Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15]C.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:15]
Reactant: COc1ccc2c(nnn2CC2CC2)c1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2c(nnn2CC2CC2)c1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4-Chloro-1-(cyclopropylmethyl)-5-methoxy-1H-benzotriazole (10.5 g, 44.2 mmol) was dissolved in dichloromethane (200 mL), cooled to 0° C. and treated with boron tribromide (88 mL, 1M dichloromethane solution, 88 mmol, 2 equiv). The ice bath was removed and the mixture was stirred for 4 hours at ambient temperature. The mixture was treated with water (10 mL) and then sodium hydroxide (1N aqueous) until pH>10. After stirring for an additional 30 minutes, ammonium chloride (aqueous saturated) was added until the pH of the mixture was adjusted to pH 6-7. The aqueous mixture was extracted exhaustively with dichloromethane containing 5% methanol. The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound as a light brown solid.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]([CH:7]2[CH2:11][CH2:10][CH2:9][O:8]2)=[N:5][N:6]=1.Br[CH2:13][CH2:14][C:15]([F:19])=[C:16]([F:18])[F:17]>O1CCOCC1.CN(C)C=O>[F:19][C:15](=[C:16]([F:18])[F:17])[CH2:14][CH2:13][S:1][C:2]1[O:3][C:4]([CH:7]2[CH2:11][CH2:10][CH2:9][O:8]2)=[N:5][N:6]=1
Reactant: FC(F)=C(F)CCBr
Reactant: Sc1nnc(C2CCCO2)o1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: FC(F)=C(F)CCSc1nnc(C2CCCO2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 1594.3 %

Procedure:
2.1 g (0.019 mol) of potassium t-butylate are introduced into a solution of 3.2 g (0.018 mol) of 2-mercapto-5-(tetrahydrofuran-2-yl)-1,3,4-oxadiazole in a mixture of 80 ml of 1,4-dioxane and 10 ml of dimethylformamide. 4.9 g (0.026 mol) of 1-bromo-3,4,4-trifluoro-3-butene are then added dropwise at 25° C. and the reaction mixture is stirred at room temperature for 16 hours. The solvent mixture is distilled off under reduced pressure and the residue is dissolved in ethyl acetate. This solution is extracted with water, ice-cold 1 N sodium hydroxide solution and water in succession, dried with sodium sulfate and filtered and the solvent is distilled off under reduced pressure. 80.43 g of the desired product are obtained as a yellow oil (nD27 =1.4904).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:20]1([C:26]2[N:30]=[C:29]([NH2:31])[NH:28][N:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:18][O:17][CH2:16][CH2:15][N:4]1[C:3](=[O:19])[C:2]([NH:31][C:29]2[NH:28][N:27]=[C:26]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:30]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13]
Reactant: Nc1nc(N2CCOCC2)n[nH]1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: COCCN1C(=O)C(Nc2nc(N3CCOCC3)n[nH]2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 3-morpholin-4-yl-1H-1,2,4-triazol-5-amine in a similar manner as described for Example 13. 1H NMR (400 MHz, CD3CN): δ 7.49-7.61 (m, 5H), 5.71 (bs, 2H), 3.94 (t, 2H), 3.71 (t, 2H), 3.58-3.62 (m, 4H), 3.37 (s, 3H), 3.10-3.14 (m, 4H); Mass Spectrum: M+H+
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:3]3[N:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(C(=O)c2ccccc2Nc2ncccc2N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C2=Nc3cccnc3Nc3ccccc32)cc1
Temperature: 25 °C

Procedure:
A solution of 3.6 g (0.012 mole) of [2-[(3-amino-2-pyridyl)amino]phenyl](4-methylphenyl)methanone in 100 ml of anhydrous toluene was treated with a catalytic amount of para toluene sulfonic acid and refluxed overnight while separating water with a Dean-Stark trap. The reaction mixture was filtered while hot. The product precipitated as the filtrate cooled to room temperature and was collected by filtration. Weight of solid after solvent evaporated was 2.5 g, m.p. 203.5°-205° C. (decomp.).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:24][CH2:23]4)[C:12]([C:35]([F:38])([F:37])[F:36])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].O.[Li+].[OH-]>C1COCC1.CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([OH:32])=[O:31])[CH2:24][CH2:23]4)[C:12]([C:35]([F:38])([F:36])[F:37])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(-c4ccc(CC)cc4)ccc3C(F)(F)F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1ccc(-c2ccc(C(F)(F)F)c(NCCCOc3ccc4c(c3)CC[C@H]4CC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 107 %

