Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18](F)=[C:19]([O:22][CH2:23][CH3:24])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:26]#[N:27].[CH3:28][O:29][CH2:30][CH2:31][OH:32]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:32][CH2:31][CH2:30][O:29][CH3:28])=[C:19]([O:22][CH2:23][CH3:24])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:26]#[N:27]
Reactant: COCCO
Reactant: CCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Product: CCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1OCCOC

Procedure:
Following the procedure used to prepare Example 17, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-fluoro-3-quinolinecarbonitrile (138 mg, 0.34 mmol) and 2-methoxyethanol provides 105 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-(2-methoxyethoxy)3-quinolinecarbonitrile, mp 215-217° C.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.N([O-])=[O:14].[Na+]>>[F:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2](=[O:14])[S:3][C:4]=2[CH:10]=1
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: O=c1[nH]c2ccc(F)cc2s1
Temperature: 50 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
22.4 g of 2-amino-6-fluorobenzothiazole (pure substance content: 97%) and 191.1 g of 30% hydrochloric acid are introduced into a 750 ml pressure vessel at room temperature. The mixture is subsequently heated for 30 minutes at 50° C. and then cooled to 10° C. Then, 46.7 g of aqueous, 40% sodium nitrite solution are metered in at a uniform rate in the course of 1 hour at 10° C., with vigorous stirring. After metering in has ended, stirring of the reaction mixture is continued for 12 hours at 20° C. Excess nitrite is then removed by adding approximately 12.5 g of 18% aqueous urea solution. The reaction vessel is subsequently sealed, and the reaction mixture is heated for 5 hours at 140°-150° C. (pressure approximately 4-5 bar). After the mixture has cooled to 20° C., the gray, crystalline product is filtered off with suction, washed with a small amount of water and dried at 60° C. to constant weight. 18.9 g of 6-fluorobenzothiazol-2-one with a pure substance content of 97.7% are obtained (corresponding to 85% yield). The product which is redissolved under alkaline conditions has a melting point of 188.4° C.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9]([C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[NH:8][N:7]=1)=[O:11]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of 25.8 g (164 mmol) of 5-nitro-1H-pyrazole-3-carboxylic acid in 250 mL of anhydrous methanol (MeOH) was added dropwise 10.3 mL (141 mmol) of thionyl chloride, and the resulting mixture was heated at reflux overnight, then cooled to rt and concentrated to give 27.6 g (98% yield) of 5-nitro-1H-pyrazole-3-carboxylic acid methyl ester as a solid. 1H NMR (CDCl3) δ 6.08 (s, 1H), 3.91 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][N:33]([CH3:48])[C:34]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:35]=1[CH:36]=[CH:37][CH:38]=[C:39]2[S:44](Cl)(=[O:46])=[O:45]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:44]([C:39]4[C:40]5[C:35](=[C:34]([N:33]([CH3:48])[CH3:32])[CH:43]=[CH:42][CH:41]=5)[CH:36]=[CH:37][CH:38]=4)(=[O:46])=[O:45])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc5c(N(C)C)cccc45)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 5-dimethylamino-1-naphthalenesulfonyl chloride. Purity (ELSD, based on MW=654.8)=90%.
Reaction SMILES: O[C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.[OH-].[K+].Cl.C(OCC)(=O)C.[C:26](#[N:28])[CH3:27]>>[OH:13][C:7]1[C:6]([CH3:14])=[C:5]([CH3:15])[C:4]2[O:3][C:2]([CH3:16])([CH2:27][C:26]#[N:28])[CH2:11][CH2:10][C:9]=2[C:8]=1[CH3:12]
Reactant: CC#N
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(O)O2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC#N)O2

