Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[C:27]([O:31][C:32]([N:34]1[CH2:37][CH:36]([CH:38]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)O)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>O1CCCC1.C(#N)C.O1CCCC1>[C:27]([O:31][C:32]([N:34]1[CH2:37][CH:36]([CH:38]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[I:20])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CC(C(O)c2ccc(Cl)cc2)C1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(C(I)c2ccc(Cl)cc2)C1
Reaction time: 0.25 h

Procedure:
Polymer supported triphenylphosphine (125 g, 370 mmol) is suspended in tetrahydrofuran: acetonitrile 9:1 (1000 ml) and treated with Iodine (95.2 g, 370 mmol) followed by stirring for 15 minutes. Imidazole (25.5 g, 370 mmol) is added followed by a solution of 3-[(4-Chloro-phenyl)-hydroxy-methyl]-azetidine-1-carboxylic acid tert-butyl ester (44.7 g, 150 mmol) in tetrahydrofuran (150 ml) and the reaction mixture stirred at ambient temperature for 20 hours. The reaction mixture is filtered through celite™ filter material and the filtrate evaporated. The residue is taken up in chloroform and washed with sodium thiosulphate solution, water and brine. The solution is dried over magnesium sulphate and evaporated to provide 3-[(4-Chlorophenyl)-iodo-methyl]-azetidine-1-carboxylic acid tert-butyl ester. 1H NMR 400 MHz, CDCl3, δ 1.35 (9H), 3.21 (1H), 3.37 (1H), 3.60 (2H), 4.05 (1H), 5.12 (1H), 7.20 (4H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].F[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].O.[OH-].[Li+]>CS(C)=O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:1][C:2]2[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=2[C:4]#[N:5])=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CC(C)c1ccc(N)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1ccc(Nc2ccc(F)cc2[N+](=O)[O-])c(C#N)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
Heat a solution of 2-amino-5-isopropyl-benzonitrile (1.482 g, 9.25 mmol) with 1,4-difluoro-2-nitro-benzene (1.47 g, 9.25 mmol) and lithium hydroxide monohydrate (0.78 g, 18.50 mmol) in DMSO (20 ml) to 70° C. for 38 hours. Cool the reaction to ambient temperature and pour into approximately 200 ml of ice water and stir for one hour. Collect by filtration the title compound which precipitates. No further purification is necessary to obtain 2.236 g (7.47 mmol, 81% yield) of the title compound as an orange amorphous solid: Mass Spectrum (m/e): 300(M+1).
Reaction SMILES: [N:1](/[C:4](=[CH:10]\[C:11]1[CH:19]=[CH:18][C:14]2[O:15][CH2:16][O:17][C:13]=2[CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-]>C1(C)C(C)=CC=CC=1>[O:17]1[C:13]2=[CH:12][C:11]3[CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:1][C:19]=3[CH:18]=[C:14]2[O:15][CH2:16]1
Reactant: CCOC(=O)/C(=C/c1ccc2c(c1)OCO2)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2cc3c(cc2[nH]1)OCO3
Yield: 112 %

Procedure:
A stirred solution of (Z)-ethyl 2-azido-3-(benzo[d][1,3]dioxol-5-yl)acrylate (I-4a: 0.6 g, 1.532 mmol) in xylene (20 mL) was maintained at 150° C. for 3 h. Xylene was distilled out completely and the crude compound was purified by column chromatography over silica gel (100-200 mesh) using a solvent gradient of 8-10% ethyl acetate in petroleum ether as eluent to afford 0.4 g (75%) of ethyl 5H-[1,3]dioxolo[4,5-f]indole-6-carboxylate (I-4b) as a pale yellow solid.
Reaction SMILES: [CH3:1]S(C1C=C(C=C(OCC)N=1)C(O)=O)(=O)=O.[ClH:17].[CH3:18][S:19]([C:22]1[CH:27]=[C:26]([C@@H:28]([NH2:30])[CH3:29])[CH:25]=[C:24]([O:31][CH3:32])[N:23]=1)(=[O:21])=[O:20].C[Mg]Br>CC(C)=O>[ClH:17].[CH3:18][S:19]([C:22]1[CH:27]=[C:26]([C@@H:28]([NH2:30])[CH2:29][CH3:1])[CH:25]=[C:24]([O:31][CH3:32])[N:23]=1)(=[O:21])=[O:20]
Reactant: CCOc1cc(C(=O)O)cc(S(C)(=O)=O)n1
Reactant: COc1cc([C@H](C)N)cc(S(C)(=O)=O)n1
Agent: C[Mg]Br
Agent: Cl
Solvent: CC(C)=O
Product: CC[C@H](N)c1cc(OC)nc(S(C)(=O)=O)c1

