Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C(N([S:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[C:31](=[O:45])[NH:32][CH:33]([C:38]([O:40]C(C)(C)C)=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])C(=O)C1C=C(F)C=CC=1)CC(C)C)(C)(C)C.F[C:48](F)(F)[C:49]([OH:51])=[O:50]>ClCCl.C1(OC)C=CC=CC=1>[C:49]([CH:48]([NH:32][C:31]([C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[S:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[C:31]([NH:32][CH:33]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:38]([OH:40])=[O:39])=[O:45])=[O:45])[CH2:37][CH:35]([CH3:34])[CH3:36])([OH:51])=[O:50]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)CC(NC(=O)c1cc(F)ccc1SSN(C(=O)c1cccc(F)c1)C(CC(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(C)CC(NC(=O)c1cc(F)ccc1SSc1ccc(F)cc1C(=O)NC(CC(C)C)C(=O)O)C(=O)O

Procedure:
The general method of Preparation 20 was followed using [S-(R*,R*)]-2-[2-[[2-(1-tert-butoxycarbonyl-3-methylbutylcarbamoyl)-4-fluorophenyldisulfanyl]-5-fluorobenzoylamino]-4-methylpentanoic acid tert-butyl ester (1.8 g, 2.6 mmol) in 20 mL dichloromethane, anisole (2 mL), and 20 mL trifluoroacetic acid. The crude product was recrystallized from methanol/water to afford 0.9 g of the title compound.
Reaction SMILES: Cl[Si](C)(C)C.[CH:6]1([NH:13][CH2:14][CH2:15][N:16]([CH2:27][CH2:28][C:29]2[C:37]3[S:36][C:35](=[O:38])[NH:34][C:33]=3[C:32]([OH:39])=[CH:31][CH:30]=2)[C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C.Cl[C:48](=[O:70])[CH2:49][CH2:50][N:51]([CH2:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:52](=[O:61])[O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>ClCCl.C(OCC)(=O)C>[CH2:19]([O:18][C:17]([N:16]([CH2:27][CH2:28][C:29]1[C:37]2[S:36][C:35](=[O:38])[NH:34][C:33]=2[C:32]([OH:39])=[CH:31][CH:30]=1)[CH2:15][CH2:14][N:13]([CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[C:48](=[O:70])[CH2:49][CH2:50][N:51]([CH2:62][CH2:63][C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:52](=[O:61])[O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OCc1ccccc1)N(CCNC1CCCCCC1)CCc1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(Cl)CCN(CCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N(CCC(=O)N(CCN(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCCCCC1)CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chlorotrimethylsilane (1.323 mL) was added to a cooled (0° C.) solution of benzyl 2-(cycloheptylamino)ethyl(2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)carbamate, prepared as in Example 23 step i) (1.260 g) and triethylamine (1.81 mL) in dichloromethane (35 mL). The reaction mixture was stirred at room temperature for 2 h then a solution of benzyl 3-chloro-3-oxopropyl(phenethyl)carbamate, prepared as in Example 5 step ii) (0.991 g) in dichloromethane (10 mL) was added. The reaction mixture was stirred at room temperature for 4 h then diluted with ethyl acetate and washed with 2M hydrochloric acid (×2) and saturated sodium hydrogen carbonate. The organic layer was separated, washed with water and saturated brine, dried over sodium sulphate, filtered and evaporated. The crude product was purified by flash silica chromatography (Biotage), elution gradient 1 to 6% methanol in dichloromethane. Fractions containing product were evaporated to dryness to afford the product as a yellow foam (1.416 g). The material was used in the next step directly.
