Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]1[O:17][CH:14]1[CH2:15][CH3:16].[OH-].[Na+]>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:13][CH:14]([OH:17])[CH2:15][CH3:16])=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCC1CO1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1ccc(OCC(O)CC)cc1
Yield: 82.4 %

Procedure:
In a closed vessel 16.7g of ethyl p-hydroxybenzoate, 7.2 g of 1,2-butylene oxide and 0.8 ml of a 50% aqueous solution of sodium hydroxide were heated at 150° C for 4 hours in the same manner as in Example 1. The reaction mixture obtained was treated in the same way as in Example 1 to afford 19.6g of 1-(p-ethoxycarbonylphenoxy)-butan-2-ol (compound No. 48) in an 82% yield, which had a melting point of 52° to 52.5° C when recrystallized from ethyl acetate and n-hexane.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][CH2:2][NH:1][C:40](=[O:42])[CH3:41])([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (120 mg, 0.264 mmol) and pyridine (41 mg, 0.528 mmol) in anhydrous CH2Cl2 (5 mL) was dropwise added acetic anhydride (30 mg, 0.291 mmol) in anhydrous CH2Cl2 (5 mL) at 0° C. under nitrogen. The above mixture was allowed to stir for overnight at ambient temperature. The mixture was diluted with CH2Cl2 and washed with water. The organic layer was dried over Na2SO4 and concentrate to give the crude product, which was purified by preparative TLC to give N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)acetamide (60 mg, 46%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:17][C:18](=O)[CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O>CCOCC>[CH2:7]([NH:17][CH2:18][CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCNC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCNCC

Procedure:
15.4 g of lithium aluminium hydride were suspended in 300 ml of abs. ether under reflux. 61 g of N-decylacetamide (product of a) were dissolved in 300 ml of ether and the solution was added dropwise in the course of 2 hours to the solution heated to reflux. The heterogeneous mixture was stirred under reflux for 15 hours. Then 32 ml of water were added dropwise at room temperature in the course of 1 hour. After stirring for 30 minutes, the solid was collected by suction filtration and washed repeatedly with ether. The filtrate was evaporated and the residue distilled in a high vacuum. Yield: 35 g of a fraction with a boiling point of 62°-64° C. (0.2 torr).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14].O>CN(C)C(=O)C>[CH3:15][C:13](=[CH2:14])[C:12]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:2]([CH3:1])[CH:3]=1)=[O:16]
Reactant: C=C(C)C(=O)Cl
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])c(C)c1
Temperature: 2.5 °C

