Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:33])[C:5]([CH3:32])([CH3:31])[CH:6]([OH:30])[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([CH3:29])[CH:20]=3)[CH:13]=2)[CH:8]=1)C.C[O-].[Na+].Cl.[OH:38][NH2:39].CO.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>>[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].[OH:30][CH:6]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([CH3:29])[CH:20]=3)[CH:13]=2)[CH:8]=1)[C:5]([CH3:31])([CH3:32])[C:4]([NH:39][OH:38])=[O:33]
Reactant: CCOC(=O)C(C)(C)C(O)c1ccc2cc(OCc3cc(C)nc4ccccc34)ccc2c1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc3cc(C(O)C(C)(C)C(=O)NO)ccc3c2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
3-Hydroxy-2,2-dimethyl-3-[6-(2-methyl-quinolin-4-ylmethoxy)-naphthalen-2-yl]-propionic acid ethyl ester (1.35 g, 3.04 mmol) was added portion wise to a 50° C. solution of sodium methoxide/hydroxyl amine HCl/methanol ˜1.34 M (230 mL, 308 mmol) under nitrogen atmosphere. The reaction was stirred for 0.5 h, cooled to 0° C., made neutral with TFA, and concentrated in vacuo. The residue was taken up in water (800 mL) and the pH adjusted to 2–3 with TFA to give a solid precipitate. The product was purified by HPLC on a C-18 column eluting with an acetonitrile:water:TFA gradient to give the title compound (0.98 g, 59%) as a white solid. MS found: (M+H)+=431.
Reaction SMILES: [C:1]([C@@H:3]([OH:18])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)#[N:2].[CH3:19][C:20]1([CH3:35])[C@@H:22](/[CH:23]=[CH:24]\[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C@H:21]1[C:32](O)=[O:33].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:19][C:20]1([CH3:35])[C@@H:22](/[CH:23]=[CH:24]\[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[C@H:21]1[C:32]([O:18][C@H:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1ccc(F)c(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)C1(C)C
Temperature: -5 °C
Yield: 87.3 %

Procedure:
A mixture of 310 g of (S)α-cyano-3-phenoxy-4-fluoro-benzyl alcohol, 310 g of (IR,cis,Z) 2,2-dimethyl-3-[3-oxo -3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylic acid and 1.55 liters of methylene chloride was stirred until total dissolution occured and the mixture was cooled to -5° C. and mixed with a solution of 263.5 go dicyclohexylcarbodiimide, 3.1 g of 4-dimethylamino-pyridine and 530 ml of methylene chloride. The mixture was stirred at -5° C. for one hour and at room temperature for 3 hours and was vacuum filtered. The filtrate was washed with N hydrochloric acid and then with water, dried and evaporated to dryness under reduced pressure. The residue in 1.185 liters of isopropanol, 80 ml of water and 72 ml of triethylamine was stirred for 36 hours and was vacuum filtered. The product was washed with isopropanol to obtain 518 g of (S)α-cyano-3-phenoxy-4-fluoro-benzyl (IR,cis,Z) 2,2-dimethyl-3-[3-oxo-3-tert.-butoxy- 1-propenyl]-cyclopropane-carboxylate melting at 114° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][NH:19][C:20]3[N:25]=[C:24]([NH2:26])[N:23]4[N:27]=[C:28]([C:30]5[O:31][CH:32]=[CH:33][CH:34]=5)[N:29]=[C:22]4[N:21]=3)[CH2:16][CH2:17][C@@H:10]2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClC1[N:48]=[CH:47][CH:46]=[CH:45][N:44]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:28]1[N:29]=[C:22]2[N:21]=[C:20]([NH:19][CH2:18][CH:15]3[CH2:14][N:11]4[CH2:12][CH2:13][N:8]([C:6]5[N:48]=[CH:47][CH:46]=[CH:45][N:44]=5)[CH2:9][CH:10]4[CH2:17][CH2:16]3)[N:25]=[C:24]([NH2:26])[N:23]2[N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](CNc3nc(N)n4nc(-c5ccco5)nc4n3)CC[C@@H]2C1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(NCC2CCC3CN(c4ncccn4)CCN3C2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-7-[(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)-methyl]-octahydro-pyrido[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (1 eq., see Example 7(b) above) in methylene chloride was added trifluoroacetic acid to reach a final concentration of 10% TFA. The mixture was stirred at room temperature for 2 hours, after which the solvent was removed under reduced pressure, and the residue was dissolved in acetonitrile. To the resulting solution was added 2-chloropyrimidine (1 eq.) and Na2CO3 (2 eq.). The mixture was stirred at around 80° C. for overnight. The solvent was removed afterwards, and the residue was purified by preparative HPLC using aqueous CH3CN (buffered with 0.1% TFA) to afford (7RS,9aSR)-2-furan-2-yl-N5-(2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J=4.7 Hz, 2H), 7.70 (d, J=2 Hz, 1H), 7.12 (d, J=3.6 Hz, 1H), 6.72 (t, J=4.7 Hz, 1H), 6.62 (dd, J=2, 3.6 Hz, 1H), 4.97 (d, J=14.1 Hz, 2H), 3.34-3.58 (m, 4H), 3.11-3.24 (m, 3H), 2.82-3.03 (m, 2H), 2.33 (m, 1H), 2.10 (d, J=14.1 Hz, 1H), 2.02 (d, J=13.2 Hz, 1H), 1.60-1.69 (m, 1H), 1.39-1.49 (m, 1H). MS m/z: 448[M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:19]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:32]1([CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:26]2[CH2:27][CH2:28][N:29]([CH2:17][CH2:16][CH2:15][C:13]3[O:12][N:11]=[C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH:14]=3)[CH2:30][CH2:31]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=CCCc1cc(-c2cccc([N+](=O)[O-])c2)no1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(-c2cc(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)on2)c1
Yield: 91.2 %