Reaction SMILES: [OH:1][C@:2]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@:23]([F:33])([C@@H:24]([O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:34])[CH:19]=[CH:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[C:3](=[O:9])[CH2:4][O:5][C:6](=[O:8])[CH3:7].ClCCl.[C:38](O)(=[O:40])[CH3:39].FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC(CC(C)C)=O>[C:38]([O:1][C@:2]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@:23]([F:33])([C@@H:24]([O:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:34])[CH:19]=[CH:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[C:3](=[O:9])[CH2:4][O:5][C:6](=[O:8])[CH3:7])(=[O:40])[CH3:39]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C
Reactant: CC(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(=O)CC(C)C
Solvent: ClCCl
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C

Procedure:
A mixture of the 17α-hydroxy-21-acetoxy-11β-trimethylsiloxy-9α-fluoro-pregn-1,4-diene-3,20-dione from Example 26 (20.6 g) dichloromethane (50 ml) and acetic acid (20 ml) was treated with trifluoro-acetic anhydride (20 ml) for a period of 5 hours at 25°. The reaction mixture was diluted with methyl-isobutylketone (200 ml) and extracted with sodium bicarbonate solution (500 ml) and then with water (200 ml). The organic layer was dried over sodium sulfate, and evaporated to dryness under reduced pressure. The residue was amorphous, homogenous in TLC (BPB, silica plates No. 254). Crystalline 17α,21-diacetoxy-11β-trimethylsiloxy-9α-fluoropregna-1,4-diene-3,20 -dione (compound 53) was obtained directly from the residue by trituration with methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].C(N(C(C)C)CC)(C)C.[C:23]([O:26][CH2:27][C:28](Cl)=[O:29])(=[O:25])[CH3:24]>ClCCl>[C:23]([O:26][CH2:27][C:28]([NH:1][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)=[O:29])(=[O:25])[CH3:24]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N#Cc1cc(N)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)Nc1cc(C#N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.4 %

Procedure:
A solution of 3-amino-5-(trifluoromethyl)benzonitrile (Intermediate 28, 2.20 g, 11.82 mmol) and di-isopropylethylamine (2.27 mL, 13.0 mmol) in dichloromethane (40 mL) was cooled in an ice-water bath before the addition of 2-chloro-2-oxoethyl acetate (1.40 mL, 13.0 mmol) dropwise. The reaction was allowed to warm to room temperature and stirred for 4 hours. To the reaction was added 2-chloro-2-oxoethyl acetate (0.14 mL) and the reaction stirred at room temperature for a further 18 hours. The reaction was diluted with DCM (100 mL) and the solution washed with 2N HCl (75 mL) and NaHCO3 (75 mL), collected via a hydrophobic frit and the solvent removed to yield the title compound as an orange oil (3.7 g)
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=N[CH:4]=1.[CH2:11]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[CH2:34](N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:11]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:34][CH:4]=2)=[CH:28][CH:27]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(Cl)c1cccnc1
Reactant: CCCCCCCCCCCCCCOc1ccc(CN)cc1
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(CNC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
To a room temperature slurry of 2.01 g of nicotinoyl chloride hydrochloride in 25 ml of methylene chloride is added, via cannula, 3.0 g of product from Example 99 in 75 ml of methylene chloride. After 10 minutes, 3.8 g of triethylamine is added, dropwise, and the solution is stirred at room temperature for 20 hours. The reaction is poured into half saturated sodium bicarbonate and extracted with chloroform. The combined organic layers are washed with saturated sodium chloride and concentrated in vacuo. The residue is purified by chromatography (silica gel: 7.5% methyl alcohol/chloroform) and recrystallized from heptane/methyl alcohol to give 3.57 g of the desired product as pale yellow needles.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]
Reactant: Fc1ccccc1CBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccccc2F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
0.5 M solution of 1-bromomethyl-2-fluoro-benzene (1.50 g, 8.0 mmol) in DMF was added dropwise to a suspension of 3-hydroxy-benzaldehyde (0.89 g, 7.3 mmol), K2CO3 (1.51 g, 11 mmol) and KI (0.12 g, 0.73 mmol) in 100 ml DMF. The reaction mixture was stirred at 90° C. overnight. After cooling to room temperature, the solid residue was filtered off and the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate, the organic layer washed twice with 1M NaOH, dried over Na2SO4 and evaporated to dryness. The residue was purified on silica gel, obtaining 167 mg of the title compound (quantitative yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1)#[CH:2].[CH3:13][O:14][C:15](=[O:37])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:33]=[C:32]([Br:34])[CH:31]=[C:30](Br)[CH:29]=2)=[CH:20][C:19]=1[CH3:36]>CN(C=O)C.C(N(CC)CC)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.[Cu]I>[CH3:13][O:14][C:15](=[O:37])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:29]=[C:30]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][CH:4]=3)[CH:31]=[C:32]([Br:34])[CH:33]=2)=[CH:20][C:19]=1[CH3:36]
