LCMS (m/z, ES+)=594.0 (M−H).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:15][NH:16][CH3:17].[OH-].[Na+]>C(O)C.O>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[C:4]([N:16]([CH3:17])[CH3:15])[N:3]=1
Reactant: CNC
Reactant: CCCCNc1cc(Cl)nc(N)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCNc1cc(N(C)C)nc(N)[n+]1[O-]
Yield: 39 %

Procedure:
1.5 g of 2-amino-4-butylamino-6-chloropyrimidine 3-oxide are placed in 10 ml of ethanol. 5 ml of dimethyl-amine are added as 33% solution in ethanol. The reaction mixture is refluxed for 4 hours and is then evaporated to dryness. The precipitate obtained is taken up in 20 ml of water. The pH is adjusted to 8 by adding sodium hydroxide. The mixture is extracted with 3×50 ml of butanol. The butanol phase is evaporated to dryness. The precipitate is recrystallized from 10 ml of acetonitrile. 610 mg of 2-amino-4-butylamino-6-dimethylaminopyrimidine 3-oxide are obtained.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:22]O>>[C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([O:16][CH3:22])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccccc1
Yield: 96 %

Procedure:
A mixture of 3-(5-phenyl-4-isoxazolyl)propionic acid (18.62 g), conc. sulfuric acid (0.2 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-(5-phenyl-4-isoxazolyl)propionate (19.03 g, yield 96%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). NMR (CDCl3) δ: 2.59–2.71 (2H, m), 2.95–3.06 (2H, m), 3.68 (3H, s), 7.42–7.56 (3H, m), 7.64–7.74 (2H, m), 8.22 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1)[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.F[P-](F)(F)(F)(F)F.[N:38]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>CN(C)C=O.O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=1)[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:38])=[O:18])=[N:14][CH:15]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Cc1cc(C(=O)O)ncc1C(Sc1ccc(C(F)(F)F)nc1)c1cc(F)ccc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C(N)=O)ncc1C(Sc1ccc(C(F)(F)F)nc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[[6-(trifluoromethyl)pyridin-3-yl]thio]methyl]-4-methylpyridine-2-carboxylic acid (176 mg, 0.40 mmol) obtained in Example 26 in N,N-dimethylformamide (4 ml), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (312 mg, 0.60 mmol), 1-hydroxybenzotriazole (81 mg, 0.60 mmol), ammonium chloride (43 mg, 0.80 mmol), and N-ethyldiisopropylamine (0.279 ml, 1.60 mmol) were added in an argon atmosphere at room temperature. After stirring for 5 hours at room temperature, ethyl acetate and water were added to the reaction mixture, and the resulting mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=2:1 was concentrated under reduced pressure to obtain the title compound (168 mg, 0.38 mmol, 96%) as a white solid.