Procedure:
About 2 min after dissolving 3-[3-(3-nitrophenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-(diphenylmethyl)piperazine (10 mg, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (26 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 18.2 hr and followed the same processes as in Example 1 to obtain 17.6 mg (89.8%) of the target compound.
Reaction SMILES: N[C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C.[CH2:27]([O:30][C:31](Cl)=[O:32])[CH:28]=[CH2:29]>C(Cl)Cl>[CH2:27]([O:30][C:31]([C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:32])[CH:28]=[CH2:29]
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Reactant: C=CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)OCC
Reaction time: 4 h
Yield: 60.4 %

Procedure:
A solution of 259A (900 mg, 3.3 mmol) in CH2Cl2 (20 mL) was treated with triethylamine (0.64 mL, 4.62 mmol) and allylchloroformate (0.35 mL, 3.96 mmol) at room temperature. The mixture was stirred for four hours, then washed with 0.1 N HCl (2×10 mL), 1N NaOH (2×10 mL) and brine (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 680 mg (yield: 58%) of Compound 259B as an oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](OC(C)(C)C)=O)[CH3:3].FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH:31]1([C:34]2[O:35][C:36]3[C:37](=[C:39]([C:51]#[N:52])[C:40]([CH3:50])=[C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)C=3F)[N:38]=2)[CH2:33][CH2:32]1>ClCCl>[CH:31]1([C:34]2[O:35][C:36]3[C:37](=[C:39]([C:51]#[N:52])[C:40]([CH3:50])=[C:41]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:10]=3[N:6]3[CH2:7][CH2:8][CH2:9][C@H:5]3[CH2:4][N:2]([CH3:1])[CH3:3])[N:38]=2)[CH2:33][CH2:32]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CN(C)C[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(N2CCC[C@H]2CN(C)C)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
tert-Butyl (2S)-2-[(dimethylamino)methyl]pyrrolidine-1-carboxylate (I-328) (92.0 mg, 0.403 mmol) was dissolved in dichloromethane (1 ml), and at room temperature, trifluoroacetic acid (1 ml) was added, followed by stirring at room temperature for 1 hour. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in dimethyl sulfoxide (2 ml), then triethylamine (84.2 μl, 0.604 mmol) and 2-cyclopropyl-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-173) (118 mg, 0.403 mmol) was added, followed by stirring in an oil bath at 100° C. for 5 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v) to obtain the entitled compound (32.0 mg, 20%) as a colorless oily substance.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:40][C:41]([C:43]([F:46])([F:45])[F:44])=[O:42].[F:47][CH:48]([F:77])[CH2:49][NH:50][C:51]1[N:52]=[C:53]2[CH2:75][CH:74]([CH3:76])[NH:73][CH2:72][C:54]2=[N:55][C:56]=1[N:57]1[CH2:62][CH2:61][CH:60]([O:63][C:64]2[CH:69]=[CH:68][C:67]([F:70])=[CH:66][C:65]=2[F:71])[CH2:59][CH2:58]1>CN(C=O)C>[CH:1]1([C:4]([N:73]2[CH:74]([CH3:76])[CH2:75][C:53]3[C:54](=[N:55][C:56]([N:57]4[CH2:62][CH2:61][CH:60]([O:63][C:64]5[CH:69]=[CH:68][C:67]([F:70])=[CH:66][C:65]=5[F:71])[CH2:59][CH2:58]4)=[C:51]([NH:50][CH2:49][CH:48]([F:77])[F:47])[N:52]=3)[CH2:72]2)=[O:6])[CH2:3][CH2:2]1.[C:41]([OH:42])([C:43]([F:46])([F:45])[F:44])=[O:40]
Reactant: O=C(O)C1CC1
Reactant: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1C(=O)C1CC1
Reaction time: 2 h

