Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(/[CH:4]=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.[CH2:18]([N:25]([CH2:31]O)[CH2:26][Si](C)(C)C)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH2:18]([N:25]1[CH2:31][C@@H:4]([CH:1]2[CH2:3][CH2:2]2)[C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)/C=C/C1CC1
Reactant: C[Si](C)(C)CN(CO)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C1CC1
Yield: 56 %

Procedure:
To a stirred solution of ethyl (2E)-3-cyclopropylacrylate (5.3 g, 37.9 mmol) and TFA (0.43 g, 3.79 mmol) in DCM (100 mL) was added dropwise {benzyl[(trimethylsilyl)methyl]amino}methanol (13.5 g, 56.8 mmol) at 0° C. After the addition, the mixture was refluxed overnight. TLC (petroleum ether: EtOAc 10:1) indicated most of ethyl (2E)-3-cyclopropylacrylate was consumed. The reaction mixture was quenched with sat. NaHCO3 (100 mL), brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether: EtOAc=50:1 to 30:1) to give the title compound (5.8 g, 54% yield) as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][S:18][CH2:17][C@H:16]1[C:21]([OH:23])=[O:22])=[O:14])([CH3:11])(C)C.C([O-])(O)=O.[Na+].C(Cl)(OCC1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)=O>C(Cl)Cl.O1CCOCC1>[CH:44]1[C:45]2[CH:11]([CH2:8][O:12][C:13]([N:15]3[CH2:20][CH2:19][S:18][CH2:17][C@H:16]3[C:21]([OH:23])=[O:22])=[O:14])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]=2[CH:41]=[CH:42][CH:43]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCSC[C@H]1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CSCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
Trifluoroacetic acid (4 mL, 23.5 mmol) was added to a stirred solution of (R)-4-(tert-butoxy carbonyl)thiomorpholine-3-carboxylic acid (1.0 g, 4.05 mmol) in CH2Cl2 (20 mL), and the reaction mixture was stirred at room temperature for 2 h. Volatile byproducts were removed at reduced pressure and the residue was concentrated from toluene (2×20 mL) and dried under high vacuum for 30 min. The crude residue was dissolved in 1,4-dioxane (10 mL) and water (10 mL) was added followed by NaHCO3 (1.02 g, 12.15 mmol) and a solution of FMOC-Cl (1.04 g, 4.05 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to remove volatile organic solvent and the residue was washed with MTBE (2×20 mL). The aqueous layer was acidified with 1N aqueous HCl to pH 2 and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reverse phase column chromatography (C18; eluent: 10-100% acetonitrile/water) to afford the title compound (1.00 g) as a white semi-solid.
Reaction SMILES: N1C=CC=CC=1C1C=CC=CN=1.Cl[C:14]1[C:15]([C:23]([OH:25])=[O:24])=[N:16][C:17]([Cl:22])=[C:18]([Cl:21])[C:19]=1[Cl:20]>[Zn].C(#N)C>[Cl:20][C:19]1[C:18]([Cl:21])=[C:17]([Cl:22])[N:16]=[C:15]([C:23]([OH:25])=[O:24])[CH:14]=1
Reactant: O=C(O)c1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: [Zn]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CC#N
Product: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Reaction time: 0.08 h

Procedure:
An 8 mL scintillation vial was charged with NiCl2.6H2O (12.5 mg, 0.053 mmol) and 2,2′-bipyridine (18.2 mg, 0.117 mmol). The vial was closed and purged with nitrogen for 5 min, after which the vial was charged with DMF (4.5 mL) and methyl alcohol (CH3OH; 0.5 mL). The mixture was allowed to stir for 5 min. To the vial was added zinc dust (0.225 g, 3.4 mmol), and the mixture was allowed to stir under nitrogen for 35 min. Solid 3,4,5,6-tetrachloropicolinic acid (0.110 g, 0.4 mmol) was added through the top of the reactor. The reaction mixture was allowed to stir at 14° C. and samples were removed periodically to determine reaction kinetics. The samples (˜0.01 mL of reaction mixture diluted to 1.5 mL with acetonitrile) were analyzed by a calibrated HPLC method.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.CCCCCC.C([Li])CCC.[C:17]1([CH2:23][C:24](=O)[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:25]([C:24]([CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:2]1[CH:1]=[CH:5][CH:4]=[CH:3]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C1=CCC=C1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C1=CC(=C(Cc2ccccc2)Cc2ccccc2)C=C1
Yield: 12.1 %