Procedure:
The Weinreb amide of 2-methanesulfonyl-6-ethoxy-isonicotinic acid was also converted to (S)-1-(2-methanesulfonyl-6-methoxy-pyridin-4-yl)-ethylamine hydrochloride according to methods described in Example 43 except during the Grignard addition methyl magnesium bromide was added to the Weinreb amide instead of ethyl magnesium chloride to afford the corresponding methyl ketone.
Reaction SMILES: CC([O-])(C)C.[K+].[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[NH:16][C:17]1[C:22]([S:23][CH2:24][CH2:25][C:26](OC)=O)=[CH:21][CH:20]=[CH:19][N:18]=1.FC1C=C[C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.C(OCC)(=O)C>CS(C)=O>[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[NH:16][C:17]1[C:22]([S:23][C:24]2[CH:32]=[CH:33][C:34]([C:35]#[N:36])=[CH:26][CH:25]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COC(=O)CCSc1cccnc1Nc1nc2cccnc2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Sc2cccnc2Nc2nc3cccnc3s2)cc1
Reaction time: 0.25 h
Yield: 32.5 %

Procedure:
Added potassium 2-methylpropan-2-olate (0.097 g, 0.87 mmol) to a solution of methyl 3-(2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)propanoate (100 mg, 0.289 mmol) in DMSO (1 mL). Stirred 15 minutes, added 4-fluorobenzonitrile (0.105 g, 0.866 mmol) and stirred overnight. Partitioned between ethyl acetate and water. Washed the organic layer with water, brine, dried, and concentrated. Purified by MPLC eluting with 3:2 hexane:ethyl acetate to afford the title compound (0.034 g, 33% yield) as a white powder: 1H NMR (CDCl3) δ 7.10-7.15 (m, 3H), 7.32 (dd, 1H), 7.52 (d, 2H), 7.87 (d, 1H), 7.96 (d, 1H), 8.42 (d, 1H), 8.58 (d, 1H), 9.10 (bs, 1H).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:9]=2[CH:8]=1)=[O:6])[CH3:3].C(=O)(O)[O-].[Na+].I[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33].O>CN(C)C=O>[ClH:1].[CH2:2]([O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH2:28][CH2:29][CH2:30][CH2:31][C:32](=[O:33])[NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:20][CH2:21]3)[C:9]=2[CH:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cc2c(N3CCNCC3)cccc2s1
Reactant: O=C(CCCCI)Nc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(N3CCN(CCCCC(=O)Nc4ccccc4)CC3)cccc2s1
Temperature: 80 °C
Yield: 6.2 %

Procedure:
To a solution of ethyl-4-(1-piperazinyl)-benzo[b]thiophene-2-carboxylate monohydrochloride prepared in Example 5 (2.00 g, 6.12 mmol) in dry N,N-dimethylformamide (31 mL) was added sodium bicarbonate (1.03 g, 12.2 mmol) and 5-iodo-N-phenylpentanamide (1.86 g, 6.12 mmol). The mixture was heated at 80° C. under nitrogen for 24 h, cooled to 20° C., treated with saturated aqueous sodium bicarbonate (50 mL) and water (100 mL), and extracted with 2:1 ether:dichloromethane (4×75 mL). The combined extracts were diluted with ethanol (50 mL) washed with water (50 mL), brine (50 mL) dried over magnesium sulfate/sodium sulfate, filtered, and concentrated in vacuo. The crude product was chromatographed using 20:80 ethanol:ethyl acetate isolating the component with an Rf of ca. 0.5 (2.20 g). A solution of the product (0.20 g) in 5:2 ethanol:dichloromethane was treated with an equivalent of 1.0M hydrochloric acid and concentrated in vacuo. Recrystallization from 3:2 methanol:acetonitrile (10 mL) gave the title compound as a white solid (0.19 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([CH3:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:38]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[CH:37][N:36]=[N:35]2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:15])[CH3:16])[C:11]([CH3:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:38]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[CH:37][N:36]=[N:35]2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N(C)C
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)c(NC(=O)OC(C)(C)C)cc1N(C)C