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(Br)c2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 75 °C

Procedure:
A mixture of 1-ethynyl-4-trifluoromethyl-benzene (149 mg, 0.88 mmol), {4-[3-(3,5-dibromo-phenyl)-prop-2-ynyloxy]-2-methyl-phenoxy}-acetic acid methyl ester (412 mg, 0.88 mmol, intermediate 2), Pd(PPh3)2Cl2 (101 mg, 0.088 mmol), CuI (46 mg, 0.246 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 20 min. at 75° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using methylene chloride/heptanes mixtures to give (4-{3-[3-bromo-5-(4-trifluoromethyl-phenylethynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester in 94 mg (19%) yield.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][Si](C=[N+]=[N-])(C)C.CCCCCC>C1(C)C=CC=CC=1.CO>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reaction time: 0.33 h
Yield: 31 %

Procedure:
66 mg (0.239 mmol) of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid was dissolved in toluene (0.6 mL) and methanol (0.6 mL), and, under ice cooling, 0.54 mL (0.324 mmol) of 0.6 M trimethylsilyldiazomethane-hexane solution was added, followed by stirring for 20 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=2/1) to afford 21.5 mg of the title compound as a colorless solid (yield 31%). The resulting solid was recrystallized with ethyl acetate-hexane, the generated precipitate was filtered off, the wet crystal was washed with hexane, and subsequently dried under reduced pressure at room temperature to afford the title compound as a colorless crystalline powder. Enantiomeric excess: 99.9% ee or more (CHIRALPAK AD-H, 4.6×1.50 mm, hexane/ethanol-2/1. UV 210 nm, flow rate 1 mL/min., retention time 12.8 min.). Mp 86° C.; [α]20D+5.3° (c 1.10, CHCl3) 1H NMR (400 MHz, CDCl3, δ): 1.65-1.70 (m, 1H), 2.03-2.12 (m, 3H), 2.90 (d, J=12.0 Hz, 1H), 3.07 (m, 1H), 3.79 (s, 3H), 4.12 (dd, J=4.6, 4.4 Hz, 1H), 4.91 (d, J=11.2 Hz, 1H), 5.06 (d, J=11.2 Hz, 1H), 7.35-7.44 (m, 5H); MS m/z: 291 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:9]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:18]([CH2:21][C:22](=[O:24])[CH3:23])(=[O:20])[CH3:19]>O.Cl.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][N:9]=[C:21]([C:22](=[O:24])[CH3:23])[C:18](=[O:20])[CH3:19])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: O=N[O-]
Reactant: CC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)C(=NNc1cccc(F)c1)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a solution of 3-fluoroaniline (1000 mg, 9.00 mmol) in 5 mL of water and 5 mL of concentrated hydrochloride solution, sodium nitrite (746 mg, 10.80 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (2220 mg, 27.00 mmol) and acetylacetone (990 mg, 9.90 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-[(3-fluorophenyl)hydrazono]pentane-2,4-dione (650 mg, 33%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[N:8]1([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][N:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][C:29](=[O:33])[NH:30]2)=[CH:26][C:25]=1[CH2:34][CH2:35]Cl>O>[CH:20]1[CH:21]=[CH:22][C:17]2[S:16][N:15]=[C:14]([N:8]3[CH2:13][CH2:12][N:11]([CH2:35][CH2:34][C:25]4[CH:26]=[C:27]5[CH2:28][C:29](=[O:33])[NH:30][C:31]5=[CH:32][C:24]=4[Cl:23])[CH2:10][CH2:9]3)[C:18]=2[CH:19]=1
Reactant: O=C1Cc2cc(CCCl)c(Cl)cc2N1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium carbonate (56.3 g) and 500 mL of water were placed into a round bottom flask. Added was 50 g of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride and 50 g of 6-Chloro-5-(2-Chloroethyl)oxindole. The reaction mixture was then refluxed for 15 hours. The reaction completion was monitored by TLC. The reaction mass was cooled to room temperature. The resulting compound was filtered and washed with 50 mL of water. The wet compound and 250 mL of acetone were placed into a flask and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered to give a solid cake, which was washed with 50 mL of acetone. The wet cake and 750 mL of methanol were placed into a flask, which was heated to 50° C., and 14 mL of methane sulfonic acid was added to the solution over 20 minutes. The resulting reaction mass was cooled to room temperature and was subjected to a filtration to give a solid compound, which was washed with methanol. The wet compound and 750 mL of water were placed into a flask, and then pH of the solution was adjusted to pH 9 with caustic lye. The reaction mixture was then stirred at room temperature for 1 hour and filtered. The filtered compound was washed with water and dried at 70° C. to give 65 g of crystalline form Ziprasidone base.