Procedure:
To a solution of ethyl [(1S)-5-(3-{[6-(4-ethylphenyl)-3-(trifluoromethyl)-2-pyridinyl]amino}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 317, 0.07 g, 0.09 mmol) in THF (2 mL), methanol (1 mL), and water (1 mL) was added LiOH (0.03 g, 1.37 mmol). The mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The residue was taken up in water and acidified to pH ˜5 using H3PO4 (a 5% aqueous solution). The aqueous solution was then extracted with EtOAc. The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure to give the product (0.048 g, 71%). 1H NMR (400 MHz, CD2Cl2) δ 7.99 (d, 2H), 7.71 (d, 1H), 7.29 (d, 2H), 7.09 (dd, 2H), 6.81 (d, 1H), 6.73 (dd, 1H), 5.41 (b, 1H), 4.11 (t, 2H), 3.84 (q, 2H), 3.53 (qt, 1H), 2.95-2.70 (m, 5H), 2.52-2.38 (m, 2H), 2.20 (qt, 2H), 1.82-1.75 (m, 1H), 1.29 (m, 3H); LC-MS: RT=4.10 min, (M+H)+ 499.3.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:29][CH:28]=[N:27]2)=[CH:24][CH:25]=1
Reactant: N#Cc1ccc(-c2cnc3ccc(Br)cn23)cc1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(Cl)cc2)OC1(C)C
Product: N#Cc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cn23)cc1

Procedure:
The title compound, white solid (78 mg, 59%), MS (ISP) m/z=396.5 [(M+H)+], mp 208° C., was prepared in accordance with the general method of example 1 from 4-(6-bromo-imidazo[1,2-a]pyridin-3-yl)-benzonitrile (intermediate N) (0.1 g, 0.335 mmol) and 1-(4-chloro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate B) (0.13 g, 0.44 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C@@:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1.[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].P.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:21][C:18]1[O:19][CH2:20][C@@:5]2([N:17]=1)[C:4]1[CH:3]=[C:2]([Br:1])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](/[CH:24]=[CH:23]/[C:22]([O:26][CH3:27])=[O:25])=[CH:9][CH:10]=1
Reactant: C=CC(=O)OC
Reactant: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1ccc(I)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: P
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(Br)ccc1O2
Temperature: 120 °C

Procedure:
A mixture of (R)-2′-bromo-7′-iodo-5H-spiro[oxazole-4,9′-xanthen]-2-amine (3.00 g, 6.56 mmol), methyl acrylate (0.621 mL, 6.89 mmol), phosphine, tri-o-tolyl (0.400 g, 1.313 mmol), palladium(ii) acetate (0.295 g, 1.313 mmol), and triethylamine 99.5% (1.826 mL, 13.13 mmol) in DMF (12 mL) in a microwave vial was purged with argon for 5 min, capped, and heated to 120° C. for 40 min in a microwave. The reaction mixture was diluted with EtOAc (100 mL) and washed with water, dried over Na2SO4, and concentrated. The product was purified with ISCO using 0-70% EtOAc in hexanes to give (S,E)-methyl 3-(2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)acrylate. MS (ESI pos. ion) m/z: 416.9 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([OH:22])[C:15]=3[C@@:5]3([C:11]2=[CH:10][C:8](=[O:9])[C:7]([O:23][CH3:24])=[CH:6]3)[CH2:4][CH2:3]1.CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5C(OC)=CC=C2[C@]5(C=34)CC1.C1C2C[C@H]3N(CC[C@@]45[C@H]3C=C[C@H](O)[C@@H]4OC(C=25)=C(O)C=1)C.CN1[C@H]2CC3C=CC(OC)=C(O)C=3[C@]3([C@@H]2C=C(OC)C(=O)C3)CC1.NC1C(OCC2C=CC=CC=2)=C(OC)C=CC=1CC1C2C(=CC(OC)=C(OC)C=2)CCN1C.[BH4-].[Na+:127]>CO>[CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][C@H:6]5[C:7]([O:23][CH3:24])=[CH:8][CH:10]=[C:11]2[C@:5]5([C:15]=34)[CH2:4][CH2:3]1.[OH-:9].[Na+:127]
Reactant: COC1=C[C@]23CCN(C)[C@H](Cc4ccc(OC)c(O)c42)C3=CC1=O
Agent: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: COC1=C[C@@H]2[C@@H]3Cc4ccc(OC)c(O)c4[C@]2(CCN3C)CC1=O
Solvent: CO
Product: [OH-]
Reaction time: 1 h

