Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][N:8]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])[CH2:7][CH2:6][C:5]2=1.C(C1C(=O)C(Cl)=C(Cl)C(=[O:28])C=1C#N)#N.C1COCC1.O>C1COCC1>[C:15]([N:8]1[CH2:7][C:6](=[O:28])[C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[C:2]([Cl:1])[CH:3]=3)[NH:11][C:10]=2[CH2:9]1)(=[O:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(c1ccccc1)N1CCc2c([nH]c3ccc(Cl)cc23)C1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1CN(C(=O)c2ccccc2)Cc2[nH]c3ccc(Cl)cc3c21
Temperature: -78 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
(6-chloro-1,3,4,9-tetrahydro-β-carbolin-2-yl)-phenyl-methanone (1.76 g, 5.66 mmol, 1 equiv.) and DDQ (2.31 g, 10.2 mmol, 1.8 equiv.) were mixed as solids and cooled to −78° C. 15 ml of a 9:1 THF/H2O solution was cooled to −78° C. and the resulting slurry was added to the cooled solids followed by an additional 15 ml of THF (also cooled to −78° C.). The deep blue solution was stirred at −78° C. for 2 hours and then gradually warmed to room temperature and stirred an additional two hours. The reaction was quenched by the addition of 1 N NaOH, and extracted with 3×150 ml EtOAc. The combined organic layers were washed with 2×100 ml 1 N HCl, 1×100 ml brine, dried over MgSO4, filtered and concentrated to yield 1.38 g (75%) of 2-benzoyl-6-chloro-1,2,3,9-tetrahydro-β-carbolin-4-one as oily orange solids. 1H-NMR (300 MHz, DMSO-d6): δ 12.11-12.48 (br, 1H), 7.29-7.88 (m, 8H), 4.93-5.18 (br, 2H), 4.60-4.46 (br, 2H). Exact Mass: 324.07. Formic acid standard conditions. DAD RT=2.15 min. M+H=325.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([CH:17]([OH:19])[CH3:18])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1>[O-2].[Mn+4].[O-2].C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17](=[O:19])[CH3:18])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: CC(O)c1nn2ccccc2c1-c1ccnc(F)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)c1nn2ccccc2c1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95 %