Procedure:
A mixture of 9.0 g (40.5 mmoles) of 2,6-dihydroxy-2,5,7,8-tetramethylchroman and 4.54 g (69 mmoles) of 85% KOH in 61 ml of acetonitrile was rapidly stirred and refluxed for 4 hr. The dark-colored mixture, which consisted of two phases, was cooled in an ice bath and treated dropwise, with stirring, with 25 ml of 3 N aqueous HCl whereupon the reaction mixture became lighter in color. This mixture was poured into 1 N aqueous HCl and worked-up with ethyl acetate in the usual manner (the organic extracts were additionally washed with saturated aqueous NaHCO3 solution) affording 14.8 g of rac.-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetonitrile as a red solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.[C:14]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)(=[S:16])[NH2:15].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[N+:11]([C:7]1[CH:6]=[C:5]([C:3]2[N:15]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:16][CH:2]=2)[CH:10]=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: NC(=S)c1cccnc1
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(-c2csc(-c3cccnc3)n2)c1
Yield: 68.6 %

Procedure:
A mixture of 2-bromo-3′-nitroacetophenone (3.66 g) and 3-thiocarbamoylpyridine (2.07 g) in ethanol (40 ml) was refluxed for 1 hour. The reaction mixture was poured into a mixture of ethyl acetate and an aqueous sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 4-(3-nitrophenyl)-2-(pyridin-3-yl)thiazole (2.91 g).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([OH:23])=O.[Cl:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:27][CH:26]=1.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:31][CH2:32][N:33]([C:21](=[O:23])[CH2:20][N:3]3[CH2:4][CH2:5][CH2:6][C:7]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]3=[O:1])[CH2:34][CH2:35]2)=[CH:27][CH:26]=1
Reactant: Clc1ccc(OC2CCNCC2)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 45 h

Procedure:
To a solution of the product of Example 68E (117 mg, 0.38 mmol), 4-(4-chlorophenoxy)piperidine (80.0 mg, 0.378 mmol), and 4-(dimethylamino)pyridine (4.6 mg, 0.038 mmol) in CH2Cl2 (2 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.067 mL, 0.378 mmol) via syringe. The reaction was stirred at ambient temperature for 45 hours. The reaction mixture was diluted with 50 mL CH2Cl2, then washed with 1 N aqueous HCl, saturated aqueous NaHCO3 solution and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Analogix® Intelliflash™ 280; SF15-24 g column; 50% ethyl acetate/hexanes) which yielded the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.36-7.17 (m, 12H), 6.86-6.80 (m, 2H), 4.55-4.45 (m, 1H), 4.40 (d, J=15.6, 1H), 4.09 (d, J=15.6, 1H), 3.80-3.33 (m, 6H), 2.72-2.57 (m, 2H), 2.00-1.74 (m, 6H); MS (ESI+) m/z 503 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH3:20])[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[CH:12][C:7]=2[CH:6]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.CO>CN1CCCC1=O>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH3:20])[C:8]2[N:9]=[C:10]([NH:31][C:30]3[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cn1c(=O)c(Oc2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cn1c(=O)c(Oc2c(Cl)cccc2Cl)cc2cnc(Nc3ccc(F)cc3)nc21
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 6-(2,6-dichlorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (see Example 12—Step A-B, (replacing methyl 2-fluorophenoxyacetate with methyl 2,6-dichlorophenoxyacetate) 0.35 g, 1 mmol) and 4-fluoroaniline (0.284 mL, 3 mmol) in 0.5 mL 1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and then cooled to room temperature. Methanol (2 mL) was added and the suspension was stirred for 30 minutes. Filtration and washing of the precipitate thoroughly with methanol followed by drying provided the crude product which was purified by column chromatography (SiO2, CH2Cl2/MeOH—95/5). The column fractions were combined and concentrated under reduced pressure to provide the free amine. This was suspended in ethyl acetate (1-2 mL) and hydrochloric acid in ether (1M, 1.2 eq) was added. Isolation of the solid via filtration and drying provided 0.131 g of the hydrochloride salt (Mass spec. M+1=430, MP=248.2-249.1° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:16][C@H:15]2[N+:17]([O-])=O)=[CH:10][CH:9]=1.Cl.[OH-].[Na+]>CC(O)C.[Zn]>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[CH2:16][C@H:15]2[NH2:17])=[CH:12][CH:13]=1
Reactant: COCCOCOc1ccc([C@@H]2C[C@H]2[N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COCCOCOc1ccc([C@@H]2C[C@H]2N)cc1
Reaction time: 16 h
Yield: 72.6 %

