Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[CH:28][C:29]([F:42])=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]([OH:40])=[O:39])=[CH:34][C:33]=5[CH3:41])[CH:31]=4)=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:47])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:51][C:52]1([F:56])[CH2:55][NH:54][CH2:53]1.CCN(CC)CC>C1COCC1>[F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[CH:28][C:29]([F:42])=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]([OH:40])=[O:39])=[CH:34][C:33]=5[CH3:41])[CH:31]=4)=[CH:24][N:23]=[C:22]([N:54]4[CH2:55][C:52]([F:56])([F:51])[CH2:53]4)[N:21]=3)[C@H:14]2[CH3:47])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC1(F)CNC1
Reactant: Cc1cc(C(=O)O)ccc1-c1cc(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)ccc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)O)ccc1-c1cc(-c2cnc(N3CC(F)(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)ccc1F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of the title compound from Step D (22 mg, 0.031 mmol), 3,3-difluoro-azetidine hydrochloride (20 mg, 0.155 mmol) and Et3N (31.3 mg, 0.309 mmol) in THF (5 mL) was stirred at 60° C. overnight. The solvent was removed. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.1% TFA, to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz) δ 8.34 (s, 1H), 8.08 (s, 1H), 8.02 (d, J=8 Hz, 1H), 7.93 (s, 1H), 7.77 (s, 2H), 7.17-7.42 (m, 4H), 5.72 (d, J=8.0 Hz, 1H), 4.90 (d, J=17 Hz, 1H), 4.55 (m, 4H), 4.40 (m, 1H), 4.08 (d, J=17 Hz, 1H), 2.35 (s, 3H), 0.77 (d, J=7 Hz, 3H). LCMS=725.3 (M+H)+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]#[CH:9].CN(C)C=O.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1[OH:26])[CH:22]([CH2:27][CH2:28][NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH2:21][CH2:20]2>O>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1[O:26][CH2:9][C:8]#[CH:7])[CH:22]([CH2:27][CH2:28][NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH2:21][CH2:20]2
Reactant: CCC(=O)NCCC1CCc2cc(F)c(O)cc21
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc2c(cc1F)CCC2CCNC(=O)CC
Temperature: 120 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
Potassium carbonate (1.37 g, 9.95 mmols) and propargyl bromide (2.4 g, 19.9 mmols) were added to a dimethylformamide (10 ml) solution of N-[2-(5-fluoro-6-hydroxyindan-1-yl)ethyl]propionamide (0.5 g, 1.99 mmols) and stirred at 120° C. for 2 hours. The reaction solution was poured into water, and the organic substance was extracted out with ethyl acetate. The extract was washed with a saturated saline solution and water and then dried with anhydrous magnesium sulfate, and the solvent was removed through distillation under reduced pressure. The resulting residue was purified through silica-gel column chromatography (ethyl acetate) to obtain 0.56 g (yield: 97%) of the target compound.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.CCCCCC.[CH3:18][O:19][B:20](OC)[O:21][CH3:22]>C1COCC1>[CH3:18][O:19][B:20]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[O:21][CH3:22]
Reactant: COB(OC)OC
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COB(C#C[Si](C)(C)C)OC
Reaction time: 0.25 h

Procedure:
A solution of trimethylsilylacetylene (0.51 mL) in THF (4 mL) was cooled to −78° C. under argon, and then a solution of n-BuLi in n-hexane (1.6 M, 2.25 mL, 3.6 mmol) was added via syringe. The resulting mixture was stirred at the same temperature for 15 min, then trimethylborate (0.4 mL, 3.6 mmol) was added. The cooling bath was removed, and the mixture was stirred at room temperature for 15 min to give a solution of the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6][O:7][C:8]2(C)C)[CH2:3]1.[CH:12](OC)(OC)[O:13]C>>[O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6][O:7][CH:8]2[O:13][CH3:12])[CH2:3]1
Reactant: COC(OC)OC
Reactant: CC1(C)OCCC2CC(=O)N21
Product: COC1OCCC2CC(=O)N21