Procedure:
A solution of 1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanol (0.1 g, 0.4 mmol), manganese(IV)oxide (0.17 g. 1.95 mmol), and methylene chloride (10 mL) were allowed to stir at room temperature for 72 hours. When judged to be complete, the mixture was filtered through a plug of Celite, and the filtrate was concentrated to provide 1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanone (97 mg, 98%) as a pale yellow solid. 1H NMR (DMSO-d6): δ 8.92 (d. 1H), 8.30 (d, 1H), 7.82 (d, 1H), 7.46 (m, 2H), 7.34 (s, 1H), 7.23 (m, 1H), 2.71 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:33]=[N:32][CH:31]=[CH:30][N:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Fc1cnccn1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cnccn5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-pyrazine following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.11 min; Mass spectrum (ESI+): m/z=437 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([C@@H:19]([NH:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1)[CH3:20])=[CH:7]2.O.[OH-].[NH4+:31]>O1CCOCC1.[Cl-].[Na+].O>[NH2:31][C:26]1[N:25]=[CH:24][N:23]=[C:22]([NH:21][C@H:19]([C:8]2[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[CH3:20])[CH:27]=1
Reactant: C[C@H](Nc1cc(Cl)ncn1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(N)ncn1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A heavy-wall glass tube with stir bar and FEP-encapsulated-silicone O-ring seal was charged with 77 (ca. 300 mg, 0.73 mmol) in 1,4-dioxane (12 mL) and concentrated ammonium hydroxide solution (10 mL), then sealed tightly and heated at 120° C. After 16 h, more ammonium hydroxide (6 mL) was added and heating continued at 150° C. during 6 h, then 160° C. during 24 h. A third portion of ammonium hydroxide (8 mL) was added and heating continued at 150° C. during 3 days. The reaction mixture was poured into a mixture of water and brine (35 mL each), stirred about 1 h at 0° C., and the resulting precipitate collected by filtration and washed with ice-water. This material was dried in vacuo to give (S)-3-(1-(6-aminopyrimidin-4-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one 78. ESI-MS m/z: 392.15 [M+H]+.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH3:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[CH:67][CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[CH3:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:75][CH2:76]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(N6CCN(C[C@H](C)O)CC6)cc5)cc34)cn2)c1
Yield: 43.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(4-(3-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)propan-2-ol (100 mg, 0.151 mmol) was hydrolyzed with lithium hydroxide (13 mg, 0.302 mmol) in THF/methanol/water (5./1/1 mL) to yield 33 mg (35.1% yield) desired product. 1H NMR (CD3OD, 400 MHz): δ 8.667-8.663 (d, 1H), 8.55-8.54 (d, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.77 (s, 1H), 7.69-7.66 (d, 2H), 7.25-7.21 (t, 1H), 7.17-7.08 (m, 5H), 5.37 (s, 2H), 4.30-4.20 (m, 1H), 4.00-3.80 (m, 2H), 3.75-3.60 (m, 2H), 3.30-3.10 (m, 6H), 2.31 (s, 3H), 1.29-1.27 (d, 3H). MS: m/z=507.65 (M+1), HPLC: 91.66% in method A.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].CC1(C)C(C)(C)OB(C2C=CC=CC=2C(NC2SC=CN=2)=O)O1.[CH3:38][C:39]1[CH:52]=[CH:51][C:42]([C:43]([NH:45][C:46]2[S:47][CH:48]=[CH:49][N:50]=2)=[O:44])=[CH:41][C:40]=1B1OC(C)(C)C(C)(C)O1>>[S:47]1[CH:48]=[CH:49][N:50]=[C:46]1[NH:45][C:43]([C:42]1[CH:41]=[C:40]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)=[CH:4][C:3]=2[CH3:14])[C:39]([CH3:38])=[CH:52][CH:51]=1)=[O:44]
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Agent: CC1(C)OB(c2ccccc2C(=O)Nc2nccs2)OC1(C)C
Product: Cc1nnc(-c2ccc(-c3cc(C(=O)Nc4nccs4)ccc3C)c(C)c2)o1

Procedure:
Example 19 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-[1,3,4]oxadiazole and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-N-(thiazol-2-yl)-benzamide (Intermediate 22).
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:13][C:14]([O-])(C)[CH3:15].[K+].C1COCC1.C(Br)C=C>O>[CH2:15]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([C:9]([F:10])([F:11])[F:12])=[CH:8][C:2]=1[I:1])[CH:14]=[CH2:13]
Reactant: Nc1ccc(C(F)(F)F)cc1I
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: O
Solvent: C1CCOC1
Product: C=CCNc1ccc(C(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.4 %