Procedure:
Under a nitrogen atmosphere, a 500-mL three-necked flask was charged with 8.0 g (121.0 mmol) of cyclopentadiene and 100 mL of dehydrated THF, and the mixture was stirred. This mixture solution was cooled in an ice bath, and 80 mL (125.6 mmol) of a 1.57 mol/L hexane solution of n-butyllithium was added. Thereafter, the mixture was stirred at room temperature for 3 hours. The thus obtained white slurry was cooled in an ice bath, and then a solution prepared by dissolving 25.0 g (118.0 mmol) of 1,3-diphenyl-2-propanone in 50 mL of dehydrated THF was added. Subsequently, the mixture was stirred at room temperature for 12 hours. The resulting yellow solution was quenched with a saturated aqueous solution of NH4Cl. The soluble fraction was extracted with 100 mL of hexane, and this organic phase was washed with water and saturated brine, and then dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography to give a target product as a yellow solid (yield 3.7 g (12%)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.C([BH3-])#[N:18].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:18])[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](c1ccc(Br)cc1)N1CCC(=O)CC1
Reactant: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](c1ccc(Br)cc1)N1CCC(N)CC1
Yield: 106.5 %

Procedure:
Prepared following the general method of Example 370 step (i) (R)-1-[1-(4-bromophenyl)ethyl]-4-piperidinone (420 mg) ammonium acetate (0.80 g) and sodium cyanoborohydride (120 mg) to give the subtitle compound (449 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH2:22][CH2:21][CH2:20][Cl:19])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(Cl)ccc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C1COc2cc(Cl)ccc2N1CCCCl
Yield: 79.2 %

Procedure:
7-Chloro-4H-benzo[1,4]oxazin-3-one (81MF2271a) (1.74 g, 9.47 mmol), Cs2CO3 (4.63 g, 14.2 mmol) and 3-chloro-1-iodopropane (2.13 g, 10.4 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF2271b) (1.95 g, 79%). 1H NMR (CDCl3) d 7.03-6.96 (m, 3H), 4.59 (s, 2H), 4.07 (t, J=7.2 Hz, 2H), 3.61 (t, J=6.4 Hz, 2H), 2.17-2.10 (m, 2H); 13C NMR (CDCl3) d 164.0, 146.0, 129.1, 127.3, 123.0, 117.8, 115.5, 67.7, 42.4, 39.2, 30.0.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1B(O)O.Br[C:15]1[CH:16]=[C:17]([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH3:28])[CH:18]=[N:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:15]1[CH:16]=[C:17]([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH3:28])[CH:18]=[N:19][CH:20]=1
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Reactant: Cn1c(B(O)O)cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1cncc(-c2cc3ccccc3n2C)c1

Procedure:
To a solution of the compound from step 36a and 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (270 mg, 1.0 mmol) in toluene (5.0 mL) was added Pd(0) (25 mg) and Na2CO3 (1 mL of a 2 M solution), and the mixture was heated at reflux for 60 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel to afford 105 mg of the title compound. MS (CI/NH3) m/z 322 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.80 (m, 3H), 2.05 (m, 1H), 2.32 (m, 1H), 2.50 (s, 3H), 2.70 (m, 1H), 3.13 (m, 1H), 3.78 (s, 3H), 4.04 (m, 2H), 6.62 (s, 1H), 7.18 (m, 2H), 7.35 (m, 2H), 7.66 (m, 1H), 8.38 (m, 2H).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]=2[C:4](O)=[N:3][CH:2]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>C[Si](C)(C)N[Si](C)(C)C>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][NH:24][C:4]2[C:5]3[CH:10]=[N:9][CH:8]=[CH:7][C:6]=3[N:1]=[CH:2][N:3]=2)=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Oc1ncnc2ccncc12
Reactant: CC(C)(C)c1ccc(CCN)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: CC(C)(C)c1ccc(CCNc2ncnc3ccncc23)cc1