Procedure:
N-demethyl-sinomenine may be also be obtained through total synthesis, e.g. by adaptation of the procedures described by Kametani et al., (Kametani, T., et al., Studies on the synthesis of heterocyclic compounds. Part ccc. Synthesis of salutridine, sinoacutine, and thebaine. Formal total syntheses of morphine and sinomenine., J. Chem. Soc. (C), 15:2030-2033 (1969)). Specifically, total synthesis begins with diazotization of (±) 1-(2-amino-3-benzyloxy-4-methoxybenzyl)-1,2,3,4,-tetrahydro-6,7-dimethoxy-2-methylisoquinoline, followed by the thermal decomposition of the resulting diazonium salt. The result would be (±) salutaridine which is converted into (±) thebaine by incubation of (±) salutaridine with methanol and sodium borohydride. After incubation at 0° C. for 1 hour, evaporation of methanol, and extraction with 10% aqueous ammonium chloride and chloroform, the resulting intermediate, a mixture of epimeric alcohols, is treated with N-hydrochloric acid for 1 hour. From this solution (±) thebaine is isolated by liquid-liquid extraction (addition of 10% sodium hydroxide and extraction into chloroform) and a solid liquid purification step using preparative thick-layer chromatography on a silica gel. (±) N-demethyl sinomenine is then synthesized from (±) thebaine using a modification of the procedure of Okabe K., et al., Jap. J. Pharm. Chem. 39:267 (1968). As an alternative to total synthesis, the intermediate products (±) salutaridine or (±) thebaine could be used as starters for N-demethyl-sinomenine synthesis.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([NH:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)=[O:15])[CH2:9][CH2:8]1.[ClH:27]>C(OCC)(=O)C>[ClH:27].[ClH:27].[NH2:19][CH2:18][CH2:17][NH:16][C:14]([NH:13][CH:10]1[CH2:11][CH2:12][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9]1)=[O:15]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)NC1CCN(c2ccccn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCNC(=O)NC1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of tert-butyl 2-[({[1-(2-pyridinyl)-4-piperidinyl]amino}carbonyl)amino]ethylcarbamate (Preparation 72) (20.6 g, 0.0567 moles) in ethyl acetate (115 ml) under an atmosphere of nitrogen was added a saturated solution of hydrogen chloride in ethyl acetate (115 ml) and the resulting thick slurry was stirred at ambient temperature for 2 hours. The solid was collected by filtration and the filter cake was washed with ethyl acetate (2×50 ml) after which it was dried in vacuo at 50° C. to give the title compound (21.0 g) as a hygroscopic colourless solid, m.p. 112-120° C.
Reaction SMILES: [C:1]([N:8]([CH3:40])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:41][C:42]1[CH:47]=[CH:46][C:45](Br)=[CH:44][N:43]=1>>[NH2:41][C:42]1[N:43]=[CH:44][C:45]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:29]([CH:30]=2)[CH2:28][N:15]([C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH:12]2[CH2:13][CH2:14][CH:9]([N:8]([CH3:40])[C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:7])[CH3:5])[CH2:10][CH2:11]2)=[CH:46][CH:47]=1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Nc1ccc(Br)cn1
Product: COc1ccc(-c2ccc(N)nc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 5 (175 mg, 0.29 mmol) is coupled to 2-amino-5-bromopyridine (62 mg, 0.36 mmol) using Method B to give the title compound.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([N:6]1[C:21]([NH2:22])=[C:9]2[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][C:8]2=[N:7]1)=[O:5].O1CCOCC1.[Cl:29]CCl>Cl>[ClH:29].[CH2:2]([O:3][C:4]([N:6]1[C:21]([NH2:22])=[C:9]2[CH2:10][NH:11][CH2:12][CH2:13][C:8]2=[N:7]1)=[O:5])[CH3:1]
Reactant: CCOC(=O)n1nc2c(c1N)CN(C(=O)OC(C)(C)C)CC2
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)n1nc2c(c1N)CNCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of 3-amino-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester (40 g, 128.9 mmol) in dichloromethane (1 L), 4 N HCl in dioxane (161 mL, 644.5 mmol) was added dropwise. The mixture was stirred at room temperature for 4 hours. The solid was filtered, washed with dichloromethane and diethylether. After drying in vacuo the title compound was obtained as white solid (36.2 g, 99%).
Reaction SMILES: C(OC(N1CCCC(NC2N=C(C)C=C(C)N=2)C1C)=O)(C)(C)C.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[NH:33][CH:34]1[CH2:39][CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH:35]1[CH3:47]>>[CH3:47][CH:35]1[CH:34]([NH:33][C:25]2[O:24][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=2)[CH2:39][CH2:38][CH2:37][NH:36]1
Reactant: CC1C(Nc2nc3ccccc3o2)CCCN1C(=O)OC(C)(C)C
Agent: Cc1cc(C)nc(NC2CCCN(C(=O)OC(C)(C)C)C2C)n1
Product: CC1NCCCC1Nc1nc2ccccc2o1