Procedure:
To a mixture of 2-iodo-4-trifluoromethyl-aniline (5 g, 17.4 mmol), KOt-Bu (2.05 g, 18.3 mmol) and THF (200 mL) at −78° C., is added allyl bromide (2.21 g, 18.3 mmol). The resulting mixture is warmed to rt and stirred for 18 h. Water is added, and the mixture is extracted with EtOAc. The organic layer is separated, dried (Na2SO4), filtered and concentrated. The residue is chromatographed through silica gel eluting with 0-50% EtOAc in heptane to afford allyl-(2-iodo-4-trifluoromethyl-phenyl)-amine (1.9 g, 33%). MS 328 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.90 (s, 1H), 7.45 (d, 1 H), 5.88-6.02 (m, 1H), 5.33 (d, 1 H), 5.25 (d, 1H), 4.72(broad s, 1H), 3.90 (s, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:35](O)=[O:36])=[C:14]([CH2:16][N:17]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][CH3:34])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1>[CH2:22]([O:21][C:19]([CH:18]1[N:17]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[O:33][CH3:34])[CH2:16][C:14]2[N:15]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=3)[S:12][C:13]=2[C:35]1=[O:36])=[O:20])[CH3:23]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(C(C)(C)C)cc2)sc1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)c2sc(-c3ccc(C(C)(C)C)cc3)nc2CN1Cc1ccc(OC)cc1OC
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
2-(4-tert-Butyl-phenyl)-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethy este (1.11 g, 2.0 mmol) was dissolved in 21 mL of anhydrous THF and cooled to −15° C. in a brine dry ice bath. A solution of 4.4 mL of 1.0 M potassium tert-butoxide in THF was added slowly to cold solution, and the reaction was stirred at −15° C. for 30 min. and then at room temperature for 2 h. The reaction was quenched with 4.4 mL of 1N HCl and 150 mL of saturated ammonium chloride aqueous solution, and extracted twice with 150 mL of chloroform. The organic fractions were washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-70% ethyl acetate in hexanes to produce 0.5 g of a yellow froth. MS: (+) m/z 508.9 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[C:17]3[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]2>>[CH3:33][C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[CH:32][C:23]=2[O:22][CH2:21][CH2:20][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][C:8]3[C:17]4[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=4[CH:11]=[CH:10][CH:9]=3)[CH2:3][CH2:2]2)[N:28]=1
Reactant: O=C1COc2c(CC3CCNCC3)cccc2N1
Reactant: Cc1ccc2c(OCCBr)cccc2n1
Product: Cc1ccc2c(OCCN3CCC(Cc4cccc5c4OCC(=O)N5)CC3)cccc2n1

Procedure:
The title compound was prepared from 8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and 5-(2-bromoethoxy)-2-methylquinoline in a similar manner to Example 1.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[Na+].[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@H:19](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:18][C@H:17]1[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>CN(C)C=O>[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@@H:19]([S:3][C:1](=[O:4])[CH3:2])[CH2:18][C@H:17]1[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCc3ccccc3)C2)cc1
Reactant: CC([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCc2ccccc2)C1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
29.34 g (257 mmol) of sodium thioacetate were added to a solution of 127.17 g (245 mmol) of (2S,4R)-1-benzyloxycarbonyl-2-(t-butyldimethylsilyloxy)methyl-4-(p-toluenesulfonyloxy)pyrrolidine [obtained as described in step (a) above] in 245 ml of dimethylformamide, and the resulting mixture was stirred for 1.5 hours at 60° C. After it was cooled to room temperature, water was added and it was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel using an 8:1 by volume mixture of hexane and ethyl acetate as the eluant to afford 91.67 g (yield: 88%) of the title compound as an orange oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=O)C.[BH4-].[Li+]>>[CH2:18]([CH:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([CH2:4][OH:3])[CH:7]=2)[NH:12][CH:11]=[C:10]1[C:16]#[N:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCc1c(C#N)cnc2ccc(C(=O)OCC)cc12
Agent: [BH4-]
Agent: [Li+]
Product: CCCCCCC1C(C#N)=CNc2ccc(CO)cc21

Procedure:
Similar procedure as described in example 46e was used, starting from 3-cyano-4-hexyl-quinoline-6-carboxylic acid ethyl ester (example 52a) and lithium borohydride to give 4-hexyl-6-hydroxymethyl-1,4-dihydro-quinoline-3-carbonitrile as a yellow solid. LC-MS m/e 271 (MH+).
Reaction SMILES: II.[O:3]1[C:11]2[CH:10]=[CH:9][NH:8][C:7](=O)[C:6]=2[CH:5]=[CH:4]1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:7]1[C:6]2[CH:5]=[CH:4][O:3][C:11]=2[CH:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2occc12
Agent: II
Product: Clc1nccc2occc12