Procedure:
A solution of cyclopropanecarboxylic acid (1.6 mg, 0.018 mmol), DIPEA (7.0 mg, 0.054 mmol), and HATU (6.9 mg, 0.018 mmol) in DMF (181 μL) was stirred at room temperature for 10 min followed by the addition of N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (10 mg, 0.018 mmol). The resulting reaction mixture was stirred for 2 h. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (5 mg) as a white solid. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) 6 ppm 0.80-1.01 (m, 4H), 1.13 (d, J=6.6 Hz, 1.4H), 1.27 (d, J=6.3 Hz, 1.6H), 1.91-2.04 (m, 2H), 2.06-2.20 (m, 2H), 2.56-2.60 (m, 0.5H), 2.66-2.70 (m, 0.5H), 3.02 (br s, 2H), 3.13-3.15 (m, 0.5H), 3.16-3.20 (m, 0.5H), 3.34-3.46 (m, 2H), 3.72-3.87 (m, 2H), 4.04 (d, J=18.2 Hz, 1H), 4.41-4.58 (m, 2H), 5.02 (d, J=17.4 Hz, 1.4H), 5.15-5.19 (m, 0.6H), 5.90-6.23 (m, 1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 507.9.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[Li+].CC([N-]C(C)C)C.[F:27][C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1.CC[O:37][C:38]([CH:40]([F:42])[F:41])=O>C1COCC1>[Br:34][C:31]1[CH:30]=[CH:29][C:28]([F:27])=[C:33]([C:38](=[O:37])[CH:40]([F:42])[F:41])[CH:32]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=C(c1cc(Br)ccc1F)C(F)F
Temperature: -40 °C

Procedure:
A solution of diisopropyl amine (17.77 ml, 126 mmol) in 320 ml THF was cooled to −75° C. and brought under N2 atmosphere. A 1.6 M solution of BuLi in hexane (79 ml, 126 mmol) was added. When the LDA solution had cooled down again, 1-fluoro-4-bromobenzene was added. The reaction temperature was kept below −60° C. After 2.5 h ethyl difluoro acetate (15.60 g, 126 mmol) was added rapidly and after 15 minutes, the reaction mixture was warmed to −40° C. After 15 minutes the mixture was quenched by pouring it on ice-cold 1N HCl. The mixture was extracted with petroleum ether (B.p. 40-60° C.) and the extract was dried with MgSO4.H2O. Chromatography on silica gel with hexane/TBME 9/1->6/1 gave 22.1 g yellow liquid.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[S:13][CH:14]=2)[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.S(Br)([Br:21])=O>>[Br:21][C:14]1[S:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=1[C:3]1[N:4]2[N:5]=[CH:6][CH:7]=[CH:8][C:9]2=[N:1][CH:2]=1
Reactant: COC(=O)c1cc(-c2cnc3cccnn23)cs1
Reactant: O=S(Br)Br
Product: COC(=O)c1cc(-c2cnc3cccnn23)c(Br)s1
Temperature: 50 °C