Reaction SMILES: C(O[C:4](=[O:6])C)=O.ClCCl.[CH3:10][C:11]1[N:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=3)[CH:18]=[CH:19][C:14]2=[N:13][N:12]=1>ClCCl.CO>[CH3:10][C:11]1[N:15]2[N:16]=[C:17]([C:20]3[CH:21]=[C:22]([NH:26][CH:4]=[O:6])[CH:23]=[CH:24][CH:25]=3)[CH:18]=[CH:19][C:14]2=[N:13][N:12]=1
Reactant: CC(=O)OC=O
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Solvent: CO
Solvent: ClCCl
Product: Cc1nnc2ccc(-c3cccc(NC=O)c3)nn12
Reaction time: 12 h

Procedure:
To 5.53 ml of acetic-formic anhydride was added 250 ml dichloromethane followed by 10 g of 3-methyl-6-[3-(amino)-phenyl]-1,2,4-triazolo[4,3-b]pyridazine. The solution was stirred for 12 hours, then diluted with 1 liter of dichloromethane-methanol (9:1). This solution was washed with saturated aqueous sodium bicarbonate, dried, and concentrated in vacuo. The residue was recrystallized from dichloromethane-methanol to give 6.7 g of an off-white powder, mp 265°-268° C.
Reaction SMILES: [CH2:1]([C:3]1[S:17][C:6]2[NH:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][O:14][CH3:15])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[N:36]=[C:35](C(Cl)(Cl)Cl)[O:34][N:33]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-:42].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:3]1[S:17][C:6]2[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]4[NH:36][C:35](=[O:42])[O:34][N:33]=4)=[CH:22][CH:21]=3)[C:8](=[O:16])[N:9]([CH2:12][CH2:13][O:14][CH3:15])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(CCOC)c(=O)[nH]c2s1
Reactant: O=C([O-])[O-]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CCOC)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.1 %

Procedure:
A mixture of 6-ethyl-3-(2-methoxyethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.25 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.47 g), potassium carbonate (0.15 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and methanol (5 mL). 1N Aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.08 g, 16%).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][C:8]([CH3:12])([CH3:11])[C:9]#[CH:10])=[CH:5][CH:4]=1)#[N:2]>CCN(C1C=CC=CC=1)CC>[CH3:12][C:8]1([CH3:11])[O:7][C:6]2[CH:13]=[CH:14][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[CH:10]=[CH:9]1
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Solvent: CCN(CC)c1ccccc1
Product: CC1(C)C=Cc2cc(C#N)ccc2O1
Yield: 70 %

Procedure:
Cyclisation of the 3-(p-cyanophenoxy)-3-methybut-1-yne (9.77 g) was accomplished by heating in diethylaniline at 210°-220° C. under nitrogen. Purification by distillation, and extraction with dilute hydrochloric acid gave 2,2-dimethyl-6-cyano-2H-benzo[b]pyran as a colourless oil (6.84 g), which slowly crystallised on standing, having a nmr spectrum showing signals at δ146, 6.25 (d, J=10), 5.67 (d, J=10), 6.74 (d, J=8), 7.18 (d, J=2), 7.34 (q, J=8,2).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([OH:8])[C@@:6]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])([CH3:9])[CH2:5][CH2:4][CH2:3]1.