Procedure:
For example, in making a compound of formula I in which Y is oxygen, Scheme A can be followed. Briefly, 2-furfural (1) is converted under heating into 3-furan-2-yl-acrylic acid (2) using malonic acid and a suitable base such as piperidine. 3-(Furan-2-yl)-acrylic acid (2) is converted into 3-(furan-2-yl)-acryloyl azide (3) using DPPA and a suitable base such as triethylamine. The azide (3) was cyclized to afford 5H-furo[3,2-c]pyridin-4-one (4) upon heating and a catalytic amount of iodine. 5H-furo[3,2-c]pyridin-4-one is chlorinated on the 4th position with POCl3 to afford 4-chloro-furo[3,2-c]pyridine (5). 4-Chloro-furo[3,2-c]pyridine is treated with bromine, and subsequently with DBU to afford compound (6). The chlorine atom of compound (6) is replaced with an amino group by the action of aqueous ammonia to afford compound (7). Compound (7) is subsequently subjected to Pd(PPh3)4, sodium carbonate, R—B(OH)2 or a compound of formula R—B(OR′)2, in which the radical —B(OR′)2 can be represented as
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[C:6]([F:13])[CH:5]=1)=[O:3].[C:14](OC)(=[O:19])[C:15]([O:17][CH3:18])=[O:16].C[O-].[Na+]>CO.C(Cl)Cl>[F:13][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[C:8]([F:10])[C:7]=1[O:11][CH3:12]
Reactant: COc1c(F)cc(C(C)=O)cc1F
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(=O)CC(=O)c1cc(F)c(OC)c(F)c1
Reaction time: 8 h

Procedure:
To a stirred solution of 3,5-fluoro-4-methoxyacetophenone from Step 1 (6.46 g, 34.70 mmol) and dimethyl oxalate (6.15 g, 52.05 mmol) in methanol (80 mL), was added sodium methoxide solution (13.4 mL of 25% solution, 58.99 mmol) in one portion and the reaction stirred overnight. The crude reaction was diluted with methylene chloride, washed with potassium bisulfate (0.1N solution), brine, dried over MgSO4, filtered, and concentrated in vacuo yielding methyl 4-(3,5-difluoro-4-methoxyphenyl)-2,4-dioxo-butanoate as an off white crystalline solid which was used as is. A mixture of 4-(3,5-difluoro-4-methoxyphenyl)-2,4-dioxo-butanoate and 4-sulfonamidophenylhydrazine hydrochloride salt (7.76 g, 34.70 mmol) dissolved in methanol was warmed to reflux for 9 hours. Upon allowing the clear reaction to cool to room temperature, a crystalline precipitate formed which was collected by vacuum filtration yielding 5.45 g, (37% based upon the 3,5-difluoro-4-methoxyacetophenone) of methyl 1-(4-aminosulfonylphenyl)-5-(3,5-difluoro-4-methoxyphenyl)-1-H-pyrazole-3-carboxylate as an off-white solid: mp 185°-190° C.; 1H NMR (CDCl3 /300 mHz) 7.95 (d, J=8.86, 2H), 7.49 (d, J=8.86, 2H), 7.02 (s, 1H), 6.77 (m, 2H), 4.99 (s, 2H, 4.04 (s, 3H), 3.98 (s, 3H); 19F NMR (CDCl3 /300 mHz) -126.66. Anal. Calc'd for C17H13 F2N3O3S: C, 51.06; H, 3.57; N, 9.92. Found: C, 51.06; H, 3.54, N, 9.99.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](/[CH:15]=[CH:16]/[C:17]#[N:18])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N.[H][H]>C(O)C.[Rh]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH2:17][NH2:18])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC1(/C=C/C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Rh]
Agent: N
Solvent: CCO
Product: CC1(CCCN)CCN(C(=O)OC(C)(C)C)CC1
Yield: 63.4 %