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (265 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (402 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow foam (420 mg, 71%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:20])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:11]=2)[CH:6]=[CH:5]1)(=O)C.C([O-])([O-])=O.[K+].[K+]>Br>[Br:20][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[N:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]1)[NH:4][CH2:5][CH2:6]2
Reactant: CC(=O)n1ccc2cc(Br)c(N3CCN(C)CC3)cc21
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1CCN(c2cc3c(cc2Br)CCN3)CC1
Yield: 58.1 %

Procedure:
A solution of 1-acetyl-5-bromo-6-(4-methylpiperazin-1-yl)-1H-indole (D12, 0.60 g, 1.8 mmole) in 2M hydrobromic acid (50 ml) was stirred at room temperature for 5 days, then basified by addition of solid K2CO3 and extracted with DCM. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a brown solid (0.31 g, 58%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5]C=CC=1.N[C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C(N)C(C)C>C(O)(=O)C>[CH2:1]([N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]=2[N:9]=[CH:8]1)[CH:6]([CH3:5])[CH3:24]
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: CC(C)CN
Product: CC(C)Cn1cnc2c(-c3ccccc3)csc2c1=O
Yield: 57 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), isobutylamine (0.099 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 69.7 mg (0.25 mmol, 57% yield) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:16]=2)[CH:4]=1.[CH3:32][S:33]([C:36]1[CH:37]=[C:38]([NH2:42])[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34].Cl>>[CH3:32][S:33]([C:36]1[CH:37]=[C:38]([NH:42][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:31])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[C:17]([O:25][CH2:26][C:27]([F:30])([F:28])[F:29])[CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:39]=[CH:40][CH:41]=1)(=[O:34])=[O:35]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.13) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (EI) 608.3 [M]; mp 207° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][C:4]([C:10]([NH:12][NH2:13])=[O:11])=[N:3]1.F[C:15](F)(F)C(O)=O.C(OC(OCC)OCC)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][C:4]([C:10]2[O:11][CH:15]=[N:13][N:12]=2)=[N:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1nc(C(=O)NN)cc1[N+](=O)[O-]
Solvent: CCOC(OCC)OCC
Solvent: ClCCl
Product: Cn1nc(-c2nnco2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methyl-5-nitro-1H-pyrazole-3-carbohydrazide (3.81 g, 20.6 mmol) in DCM (30 mL) was added 2,2,2-trifluoroacetic acid (4 mL, 51.9 mmol). The mixture was stirred for about 2 h then concentrated under reduced pressure. To the residue was added triethoxymethane (31.4 mL, 206 mmol) and the mixture was refluxed for about 24 h. The reaction was cooled to ambient temperature and continued to stir for about 16 h. The reaction mixture was concentrated under reduced pressure and the material was partitioned between DCM (25 mL) and saturated NaHCO3 (10 mL). The organic layer was separated and the aqueous layer was back extracted with DCM (25 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure and triturated with ether (2×30 mL).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH3:11].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:10]([S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: Fc1ccc(S)cc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a stirred solution of 4-fluorobenzenethiol (80 g, 0.625 mol) and bromoethane (71.88 g, 0.666 mol) in DMF (1.25 L) under nitrogen atmosphere, Cs2CO3 (213.75 g, 0.666 mol) was added. The reaction mixture was stirred at 25° C. overnight. TLC (petroleum ether) indicated the reaction was complete. The mixture was diluted with water (800 mL), extracted with ethyl acetate (600 mL×3). The combined organic layers were washed with water (500 mL×2) and brine (500 mL), dried over Na2SO4 and concentrated in vacuum to give ethyl(4-fluorophenyl)sulfane (60 g, 61.5%) as a colorless oil. A mixture of ethyl(4-fluorophenyl)sulfane (60 g, 0.38 mol), acetic acid (1 L) and 30% H2O2 (180 mL) was stirred at reflux under N2 overnight. TLC (petroleum ether:ethyl acetate=4:1) indicated the reaction was complete. After cooled to room temperature, the reaction mixture was poured into water (500 mL). Then NaHSO3 (200 g) was add. The mixture was extracted with ethyl acetate (500 mL×3), dried over Na2SO4 and concentrated in vacuum to remove the remaining acetic acid. Then the residue was poured into saturated aq. NaOH (800 mL) and extracted with ethyl acetate (500 mL×3) again. The organic layer was dried over Na2SO4 and concentrated in vacuum to give the title compound (66 g, 92.4%) as a colorless liquid.
Reaction SMILES: N1(C[C@]23CC[C@@H](C(C)=C)[C@@H]2[C@@H]2[C@@](C)(CC3)[C@@]3(C)[C@@H]([C@]4(C)[C@@H](CC3)C(C)(C)C(C3C=CC([C:31](OC(C)(C)C)=[O:32])=CC=3)=CC4)CC2)CC1.[CH3:47][C@:48]12[C@@:65]3([CH3:66])[C@@H:56]([C@:57]4([CH3:78])[C@@H:62]([CH2:63][CH2:64]3)[C:61]([CH3:68])([CH3:67])[C:60]([C:69]3[CH:77]=[CH:76][C:72]([C:73]([OH:75])=[O:74])=[CH:71][CH:70]=3)=[CH:59][CH2:58]4)[CH2:55][CH2:54][C@@H:53]1[C@H:52]1[C@H:79]([C:82]([CH3:84])=[CH2:83])[CH2:80][CH2:81][C@:51]1([CH2:85][NH:86][CH2:87][CH2:88]N1CCN(S(C)(=O)=O)CC1)[CH2:50][CH2:49]2>CO>[CH3:31][O:32][CH2:88][CH2:87][NH:86][CH2:85][C@:51]12[CH2:81][CH2:80][C@@H:79]([C:82]([CH3:84])=[CH2:83])[C@@H:52]1[C@@H:53]1[C@@:48]([CH3:47])([CH2:49][CH2:50]2)[C@@:65]2([CH3:66])[C@@H:56]([C@:57]3([CH3:78])[C@@H:62]([CH2:63][CH2:64]2)[C:61]([CH3:67])([CH3:68])[C:60]([C:69]2[CH:77]=[CH:76][C:72]([C:73]([OH:75])=[O:74])=[CH:71][CH:70]=2)=[CH:59][CH2:58]3)[CH2:55][CH2:54]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CN3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCN(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(CNCCOC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-ylmethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the procedure described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperazin-1-yl)ethylamino)methyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, using methanol as reagent in step 1. The product was isolated as a white solid (1.6 mg, 5.2%). LCMS: m/e 602.49 (MH+), 2.40 min (method 9). 1H NMR (500 MHz, METHANOL-d4) δ 7.85 (d, J=7.6 Hz, 2H), 7.12 (d, J=7.6 Hz, 2H), 5.29 (s, 1H), 4.79-4.76 (s, 1H), 4.66 (s, 1H), 3.67-3.64 (m, 2H), 3.43 (s, 3H), 3.21-3.15 (m, 3H), 2.69-2.62 (m, 1H), 2.52 (m, 1H), 2.19-2.10 (m, 1H), 2.07-2.00 (m, 1H), 1.79 (m, 8H), 1.57 (m, 8H), 1.40-1.24 (m, 7H), 1.18 (m, 4H), 1.09 (3H, s), 1.05 (3H, s), 0.97 (3H, s), 0.96 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7](I)[C:8](=[O:19])[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:10]=1.[CH2:26]([O:28]C=C[Sn](CCCC)(CCCC)CCCC)[CH3:27]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:26]([C:7]1[C:8](=[O:19])[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:10]=[C:5]([CH2:4][C:3]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:2]=2[F:1])[CH:6]=1)(=[O:28])[CH3:27]
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: O=c1c(I)cc(Cc2ccc(F)cc2F)cn1Cc1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Cc2ccc(F)cc2F)cn(Cc2ccccc2F)c1=O
Reaction time: 0.25 h

