Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](O)[CH:9]=[CH2:10].CCCCCC>O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:10][CH:9]=[CH2:8])=[O:6]
Reactant: C=CCO
Reactant: O=C(O)CCCCl
Solvent: O
Solvent: CCCCCC
Product: C=CCOC(=O)CCCCl
Temperature: 25 °C
Yield: 79 %

Procedure:
To a mixture of 4-chlorobutyric acid (48 ml; 0.48 mole), allyl alcohol (200 ml) and hexane (1.2 l) p-toluenesulfonic acid (16.0 g; 0.08 mole) was added. The obtained mixture was heated for 5 hours at reflux temperature in such a way that water was simultaneously removed with Dean-Stark apparatus (Vogel's Textbook of Practical Organic Chemistry, Fourth Ed., Longman, London, 1978, p. 411). The mixture was then cooled to room temperature and shaken with 7% aqueous sodium hydrogencarbonate solution (2×500 ml). The obtained solution was dried with magnesium sulfate and after the filtration of the drying agent hexane was evaporated. The crude residue was distilled under reduced pressure 10 mbar at the temperature of 95° C. and the title compound (61.2 g; 79%) was obtained in the form of a colourless oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[OH:2]>[OH-].[Na+].C(O)C>[C:4]1(=[O:10])[NH:3][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:1]=[O:2]
Reactant: O=C1CCCCCN1CO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=O
Product: O=C1CCCCCN1
Yield: 50 %

Procedure:
It has already been disclosed that N-methylolcaprolactam can be prepared in a yield of 67% of the theoretical yield from caprolactam and excess paraformaldehyde (50% excess) in 95% strength ethanol in the presence of 4.2 mol % of sodium hydroxide as catalyst (J. Am. Chem. Soc. 70 (1948), 2115-2118). The reaction specified is carried out in approximately 50% strength solution.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:13](=[O:14])[CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[S:9][C:8]=2[CH:19]=1)=[O:3].[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][OH:24]>O1CCCC1>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][O:24][C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:13](=[O:14])[CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[S:9][C:8]=2[CH:19]=1)=[O:3]
Reactant: CN(C)CCO
Reactant: O=C(Cl)c1ccc2c(c1)Sc1ccccc1CC2=O
Solvent: C1CCOC1
Product: CN(C)CCOC(=O)c1ccc2c(c1)Sc1ccccc1CC2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 1.0 gm. of 3-chlorocarbonyl-10,11- dihydro-11-oxodibenzo[b,f]thiepin as prepared in Example 31, Step 1, in 10 cc. of anhydrous tetrahydrofuran with stirring and add 2 ml. of N,N-dimethylethanolamine. Stir at room temperature for 18 hours and strip the mixture to dryness. Partition the residue between ether and dilute hydrochloric acid and separate the aqueous layer. Basify the aqueous layer with aqueous ammonia and extract with ethyl acetate. Evaporate the organic phase and chromatograph the residue over silica-gel eluting with 90% chloroform in methanol to obtain the title product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([NH2:23])[N:17]=2)=[C:11]([N+:24]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].O1CCCC1.O>CO.[Fe]>[NH2:24][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][C:12]=1[S:15][C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([NH2:23])[N:17]=1
Reactant: Nc1nc(Cl)cc(Sc2ccc(OCc3ccccc3)cc2[N+](=O)[O-])n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(Sc2ccc(OCc3ccccc3)cc2N)n1
Yield: 43.4 %

