Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C:7](=[CH:8][CH:9]=[C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:21].CC(=O)CC.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C:7](=[CH:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21]
Reactant: C[C@]12CC[C@H]3C(=CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: CCC(C)=O
Product: C[C@]12CCC(=O)C=C1CC=C1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
A solution of androst-5,7-diene-3β,17β-diol (2.9 g, 10 mmol) in 150 ml toluene is azeotropically dried for one hour. Butanone (15 ml) is added followed by aluminum isopropoxide (1.7 g, 8 mmol) and the mixture is heated at reflux for 2.5 hours. The solution is then concentrated to a volume of 25 ml, diluted with trichloromethane, and washed with 5% hydrochloric acid, aqueous sodium bicarbonate, and brine. Concentration and chromatography affords androst-4,7-diene-3,17-dione.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[CH2:27]([O:34][C:35](=[O:41])[NH:36][C@H:37]([CH3:40])[CH2:38]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl.O>[CH2:27]([O:34][C:35](=[O:41])[NH:36][C@H:37]([CH3:40])[CH2:38][I:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[C@H](CO)NC(=O)OCc1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: C[C@H](CI)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triphenylphospine (24 g, 91.8 mmol) was added to a solution of imidazole (12.5 g, 184 mmol) in CH2Cl2 (231 ml), then was cooled to 0 degrees C. Iodine (23.3 g, 91.8 mmol) was added to the suspension. The reaction mixture turned yellow, then faintly brown. After 5 minutes ((R)-2-hydroxy-1-methyl-ethyl)-carbamic acid benzyl ester (9.59 g, 45.9 mmol) was added and the reaction mixture was warmed to RT then stirred for 3 h. Then, H2O (7 ml) was added and the reaction mixture was partitioned between CH2Cl2 (300 ml) and H2O (600 ml). The aqueous layer was extracted again with CH2Cl2 (200 ml). The combined organic layer was then washed with a solution of 1:9 aq. saturated Na2S2O3: H2O (140 ml), then brine (400 ml). The combined organics were dried with MgSO4, filtered, concentrated in vacuo, then filtered through a plug of silica gel washing with 15% EtOAc/hexanes (1.5 liter). The solution was concentrated in vacuo, then the solid was washed with hexane and the resultant white solid was used in the next reaction without further purification (11 g, 75%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=2)[CH:12]=1)=[O:7])[CH3:4].Cl[CH2:22][C:23]1[N:24](C)[CH:25]=[CH:26][N:27]=1.[CH2:29]1COCC1>>[CH2:3]([O:5][C:6]([C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([O:20][CH2:22][C:23]3[NH:24][CH:25]=[CH:26][N:27]=3)[CH3:29])[CH:14]=2)[CH:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cn(-c2cccc(CO)c2)cn1
Reactant: C1CCOC1
Reactant: Cn1ccnc1CCl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cn(-c2cccc(C(C)OCc3ncc[nH]3)c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a suspension of NaH (308 mg, 7.7 mmol, 60% in mineral oil) in dry THF (6 mL) under N2 atmosphere was added a solution of alcohol 7 (410 mg, 1.38 mmol) in THF (2 mL) while stirring for 30 min at room temperature. The reaction mixture was cooled to 0° C. and the compound 14 (crude 200 mg, 1.53 mmol) in THF (1 mL) was added dropwise and allowed to come to room temperature during a period of 30 min after which it was refluxed for 12 h. The mixture was quenched with ice water (5 mL), acidified to pH 2-3 by adding aqueous HCl solution (2N). The reaction mixture was extracted with CH2Cl2 (3×20 mL), washed with brine, dried over Na2SO4 and concentrated. The crude mass was taken in ethanol (10 mL), purged HCl gas for 30 min. and stirred at room temperature for 3 h. After evaporation of solvent, the crude mass was purified by column chromatography using 28% ethylacetate in hexane to furnish 14a (150 mg, 25%) as a white solid, mp-83.8-88.6° C.
Reaction SMILES: [Br-].C[O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:8][C:7]=1[CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O.[CH3:41][CH:42]([CH3:45])[CH:43]=O>>[CH2:21]([C:7]1[O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:10][C:6]=1[CH2:4][OH:3])[CH2:41][CH:42]([CH3:45])[CH3:43]
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)C=O
Agent: [Br-]
Product: CC(C)CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1CO

Procedure:
Prepared from intermediate 62 and 2-methylpropanal
Reaction SMILES: [CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][C:11]=1[N+]([O-])=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CO.ClCCl>[CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=2)=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC[C@H](C)Oc1ccc(O)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CO
Product: CCCCCC[C@H](C)Oc1ccc(-c2ccc(O)cc2)cc1