Procedure:
Prepared analogous to Example 1 substituting (±)-tert-butyl-3-((4,6-dimethylpyrimidin-2-yl)amino)-2-methylpiperidine-1-carboxylate with the title compound from step A.
Reaction SMILES: O.[OH-].[Li+].[C:4]1([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)[CH:21]=2)[C:15]([O:17]C)=[O:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C1COCC1>[C:4]1([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)[CH:21]=2)[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@H]2CCOC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(OCc2ccccc2)cc(O[C@H]2CCOC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
A solution of lithium hydroxide monohydrate (3.78 g; 90.0 mmol) in water (50 mL) was added to a solution of methyl 3-[(phenylmethyl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (10.0 g, 30 mmol) in THF (100 mL) and the mixture stirred at RT for 18 hours. The THF was removed in vacuo, the aqueous residue treated with 1M hydrochloric acid (90.0 mL) then extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give the desired material (9.00 g). 1H NMR δ (CDCl3): 2.0-2.2 (m, 2H), 3.7-3.95 (m, 4H), 4.85 (m, 1H), 5.0 (s, 2H), 6.65 (m, 1H), 7.15 (m, 1H), 7.25-7.4 (m, 6H); m/z 315 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:10]([F:11])=[C:9]([S:12][CH3:13])[N:8]=[C:7]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][CH:15]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:32])C=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([C:5]1[C:10]([F:11])=[C:9]([S:12]([CH3:13])=[O:32])[N:8]=[C:7]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][CH:15]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(-c2c[nH]c3ncc(Cl)cc23)nc(C(C)(C)C)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc(-c2c[nH]c3ncc(Cl)cc23)nc(C(C)(C)C)c1F
Reaction time: 1 h

Procedure:
To the solution of 3-(tert-butyl-5-fluoro-6-(methylthio)pyrimidin-2-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridine, 40b, (0.05 g, 0.11 mmol) in CH2Cl2 (3.4 mL) was added mCPBA (0.02 g, 0.11 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was diluted with CH2Cl2 (10 mL) and saturated NaHCO3 solution (5 mL). The aqueous layer was extracted with CH2Cl2 (10 mL). The combined organic phases were washed again with aqueous saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product that was used without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[O:22][C:21](=O)[N:20](C)[CH2:19]2)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.[OH-].[K+]>C(O)C>[OH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:22])[CH2:19][NH:20][CH3:21])=[CH:14][CH:13]=1
Reactant: CN1CC(c2ccc(OCCO[Si](C)(C)C(C)(C)C)cc2)OC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CNCC(O)c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.9 %