Procedure:
Zn dust (0.99 g, 15.1 mol) was added in small portions, over a period of 20 min, to a vigorously stirred solution of 1-((2-methoxyethoxy)methoxy)-4-((trans)-2-nitrocyclopropyl)benzene (Intermediate K, 0.40 g, 1.51 mmol) in i-PrOH (15 mL) and HCl (5.6 mL of 2.7 N aqueous solution, 15.1 mmol). After 16 h, the mixture was basified with NaOH (10% aqueous solution, 10 mL) and filtered through a pad of celite, that was washed with 10 mL of methanol. The filtrate was concentrated and 15 mL of water were added, extracting with CH2Cl2 (3×15 mL); the organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the crude product was purified by column chromatography on silica gel (2-5% MeOH/CH2Cl2) affording 0.26 g of (trans)-2-(4-((2-methoxyethoxy)methoxy)phenyl)cyclopropanamine [Rf=0.1 (5% MeOH/CH2Cl2), white solid, 73% yield].
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([OH:9])=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.S(Cl)(Cl)=O.[C:20]1([CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=3)[CH2:29][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(NC(C)C)C>C(Cl)Cl.CN(C=O)C>[C:20]1([CH2:26][N:27]2[CH2:28][CH2:29][CH:30]([C:33]3[CH:34]=[CH:35][C:36]([NH:39][C:7]([C:2]4[C:1]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:9])=[CH:37][CH:38]=3)[CH2:31][CH2:32]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ccc(C2CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: O=C(Nc1ccc(C2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccccc1
Yield: 112 %

Procedure:
[1,1′-Biphenyl]-2-carboxylic acid (0.25 mol) was dissolved in DCM (500 ml) and DMF (0.5 ml). Thionyl chloride (0.51 mol) was added dropwise. The mixture was stirred and refluxed for 1 hour under nitrogen flow. The solvent was evaporated. DCM (500 ml) was added twice. The solvent was evaporated twice. The residue was dissolved in DCM (200 ml) and then added dropwise at 0° C. to a mixture of 4-[1-(phenylmethyl)-4-piperidinyl]-benzenamine (0.25 mol) and N-(1-methylethyl)-2-propanamine (0.75 mol) in DCM (800 ml). The mixture was brought to room temperature and then stirred at room temperature overnight under nitrogen flow. The mixture was washed three times with water (800 ml). The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 125 g of N-[4-[1-(phenylmethyl)-4-piperidinyl]phenyl]-[1,1′-biphenyl]-2-carboxamide (intermediate 18).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][CH2:5][C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)([C:8](OCC)=[O:9])[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][CH2:5][C:4]([CH2:8][OH:9])([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:3]1
Reactant: CCOC(=O)C1(N2CCOCC2)CCCC(C)(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCCC(CO)(N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of EXAMPLE 145D (3.7 g) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (720 mg). The cooling bath was removed, and the reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched by the sequential addition of water (0.8 mL) and 15% aqueous NaOH solution (2 mL). The mixture was dried with MgSO4, filtered and concentrated to give the title compound, which was used in the subsequent step without further purification.
Reaction SMILES: Cl.[N:2]1([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:17][C:18]1[CH:19]=[CH:20][C:21]([N+:28]([O-:30])=[O:29])=[C:22]([CH2:24][C:25](O)=[O:26])[CH:23]=1>>[S:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([N:2]2[CH2:7][CH2:6][N:5]([C:25](=[O:26])[CH2:24][C:22]3[CH:23]=[C:18]([F:17])[CH:19]=[CH:20][C:21]=3[N+:28]([O-:30])=[O:29])[CH2:4][CH2:3]2)=[N:9]1
Reactant: O=C(O)Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Product: O=C(Cc1cc(F)ccc1[N+](=O)[O-])N1CCN(c2nsc3ccccc23)CC1
Yield: 50 %