Procedure:
3-Methyl-4-nitroaniline (2.0 g, 13 mmol) in N,N-dimethylacetamide (DMAC) (6 ml) was added dropwise to a cooled solution of methacryloyl chloride (2.0 ml, 20.7 mmol) in a nitrogen atmosphere while the temperature of the reaction mixture was maintained between 0-5° C. The solution was allowed to warm to room temperature and the mixture was stirred over night. The mixture was poured into water (70 ml) and extracted with ethyl acetate (4×40 ml). The organic phase was washed with saturated Na2CO3 (3×20 ml) and water (1×50 ml), dried over Na2SO4 and evaporated. The yield of the crude product was 4.17 g (contains DMA, theoretical yield 2.9 g), and it was used without further purifications. 1H NMR (DMSO-d6): 1.97 (3H, s), 2.55 (3H, s), 5.62 (1H, m), 5.96 (1H, m), 7.80 (2H, m), 8.05 (1H, m), 10.22 (1H, s).
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>O.CO>[C:1]([CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(CC#N)cccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of KCN (474 mg, 7.2 mmol) in water (1 mL) was slowly added to a solution of methyl 2-(bromomethyl)-6-nitrobenzoate (1 g, 3.6 mmol) in methanol (20 mL). This mixture was allowed to stir for 4 h at 50° C. The reaction mixture was concentrated to remove methanol, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried (Na2SO4), concentrated and purified by flash column chromatography (25% EtOAc in hexanes) to give the title compound as 0.5 g of an oily liquid (62%). 1H NMR (CDCl3, 600 MHz): δ 3.9 (s, 2H), 3.97 (s, 3H), 7.65 (t, J=7.8 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H).
Reaction SMILES: [Cl:1][CH:2]([O:4][C:5]([N:7]([CH3:15])[C:8](=[N:11][N+:12]([O-:14])=[O:13])SC)=[O:6])[CH3:3].[Cl:16][C:17]1[S:18][C:19]([CH2:22][NH2:23])=[CH:20][N:21]=1>C(Cl)(Cl)Cl>[Cl:1][CH:2]([O:4][C:5]([N:7]([CH3:15])[C:8]([NH:23][CH2:22][C:19]1[S:18][C:17]([Cl:16])=[N:21][CH:20]=1)=[N:11][N+:12]([O-:14])=[O:13])=[O:6])[CH3:3]
Reactant: CSC(=N[N+](=O)[O-])N(C)C(=O)OC(C)Cl
Reactant: NCc1cnc(Cl)s1
Solvent: ClC(Cl)Cl
Product: CC(Cl)OC(=O)N(C)C(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
To a stirred solution of N-(1-chloroethoxycarbonyl)-S,N-dimethyl-N'-nitroisothiourea (6.50 g) in CHCl3 (15 ml) was added a solution of 2-chloro-5-thiazolylmethylamine (3.78 g) in CHCl3 (5 ml) dropwise below -20° C. over 20 minutes. After stirring at -20° C. for 30 minutes, insolubles were removed by filtration and the filtrate was concentrated in vacuo. The residue was applied to column chromatography on silica gel. The column was eluted with hexane-AcOEt (1:1) to afford 3.50 g of 1-(1-chloroethoxycarbonyl)-3-(2-chloro-5-thiazolylmethyl)-1-methyl-2-nitroguanidine (Compound No. 12) as an orange oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:8]([C@@H:18]([NH:20][C:21]1[N:29]=[CH:28][N:27]=[C:26]3[C:22]=1[N:23]=[CH:24][NH:25]3)[CH3:19])=[CH:7]2.[CH3:30][N:31](C=O)C>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.[C-]#N.[C-]#N.[Zn+2]>[N:29]1[C:21]([NH:20][C@H:18]([C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[C:30]#[N:31])[CH3:19])=[C:22]2[C:26]([NH:25][CH:24]=[N:23]2)=[N:27][CH:28]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2nc1-c1ccccn1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(C#N)c2nc1-c1ccccn1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of N—((S)-1-(8-chloro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (80 mg, 0.2 mmol), Pd(PPh3)4 (23 mg, 0.1 eq) and Zn(CN)2 (117 mg, 5.0 eq) in DMF (5 mL) was purged with N2 for 5 min before heating to 130° C. After 3 h, LCMS showed formation of trace amount of 2. The reaction was then heated to 165° C. over night. After cool to rt, the reaction was filtered through Celite™ and purified by reverse HPLC (MeCN/H2O, 0.1% TFA) to give a white solid. 1H-NMR (400 Hz, DMSO-d6) δ 8.83 (s, 1H), 8.72 (s, 1H), 8.52 (s, 1H), 8.42-8.37 (m, 3H), 8.14 (d, J=8.0 Hz, 1H), 8.08 (t, J=8.0 Hz, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 6.24 (s, 1H), 1.72 (d, J=8.0 Hz, 3H). Mass Spectrum (ESD m/e=393 (M+1).
Reaction SMILES: C([Mg]Cl)C=C.BrCCl.[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.C([Li:22])CCC.Cl>C1COCC1>[CH:9]1([Li:22])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: [Li]CCCC
Reactant: C1=Cc2ccccc2C1
Agent: C=CC[Mg]Cl
Agent: Cl
Agent: ClCBr
Solvent: C1CCOC1
Product: [Li]C1C=Cc2ccccc21
Temperature: 30 °C
Reaction time: 14 h