Procedure:
5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)phenyl]-3-methyl-1,3-oxazolidin-2-one (0.66 g, 1.87 mmol) and potassium hydroxide (4M aqueous solution, 1.4 mL, 5.61 mmol) dissolved in ethanol (8 mL) is refluxed for 2.5 h and then stirred at room temperature for 16 h. Reaction mixture is concentrated under reduced pressure, water (5 mL) is added and the mixture is extracted with chloroform:methanol (9:1) (5×10 mL). The combined organic layers are dried over magnesium sulfate and concentrated to provide a residual oil. This oil is triturated with ether to provide a white solid (0.28 g).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[N:26]=[CH:25][CH:24]=[C:23]2[O:32][C:33]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:34]=1[CH:35]=O.O>O1CCCC1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[N:26]=[CH:25][CH:24]=[C:23]2[O:32][C:33]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:34]=1/[CH:35]=[C:8](\[CH3:9])/[C:6]([O:5][CH2:4][CH3:3])=[O:7]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1cc(OC)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
Sodium hydride (60 wt % oil, 52 mg) was dissolved in anhydrous tetrahydrofuran (1 ml), and a solution (0.5 ml) of triethyl 2-phosphonopropionate (119 mg) in tetrahydrofuran was added dropwise thereto under an argon atmosphere at 0° C. The mixture was stirred at 0° C. for 30 min, and a solution (0.5 ml) of 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde (100 mg) in tetrahydrofuran was then added dropwise thereto. The reaction mixture was stirred at room temperature for one hr, and water (1 ml) was then added dropwise to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (64 mg, yield 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]3[CH2:14][CH2:15][CH2:16][CH:17]([C:19]([O:21]C)=[O:20])[CH2:18][C:12]3(N3CCCC3)[O:11][N:10]=2)=[CH:5][CH:4]=1>C(O)(=O)C.O.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH2:14][CH2:15][CH2:16][CH:17]([C:19]([OH:21])=[O:20])[CH2:18][C:12]=3[O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)C1CCCC2C(c3ccc(OC)cc3)=NOC2(N2CCCC2)C1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2noc3c2CCCC(C(=O)O)C3)cc1
Reaction time: 1 h
Yield: 60.3 %

Procedure:
2.32 g (0.006 mol) of methyl 3a,5,6,7,8,8a-hexahydro-3-(4-methoxyphenyl)-8a-pyrrolidino-4H-cyclohept[d]isoxazole-7-carboxylate were dissolved in a mixture of 6 ml of glacial acetic acid, 6 ml of water and 6 ml of concentrated sulfuric acid. The mixture was held at 100° C. for 1 hour, cooled and diluted with 20 ml of water to give a white precipitate which was filtered off, washed and dried. Crystallization from ethyl acetate gave 1.04 g of 5,6,7,8-tetrahydro-3-(4-methoxyphenyl)-4H-cyclohept[d]isoxazole-7-carboxylic acid of melting point 194°-196° C.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Br.[CH3:47][C:48]1[CH:53]=[C:52]([NH:54][NH2:55])[CH:51]=[CH:50][N:49]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:54]([C:52]3[CH:51]=[CH:50][N:49]=[C:48]([CH3:47])[CH:53]=3)[N:55]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: Cc1cc(NN)ccn1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Agent: Br
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: Cc1cc(-n2nc(C(=O)O)cc2-c2cc(Br)cc(OC(F)(F)F)c2)ccn1

Procedure:
500 mg (1.03 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 315 mg (1.54 mmol) of 2-methylpyridin-4-yl-hydrazine hydrobromide. After hydrolysis, 182 mg (40% of theory) of the title compound is obtained.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][C:10]1=[O:15].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:25]([CH2:35][C:36](Cl)=[O:37])[N:24]=2)=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:27]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:25]([CH2:35][C:36]([N:12]3[CH2:13][CH2:14][N:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=4)[C:10](=[O:15])[CH2:11]3)=[O:37])[N:24]=2)=[CH:21][CH:22]=1
Reactant: O=C1CNCCN1c1ccccn1
Reactant: O=C(Cl)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(c2ccccn2)C(=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.6 %

Procedure:
160 mg 1-pyridin-2-yl-piperazin-2-one dihydrochloride was added to 216 mg (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetyl chloride and 300 μL triethylamine in 10 mL dichlormethane. The reaction was stirred for 1 day at RT, the solvent was evaporated and the residue was purified by HPLC to yield 93 mg of the desired product.