Procedure:
A solution of the product from Example 217C (0.1 g, 0.257 mmol), iron powder (0.058 g, 1.03 mmol) and ammonium chloride (0.017 g, 0.310 mmol) in a methanol (5 mL), tetrahydrofuran (5 mL), and water (2 mL) solution was heated to reflux for 1.5 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.04 g, 43%).
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].FC(F)(F)[C:17]([O:19][C:20](=O)[C:21](F)(F)F)=[O:18].C(OC(=O)[C:32]([C:34]1[O:35][CH:36]=[CH:37][CH:38]=1)=[CH2:33])C.Cl(O)(=O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>CCOCC>[O:14]=[C:1]([C:36]1[O:35][C:34](/[CH:32]=[CH:33]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:38][CH:37]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=C(C(=O)OCC)c1ccco1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCCCCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: CCCCCCCCCCCC(=O)c1ccc(/C=C/C(=O)OCC)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 11.8 g (0.0589 mole) of lauric acid and 14.8 g (0.0707 mole) of trifluoroacetic anhydride is stirred at room temperature for 1/2 hour. To the mixture 10.0 g (0.060 mole) of ethyl-2-furanylacrylate is added and the mixture is cooled to about -10° C. One ml of 70% perchloric acid is added and the mixture is warmed to room temperature and stirred for 1 hour. The mixture is diluted with 100 ml of ether and treated with saturated aqueous Na2CO3 until basic. The layers are separated and the ether layer washed with saturated aqueous Na2CO3, water, brine and then evaporated to dryness. The residue is distilled 160°-190° C. (0.1 mm Hg) to give ethyl (E)-3-[5-(1-oxododecyl)-2-furanyl]-2-propenoate, mp 50°-51° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[Pd].CCOC(C)=O.CO>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C2=CCC3(CC2)OCCO3)cc1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C2CCC3(CC2)OCCO3)cc1
Yield: 92.9 %

Procedure:
A mixture of methyl 4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzoate (514 mg, 1.87 mmol) and 10% Pd/C (127 mg) in 15 mL of 1:2 v/v EtOAc/CH3OH was shaken for 6.5 h under 45 Psi of H2 using a Parr shaker. Catalyst was filtered off through a cake of Celite and washed with copious of EtOAc. The filtrate was concentrated to give 480 mg of the title compound.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:35][CH:34]=1)[C@@H:10]([OH:31])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:44]([Si:48]([CH3:51])([CH3:50])Cl)([CH3:47])([CH3:46])[CH3:45].N1C=CN=C1>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:37][CH:38]=1)[C@@H:10]([O:31][Si:48]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:51])[CH3:50])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: COCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.85 g (6.48 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-[p-(2-methoxyethoxy)phenyl]-2(R)-[(p-benzyloxyphenyl)methyl]hexanoic acid in 11 ml of DMF are silylated, at RT for 16 h and under a protective gas, with 4.49 g (29.8 mmol) of tert-butyldimethylchlorosilane and 3.6 g (53.1 mmol) of imidazole. The reaction mixture is poured onto ice-water and the whole is extracted 3 times with ethyl acetate. The organic phases are washed with 10% citric acid solution, 2 times with water and with saline, dried with Na2 SO4 and evaporated. The residue is dissolved in 79 ml of methanol and 30 ml of THF, and this solution is treated with 5.37 g of potassium carbonate and 30 ml of water and stirred at RT for 3 h. The reaction mixture is subsequently poured onto an ice-cold 10% citric acid solution, and this mixture is extracted 3 times with ethyl acetate. The organic phases are washed with 2 portions of H2O and saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 1:1) affords the title compound: TLC Rf (C)=0,28; tRet (II)=20.9 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH-].[K+].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([O:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(O)cc1F
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCOc1ccc(C#N)c(F)c1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
60 g of 3-fluoro-4-cyanophenol and 16 g of potassium hydroxide were dissolved in a solvent mixture of 600 ml of ethanol and 60 ml of water. To the resulting solution, was added dropwise 55.8 g of octyl bromide. After the completion of the addition, the obtained mixture was refluxed for six hours and then allowed to cool to room temperature. The solvent was distilled off and 300 ml of ethyl acetate was added to the residue. The organic layer was washed with water until the aqueous layer became neutral. The organic layer was dehydrated over anhydrous sodium sulfate and the solvent was distilled off. After purifying by distillation (main fraction: 0.5 mmHg, 157° to 160° C.), 63 g of 2-fluoro-4-octyloxybenzonitrile was obtained. Yield: 58%. 63 g of the 2-fluoro-4-octyloxybenzonitrile thus obtained was dissolved in 70 ml of absolute ether and 12.7 g of absolute ethanol was added thereto. The obtained mixture was cooled to -10° C. Then hydrogen chloride gas was bubbled therein for 30 minutes under stirring. After confirming that no hydrogen chloride was absorbed any more, the mixture was stirred at room temperature for 72 hours. 400 ml of absolute ether was added to the mixture. The crystals thus precipitated were filtered and vacuum-dried to thereby give 42 g of imino ester hydrochloride. Yield: 52%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][C:5](=[O:7])[O:4][C:3]1=O.[CH2:9]([N:11](CC)CC)C.Cl.CN.C1N=CN(C(N2C=NC=C2)=O)C=1>ClCCl>[CH3:9][N:11]1[C:5](=[O:7])[CH2:6][C@H:2]([CH3:1])[C:3]1=[O:4]
Reactant: CCN(CC)CC
Reactant: C[C@H]1CC(=O)OC1=O
Agent: CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[C@H]1CC(=O)N(C)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
600 mg (5.26 mmol) of (3S)-3-methyldihydro-2,5-furandione (preparation: S. G. Davies, D. J. Dixon, J. Chem. Soc., Perkin Trans. 1, 1998, 17, 2635-2643) are introduced to a vessel together with 559 mg (0.77 ml, 5.52 mmol) of triethylamine in 5 ml of dichloromethane at 0° C., and 373 mg (5.52 mmol) of methylamine hydrochloride are added. The reaction mixture is stirred at room temperature overnight and then 938 mg (5.78 mmol) of N,N-carbonyldiimidazole are added in portions. The mixture is stirred at room temperature for 1.5 h and at reflux temperature for 30 minutes. After it has cooled to room temperature the reaction mixture is washed with 5% strength hydrochloric acid and water, the organic phase is dried over magnesium sulfate, filtered and concentrated and the product is dried under a high vacuum. This gives 605 mg of the product (88% of theory).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH:4]=[CH:3][N:2]=1.S(Cl)(Cl)=O.[CH3:18][O:19][CH2:20][CH2:21][N:22]1[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:23]1=[NH:29].CCN(CC)CC>C1COCC1>[CH3:18][O:19][CH2:20][CH2:21][N:22]1[C:26]([CH3:27])=[C:25]([CH3:28])[S:24]/[C:23]/1=[N:29]\[C:11]([C:6]1[C:5]2[CH:4]=[CH:3][N:2]=[CH:1][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:13]
Reactant: O=C(O)c1cccc2cnccc12
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cccc2cnccc12
Yield: 26.4 %