Procedure:
In Example 5, 3H-1-(but-3-enyl)indene was prepared. About 100 mL of a 2 M solution of allylmagnesium chloride in THF was added to a solution of 13 mL of bromochloromethane (200 mmol) in 50 mL of THF. This mixture was refluxed for 3 hr and then stirred for 14 hr. A solution of indenyl lithium was prepared from 30 mL of 90% indene (232 mmol) and 85 mL of 2.5 M n-butyllithium in 100 mL of THF. This solution was then added by cannula to the mixture over 1 hr, and the resulting mixture was refluxed for 6 hr. Then, the mixture was poured into 200 mL of 1M HCl, followed by extraction with 100 mL of pentane. The extract was washed with 3×100 mL of water, dried over sodium sulfate and concentrated with a rotary evaporator while heating to 30° C. The residue was distilled through a 6-inch 14/20 Vigreux column at 0.01 mm Hg, and product collected at 79-80° C. Next, the product was evacuated to further remove light materials. The resulting indene material contained greater than 90% butenylindene.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:15][C@@:9]1([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:10](=[O:25])[CH:11]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>CO.[OH-].[Pd+2].[OH-]>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:17])=[O:18])[CH2:15][C@@:9]1([C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:10](=[O:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=C[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccc(F)cc1)N2Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CC[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccc(F)cc1)N2Cc1ccccc1
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
(1R*,5S*,6R*)-8-Benzyl-1-(4-fluorophenyl)-6-phenylsulphonyl-8-azabicyclo[3.2.1]oct-3-ene-2-one (Description 12; 13.88 g, 31.05 mmol) was dissolved in methanol (25 ml) and ethyl acetate (25 ml) and 10% palladium hydroxide (1.80 g) added and the mixture hydrogenated at 30 psi for 30 minutes. The mixture was filtered and concentrated in vacuo to give the title compound as a yellow oil (11.65 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([CH:16]=[O:17])[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C:18]([O:21][CH:22]=[CH2:23])(=[O:20])[CH3:19]>C(OCC)C>[C:18]([O:21][CH:22]1[C:5]2([CH:16]=[O:17])[C:6]3[C:11]([CH:12]([C:13]4[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=42)[CH2:23]1)=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:20])[CH3:19]
Reactant: C=COC(C)=O
Reactant: O=Cc1c2ccccc2cc2ccc(Cl)cc12
Solvent: CCOCC
Product: CC(=O)OC1CC2c3ccccc3C1(C=O)c1cc(Cl)ccc12
Temperature: 200 °C
Yield: 463.8 %

Procedure:
A mixture of 2-chloro-9-formylanthracene (described in example 1b) (100.0 g, 0.415 mol) and vinyl acetate (400 ml, 374 g, 4.34 mol) was placed in a stainless steel bomb (PARR) and heated at 200° C. (sand bath temp.) for 24 h, then cooled. The reaction mixture was concentrated on the rotary evaporator to remove the excess vinyl acetate, leaving the crude product as a tan crystalline solid. The crude product from several batches, which consumed 670.0 g (2.78 mol) of the 2-chloro-9-formylanthracene, was pooled. Trituration with diethyl ether (1.0 L) gave an off-white crystalline solid which was collected by filtration, washed with diethyl ether (2×300 ml), then vacuum dried to afford 629.0 g (69.1%) of the title compound (mp 145°-153° C.). 1H NMR (CDCl3) 10.58 (s) and 10.64 (s, 1H), 7.63 (m) and 7.76 (d, J=1.5 Hz, 1H), 7.15-7.36 (m, 6H), 5.46 (m, 1H), 4.29 (s, 1H), 2.55 (m, 1H), 1.88 (s) and 1.91 (s, 1H), 1.55 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1([CH3:14])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([OH:13])[C:6]=2[O:5]1)[CH3:2].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][N:16]([CH3:20])[C:17](=[O:18])[O:13][C:12]1[C:6]2[O:5][C:4]([O:3][CH2:1][CH3:2])([CH3:14])[O:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC1(C)Oc2cccc(O)c2O1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC1(C)Oc2cccc(OC(=O)N(C)C)c2O1
Yield: 77 %