Procedure:
Following the procedure described for the preparation of 8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane from 4-(2'.hydroxyethyl)-2-azetidinone and using trimethyl orthoformate instead of 2,2-dimethoxypropane one obtains 8-oxo-2-methoxy-3-oxa-1-azabicyclo[4.2.0]octane.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.[CH3:46][C@@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH2:46][C@H:47]([OH:48])[CH3:49])[CH2:31][CH2:32]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:34])=[O:35])[CH:13]=2)[CH:9]=[N:8]1
Reactant: C[C@@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@@H](C)O)CC5)cc4)cnc32)cc1
Yield: 64.9 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (step 1 example 103) (150 mg. 0.606 mmol) was alkylated using (R)-2-methyloxirane (22 mg, 0.371 mmol), DIPEA (96 mg, 0.74 mmol) and ethanol (3 mL) to get 160 mg (97.5% yield) of the titled compound. MS: m/z=665.3 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:44][CH:43]=1)[C:19]([N:21]([CH2:31][C:32]1[C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=2[S:35][CH:36]=1)[C@@H:22]([CH3:30])[CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[O:20]>>[S:35]1[CH:36]=[C:32]([CH2:31][N:21]([C@@H:22]([CH3:30])[CH:23]([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[C:19](=[O:20])[C@@H:18]([NH:17][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16])[CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[CH:46][CH:47]=2)[C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: O=C(O)CONC(=O)NCc1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-benzylureidooxy)acetic acid (Compound VI-1) 66 mg (0.29 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-6) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6]2([C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:5][CH2:4]1.[Cl:22]N1C(=O)CCC1=O>ClCCl>[ClH:22].[Cl:1][C:11]1[CH:12]=[CH:13][C:14]2[O:15][C:16]3[C:21]([C:6]4([CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]4)[C:9]=2[CH:10]=1)=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3
Reactant: CN1CCC2(CC1)c1ccccc1Oc1ccccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: ClCCl
Product: CN1CCC2(CC1)c1cc(Cl)ccc1Oc1ccc(Cl)cc12

Procedure:
A mixture of 1'-methylxanthene-9-spiro-4'-piperidine hydrochloride (5 g.), N-chlorosuccinimide (4.5 g.) and dichloromethane (100 ml.) is refluxed for 72 hours. The solution is washed with saturated sodium bicarbonate solution then water and dried with MgSO4. The solution is evaporated to give a gummy residue which is chromatographed on grade 3 aluminium oxide, Woelm basic. The product is eluted with 30% petroleum-ether (b.p. 60°-80° C.)/chloroform, taken up in ether and the solution treated with ethereal hydrochloric acid. The precipitate is filtered and recrystallised from ethanol-ether to give 2,7-dichloro-1'-methylxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 285° C.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]>C1(C)C=CC=CC=1>[CH3:15][O:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][CH:18]=[C:9]([O:8][S:2]([NH2:5])(=[O:3])=[O:4])[CH:10]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)c1cccc(O)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(OS(N)(=O)=O)c1

Procedure:
Following the procedure of Example 78, a reaction of 8.8 ml (0.10 mole) chlorosulfonyl isocyanate and 15.2 g (0.10 mole) of methyl 3-hydroxybenzoate in 200 ml of toluene was heated at reflux for 7.5 hr and worked up to obtain 10.53 g, mp 145°-146° C.
Reaction SMILES: [CH2:1]([C:3]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:21][CH3:22]>>[CH2:21]([O:11][C:10]1[C:3]([CH2:1][CH3:2])=[C:4]([C:7]([CH2:12][CH3:13])=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH3:22]
Reactant: CCc1ccc(O)c(CC)c1C=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1ccc(CC)c(C=O)c1CC