Procedure:
The isoquinoline-5-carboxylic acid (Lancaster, 0.25 g, 1.4 mmol) was converted to the corresponding acid chloride with 5 mL of thionyl chloride using the method described in Example 134A. The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.3 mL, 2.2 mmol) and the acid chloride in 30 mL THF were processed as in Example 134B to afford the title compound (98 mg, 0.29 mmol, 27% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.31 (s, 3H), 2.35 (s, 3H), 3.31 (s, 3H), 3.81 (t, J=5.3 Hz, 2H), 4.50 (t, J=5.3 Hz, 2H), 7.76 (dd, J=7.5, 7.5 Hz, 1H), 8.23 (d, J=8.1 Hz, 1H), 8.48 (d, J=6.4 Hz, 1H), 8.61 (dd, J=7.1, 1.4 Hz, 1H), 9.03 (d, J=6.1 Hz, 1H), 9.27 (d, J=1.0 Hz, 1H); MS (DCI/NH3) m/z 342 (M+H)+; Anal. calculated for C18H19N3O2S: C, 63.32; H, 5.61; N, 12.31. Found: C, 62.97; H, 5.54; N, 12.07.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=3F)[N:7]=[N:6][N:5]=2)[CH2:3][CH2:2]1.[Si:19]([O:26][CH2:27][CH2:28][OH:29])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.O>[Si:19]([O:26][CH2:27][CH2:28][O:29][C:10]1[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=1[N:8]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]=[N:7]1)([C:22]([CH3:24])([CH3:25])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCCO
Reactant: O=[N+]([O-])c1ccc(F)c(-n2nnnc2C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc([N+](=O)[O-])cc1-n1nnnc1C1CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 12.6 %

Procedure:
A mixture of 5-cyclopropyl-1-(2-fluoro-5-nitrophenyl)-1H-tetrazole (112 mg, 0.45 mmol), 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (159 mg, 0.9 mmol) and Cs2CO3 (325 mg, 1.0 mmol) in DMF (3 mL) was heated to 50° C. and stirred for 4 hr. The reaction was cooled and then poured in to EtOAc (30 mL) and H2O (20 mL). The aqueous and organic layers were partitioned and the aqueous was extracted with EtOAc (2×20 mL). The combined organic layers were dried (Na2SO4), filtered and the solvent removed under vacuum to leave a crude residue. The residue was dry-loaded on to silica gel and purified by column chromatography on silica gel using EtOAc/heptane (4:6 to 1:0) to give the desired product (23 mg, 13% yield), followed by the desired product as de-silylated material, 2-(2-(5-cyclopropyl-1H-tetrazol-1-yl)-4-nitrophenoxy)ethan-1-ol (82 mg, 63%). Both products were taken to the final desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([NH2:20])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>N1C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([NH:20][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc([N+](=O)[O-])ccc21
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1nc(NC(=O)c2cccc(Cl)c2)c2cc([N+](=O)[O-])ccc21
Reaction time: 6 h
Yield: 36 %