Procedure:
A mixture consisting of 0.45 g of pyrido[4,3-d]pyrimidine-4-ol, 0.53 g of 2-[4-(t-butyl)phenyl]ethylamine, about 40 mg of (NH4)2SO4 in 4 mL of hexamethyldisilazane was refluxed for about five hours. The mixture was then cooled and excess disilazane was removed in vacuo. The residue was dissolved in CH2Cl2, and the solution was washed with water and filtered through phase separating paper. Evaporated the CH2Cl2 and adsorbed the residue onto silica gel, which was applied to a thin silica pad and eluted with CH2Cl2 →50% EtOAc/50% CH2Cl2 →EtOAc. Fractions containing the major product were combined and the product which crystallized was recrystallized from hexane/EtOAc. Yield 0.2 g. M.P. 157°-158° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:37])=[N:14][C:15]2[N:16]([N:29]=[C:30]([C:32]([O:34]CC)=[O:33])[CH:31]=2)[C:17]=1[C:18]1[C:27]([F:28])=[CH:26][C:21]2[O:22][CH2:23][CH2:24][NH:25][C:20]=2[CH:19]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:37])=[N:14][C:15]2[N:16]([N:29]=[C:30]([C:32]([OH:34])=[O:33])[CH:31]=2)[C:17]=1[C:18]1[C:27]([F:28])=[CH:26][C:21]2[O:22][CH2:23][CH2:24][NH:25][C:20]=2[CH:19]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(-c3cc4c(cc3F)OCCN4)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1-c1cc2c(cc1F)OCCN2
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
To a solution of ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (130 mg, 0.253 mmol) in EtOH (4 mL) was added 1N NaOH (0.303 mL, 0.303 mmol) and the resulting mixture was stirred at room temp for 4 h. At this point LCMS indicated completion of reaction. The reaction mixture concentrated and the residue diluted with water (3 mL), acidified with 1N HCl, extracted with ethyl acetate (25 mL), washed with brine (10 mL), dried (Na2SO4), filtered and concentrated to afford 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (110 mg, 0.226 mmol, 89% yield) as off-white solid (mixture of mono and diacid and also atrope isomers) which was used as is in the next step without further purification. LCMS (M+H)=487.3.
Reaction SMILES: [C:1]([CH:3]=[C:4]([NH:13][C:14](=O)[O:15]CC)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])#[N:2].[N:19]1([CH2:25][C:26]([NH:28][NH2:29])=O)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(OCC)(=O)C.O>CN1C(=O)CCC1>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:4]1[N:13]=[C:14]([OH:15])[N:29]2[N:28]=[C:26]([CH2:25][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:2]=[C:1]2[CH:3]=1
Reactant: CCOC(=O)NC(=CC#N)c1ccc(Cl)cc1Cl
Reactant: NNC(=O)CN1CCOCC1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Oc1nc(-c2ccc(Cl)cc2Cl)cc2nc(CN3CCOCC3)nn12
Temperature: 160 °C
Reaction time: 3 h

Procedure:
1.33 g (4.7 mmol) of ethyl [2-cyano-1-(2,4-dichlorophenyl)ethenyl]carbamate (Example 128A) and 740 mg (4.7 mmol) of 2-morpholin-4-ylacetohydrazide are dissolved in NMP (6 ml) and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 160° C. for 3 h. The reaction mixture is cooled to RT and ethyl acetate (100 ml) and water (50 ml) are added. The organic phase is separated off, dried with magnesium sulphate and concentrated. The residue is chromatographed on silica gel (mobile phase dichloromethane/methanol 100:1 to 50:1). 1.25 g (70% of theory) of the product are obtained.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH:10]([P:18]([CH:23]([NH:31]C(OC(C)(C)C)=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:22])[O:19][CH2:20][CH3:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C>CO>[ClH:1].[NH2:31][CH:23]([P:18]([CH:10]([NH2:9])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:22])[O:19][CH2:20][CH3:21])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOP(=O)(C(Cc1ccccc1)NC(=O)OC(C)(C)C)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCOP(=O)(C(N)Cc1ccccc1)C(N)Cc1ccccc1
Reaction time: 3 h
Yield: 97 %

Procedure:
An about 3N methanolic hydrochloric acid (10 ml) is added at room temperature with stirring to a solution of the bisalkylated phosphinic acid ester 10 (103 mg, 0.19 mol) in methanol (5 ml). After 3 hours, the reaction solution is concentrated under reduced pressure. The phosphinic acid ester hydrochloride 15 (69 mg, 97% of theory) is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.FC(F)(F)S(O[C:16]1[CH:29]=[C:28]2[C:19]([O:20][C:21]3[C:22]([F:42])=[CH:23][C:24]([C:36]4[CH2:37][O:38][CH2:39][CH2:40][CH:41]=4)=[CH:25][C:26]=3[C@:27]32[N:34]=[C:33]([NH2:35])[CH2:32][O:31][CH2:30]3)=[CH:18][CH:17]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:38]1[CH2:39][CH2:40][CH:41]=[C:36]([C:24]2[CH:23]=[C:22]([F:42])[C:21]3[O:20][C:19]4[C:28](=[CH:29][C:16]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)=[CH:17][CH:18]=4)[C@:27]4([N:34]=[C:33]([NH2:35])[CH2:32][O:31][CH2:30]4)[C:26]=3[CH:25]=2)[CH2:37]1
Reactant: NC1=N[C@@]2(COC1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1c(F)cc(C3=CCCOC3)cc12
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3)ccc1Oc1c(F)cc(C3=CCCOC3)cc12
Temperature: 85 °C
Yield: 57.7 %