Procedure:
3-Ethoxy-2,6-diethyl-benzaldehyde was prepared from 2,6-diethyl-3-hydroxy-benzaldehyde, cesium carbonate and iodoethane in analogy to Example 213b): yellow oil; 1H-NMR (CDCl3): 1.21 (3H, t, CH3), 1.23 (3H, t, CH3), 1.43 (3H, t, CH3), 2.86 (2H, q, CH2), 2.96 (2H, q, CH2), 4.04 (2H, q, OCH2), 6.96 (1H, d, ArH), 7.05 (1H, d, ArH), 10.57 (1H, s, CH═O).
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)[CH2:2][CH:3]=C.[BH4-].[Na+].C[OH:19]>C(Cl)Cl>[C:10]1([C:7]2[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][OH:19])[NH:9][N:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CO
Reactant: C=CCCc1cc(-c2ccccc2)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: OCCCc1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(But-3-enyl)-3-phenyl-1H-pyrazole (5.4 g, 27.2 mmol) was dissolved in MeOH (40 mL) and DCM (10 mL). The reaction was cooled on a dry-ice/acetone bath and ozone was bubbled through the solution for 2 h. The reaction was transferred into an ice bath and NaBH4 (1.546 g, 40.9 mmol) was added slowly portion-wise (bubbling was observed). Upon complete addition, the reaction was removed from the ice bath and stirred at room temperature for 1 h. Excess solvent was evaporated and the reaction was extracted (100 mL each of H2O and EtOAc). The aqueous layer was extracted again with EtOAc (100 mL). The combined organic layer was dried, concentrated, and the residue was purified by column chromatography to yield the title compound (3.0 g) as a white solid. LCMS m/z=203.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72-1.82 (m, 2H), 2.54-2.69 (m, 2H), 3.46 (q, J=6.11 Hz, 2H), 4.40-4.54 (m, 1H), 6.45 (s, 1H), 7.21-7.45 (m, 3H), 7.66-7.79 (m, J=7.45 Hz, 2H), 12.53 (s, 1H).
Reaction SMILES: [CH2:1]1[C:14]2[CH:5]([NH:6][CH:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH2:8]3)[CH:4]([C:15]([NH2:17])=O)[CH2:3][CH2:2]1.S.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20]>N1C=CC=CC=1>[CH2:1]1[C:14]2[CH:5]([NH:6][CH:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH2:8]3)[CH:4]([C:15](=[S:20])[NH2:17])[CH2:3][CH2:2]1
Reactant: NC(=O)C1CCCC2=CC3=CC=CCC3NC21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Solvent: c1ccncc1
Product: NC(=S)C1CCCC2=CC3=CC=CCC3NC21