Procedure:
Cis/trans-4-(2-cyanovinyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (1.00 g, 4.0 mmol), 5% Rh/Al2O3 (0.500 g) and 28% aqueous NH3 (1.25 mL) are heated at 35° C. in ethanol (20 mL) and 50 psi hydrogen gas for 18 hours. The reaction mixture is filtered through Celite®, concentrated, and chromatographed with 0-20% (2M NH3 in MeOH) in dichloromethane to give the title compound as a clear oil (0.65 g, 63% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[N:4]=[C:5]([S:29][CH3:30])[C:6]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:39][CH3:40].O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:31])[N:4]=[C:5]([S:29][CH3:30])[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:39][CH3:40])=[C:22]([O:27][CH3:28])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: CCI
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
After dissolving 500 mg of {2-(4-hydroxy-3-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 10 ml of DMF, 314 mg of potassium carbonate and 118 μl of iodoethane were added and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (435 mg, isomeric mixture) as a light yellow solid.
Reaction SMILES: C([O:4][N:5]1[C:10]([NH2:11])=[CH:9][C:8](Cl)=[N:7][C:6]1=[NH:13])(=O)C.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[NH2:11][C:10]1[N:5]([OH:4])[C:6](=[NH:13])[N:7]=[C:8]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:9]=1
Reactant: CC(=O)On1c(N)cc(Cl)nc1=N
Reactant: C1CCNCC1
Product: N=c1nc(N2CCCCC2)cc(N)n1O
Yield: 86 %

Procedure:
2.02 g (10 mmoles) of 1-acetoxy-6-amino-4-chloro-1,2-dihydro-2-iminopyrimidine are added to 8 ml of piperidine at room temperature while stirring. The mixture is stirred at room temperature for 2 hours, then piperidine is evaporated under reduced pressure. The residue is taken up in a mixture containing 20 ml of ethanol and 10 ml of 1N aqueous sodium hydroxide solution and refluxed for 30 minutes, then evaporated under reduced pressure. The residue is taken up in 20 ml of water, the crystals are filtered, washed with water and dried to give 1.74 g (86% yield) of the aimed compound which shows no melting point depression when mixed with the product of Example 1.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[S:34])[CH:29]=[CH:30][CH:31]=1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:33](=[S:34])[NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Reactant: O=C1c2ccccc2SCCC1(CO)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2SCCC1(CO)COC(=S)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]thiepin-5-one (555 mg, 2.33 mmol) in 29 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.35 ml, 2.56 mmol) and 3-(trifluoromethyl)phenyl isothiocyanate (885 μl, 5.82 mmol). The mixture was heated to reflux for 72 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 ethyl acetate/hexane). The product was obtained in a yield of 320 mg (31%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][CH2:10]1)(=[O:24])=[O:23]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccccc1Cl)N1CCN(c2ccccc2F)CC1
Yield: 75.5 %

Procedure:
Sulfonylation of 1-(2-fluorophenyl)piperazine.HCl (325 mg, 1.5 mmol) with 2-chlorobenzene-1-sulfonyl chloride (316.6 mg, 1.5 mmol) was carried out according to a similar procedure described for step 1A using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (0.575 mL, 3.3 mmol) as base. 1-[(2-chlorophenyl)sulfonyl]-4-(2-fluorophenyl)piperazine was obtained in 75.5% yield (402 mg) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8](=[O:19])[CH2:9][N:10]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH:12]=[C:11]3[C:4]=2[CH:3]=1.[Si]([C:26]([F:29])([F:28])[F:27])(C)(C)C.[F-].[Cs+]>COCCOC.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8]([C:26]([F:29])([F:28])[F:27])([OH:19])[CH2:9][N:10]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH:12]=[C:11]3[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: OC1(C(F)(F)F)COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.9 %

Procedure:
A mixture of 2-bromo-6H-benzo[2,3][1,5]oxazocino[5,4-a]indol-7(8H)-one (60 mg, 0.18 mmol), TMSCF3 (275 mg, 0.194 mmol) and CsF (3 mg, 0.018 mmol) in DME (1 mL) was stirred at room temperature for 3 hours. The mixture was then diluted with TBAF (5 mL) and stirred for 1 hour at room temperature. The mixture was then diluted with water (25 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EA=3:1) to provide 2-bromo-7-(trifluoromethyl)-7,8-dihydro-6H-benzo[2,3][1,5]oxazocino[5,4-a]indol-7-ol (40 mg, yield: 55.6%). MS (M+H)+: 412/414.