[Cl:18][C:19]1[CH:20]=[C:21]2[C:27]([C:28]3[N:33]=[C:32](S(C)=O)[C:31]([F:37])=[CH:30][N:29]=3)=[CH:26][N:25]([S:38]([C:41]3[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=3)(=[O:40])=[O:39])[C:22]2=[N:23][CH:24]=1.C(N(C(C)C)C(C)C)C.O>C1COCC1>[Si:11]([O:10][C@:6]1([CH3:9])[CH2:5][CH2:4][CH2:3][C@H:2]([NH:1][C:30]2[C:31]([F:37])=[CH:32][N:33]=[C:28]([C:27]3[C:21]4[C:22](=[N:23][CH:24]=[C:19]([Cl:18])[CH:20]=4)[N:25]([S:38]([C:41]4[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=4)(=[O:40])=[O:39])[CH:26]=3)[N:29]=2)[C@H:7]1[OH:8])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@]1(C)CCC[C@H](N)[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@](C)(O[Si](C)(C)C(C)(C)C)[C@@H]4O)n3)c3cc(Cl)cnc32)cc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To a stirred suspension of (1R,2R,6S)-6-amino-2-[tert-butyl(dimethyl)silyl]oxy-2-methyl-cyclohexanol, 50e, (0.16 g, 0.62 mmol) in THF (8 mL) in a microwave sealed tube vessel was added 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 1a, (0.29 g, 0.63 mmol) followed by N-ethyl-N-isopropyl-propan-2-amine (0.13 mL, 0.74 mmol). The resulting reaction mixture was capped and warmed to 70° C., stirred for 14 h. The reaction mixture was cooled to ambient temperature, added water (2 mL), concentrated under reduced pressure to remove THF. The crude product was diluted with ethyl acetate (25 mL), insoluble material (sulfone 1a) was removed by filtration. The organic layer was separated, washed with brine (2×5 mL), dried over Na2SO4, filter and concentrated under reduced pressure. The crude product was purified by silica-gel plug using 10-30% ethyl acetate in hexanes as eluant to afford 350 mg of (1R,2R,6S)-2-[tert-butyl(dimethyl)silyl]oxy-6-[[2-methyl[5-chloro-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyridin-4-yl]amino]cyclohexanol (50f).
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)[CH3:4].C[O:15][CH:16](OC)[C:17](=O)[CH:18]=[CH:19]N(C)C>C(O)C>[CH3:4][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17]([CH:16]=[O:15])=[CH:18][CH:19]=[N:13]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: COC(OC)C(=O)C=CN(C)C
Reactant: CC(C)Oc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: CC(C)Oc1ccc(-n2nccc2C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
A solution of [4-(propan-2-yloxy)phenyl]hydrazine hydrochloride (1 g, 4.93 mmol, 1.00 equiv) and (4,4-dimethoxy-3-oxobut-1-en-1-yl)dimethylamine (1.4 g, 8.08 mmol, 1.64 equiv) in ethanol (20 mL) was refluxed for 3 h. The resulting mixture was cooled to room temperature and concentrated under vacuum. Acetone (10 mL) and 6N hydrochloric acid (10 mL) was added to dissolve the residue and the resulting solution was stirred at room temperature overnight. The reaction was diluted with 100 mL of dichloromethane and then washed with 3×50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 3.0-7.0% of methanol in dichloromethane to yield 200 mg (18%) of 1-[4-(propan-2-yloxy)phenyl]-1H-pyrazole-5-carbaldehyde as a yellow oil. LCMS (method A, ESI): RT=1.48 min, m/z=230.9 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[C:29]([C:30](O)=[O:31])=[C:28]([CH3:33])[O:27][N:26]=1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:30]([C:29]2[C:25]([CH3:24])=[N:26][O:27][C:28]=2[CH3:33])=[O:31])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: Cc1noc(C)c1C(=O)O
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)noc2C)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 3,5-Dimethyl-isoxazole-4-carboxylic acid. LC-MS (basic): tR=0.87 min; [M+H]+=471.3.