Procedure:
Methyl 4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxylate (690 mg, 2.66 mmol) was dissolved in thionyl bromide (5 mL, 64.5 mmol) and heated at 50° C. in a sealed tube for 4 h. The solution poured over ice and quenched with ammonium hydroxide. The aqueous layer was extracted with dichloromethane (×3). The organic layers put together, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound as a light brown solid. 1H NMR (500 MHz, CD3SOCD3) δ 8.66 (d, 1H); 8.27 (s, 1H); 8.25 (s, 1H); 8.25 (d, 1H); 7.35 (dd, 1H); 3.85 (s, 3H). LRMS (APCI) calc'd for (C12H8BrN3O2S) [M+H]+, 338.0. found 337.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)=[C:5]2[CH3:16].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]>CN(C)C=O.O>[ClH:1].[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([CH3:16])=[C:6]1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)([OH:27])=[O:26]
Reactant: Cc1c(-n2ccnc2)[nH]c2ccc(Cl)cc12
Reactant: O=C(O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-n2ccnc2)n(CCCCCC(=O)O)c2ccc(Cl)cc12
Product: Cl

Procedure:
A solution of 5-chloro-2-(1-imidazolyl)-3-methylindole (0.37 g) in anhydrous dimethylformamide (4 ml is added dropwise to a suspension of a 50% dispersion of sodium hydride in mineral oil (0.17 g) in anhydrous dimethylformamide (3 ml) while stirring under nitrogen at 0°. The mixture is stirred at 0° for 1/2 hour. To the suspension is then added a solution of 6-bromohexanoic acid (0.35 g) in anhydrous dimethylformamide (4 ml) dropwise. The reaction mixture is stirred at 0° for 1/2 hour and then at room temperature for several hours. The resulting suspension is diluted with water (30 ml) and washed with ether (2×15 ml). The aqueous solution is acidified to pH 5 with 1N hydrochloric acid and extracted with ether (3×30 ml). The extract is dried over magnesium sulfate, filtered and concentrated in vacuo to give an oil which crystallizes. This material is dissolved in ethanol (3 ml) and the solution is treated with 0.11 ml of 7N ethanolic hydrogen chloride. The solution is concentrated in vacuo and the residue is triturated with ether. The hydrochloride salt is collected and is purified by recrystallization from acetonitrile/ether to give 1-(5-carboxypentyl)-5-chloro-2-(1-imidazolyl)-3-methylindole hydrochloride, m.p. 149°-152°.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1.[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CN=C1>CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:5][C@@H:4]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1F)(c1ccccc1)c1ccccc1

Procedure:
The title compound was synthesised following a similar procedure as described for Example 12. 3′-Fluoro-2′,3′-dideoxyuridine (0.176 g, 0.77 mmol) was reacted with tert-butyldiphenylsilyl chloride (0.238 g, 0.87 mmol) and imidazole (0.116 g, 1.70 mmol) in dry DMF (4 mL) for 3 h. Compound WSP948 was obtained as a white solid (0.331 g, 92%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][CH2:20][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:12]=1)(=O)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:31][CH:30]=1>>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:7]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:33][CH:34]=3)[C:8]3[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][CH2:20][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=S1(=O)CCCc2nc(-c3cccc(Cl)c3)nc(OS(=O)(=O)C(F)(F)F)c21
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 77.5 %

Procedure:
Following general procedure H, 2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (1.0 g, 2.26 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.445 g, 2.49 mmol) to afford the title compound (0.827 g, 78%) as a light yellow solid. MW=471.96. APCI MS m/z 472 [M+H]+.
Reaction SMILES: C(O)=O.[CH2:4]([NH:11][CH2:12][CH2:13]O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[Cl:26])=[O:18]>C(Cl)Cl>[CH2:4]([N:11]1[CH2:12][CH2:13][O:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[Cl:26])[CH2:16]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccc(F)cc1Cl
Reactant: OCCNCc1ccccc1
Solvent: ClCCl
Solvent: O=CO
Product: Fc1ccc(C2CN(Cc3ccccc3)CCO2)c(Cl)c1
Reaction time: 20 h
Yield: 99.7 %