Procedure:
A mixture of 5-(2,4-difluorobenzyl)-1-(2-fluorobenzyl)-3-iodopyridin-2(1H)-one 5 (6.61 g, 14.5 mmol), bis(triphenylphosphine)palladium(II) chloride (1.02 g, 1.5 mmol), and ethoxyvinyl(tributyl)tin (10.81 g, 29.0 mmol) in anhydrous DMF (145 ml) was heated at 700 under argon condition for 1 h. DMF was distilled off and the resulting residue was dissolved in ethyl acetate (145 ml) and filtered through a pad of celite. The filtrate was stirred with 1N HCl (145 ml) for 15 min, washed with water (2×145 ml), brine (145 ml), dried over anhydrous sodium sulfate, and distilled off. The residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate, 80:20). Yield 4.21 g (78%). 1H NMR (CDCl3, 500 MHz): δ 7.98 (d, 1H, J=2.6 Hz), 7.49-7.44 (m, 2H), 7.35-7.30 (m, 1H), 7.16-7.07 (m, 3H), 6.85-6.78 (m, 2H), 5.17 (s, 2H), 3.71 (s, 2H), 2.67 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 197.6, 162.4, 162.1, 160.5, 160.4, 160.2, 144.4, 141.4, 131.4, 131.2, 130.4, 127.7, 124.6, 122.6, 122.1, 116.9, 115.6, 111.5, 104.1, 47.2, 30.9, 30.5.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([O:16][CH3:17])=[N:10][C:11]([CH3:15])=[CH:12][C:13]=2[CH3:14])[C:5]([F:18])=[CH:4][C:3]=1[C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:22]=[CH:21][C:20]=1[C:30]([NH2:32])=[O:31].[Cl-].[NH4+].O>CN1C(=O)CCC1>[F:18][C:5]1[C:6]([C:8]2[C:9]([O:16][CH3:17])=[N:10][C:11]([CH3:15])=[CH:12][C:13]=2[CH3:14])=[CH:7][C:2]2[NH:32][C:30](=[O:31])[C:20]3[CH:21]=[N:22][N:23]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:19]=3[C:3]=2[CH:4]=1
Reactant: COc1nc(C)cc(C)c1-c1cc(F)c(-c2c(C(N)=O)cnn2C2CCOCC2)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1nc(C)cc(C)c1-c1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
KTB (41 mg) was added to a solution of 5-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide (81 mg) in NMP (0.4 mL), and the mixture was heated to 90° C. After one hour, KTB (20 mg) was further added, followed by stirring for 30 minutes. The reaction mixture was cooled to room temperature, followed by adding a saturated aqueous ammonium chloride solution (2 mL) and water (1 mL). The generated solid was filtered off, washed with water (2 mL) and dried under reduced pressure at 60° C. to give the title compound (57 mg).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.[OH-].[NH4+]>O>[CH:1]([C:10]1=[CH:11][C:12]([O:14][C:9]1=[O:15])=[O:13])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: O=C1C=CC(=O)O1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C1C=C(C=Cc2ccccc2)C(=O)O1