Procedure:
A solution of sym. octahydroacridine-4-carboxamide (1.8 gm.) in pyridine (17 ml.) was treated with hydrogen sulphide for 5 mins. The reaction mixture was treated with phosphorus pentasulphide (1.4 g.) and heated at reflux for 45 mins maintaining a slow stream of hydrogen sulphide throughout. The cooled reaction mixture was evaporated and the residue treated with 10% sodium hydroxide until alkaline. The aqueous solution was extracted with chloroform (3 × 50 ml.) and the combined extracts washed with brine, dried and evaporated and the residual solid recrystallised from di-isopropyl ether giving the title compound as a pale yellow powder (0.3 g. 16%) m.p. 104-6° (solidifies and remelts at 148°). (Found: C, 68.69; H, 7.54; N, 10.98%. C14H18N2S requires: C, 68.26; H, 7.36; N, 11.37%).
Reaction SMILES: [CH2:1](I)[CH3:2].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9](=[CH2:13])[C:10]([OH:12])=[O:11].C(N(C(C)C)CC)(C)C>C(#N)C>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9](=[CH2:13])[C:10]([O:12][CH2:1][CH3:2])=[O:11]
Reactant: C=C(C(=O)O)c1ccco1
Reactant: CCI
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C(=O)OCC)c1ccco1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Ethyl iodide (64 mL, 0.796 mol) was added to furylacrylic acid (100 g, 0.724 mol), diisopropylethyl amine (140 mL, 0.796 mmol), in acetonitrile (1100 mL), and the mixture was heated to 60° C. After 18 h, the dark solution was cooled to room temperature and concentrated in vacuo. The resulting brown sludge was diluted with Et2O (500 mL), washed with 1 N aqueous HCl (2×250 mL), washed with 0.2 N aqueous NaOH (2×250 mL), washed with saturated aqueous NaH.CO3 (1×250 ML), dried (MgSO4), filtered, and concentrated to a black oil (114 g, 95%). 1H NMR (DMSO-d6, 300 MHz) δ 7.84 (d, J=1.7 Hz, 1H), 7.46 (d, J=15.6 Hz, 1H), 6.97 (d, J=3.4 Hz, 1H), 6.33 (dd, J=3.4 Hz, J=1.7 Hz, 1H), 6.22 (d, J=15.9 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H); MS (APCI) m/z 167 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Cl:18][S:19](O)(=[O:21])=[O:20]>ClCCl>[F:17][C:2]([F:1])([F:16])[C:3]([N:5]1[CH2:6][CH2:7][C:8]2[CH:15]=[CH:14][C:13]([S:19]([Cl:18])(=[O:21])=[O:20])=[CH:12][C:9]=2[CH2:10][CH2:11]1)=[O:4]
Reactant: O=C(N1CCc2ccccc2CC1)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2CC1)C(F)(F)F
Reaction time: 18 h
Yield: 84.1 %

Procedure:
A solution of 3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine (see WO02/40471) (20 g, 80 mmol) in dichloromethane (50 mL) was added dropwise to a solution of chlorosulfonic acid (33 mL, 240 mmol) in more dichloromethane (200 mL) at 0° C. The resulting solution was stirred for 18 h without cooling then poured onto ice (250 g). The resulting organic layer was washed with brine (100 mL), dried (MgSO4), and evaporated to give the subtitle compound as a white solid (23 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[BrH:9].[NH+]1C=CC=CC=1>C(O)(=O)C>[Br:9][C:5]1[O:1][CH:2]=[C:3]([C:6]([OH:8])=[O:7])[CH:4]=1
Reactant: O=C(O)c1ccoc1
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(O)c1coc(Br)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 21 %

Procedure:
Furan-3-carboxylic acid (1 g, 8.93 mmol) is added to a solution of pyridinium hydrobromide perbromide (3.02 g, 9.46 mmol) in acetic acid (5 mL). The reaction mixture is stirred at 50° C. for 5 hours, then at room temperature overnight. After removing the solvent in vacuo, water is added and a precipitate is formed. The solid is collected by filtration and dried to yield the title compound (0.364 g, 21%). HPLC (254 nm): Rt 2.65 min (88%).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH2:13][C:12]([C:15]3[C:20]([F:21])=[CH:19][C:18]([N:22]4[CH2:26][C@H:25]([CH2:27][OH:28])[O:24][C:23]4=[O:29])=[CH:17][C:16]=3[F:30])=[CH:11][CH2:10]2)=[O:8])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1([CH3:31])[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH2:13][C:12]([C:15]3[C:16]([F:30])=[CH:17][C:18]([N:22]4[CH2:26][C@H:25]([CH2:27][O:28][S:40]([CH3:39])(=[O:42])=[O:41])[O:24][C:23]4=[O:29])=[CH:19][C:20]=3[F:21])=[CH:11][CH2:10]2)=[O:8])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](C(=O)N2CC=C(c3c(F)cc(N4C[C@H](CO)OC4=O)cc3F)CC2)O1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@@H](C(=O)N2CC=C(c3c(F)cc(N4C[C@H](COS(C)(=O)=O)OC4=O)cc3F)CC2)O1
Reaction time: 2 h
Yield: 93 %