Procedure:
Combine formic acid (98-100%; 0.30 mL, 8 mmol) and 2-benzylaminoethanol (1.21 g, 8 mmol) and cool the resulting mixture with an ice bath. Add 2-bromo-1-(2-chloro-4-fluoro-phenyl)ethanone (1.0 g, 4 mmol); heat the mixture to reflux; and stir at that temperature for 20 h. Dilute the mixture with DCM and wash with saturated aqueous Na2CO3 solution. Dry organic phases over MgSO4; filter; collect the filtrate; and concentrate under reduced pressure. Purify via flash column chromatography eluting with a gradient of 0-20% methyl tertiary-butyl ether in hexanes. Combine the product fractions and remove the solvents under reduced pressure to give the title compound as a yellow oil (1.22 g, 43%). MS (m/z): 306 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[N:23][CH:24]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:21]1[CH:22]=[N:23][CH:24]=[C:19]([F:18])[CH:20]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)c1cncc(F)c1
Product: COC(=O)c1c(O)c2ccc(-c3cncc(F)c3)cc2sc1=O

Procedure:
7-(5-Fluoro-pyridin-3-yl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and 5-fluoro-3-pyridyl-boronic acid under conditions analogous to Example 14(a). MS ESI(+) m/e: 332.08 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17](C(=O)C)[N:16]=[CH:15]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.C(=O)([O-])O.[Na+].C(OC(C)C)(C)C>O>[F:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[CH:15]3)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)n1ncc2cc(OS(=O)(=O)c3cccc(F)c3)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)OC(C)C
Product: O=S(=O)(Oc1ccc2[nH]ncc2c1)c1cccc(F)c1
Yield: 59.3 %

Procedure:
1H-Indazol-5-yl 3-fluorobenzenesulfonate can be obtained in the following way: a suspension of 193 mg of 1-acetyl-1H-indazol-5yl 3-fluorobenzenesulfonate and of 0.19 ml of hydrochloric acid (d=1.18) in 1.65 ml of distilled water is brought to reflux for 16 hours. After returning to a temperature in the region of 20° C., the reaction medium is basified to a pH in the region of 8 with a saturated aqueous sodium hydrogencarbonate solution and extracted with two times 10 ml of dichloromethane. The pooled organic extracts are dried over calcium chloride, filtered and concentrated by evaporation under reduced pressure. The translucent oil obtained is taken up with 2 ml of diisopropyl ether and concentrated by trituration. The solid obtained is separated by filtration, washed with two times 1 ml of diisopropyl ether and dried under reduced pressure. 100 mg of 1H-indazol-5-yl 3-fluorobenzenesulfonate are thus obtained in the form of a whitish solid melting at 104° C. (analysis C13H9FN2O3S, % calculated C, 53.42; H, 3.10; F, 6.50; N, 9.58; O, 16.42; S, 10.97. % found C, 53.5; H, 2.9; F, 6.2; N, 9.6).
Reaction SMILES: [F:1][C:2]1[C:7](O)=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH:10]C(=O)OC.C1(C)C=CC(S([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)(=O)=O)=CC=1.[OH-].[K+].Cl>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([Cl:9])[C:5]([O:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[CH:4][C:3]=1[NH2:10]
Reactant: COC(=O)Nc1ccc(Cl)c(O)c1F
Reactant: Cc1ccc(S(=O)(=O)OC2CCCCC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1cc(OC2CCCCC2)c(Cl)cc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 25.6 %

Procedure:
Methyl N-(2-fluoro-4-chloro-hydroxyphenyl)carbamate (2.03 g, 9.23 mmol), cyclohexyl p-toluenesulfonate (2.51 g, 9.85 mmol) and N,N-dimethylformamide (30 ml) were charged into a 100 cc round-bottom flask, and then potassium hydroxide (1.0 g, 17.8 mmol) in a powder form was added thereto. The mixture was stirred for 4 hours on an oil bath at 80° C. After completion of the reaction, the reaction solution was cooled to room temperature, 1N hydrochloric acid (100 ml) was added thereto, and the mixture was extracted with ethyl acetate (20 ml×8). The organic layers were combined, washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product. The product was isolated and purified by silica gel column chromatography (development solvent: hexane/ethyl acetate=9/1) to obtain 2-fluoro-4-chloro-5-cyclohexyloxyaniline (574 mg, 2.36 mmol, 26% yield) and the unreacted starting material, methyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate (1.22 g, 5.54 mmol, 60% recovery ratio). The spectral data and the like are as shown in Reference Example 11.