Procedure:
1-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-2-(5-fluoro-2-nitro-phenyl)-ethanone was prepared according to the general method as outlined in Preparation 12 starting from 3-piperazin-1-yl-benzoisothiazole hydrochloride (1.31 g, 5.1 mmol) and (5-fluoro-2-nitro-phenyl)-acetic acid (800 mg, 4.3 mmol). The product was isolated via column chromatography to afford 870 mg of an off white foam. Yield 50%; mp 72° C.; MS (APCI): 401 [M+H]+.
Reaction SMILES: Br.[C:2]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=CC=C[CH:3]=1.C(O)C=C.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:25]([O:29][CH3:30])(=[O:28])/[CH:26]=[CH:27]/[CH:3]=[CH:2]/[CH3:7]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: Br
Agent: CC(=O)[O-]
Solvent: C=CCO
Product: C/C=C/C=C/C(=O)OC
Temperature: 120 °C

Procedure:
A quantity of 1.1 grams palladium acetate, 0.61 cc-47° by weight hydrogen bromide, 5.25 grams triphenyl phosphine, 45 cc allyl alcohol, and 60 cc methyl acrylate is introduced into a reaction chamber and heated to 120°C for a period of 15 hours. Methyl sorbate is produced to the extent of 15% by weight of the final reaction solution.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:17]3[C@H:12]([CH2:13][O:14][CH:15](O)[C:16]3=[O:18])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Br-:20].[C:21]1([PH+:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[Br-:20].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:17]3[C@H:12]([CH2:13][O:14][CH:15]([P+:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:16]3=[O:18])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: O=C1C(O)OC[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Agent: [Br-]
Solvent: CC#N
Product: O=C1C([P+](c2ccccc2)(c2ccccc2)c2ccccc2)OC[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of (6R*,9aS*)-6-(4-fluorophenyl)-3-hydroxyhexahydropyrido[2,1-c][1,4]oxazin-4-one (26 mg) and triphenylphosphonium bromide (40 mg) in acetonitrile (3 mL) was heated under reflux for one hour and 30 minutes. The reaction solution was left to cool to room temperature, and then the solvent was evaporated under reduced pressure to obtain 57 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [F:1][C:2]([F:17])([S:13]([OH:16])(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[OH-].[CH2:19]([N+:22]([CH2:29][CH2:30][CH3:31])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21]>>[CH2:26]([N+:22]([CH2:19][CH2:20][CH3:21])([CH2:23][CH2:24][CH3:25])[CH2:29][CH2:30][CH3:31])[CH2:27][CH3:28].[F:17][C:2]([F:1])([S:13]([O-:16])(=[O:15])=[O:14])[C:3]([F:11])([F:12])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CCC[N+](CCC)(CCC)CCC
Agent: [OH-]
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Perfluorobutanesulfonic acid tetrapropylammonium salt is prepared by neutralising perfluorobutanesulfonic acid and tetrapropylammonium hydroxide in aqueous solution. Tetrapropylammonium hydroxide is obtainable from Aldrich.
Reaction SMILES: [Br:1]Br.[C:3]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COC(=O)CC(=O)OCc1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)C(=O)OCc1ccccc1
Yield: 97.5 %