Procedure:
2-Ethoxy-2-methyl-4-hydroxy-1,3-benzodioxole, prepared as in Example 1, (10g) was dissolved in dry acetone (100 ml). Dimethylcarbamoylchloride (8g) and potassium carbonate (12g) were added and the mixture stirred and heated under reflux for six hours. The mixture was then filtered and the solvent evaporated from the filtrate under reduced pressure. Distillation of the residue gave 2-ethoxy-2-methyl-1,3-benzodioxol-4-yl dimethylcarbamate (9.5g, 77% yield), boiling oint 120°-124° C/0.3 mmHg.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([Cl:22])[CH:13]=1)=[CH:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[K+]>C(O)C.O>[Cl:22][C:14]1[CH:13]=[C:12](/[C:5](=[CH:6]\[CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)/[C:4]([OH:23])=[O:3])[CH:17]=[CH:16][C:15]=1[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CCOC(=O)C(=CC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the isomeric mixture of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-acrylic acid ethyl ester [500 mg, 1.40 mmol, (E):(Z)=2:1] in ethanol (16 mL) was treated with a solution of potassium hydroxide (393.6 mg, 7.00 mmol) in water (3.7 mL). The yellow solution was stirred for 3 h at 25° C. and then concentrated in vacuo to remove the ethanol. The remaining aqueous layer was acidified to pH=2 with a 1N aqueous hydrochloric acid solution and then extracted with methylene chloride (3×15 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate plus 1% acetic acid) afforded (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-acrylic acid (458 mg, 99%, 95% is the E isomer) as a white foam: FAB-HRMS m/e calcd for C15H17ClO4S (M+H)+329.0614, found 329.0628.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][N:13]=[C:12]([C:15]([OH:17])=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:42]1([C@@H:48]([NH2:50])[CH3:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][N:13]=[C:12]([C:15]([NH:50][C@H:48]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH3:49])=[O:17])[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C(O)c1cc(-c2ccc3[nH]ncc3c2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cc(-c2ccc3[nH]ncc3c2)on1)c1ccccc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
5-(1H-Indazol-5-yl)isoxazole-3-carboxylic acid (36 mg, 0.16 mmol, Example 71A), was dissolved in N,N-dimethylformamide (1.0 mL) followed by the addition of HATU (60 mg, 0.16 mmol) dissolved in N,N-dimethylformamide (0.5 mL). Then a solution of (S)-1-phenylethanamine (22 mg, 0.18 mmol), dissolved in N,N-dimethylformamide (0.6 mL) was added, followed by diisopropylethylamine (56 μL, 0.32 mmol) dissolved in N,N-dimethylformamide (0.2 mL). The resulting mixture was shaken for 3 hours at 40° C. The reaction was filtered, checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase HPLC (Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm), 50 mL/min, 10-100% acetonitrile/0.1% trifluoroacetic acid in water) to provide the title product. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 1.50 (d, 3H), 5.06-5.22 (m, 1H), 7.23-7.29 (m, 2H), 7.34-7.38 (m, 2H), 7.40-7.45 (m, 2H), 7.70-7.75 (m, 1H), 7.87-7.92 (m, 1H), 8.25-8.27 (m, 1H), 8.39-8.41 (m, 1H), 9.28 (d, 1H). MS (ESI+) m/z 333 (M+H)+; (ESI−) m/z 331 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: CN(C)CCCOc1ccccc1C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCCOc1ccccc1C=Nc1ccccc1
Yield: 45.4 %

Procedure:
A solution of 32.5 g (0.156 mole) of 2-(3-dimethylaminopropoxy)benzaldehyde and 14.6 g (0.157 mole) of aniline in 150 ml of toluene is refluxed for 9 hours. Water which is formed very slowly is collected in a Dean-Stark trap. The bulk of solvent is removed on a rotary evaporator and the oily residue is fractionated to give 20.0 g of product; boiling point 165°-170° C./0.2 mm of Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[C:10]([N:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[CH3:17])[CH:11]=[CH:12]2)=[N:7]1.[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>C(O)(C)C.Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[C:10]([N:16]([CH3:17])[C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:28][C:29]4[CH:30]=[C:31]([S:35]([NH2:38])(=[O:36])=[O:37])[CH:32]=[CH:33][CH:34]=4)[N:19]=3)[CH:11]=[CH:12]2)=[N:7]1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: Cc1c2ccc(N(C)c3ccnc(Cl)n3)cc2nn1Cc1cccc(Cl)c1
Agent: Cl
Solvent: CC(C)O
Product: Cc1c2ccc(N(C)c3ccnc(Nc4cccc(S(N)(=O)=O)c4)n3)cc2nn1Cc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 2-(3-chlorobenzyl)-N-(2-chloropyrimidin-4-yl)-N,3-dimethyl-2H-indazol-6-amine (40 mg, 0.1 mmol) and 3-aminobenzenesulfonamide (17.3 mg, 0.1 mmol) in isopropanol (2 ml) was added 2 drops of conc. HCl. The mixture was heated to reflux overnight. The mixture was cooled to rt. Precipitate was collected via filtration and washed with EtOH. HCl salt of 3-({4-[[2-(3-chlorobenzyl)-3-methyl-2H-indazol-6-yl](methyl)amino]-pyrimidin-2-yl}amino)benzenesulfonamide was isolated as off-white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) δ 9.52 (br s, 1H), 8.54 (br s, 1H), 7.85 (d, J=5.9 Hz, 1H), 7.77-7.79 (m, 2H), 7.49 (s, 1H), 7.30-7.36 (m, 5H), 7.22 (br, s, 2H), 7.14 (br s, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.80 (d, J=5.8 Hz, 1H), 5.64 (s, 2H), 3.48 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 534 (M+H).
Reaction SMILES: [O:1]=[CH:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C@H:24]2[CH:23]=[CH:22][N:21]([S:18]([C:15]3[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=3)(=[O:20])=[O:19])[C:2](=[O:1])[C@H:3]2[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:26][CH:27]=1
Reactant: COc1ccc(/C=C/C=NS(=O)(=O)c2ccc(OC)cc2)cc1
Reactant: CCOC(=O)/C=C/C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C[C@@H]1C(=O)N(S(=O)(=O)c2ccc(OC)cc2)C=C[C@@H]1c1ccc(OC)cc1
Yield: 81 %