Procedure:
3-(4-(1-(2,2-Dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4yl)-3,5-difluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one (2.19 g, 5 mM) was dissolved in dry dichloromethane (40 ml) under nitrogen at 0°, and treated with triethylamine (0.81 g, 8 mM). Methanesulfonyl chloride (0.687 g, 6 mM) was added, and stirring continued for 2 hours, allowing the temperature to rise to ambient. Aqueous sodium bicarbonate (5%, 20 ml) was added, and stirring continued for 10 minutes. The organic phase was separated, dried (magnesium sulfate), filtered, and evaporated to dryness. The resulting gum was triturated with diethyl ether (50 ml) and solid filtered to give the title compound (2.4 g). NMR (DMSO-d6) δ: 1.30 (s, 3H); 1.33 (s, 3H); 2.30 (br, 1H); 2.39 (br, 1H); 3.26 (s, 3H); 3.67 (t overlapping m, 2H); 3.82 (dd, 1H); 4.01-4.31 (complex overlapping m, 5H); 4.45 (dd, 1H); 4.51 (dd, 1H); 4.90 (dd, 1H); 5.03 (m, 1H); 5.87 (s, 1H); 7.35 (d, 2H). MS (ESP): 517 (MH+) for C22H26F2N2O8S
Reaction SMILES: C(O)=O.[C:4](OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>C(Cl)Cl>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([NH:11][CH3:4])=[CH:13][CH:14]=1)#[N:17]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(N)cc1
Solvent: O=CO
Solvent: ClCCl
Product: CNc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of formic acid 30 mL and acetic anhydride 30 mL stirred at room temperature for 1 h was added a solution of 4-aminobenzonitrile 2.36 g (20.0 mmol) in CH2Cl2 150 mL dropwise at 0° C. The reaction mixture was stirred at room temperature for 4 h (EMI-mass: 146 [M]+). After concentration, the crude intermediate was dissolved in THF 50 mL, and was added BH3 in Me2S 15 mL. The reaction mixture was then stirred for 5 h under reflux. The crude product was extracted with EtOAc, washed with water, sat. Na2CO3 aqueous solution and dried on anhydrous MgSO4. After removal of solvents, 4-cyano-N-methylaniline was obtained in 80% purity based on GC/MS (EMI-mass: 132 [M]+). A mixture of crude 4-cyano-N-methylaniline 0.40 g (ca. 2 mmol) and 4-chloro-2-methylquinazoline 0.357 g (2.0 mmol) with NaOAc 0.2 g (2.3 mmol) in THF 20 mL and H2O 12 mL was stirred at 23° C. for 4 days. After removing solvents, the crude product was purified with preparative HPLC to give the titled compound in 1% yield (10 mg). 1H NMR (CD3OD, 400 MHz): δ 7.94 (d, 2H, J=8.8 Hz), 7.91-7.86 (m, 1H), 7.76-7.73 (m, 1H), 7.65 (d, 2H, J=8.8 Hz), 7.34-7.30 (m, 1H), 6.99-6.96 (m, 1H), 3.87 (s, 3H), 2.81 (s, 3H). m/e: 275.1420 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2ccccc2nc1-c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2ccccc2nc1-c1ccccc1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
A mixture of 2-methyl-3-phenylquinoxaline (2.00 g, 9.08 mmol), NBS (1.45 g, 8.17 mmol) and benzoyl peroxide (catalytic amount) in carbon tetrachloride (75 mL) was heated at reflux for 5 h, then allowed to cool to r.t. The reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue purified by column chromatography (SiO2, 0-20% EtOAc in heptane) to give the title compound (1.22 g, 45%) as a cream-coloured solid. δH (CDCl3) 8.11-8.19 (m, 2H), 7.75-7.85 (m, 4H), 7.52-7.62 (m, 3H), 4.76 (s, 2H). LCMS (ES+) 299.1, 301.1 (M+H)+, RT 4.10 minutes (Method 3).
Reaction SMILES: FC(F)(F)C1C=CC(N2C3C(=CC=CC=3)C([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=N2)=CC=1.C1([N:32]=[C:33]=[O:34])C=CC=CC=1>C1(C)C=CC=CC=1>[N:21]1([C:33]([NH2:32])=[O:34])[CH2:20][CH2:19][CH2:18][CH2:23][CH2:22]1
Reactant: O=C=Nc1ccccc1
Reactant: FC(F)(F)c1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Solvent: Cc1ccccc1
Product: NC(=O)N1CCCCC1