Procedure:
Polymers of hydrolyzed styrene-maleic anhydride and starch were prepared according to the following process: Three or six parts of starch and one part SMA 3000 (styrene-maleic anhydride copolymer sold by Arco Chemical Company, having a ratio of styrene or maleic anhydride of 3:1, a molecular weight of 1900 and an acid number of 275) were added to and heated in water for 45 minutes at a temperature of 160° F. with stirring. Then 0.88 parts of 28% ammonium hydroxide (per part of SMA) was added with mixing for an additional 20 minutes and the final pH was adjusted to 9.5 with additional ammonium hydroxide resulting in binders having about a 25% solids content. Four polymers prepared by this process are shown in Table I.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=O)=[CH:4][CH:3]=1.Cl.[NH:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH2:15]>C(O)C>[NH2:10][C:9]1[N:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=[C:6]([C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=2)[CH:8]=1
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cn1nc(-c2ccc(F)cc2)cc1N
Yield: 91.6 %

Procedure:
A mixture of 4-fluorobenzoylacetonitrile (5 g, 30.7 mmol) and ethyl hydrazinoacetate hydrochloride (4.74 g, 30.7 mmol) in ethanol (50 mL) was heated to reflux for 2 h. The reaction mixture was concentrated in vacuo. The crude reaction mixture was partitioned between CH2Cl2 and concentrated aqueous ammonia. The aqueous phase was extracted with CH2Cl2 and the organic phases combined, dried over MgSO4, filtered and evaporated to give ethyl 2-(5-amino-3-(4-fluorophenyl)-1H-pyrazol-1-yl)acetate as a solid (7.4 g), which was used as such in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16]>C1CCCCC1.O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:16][CH:15]=[CH2:14])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CCBr
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Product: C=CCC(C#N)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 386 %

Procedure:
To a stirred solution of 3,4-dichlorophenylacetonitrile (800 g, 4.3 mol) in cyclohexane (16 L) at room temperature was carefully added aqueous sodium hydroxide solution (1600 g of sodium hydroxide in 8 L of water). This addition caused an elevation of the reaction temperature to 50°. Allyl bromide (572 g, 1.1 mol. equiv.) and tetra-n-butylammonium chloride hydrate (40 g, 0.03 mol. equiv.) were then added and the reaction stirred for one hour at 50° C. The aqueous phase was removed and the organic layer washed with water (10 L). The organic phase was filtered through silica gel (1 kg) under reduced pressure to give a yellow filtrate solution. The solvent was removed from the filtrate under reduced pressure to give the title compound as an oil (960 g) of 70% purity which was used without any further purification.