Procedure:
The title compound was prepared according to the general procedure from ethyl trans-4-oxo-2-butenoate and trans-N-(4-methoxybenzenesulfonyl)-3-(4-methoxyphenyl)prop-2-en-1-imine using 10 mol % 9 as the catalyst in 81% yield as a yellow solid. [α]D20 (c 1.04, CHCl3)=+143.6; mp=107-110° C.; 1H NMR (400 MHz, CDCl3) δ 8.03 (dd, 2H, J=7.1, 1.8 Hz), 7.13 (d, 1H, J=8.1 Hz), 7.05 (dd, 2H, J=7.1, 1.8 Hz), 6.55-6.48 (m, 4H), 5.59 (dd, 1H, J=8.0, 6.6 Hz), 4.16-4.09 (m, 2H), 3.92 (s, 3H), 3.71 (s, 3H), 3.60 (t, 1H, J=6.9 Hz), 3.52-3.47 (m, 1H), 2.58 (dd, 1H, J=17.2, 6.0 Hz), 1.95 (dd, 1H, J=17.2, 7.7 Hz), 1.22 (t, 3H, J=7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 171.8, 169.1, 164.3, 159.2, 131.4, 129.2, 128.5, 124.3, 114.3, 114.3, 113.9, 113.6, 61.0, 56.0, 55.3, 44.3, 41.2, 31.5, 14.4; IR (thin film) ν 3055, 2840, 1720, 1647, 1511, 1498, 1463, 1442, 1366, 1263, 1167, 1090, 1028 cm−1; HRMS (ESI) calcd for C23H25NO7S [M+Na]+ 482.1243, found 482.1253; >99% ee (3S,4S)-isomer as determined by HPLC (AS-H, 4:1 hexanes/i-PrOH), tr (3S,4S)=49.3 min, tr (3R,4R)=29.6 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8][C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[CH2:12][CH2:13][N:14]([CH2:22][CH2:23]Cl)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[H-].[Na+]>CS(C)=O.ClCCl>[Br:1][C:2]1[C:3]([C:8]2([C:9]#[N:10])[CH2:23][CH2:22][N:14]([C:15]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:21])[CH2:13][CH2:12]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1ncccc1Br
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ncccc2Br)CC1
Temperature: 18 °C
Reaction time: 18 h

Procedure:
The (3-bromopyridin-2-yl)acetonitrile (2.00 g, 10.2 mmol) and tert-butyl bis(2-chloroethyl)carbamate (2.46 g, 10.2 mmol) were dissolved in 102 mL of DMSO. The reaction was purged with a stream of nitrogen and cooled to 18° C. To this reaction was added sodium hydride (0.564 g, 22.3 mmol), which was then warmed to 50° C. and stirred for 18 hours. The mixture was diluted with dichloromethane (150 mL), washed with water (3×150 mL), and partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered, concentrated, and subjected to silica gel chromatography eluting with 5-30% EtOAc in hexanes to yield tert-butyl 4-(3-bromopyridin-2-yl)-4-cyanopiperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:24]Br>>[CH3:20][C:21]1[CH:28]=[C:27]([CH:26]=[C:23]([CH3:24])[CH:22]=1)[CH2:29][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Cc1cc(C)cc(CBr)c1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cc(C)cc(C)c2)c(=O)[nH]c1=O
Yield: 57.3 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-dimethylbenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (217 mg, yield: 57.3%).