Procedure:
A stirred mixture of 4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 77 (15 g, 0.041 moles) and 25% H2SO4 (100 ml) was refluxed for 20 hours. The mixture was cooled, poured into H2O, and basified with a 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 13 g (93%) of 1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil. To a stirred suspension of the indazole (4.0 g, 0.012 moles) in toluene (60 ml) was added phenyl isocyanate (1.38 ml, 0.013 moles). The reaction temperature rose to 35° C. and the product precipitated from the solution. The product was collected and recrystallized twice from toluene to yield 3.57 g (66%) of N-phenyl-4-[1-(4-trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamide, m.p. 190°-192° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1.O.[NH2:12][NH2:13].O>C(O)C>[NH:12]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1)[NH2:13]
Reactant: Cc1nc(Cl)ccc1C#N
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1nc(NN)ccc1C#N
Temperature: 80 °C
Yield: 59.9 %

Procedure:
To a suspension of 6-chloro-2-methylnicotinonitrile (6.2 mmol) in 6.2 mL of ethanol, hydrazine monohydrate (9.3 mmol) was added. The resulting mixture was then heated to 80° C. overnight. The mixture was cooled to room temperature and 2 mL of water was added. It was heated to 80° C. again to a clear solution and then allowed to cool down to room temperature and finally in an ice-bath. The solid was collected by filtration, washed with cold 50% ethanol, and dried under vacuum to give 550 mg of the desired solid product. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.41 (s, 3H), 4.41 (s, 2H), 6.60 (br. s., 1H), 7.66 (d, J=8.59 Hz, 1H), 8.47 (s, 1H); ES-MS m/z 149 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([OH:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[N:5]1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=1>CN(C)C(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:9][C:8]2[N:4]([CH3:3])[N:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=2)[N:16]=1
Reactant: Clc1cccc(Cl)n1
Reactant: Cn1nc(C(F)(F)F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1nc(C(F)(F)F)cc1Oc1cccc(Cl)n1
Temperature: 135 °C

Procedure:
1.8 g (71 mmol) of sodium hydride (95 percent) was suspended in 25 ml of N,N-dimethylacetamide. A solution of 12.46 g (67 mmol) of 1-methyl-5-hydroxy-3-(trifluoromethyl)pyrazole (J Heterocycl. Chem. 1990, 27, 243) in 40 ml of N,N-dimethylacetamide was added dropwise over 1 hour at 22° C. The resulting solution was added dropwise over 3 hours, under nitrogen, to a solution of 18.5 g (125 mmol) of 2,6-dichloropyridine in 37.5 ml of N,N-dimethylacetamide, heated to 135° C. After a further 5 hours of reaction time, the mixture was cooled to room temperature, the sodium chloride which had precipitated out was filtered off and the filtrate was concentrated. The residue was taken up with toluene and water and the organic phase was washed with saturated sodium chloride solution and concentrated. The solid residue was distilled under vacuum. The title compound distills at 175° C. under 25 mbar. This gave 12.5 g of crude product in the form of a yellow solid (96 percent pure, GC). This was purified by recrystallization from diisopropyl ether. The yield was 11.55 g (62 percent) of colorless crystals, content (GC): 99.9 percent. Other data concerning the product was: