Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:22][CH2:23][CH2:24][S:25]([OH:28])(=O)=[O:26].[CH3:29][N:30](C=O)C>>[O:26]=[S:25]1(=[O:28])[CH2:24][CH2:23][CH2:22][N:30]1[CH2:29][C:16]1[CH:17]=[CH:18][C:12]2[S:11][C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]3)=[N:14][C:13]=2[CH:15]=1
Reactant: O=S(=O)(O)CCCCl
Reactant: CC(C)N1CCN(c2nc3ccccc3s2)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCN(c2nc3cc(CN4CCCS4(=O)=O)ccc3s2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of 5-aminomethyl-[2-(4-isopropylpiperazin-1-yl)benzothiazole (439 mg, 1.51 mmol) in DMF (10 mL) was added NaH (181 mg, 4.53 mmol) at 0° C. The mixture was allowed to warm to rt. After 30 min, a solution of 3-chloropropane-1-sulfonic acid (373 mg, 2.11 mmol) in DMF (1.67 mL) was added at rt. The reaction mixture was stirred at rt for 2 h and then quenched with water. The volatiles were removed and the residue was extracted with ethyl acetate. The organic extract was washed with brine and concentrated. The residue was purified by the preparative HPLC to give 267 mg (45%) of 5-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)-2-(4-isopropylpiperazin-1-yl)benzothiazole as a trifluoroacetate salt.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](O)=O)[CH:9]=2)[NH:4][N:3]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].[OH-].[K+]>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:17][C:16]([NH2:18])=[N:15][N:14]=3)[CH:9]=2)[NH:4][N:3]=1
Reactant: NNC(N)=S
Reactant: Cc1n[nH]c2ccc(C(=O)O)cc12
Agent: [K+]
Agent: [OH-]
Product: Cc1n[nH]c2ccc(-c3nnc(N)s3)cc12
Temperature: 90 °C
Yield: 53 %

Procedure:
To a round bottom flash equipped with an overhead stir motor was added 80 g of polyphosphoric acid. The flask was heated to 90° C. and a finely ground mixture of 3-methyl-1H-indazole-5-carboxlic acid 4e (8.0 g, 45.5 mmol) and thiosemicarbazide (4.1 g (45.4 mmol) was slowly added over a period of 30 min. The resulting mixture was stirred for 24 hr. At this point 200 ml of ice water was added to the solution, and the pH of the resulting mixture was adjusted to 7.0 using solid KOH. A precipitate was formed in the process. The precipitate was isolated by filtration, washed sequentially with water and ether, and dried at reduced pressure, affording 5-(3-Methyl-1H-indazol-5-yl)-[1,3,4]thiadiazol-2-ylamine (4f) (5.50 g, 53% yield) as a tan colored solid. 1H 400 MHz NMR (d6 DMSO), 2.54 (3 H, s), 3.17 (1 H, s), 7.54 (1H, d, J=8.0 Hz), 7.83 (1H, t, J=8.0 Hz), 8.06 (1H, s). MS (API-ES) m/z (%): 232 (100%, M++H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9]C=O)=[C:4]([Cl:12])[N:3]=1.C(O)C>Cl>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Agent: Cl
Solvent: CCO
Product: Nc1nc(Cl)c(N)c(Cl)n1
Yield: 64.6 %

Procedure:
N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 500 mg. 2.42 mmol) was dissolved in 0.1 N hydrochloric acid (5 mL, 2.5 mequiv) and ethanol (7 mL) at reflux. The solution was refluxed for 5 hours. Volatiles were removed in vacuo. The residue was partitioned between water (30 mL) adjusted to pH 8 with dilute ammonium hydroxide and ethyl acetate (75 mL). The ethyl acetate layer was dried (sodium sulfate). Evaporation of the ethyl acetate left pink solid (0.40 g). Recrystallization of the solid from 95% ethanol gave the title compound (IV) as light pink needles (280 mg, 65%); darkens and shrinks to black solid above 185° C., does not become fluid below 300° C.; 1H-NMR (DMSO-d6) and mass spectra identical to those described in Example 4.
Reaction SMILES: [CH:1]1([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:16]([OH:26])[CH2:17][CH2:18][NH:19]C(=O)C(F)(F)F)[CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N.CO>ClCCl>[NH2:19][CH2:18][CH2:17][CH:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]#[C:8][CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:11]=1)[OH:26]
Reactant: O=C(NCCC(O)c1cccc(C#CC2CCCCCC2)c1)C(F)(F)F
Agent: N
Solvent: CO
Solvent: ClCCl
Product: NCCC(O)c1cccc(C#CC2CCCCCC2)c1

Procedure:
Deprotection of N-(3-(3-(cycloheptylethynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide followed by flash chromatography (5% (7N NH3/MeOH)/dichloromethane) gave 3-amino-1-(3-(2-cycloheptylethynyl)phenyl)propan-1-ol as a yellow oil. Yield (0.173 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 7.18-7.30 (m, 3H), 4.91 (d, J=6.8 Hz, 1H), 3.00 (br s, 5H), 2.74-2.82 (m, 1H), 1.80-1.94 (m, 3H), 1.68-1.80 (m, 5H), 1.44-1.64 (m, 6H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([N:9]([CH3:11])[CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:19])=[O:18])=[CH:15][CH:14]=1>N1C=CC=CC=1>[ClH:19].[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][CH2:2][C:3]2([N:9]([CH3:11])[CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN(C)C1(CN)CCCCC1
Solvent: c1ccncc1
Product: CN(C)C1(CNC(=O)c2ccc(F)cc2)CCCCC1
Product: Cl
Reaction time: 1 h

Procedure:
A mixture of 1-aminomethylcyclohexyldimethylamine (1.0 g), 4-fluorobenzoyl chloride (2 ml) and pyridine (10 ml) was allowed to stand at room temperature for 1 hr. The crystalline material produced was filtered and recrystallised several times from ethanol/ether to give colourless needles of 1-(4-fluorobenzamidomethyl)-cyclohexyl dimethylamine hydrochloride m.p. 238°-239°.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].[O:8]1[C:10]2[CH2:11][CH2:12][CH2:13][C:9]1=2>[Pd].O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:8][CH:9]1[CH2:13][CH:12]([N:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]2=[O:7])[CH:11]=[CH:10]1
Reactant: O=c1cccc[nH]1
Reactant: C1CC2=C(C1)O2
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: O=c1ccccn1C1C=CC(O)C1
Yield: 18.5 %

Procedure:
21 g (0.22 mol) of 2-pyridone are added at 0° C. to a solution of the palladium(0) catalyst prepared as above (2 mol % of palladium(II) acetate) in 200 ml of dry tetrahydrofuran, and 20.1 g (0.245 mol) of epoxycyclopentene, dissolved in 80 ml of tetrahydrofuran, are then added dropwise over a period of 2 hours, while stirring. The solution which forms is stirred at room temperature for 2 days and then concentrated, the residue is dissolved in methylene chloride, the solution is extracted by shaking with 1 A sodium carbonate solution and the organic phase is concentrated. The residue is chromatographed over silica gel using ethyl acetate/methanol 9/1. 7.2 g (18.49% of theory) of 1-[(1RS,4SR)-4-hydroxycyclopent-2-en-1-yl]pyridin-2(1H)-one are obtained as a viscous oil. 1H NMR (60 MHz, d6 -DMSO), δ[ppm]: 7.65-7.25 (m, 2H), 6.55-6.08 (m, 3H), 5.95-5.63 (m, 2H), 5.26 (d, 1H), 4.73 (m, 1H), 2.85 (m, 1H), 1.32 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([OH:8])=O)[CH3:2].O1CCCC1.[F:17][C:18]([F:22])([F:21])[CH2:19][NH2:20].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([NH:20][CH2:19][C:18]([F:22])([F:21])[F:17])=[O:8])[CH3:2]
Reactant: CCOC(=O)C(C)(O)C(=O)O
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(O)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of 31.5 g (15.5 mmol) 2-hydroxy-2-methyl-malonic acid monoethyl ester in 400 ml of tetrahydrofuran 16.9 g (17.1 mmol) of 2,2,2-trifluoroethylamine, 32.7 g (17.1 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 23.1 g (17.1 mmol) of 1-hydroxybenzotrizole hydrate and 58.1 ml (34.2 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. The solvent was removed by distillation and the residue was extracted with water/ethylacetate. Chromatography on silicagel with heptane/ethylacetate 1:1 yielded 25.4 g (67%) 2-hydroxy-2-methyl-N-(2,2,2-trifluoroethyl)-malonamic acid ethyl ester, MS m/e (%): 242.1 (M−H, 100).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2O[C:34](C=O)=[CH:35][CH:36]=2)=[CH:4][N:3]=1.C([NH:41]CC)C>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[NH:41][CH:34]=[CH:35][CH:36]=2)=[CH:4][N:3]=1
Reactant: CCNCC
Reactant: COc1cc(-c2csc3c(-c4ccc(C=O)o4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(-c4ccc[nH]4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-{4-[4-Amino-7-(5-formyl-2-furyl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide, diethylamine, and the procedure described in General Procedure B.
Reaction SMILES: C([O-])(=O)C.[Na+].[NH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:22])[CH2:8][CH2:7]1.[Br:23]Br>C(O)(=O)C.O>[BrH:23].[Br:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:22])[N:12]([CH:9]1[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]1)[CH2:21]2
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Br
Product: O=C1Nc2ccc(Br)cc2CN1C1CCNCC1
Temperature: 14 °C

Procedure:
To a solution of 6.16 g (0.075 mol) of sodium acetate and 11.565 g (0.05 mol) of 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone in a mixture of 150 ml of glacial acetic acid and 35 ml of water a solution of 8.8 g (0.055 mol) of anhydrous bromine in 20 ml of glacial acetic acid was added dropwise, with stirring and whilst maintaining a reaction temperature of 13 to 15° C. The mixture was filtered and the filtrate was evaporated down in vacuo. To remove any inorganic components the residue was taken up five times in 50 ml of dichloromethane, filtered and evaporated down, then triturated with a little acetonitrile, whereupon crystallisation occurred. The crystals were suction filtered, washed with acetonitrile/diethylether (1/1 v/v) and after drying in vacuo 5.5 g of colourless crystals of melting point 288° C. (decomposition) were obtained. By working up the mother liquors a further 4.5 g of material of the same quality was obtained. Total yield: 10.0 g (51% of theory).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[C:17]([F:25])[CH:16]=3)[CH2:10][C:11](O)([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[N:32]=[C:33]([Si:36]([CH3:39])([CH3:38])[CH3:37])[S:34][CH:35]=1)CCC>>[F:25][C:17]1[CH:16]=[C:15]([N:9]2[CH:10]=[C:11]([CH3:13])[N:12]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([C:31]3[N:32]=[C:33]([Si:36]([CH3:39])([CH3:38])[CH3:37])[S:34][CH:35]=3)=[CH:3][CH:4]=2)[CH:20]=[CH:19][C:18]=1[S:21]([NH2:24])(=[O:23])=[O:22]
Reactant: CC1(O)CN(c2ccc(S(N)(=O)=O)c(F)c2)C(c2ccc(Br)cc2)=N1
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc([Si](C)(C)C)n1
Product: Cc1cn(-c2ccc(S(N)(=O)=O)c(F)c2)c(-c2ccc(-c3csc([Si](C)(C)C)n3)cc2)n1

Procedure:
The title compound was prepared according to the procedure of Example 153 (step 4) using 4-[2-(4-bromophenyl)-4-hydroxy-4-methyl-1H-imidazol-1-yl]-2-fluorobenzenesulfonamide instead of 2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole and using 4-(tributylstannyl)-2-trimethylsilylthiazole instead of 4-(tributylstannyl)thiazole. The crude product was used next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:10]2[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].Cl[C:14]1[N:19]=[C:18]([OH:20])[C:17]([Cl:21])=[CH:16][N:15]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Cl:21][C:17]1[C:18]([OH:20])=[N:19][C:14]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:10]3[CH2:11][CH2:12]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:15][CH:16]=1
Reactant: N#Cc1cc(N)ccc1C1CC1
Reactant: Oc1nc(Cl)ncc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: N#Cc1cc(Nc2ncc(Cl)c(O)n2)ccc1C1CC1
Temperature: 110 °C

Procedure:
5-amino-2-cyclopropylbenzonitrile (25.4 mmol; from the previous reaction) was transferred to a large reaction tube with magnetic stir bar in 250 mL isopropyl alcohol. 2,5-dichloropyrimidin-4-ol (4.20 g, 25.5 mmol) and p-toluenesulfonic acid monohydrate (14.50 g, 76.2 mmol) were weighed out and added. This was heated overnight at 110° C. After that time, it was allowed to cool to room temperature and an orange precipitate was filtered off. The filtrate was concentrated to half volume, and a second precipitate crashed out which was filtered off. Again, the filtrate was concentrated to half volume and a third precipitate crashed out which was filtered off. Finally, further concentration crashed out a fourth precipitate which was collected and washed with hexane. This was dried on high vacuum to give 5.63 g of 5-(5-chloro-4-hydroxypyrimidin-2-ylamino)-2-cyclopropylbenzonitrile as a tosylate salt, containing 1.2 equivalents of p-toluenesulfonic acid (45% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 59 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (70 mg, 59%).
Reaction SMILES: [C:1]1([C:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[C:19]([C:20]4[CH:25]=[CH:24][N+:23]([O-])=[CH:22][CH:21]=4)=[CH:18][N:17]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[N:16]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.ClCCl>FC(C1C=CC=CC=1)(F)F>[C:42]([NH:46][C:24]1[CH:25]=[C:20]([C:19]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([N:8]=[C:7]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:10]=3)=[N:16][N:17]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[CH:18]=2)[CH:21]=[CH:22][N:23]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)N
Reactant: COc1ccc(Cn2cc(-c3cc[n+]([O-])cc3)c(-c3cccc(N=C(c4ccccc4)c4ccccc4)c3)n2)cc1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: FC(F)(F)c1ccccc1
Solvent: ClCCl
Product: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(N=C(c4ccccc4)c4ccccc4)c3)n2)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
200 mg (0.4 mmol) of N-(diphenylmethylidene)-3-[1-(4-methoxybenzyl)-4-(1-oxidopyridin-4-yl)-1H-pyrazol-3-yl]aniline were suspended in 50 ml of trifluoromethylbenzene and 210 μl (2 mmol) of tert-butylamine were added under stirring at room temperature. The mixture was cooled to 0° C. and 260 mg (0.8 mmol) of p-toluensulfonic anhydride were added. The reaction was maintained in the same conditions for 2.5 hours. Then the same amounts of reactants and 2 ml of dichloromethane to obtain a clear solution were added and after further 2 hours the reaction went to completion. The solvent was evaporated and the residue taken up in dichloromethane and washed with water. The organic phase was dried over Na2SO4 and evaporated to dryness, giving 161 mg (73% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C(O[O:14][C:15]([CH3:18])(C)C)(C)(C)C.[C]=O.[CH2:21]([OH:23])C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:21]([O:14][CH2:15][CH3:18])=[O:23])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C)cc1
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CCO
Agent: [C]=O
Product: CCOC(=O)Cc1ccc(C)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
p-Xylene (1.59 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 85 mg ethyl p-methylphenylacetate was obtained by column chromatography, in a yield of 96%. 1HNMR (400 MHz, CDCl3) δ 1.23 (t, J=7.2 Hz, 3H), 2.33 (s, 3H), 3.57 (s, 2H), 4.11 (q, J=7.2 Hz, 2H), 7.11-7.18 (m, 4H); 13CNMR (100 MHz, CDCl3) δ 14.2, 21.1, 41.0, 60.8, 129.1, 139.3, 131.1, 136.6, 171.8; HRMS (ESI) calcd. for C11H14NaO2 [M+Na]: 201.0886. found: 201.0882. The ethyl p-methylphenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 69 mg product p-methylphenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 96%.
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[CH:5]([CH2:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[C:4](=[O:18])[O:3]1.C(O)(C(F)(F)F)=O.[O-]S([O-])(=O)=O.[Ca+2]>O>[C:13]([C:12]1[CH:11]=[C:10]([CH:17]=[CH:16][CH:15]=1)[CH2:9][CH:5]([C:4]([OH:18])=[O:3])[C:6]([OH:8])=[O:7])#[N:14]
Reactant: CC1(C)OC(=O)C(Cc2cccc(C#N)c2)C(=O)O1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(CC(C(=O)O)C(=O)O)c1

Procedure:
A flask containing a mixture of 3-((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)methyl)benzonitrile (4.53 g, 17.5 mmol, Intermediate 70: step a) TFA (30 mL) and water (14 mL) was equipped with a reflux condenser and Drierite® at the outlet, then heated in a 65° C. oil bath for 4 hours. The mixture was concentrated and the title compound was precipitated from water and filtered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][C@H:18]2[CH2:38][CH2:37][C:20]3([O:24][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C@@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:21]3)[CH2:19]2)[C:13](=[O:16])[CH:14]=[CH2:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH:45]=[O:46].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][C@H:18]2[CH2:38][CH2:37][C:20]3([O:21][C@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:23]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:24]3)[CH2:19]2)[C:13](=[O:16])[CH2:14][CH2:15][C:45]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=2)=[O:46])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: C=CC(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: O=Cc1ccccn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2ccccn2)cc1Cl
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of 4-[3-chloro-4-(methylsulfonyl)phenyl]-5-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]pent-1-en-3-one (882 mg) in ethanol (5 mL) were added pyridine-2-carbaldehyde (183 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (47.5 mg) and triethylamine (96 μL), and the mixture was stirred with heating under reflux for 1.5 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (698 mg, yield 66%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[O:13]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14]1.O>ClCCl>[O:13]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][O:20][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:14]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCC1CCOC1
Reaction time: 0.33 h

Procedure:
Triethylamine (2.1 mL, 15 mM) and methanesulfonyl chloride (0.85 mL, 11 mM) were added drop wise to a cold (−5 to −10° C.) solution of 2-(tetrahydro-furan-3-yl)-ethanol (1.14 g, 10 mM) in dichloromethane (15 mL). The reaction was stirred for 20 min at this temp then water (10 mL) was added and the reaction was stirred an additional 10 min then the phases were separated and the aqueous phase was extracted with dichloromethane (3×20 mL). The combined organics were washed with 50% aqueous HCl, sat. NaHCO3, dried (MgSO4), filtered and concentrated to give a quantitative yield of methanesulfonic acid 2-(tetrahydrofuran-3-yl)-ethyl ester.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:2]1.Cl.[C:9]1([CH3:16])[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1>>[CH3:16][C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][C:14]=1[CH:3]([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:2][OH:1]
Reactant: CCCCC1CO1
Reactant: Cc1cccc(C)c1
Agent: Cl
Product: CCCCC(CO)c1ccc(C)cc1C
Temperature: 3 °C
Reaction time: 0.5 h

Procedure:
To a stirred, 0° C. mixture of m-xylene 173g (1.63 mole) and anhydrous stannic chloride 78.0g (0.30 mole) which is constantly swept with nitrogen, is added dropwise, 1,2-epoxyhexane, 30.0g (0.30 mole) in 50 g m-xylene. The exothermic temperature is maintained at 3° C. by the rate of addition. After the addition is completed, the reaction which now contains 223 g (2.0 mole) m-xylene is stirred for 30 minutes at 0° C. then poured into iced concentrated hydrochloric acid. The aqueous and organic layers are separated. After extracting the aqueous portion with ethyl ether, this organic layer is combined with the previous organic fraction. This combined organic material is washed successively with water, sodium bicarbonate and again water. The dried organic solvent mixture of ethyl ether and excess unreacted m-xylene is then removed on rotary evaporator. The concentrated residue is fractionally distilled in vacuo. The third fraction, 112° C./0.5 mm, is shown to be the desired product by spectral and analytical data. The yield is 35.6g (57.6% theory).