Procedure:
Bromine (17.6 g, 0.11 mol) was added to a stirred solution of benzyl methyl malonate (20.8 g, 0.10 mol) in carbon tetrachloride. After 30 minutes the solvent was removed under reduced pressure to give 28 g of product (85% pure by gc, containing 7% benzyl methyl malonate) which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[C:10](I)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([Zn]CC)[CH3:22].CO.ClCCl>O1CCOCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:21][CH3:22])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc2c1c(I)nn2Cc1ccccc1
Reactant: CC[Zn]CC
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CCc1nn(Cc2ccccc2)c2cccc([N+](=O)[O-])c12
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
To a mixture of 1-benzyl-3-iodo-4-nitro-1H-indazole (304 mg, 0.802 mmol) (prepared as in Example 1, steps E-F) and 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (196 mg, 0.241 mmol) in dioxane (4.0 mL) under an atmosphere of dry nitrogen was added a solution of diethylzinc (1.6 mL, 1.60 mmol; 1 molar in hexane) with magnetic stirring. The mixture was heated at reflux for 2 hours. After allowing to cool methanol (1 mL) was added followed by dichloromethane (30 mL) and the mixture was stirred for 30 minutes. The mixture was transferred to a separatory funnel and washed with water (30 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica, eluting with 15-20% ethyl acetate in hexanes. Fractions containing product were concentrated under reduced pressure to give 1-benzyl-3-ethyl-4-nitro-1H-indazole (46 mg).
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[CH:6][C:7]([F:10])=[N:8][CH:9]=1)[CH3:3].C(#N)C.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([CH3:27])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(Cl)Cl>[F:10][C:7]1[N:8]=[CH:9][C:4]([CH:2]([N:24]2[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22][C@H:23]2[CH3:27])[CH3:3])=[CH:5][CH:6]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CC(Br)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CC(c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a 100 mL round-bottomed flask was added 5-(1-bromoethyl)-2-fluoropyridine (3.9 g, 19.11 mmol), acetonitrile (75 mL, 1435 mmol), (R)-4-N-boc-2-methyl-piperazine (4.02 g, 20.07 mmol), (Aldrich), potassium carbonate (1.384 mL, 22.94 mmol), (Aldrich), potassium iodide (0.205 mL, 3.82 mmol), (Fluka). The reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with water (50 mL) and DCM (50 mL) and extracted with DCM (3×50 mL) dried over sodium sulfate, filtered and concentrated under a vacuum to give (3R)-tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (3.05 g, 9.43 mmol, 49.3% yield). The crude product was adsorbed onto a plug of silica gel and chromatographed through a silica gel column (80 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide (3R)-tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (3.05 g, 9.43 mmol, 49.3% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[CH:6]=[CH:7][CH:8]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[Li].[Cl-].[NH4+]>O1CCCC1>[OH:21][C:12]1([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)[C:13]2[C:14](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:16])[N:11]1[CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: [Li]c1cccs1
Reactant: COc1cccc(CCN2C(=O)c3ccccc3C2=O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(CCN2C(=O)c3ccccc3C2(O)c2cccs2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.3 g (1.07 mmol) of N-(2-(3-methoxyphenyl)ethyl)phthalimide was dissolved in 10 ml of absolute tetrahydrofuran and, at 0° C., admixed dropwise with a 1 M solution of 0.14 g (1.6 mmol) of 2-thienyllithium. The reaction mixture was allowed to warm to room temperature, after which stirring was continued for 2 h, and the mixture was then admixed with 10 ml of saturated ammonium chloride solution. The mixture was extracted three times with diethyl ether and the combined organic phases were washed once with saturated sodium chloride solution, dried and evaporated to dryness using a rotary evaporator. The oily crude product was purified by chromatography. Elution was carried out using a dichloromethanelmethanol gradient (0 to 1% methanol). Yield: 0.2 g of an oil.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11](Br)[C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25]>>[CH2:1]([S:8][C:9]1[C:10]([O:17][CH3:18])=[C:11]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]2=[O:25])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCN1
Reactant: COc1c(Br)cc(F)cc1SCc1ccccc1
Product: COc1c(SCc2ccccc2)cc(F)cc1N1CCCCC1=O

Procedure:
Intermediate 13 (4.22 g, 12.9 mmol) was treated with piperidin-2-one (1.41 g, 14.2 mmol) according to the procedure described in 1.5). Yield after triturating (with n-heptane-ethyl acetate, 4:1) and filtration: 2.67 g (60%), crystalline solid.