Procedure:
In a microwave vial, the pyridin-3-ylboronic acid (0.061 g, 0.495 mmol), (S)-5-amino-2′-(5,6-dihydro-2H-pyran-3-yl)-4′-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-7′-yl trifluoromethanesulfonate (0.196 g, 0.381 mmol), and Pd(PPh3)4 (0.044 g, 0.038 mmol) were suspended in dmf (4.1 mL). Aqueous sodium carbonate (1.0 M, 1.143 mL, 1.143 mmol) was added. Argon was blown through the vessel, which was sealed and heated in an 85° C. oil bath (11:40). After 1.5 h the reaction was concentrated. The residue was taken up in EtOAc (100 mL) and the organic layer was extracted with water (15 mL), brine (, then was dried over sodium sulfate and concentrated. The residue was purified by chromatography (7.5% MeOH/DCM) to afford (S)-2′-(5,6-dihydro-2H-pyran-3-yl)-4′-fluoro-7′-(pyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (99 mg, 0.22 mmol). MS (m/z) 444 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm; 8.85 (s, 1H), 8.57 (d, 1H, J=4.5 Hz), 7.86 (d, 1H, J=8.0 Hz), 7.50 (m, 2H), 7.36 (m, 2H), 7.08 (dd, 1H, J=11.7, 2.0 Hz), 6.99 (s, 1H), 6.17 (s, 1H), 4.46 (m, 2H), 4.33 (s, 2H), 3.85 (t, 2H, J=5.7 Hz), 3.57 (m, 2H), 2.33 (m, 2H).
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]([CH:8]1[CH2:10][CH:9]1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[N:13]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:12]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:28]1([CH3:31])[CH:27]=[CH:26][C:25]([S:22]([N:13]2[C:14]3[C:19](=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=3)[C:11]([CH:9]3[CH2:10][CH:8]3[CH:6]=[CH2:1])=[CH:12]2)(=[O:23])=[O:24])=[CH:30][CH:29]=1
Reactant: [Li]CCCC
Reactant: Cc1ccc(S(=O)(=O)n2cc(C3CC3C=O)c3cc(C#N)ccc32)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC1CC1c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccc(C#N)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Butyl lithium (1.4 ml of 2.4M in hexane, 3.36 mmol) was added drop wise over a five min period under a nitrogen atmosphere to a stirred solution of methyltriphenylphosphonium bromide (1.186 g, 3.32 mmol) in dry THF (25 ml). The solution was stirred for 30 min at ambient temperature and then added dropwise to a solution of 3-(2-formyl-cyclopropyl)-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile (1.10 g, 3.018 mmol) in 25 ml THF. The mixture was stirred for 24 hr, and then quenched with saturated aqueous ammonium acetate (2 ml). The mixture was concentrated in vacuo and then extracted with ethyl acetate (20 ml). The ethyl acetate extract was washed with water (10 ml), then washed with brine (10 ml), dried over sodium sulfate, and concentrated in vacuo. The residue was chromatographed on silica gel using methylene chloride as the eluent to give 1-(toluene-4-sulfonyl)-3-(2-vinyl-cyclopropyl)-1H-indole-5-carbonitrile (755 mg, 71%). 1H NMR (300 MHz, CDCl3): δ8.04 (d, 1H), 7.91 (s, 1H), 7.74 (d, 2H), 7.56 (d, 1H), 7.54 (s, 1H), 7.25 (m, 2H), 5.57 (m, 1H), 5.19 (d, 1H), 5.01 (d, 1H), 2.36 (s, 3H), 1.86 (m, 1H), 1.63 (m, 1H), 1.16(m, 2H). MS m/e 363.16 (MH+).
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([F:33])([F:32])[C:22]2[N:27]=[C:26]([C:28]([O:30]C)=[O:29])[CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH:1]([O:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([F:33])([F:32])[C:22]2[N:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[CH:24][CH:23]=2)[CH2:19][CH2:20]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(C(F)(F)N2CCC(OC(c3ccccc3)c3ccccc3)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(C(F)(F)N2CCC(OC(c3ccccc3)c3ccccc3)CC2)n1
Yield: 83.1 %