Procedure:
3-Amino-5-nitroindazole-1-carboxylic acid tert-butyl ester (600 mg, 2 mmol) was dissolved in dry pyridine (15 mL) under nitrogen. The solution was cooled on an ice bath and 3-chlorobenzoyl chloride (0.3 mL, 2 mmol) added. After 6 hours, the mixture was diluted with EtOAc, washed with 1M hydrochloric acid solution (×3) and brine then dried over magnesium sulfate and concentrated to a solid. Purification by column chromatography (silica, 7:3 petrol)-EtOAc) afforded the title compound as a solid (300 mg, 39%); 1H NMR (400 MHz, CDCl3) 1.77 (9H, s), 7.52 (1H, t), 7.62 (1H, d), 7.90 (1H, d), 8.07 (1H, m), 8.32 (1H, d), 8.45 (1H, d), 9.22 (1H, brs), 9.32 (1H, s); MS (ES+) m/e=417.
Reaction SMILES: [C:1]1(=[S:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Br[CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH-:15].[OH:15][C:14]1[N+:2]2[CH2:3][CH2:4][C:5]3[C:10]([C:1]=2[S:11][C:13]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: S=C1NCCc2ccccc21
Reactant: O=C(Cl)C(Br)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccccc1-2
Product: [OH-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(aa) Method A: 23.65 g of 3,4-dihydroisoquinoline-1(2H)-thione was dissolved in 750 ml of chloroform, whereupon the solution was treated at room temperature while cooling firstly with 54 g of α-bromophenylacetyl chloride and 90 minutes later with 53 ml of triethylamine and the mixture was stirred at room temperature overnight. The reaction mixture was washed with water, dried over magnesium sulfate and evaporated in vacuo. There was obtained 5,6-dihydro-3-hydroxy-2-phenylthiazolo[2,3-a]isoquinolinium hydroxide (internal salt) of m.p. 210° (dec.) (from acetonitrile/dioxane).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]#N)[CH:7]=[CH:6][C:5]=12.[OH:12]S(O)(=O)=O.[CH3:17][CH2:18][OH:19]>>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([O:19][CH2:18][CH3:17])=[O:12])[CH:7]=[CH:6][C:5]=12
Reactant: N#Cc1ccc2nonc2c1
Reactant: CCO
Reactant: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2nonc2c1
Yield: 75 %

Procedure:
To a solution of benzo[c][1,2,5]oxadiazole-5-carbonitrile (700 mg, 1.33 mol) in EtOH (100 mL) was added H2SO4 (20 mL) and the reaction mixture was refluxed for 14 h. The reaction was concentrated in vacuo and the residue was diluted with water (50 mL), and extracted with DCM (2×100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and then concentrated in vacuo to afford ethyl benzo[c][1,2,5]oxadiazole-5-carboxylate (0.7 g, 75%) as a yellow, sticky solid.
Reaction SMILES: [C:1](=[O:29])([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][NH2:23])=[O:21])[N:14]=2)[CH:4]=1.[CH3:30]OC(OC)OC.CS(O)(=O)=O.CO.ClCCl>C1COCC1>[C:1](=[O:29])([O:24][CH2:25][CH:26]([CH3:27])[CH3:28])[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]3[O:21][CH:30]=[N:23][N:22]=3)[N:14]=2)[CH:4]=1
Reactant: COC(OC)OC
Reactant: CC(C)COC(=O)Oc1cc(-c2ncn(/C=C\C(=O)NN)n2)cc(C(F)(F)F)c1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)COC(=O)Oc1cc(-c2ncn(/C=C\c3nnco3)n2)cc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 4.9 %