Procedure:
Into a 50-mL recovery flask (eggplant flask), 380 mg (0.84 mmol) of methyl 6-[(4-benzhydryloxypiperidin-1-yl)difluoromethyl]pyridine-2-carboxylate synthesized in Production Example 51 was fed and dissolved in 10 mL of ethanol. Thereto, 1.7 mL of a 1-N sodium hydroxide aqueous solution was added, and the reaction was conducted at a room temperature. After the completion of the reaction was confirmed, the contents in the system were concentrated, and the residue was diluted with water. The diluted residue was neutralized with 1-N hydrochloric acid and then extracted with chloroform. The organic layer was washed with water and a saturated saline solution in order and then dried over sodium sulfate. After the solvent was concentrated, the resulting brown oily substance was purified by column chromatography (chloroform/methanol (volume ratio)=3:1) to give the title compound (306 mg (83%)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH:14]=O)[CH:11]=[N:10]2)=[CH:5][CH:4]=1.II.[OH-].[NH4+:19]>O1CCCC1.S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([C:14]#[N:19])[CH:11]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2cc(C=O)cn2)cc1
Reactant: [NH4+]
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-n2cc(C#N)cn2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a mixture of 1-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (80 mg, 0.54 mmol) in tetrahydrofuran (3 mL) and ammonium hydroxide (3 mL) was added iodine (138 mg, 0.54 mmol). The reaction was stirred at room temperature for 5 hours. The reaction was diluted with saturated sodium thiosulphate (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give 1-(4-methoxyphenyl)-1H-pyrazole-4-carbonitrile (78 mg, 100%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.19 (s, 1H), 7.96 (s, 1H), 7.56 (d, J=9.2 Hz, 2H), 7.01 (d, J=9.2 Hz, 2H), 3.86 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][C:6]=1[CH3:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([C:8]([F:9])([F:11])[F:10])=[N:4][N:5]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)[C:6]=1[CH3:7]
Reactant: C1=COCCC1
Reactant: Cc1[nH]nc(C(F)(F)F)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1c(Br)c(C(F)(F)F)nn1C1CCCCO1
Temperature: 0 °C
Yield: 72.1 %

Procedure:
To a solution of 4-bromo-5-methyl-3-trifluoromethyl-1H-pyrazole (1.4 g, 6.2 mmol, 1.0 equiv) in chloroform (31 ml) was added p-toluene sulphonic acid monohydrate (118 mg, 0.62 mmol, 0.1 equiv). The solution was cooled to 0° C. and 3,4-dihydro-2H-pyran (0.85 ml, 9.3 mmol, 1.5 equiv) was added drop-wise over 5 minutes. The mixture was allowed to warm to room temperature for 1 hour and the solvents were removed under reduced pressure. The crude mixture was purified by column chromatography (SiO2), eluting with 0→25% EtOAc-petrol over a linear gradient to afford the title compound 1.4 g (59%), LCMS (PS-A) Rt 3.72 mm [M+H]+ 314.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-])=O.C(OCC)(=O)C>CO.[Pt](=O)=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[N:15]=[CH:14]3)=[N:8][CH:9]=1
Reactant: N#Cc1ccc(-n2ncc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc32)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccc(-n2ncc3cc(Oc4ccc(N)cn4)ccc32)cc1
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of 4-[5-(5-Nitro-pyridin-2-yloxy)-indazol-1-yl]-benzonitrile (0.79 mmol) in 10 mL of methanol was added 10 mL of ethyl acetate and 30 mg of platinum (IV) oxide. After shaking under 50 psi of H2 for 3 h, the mixture was filtered through a pad of Celite and concentrated in vacuo, affording 0.25 g of 4-[5-(5-Amino-pyridin-2-yloxy)-indazol-1-yl]-benzonitrile.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31][O:32][CH2:33][CH2:34][OH:35])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:36]1[CH:40]=[CH:39][C:38]([C:41](O)=[O:42])=[CH:37]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:16]=[CH:17][N:18]=[C:19]([CH2:31][O:32][CH2:33][CH2:34][O:35][C:41]([C:38]3[CH:39]=[CH:40][O:36][CH:37]=3)=[O:42])[C:20]=2[O:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[Cl:30])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccoc1
Reactant: COc1ccc(Cl)c(Oc2c(COCCO)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: COc1ccc(Cl)c(Oc2c(COCCOC(=O)c3ccoc3)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
By reacting 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy-methyl)-pyrimidin-4-yl]-benzenesulphonamide with 3-furancarboxylic acid there was obtained furan-3-carboxylic acid 2-[6-(4-tert-butyl-phenylsulfonylamino)-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-ylmethoxy]-ethylester. MS: (M+H)+=618.