Procedure:
In a 100-mL, 3-neck round-bottomed flask equipped with nitrogen inlet, and a rubber septum, (Z)-3-(1-(3-hydrazinyl-3-oxoprop-1-enyl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)phenyl isobutyl carbonate (2 g, 1.0 eq.) was dissolved in THF (20 mL, 10V). Trimethylorthoformate (0.56 g, 1.1 eq.) and methanesulphonic acid (0.23 g, 0.5 eq.) were added and the reaction was refluxed at 70° C. for 2-3 h. The progress of the reaction was followed by TLC analysis on silica gel with 10% MeOH-dichloromethane as mobile phase. SM Rf=0.40 and Product Rf=0.5. Reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine solution (3×50 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 2.5 g of crude compound. The crude reaction mixture was purified by column chromatography using silica 60/120 using dichloromethane:Methanol as mobile phase. The column was packed in dichloromethane and started eluting in dichloromethane in gradient manner starting with fraction collection (25-mL fractions). Compound started eluting with 0.8% Methanol in dichloromethane. Fractions containing such TLC profile was collected together to obtain pure compound (0.1 g).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:14]([C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=1[S:29](Cl)(=[O:31])=[O:30])([CH3:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH:14]([C:17]1[CH:22]=[C:21]([CH:23]([CH3:24])[CH3:25])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=1[S:29]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1)(=[O:31])=[O:30])([CH3:15])[CH3:16]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)c2ccc3c(c2)Cc2ccccc2-3)c(C(C)C)c1

Procedure:
For example, fluorene can be reacted with 2,4,6-triisopropylbenzenesulfonyl chloride in the presence of aluminum chloride to yield 2-(2,4,6-triisopropylphenylsulfonyl)fluorene, which can be refluxed with sodium dichromate dihydrate in glacial acetic acid to yield 2-(2,4,6-triisopropylphenylsulfonyl)fluorenone, which in turn can be refluxed with malononitrile in methanol in the presence of piperidine to yield 2-(2,4,6-triisopropylphenylsulfonyl)-9-(dicyanomethylene)fluorene.
Reaction SMILES: Br[C:2]1[C:10]([Cl:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:14]1([NH2:17])[CH2:16][CH2:15]1.C([O-])(=O)C.[K+].C(N(CC)CC)C>C(O)(C)C>[Cl:11][C:10]1[C:2]([NH:17][CH:14]2[CH2:16][CH2:15]2)=[C:3]([CH:7]=[C:8]([F:13])[C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: NC1CC1
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C(O)c1cc(F)c(F)c(Cl)c1NC1CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
In a sealed tube a mixture of 2-bromo-3-chloro-4,5-difluorobenzoic acid (Example 20, 7.96 g, 29.3 mmol), cyclopropyl amine (4.20 mL, 58.7 mmol), potassium acetate (5.77 g, 58.6 mmol), cupric acetate monohydrate (0.50 g, 2.5 mmol), and triethylamine (4.9 mL, 35.19 mmol) in isopropyl alcohol is stirred at 80° C. After 16 hours, the reaction mixture is concentrated under vacuum, and the resulting residue is dissolved in ethyl acetate. The organic layer is washed with 1.0 M hydrochloric acid, water, and brine. The organic layer is dried over MgSO4 and filtered. The filtrate is concentrated under vacuum and purified via flash column chromatography (5% isopropyl alcohol/1% formic acid/94% dichloromethane) to afford the title compound (4.62 g). MS CI: m/z 248 (MH+).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][N:7]1[C:11](O)=[CH:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:8]1.[C:19]([O-:22])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Cl:3][C:11]1[N:7]([CH3:6])[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:10]=1[CH:19]=[O:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(-c2ccccn2)cc1O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccccn2)c(C=O)c1Cl
Temperature: 80 °C
Yield: 64 %

Procedure:
DMF (35 mL) was cooled to 0° C. in an ice bath. POCl3 (99 mL, 1059 mmol) was added dropwise followed by addition of 1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-ol (26.5 g, 151 mmol). The resulting suspension was heated at about 80° C. for about 18 h. The mixture was allowed to cool to rt then added to ice-water (2000 mL). Saturated aqueous Na2CO3 was slowly added until the solution reached a pH>7. The resulting suspension was filtered and the solids washed with H2O (200 mL). The filter cake was dissolved in DCM (500 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazole-4-carbaldehyde (21.38 g, 64%) as a yellow solid: LC-MS (Table 1, Method g) Rt=1.72 min, m/z 222 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 10.58 (s, 1H), 8.68-8.64 (m, 1H), 8.01-7.87 (m, 2H), 7.49-7.40 (m, 1H), 3.91 (s, 3H).