Procedure:
The same procedure as that used for saponification of (S)-4-(1-methylheptyloxy)-3-nitro-phenol was used except the reaction was carried out in a methanol/dichloromethane [4:1] mixture at 60° C. Flash chromatography with hexanes/ethyl acetate [93/7] afforded (S)-4'-(1-methylheptyloxy)-4-hydroxybiphenyl (Compound 40, Scheme VIII, R2 =(S)-OCH(CH3)C6H13) as a white solid (mp 100.5° C.); Rf [hexanes/ethyl acetate 90/10]: 0.2; 1H NMR (300 MHz, CDCl3): δ 0.88(t, 3H, J=6.6 Hz), 1.20-1.64(m, 9H), 1.33(d, 3H, J=6.1 Hz), 1.74(m, 1H), 4.38(m, 1H), 5.07(s, 1H), 6.87(d,2H, J=8.5 Hz), 6.93(d, 2H, J=8.5 Hz), 7.42(d, 2H, J=8.5 Hz), 7.44(d, 2H, J=8.5 Hz); 13C NMR (300 MHz, CDCl3): δ 14.02, 19.73, 22.54, 25.51, 29.22, 31.74, 36.45, 74.17, 115.59, 116.16, 127.74, 127.94, 133.22, 133.77, 154.55, 157.31; IR (CHCl3): 3560, 3350(broad), 3020, 2920, 2840, 1610, 1500, 1250, 1220, 1175, 825 cm -1 ; Mass spectrum, m/z(rel.intensity): 298(M+ 11), 186(100), 185(4), 157(4).
Reaction SMILES: CC1C=CC(S([O-])(=O)=O)=CC=1.CN1C2C(S/C/1=[CH:22]\[C:23]1[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N+:26]([CH3:33])=[CH:25][CH:24]=1)=CC=CC=2.[Br:34]C[CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].N1C2C(=CC=CC=2)C(C)=CC=1>O1CCOCC1>[Br-:34].[C:39]([CH2:38][CH2:37][CH2:36][CH2:33][NH+:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]([CH3:22])[CH:24]=[CH:25]1)([OH:41])=[O:40]
Reactant: O=C(O)CCCCBr
Reactant: CN1/C(=C/c2cc[n+](C)c3ccccc23)Sc2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cc1ccnc2ccccc12
Solvent: C1COCCO1
Product: CC1C=C[NH+](CCCCC(=O)O)c2ccccc21
Product: [Br-]
Temperature: 25 °C
Yield: 70 %

Procedure:
The synthesis of the carboxylic acid derivative of thiazole orange was adapted from published procedures, L. G. S. Brooker, et al., J. Am. Chem. Soc. 64:199-210 (1942); H. S. Rye, et al., Nucl. Acids Res. 20:2803-2812 (1992). 5.7 g (32 mmol) of 5-bromovaleric acid and 1.5 mL (11 mmol) of lepidine were refluxed in 30 mL of distilled dioxane under nitrogen overnight. The reaction mixture was allowed to cool to room temperature and filtered. The precipitate was washed twice with 10 mL of dioxane followed by 50 mL of petroleum ether to yield 2.6 g (70%) of pure 1-(4-Carboxybutyl)-4 -methyl-1,4-dihydro-quinolinium bromide.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:10][CH2:11][CH:12]3[O:14][CH2:13]3)[C:4]=2[CH:3]=[CH:2]1.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:18]=2[N:17]=[CH:16]1>>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][N:27]3[CH2:28][CH2:29][N:24]([C:23]4[C:18]5[N:17]=[CH:16][NH:15][C:19]=5[CH:20]=[CH:21][CH:22]=4)[CH2:25][CH2:26]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: c1cc(N2CCNCC2)c2nc[nH]c2c1
Product: OC(COc1cccc2[nH]ccc12)CN1CCN(c2cccc3[nH]cnc23)CC1

Procedure:
The title compound is prepared from the reaction of 1-(indole-4-oxy)-2,3-epoxypropane (2.0 mmole) and 1-(1H-benzimidazole-4-yl)piperazine (2 mmole) according to the above procedures.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[O:23]>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([NH:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[O:23])=[O:5]
Reactant: NC(=O)c1ccc(F)cc1N
Reactant: O=C(O)C(Br)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1ccc(F)cc1NC(=O)C(Br)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromo-2-(4-fluorophenyl)acetic acid (425 mg, 1.82 mmol) in DCM (5 mL) and DMF (0.05 mL) was added oxalyl chloride (0.17 mL, 1.91 mmol) and the solution was stirred for 0.75 h. The solution was then cooled to 0° C. and a solution of 2-amino-4-fluorobenzamide (267 mg, 1.73 mmol) in pyridine (1 mL) was added. The solution was stirred at rt for 1 h and then evaporated. The crude residue was partitioned between EtOAc and 2 N HCl. The EtOAc layer was evaporated to give 2-(2-bromo-2-(4-fluorophenyl)acetamido)-4-fluorobenzamide as a crude oil which was used without further purification. (420 mg, 62%). LC-MS (ESI) m/z 369 (M−H)—.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([CH2:8][CH2:9][C:10]([CH3:12])=[O:11])[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=1.C(OCC)(OCC)O[CH2:17][CH3:18].B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)C>[CH2:17]([O:11][C:10]1([CH3:12])[CH2:9][CH2:8][CH:7]2[C:2](=[CH2:1])[CH:3]1[CH2:4][CH2:5][C:6]2([CH3:14])[CH3:13])[CH3:18]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)CCC1C(C)=CCCC1(C)C
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: C=C1C2CCC(C)(OCC)C1CCC2(C)C
Temperature: 25 °C
Yield: 97.8 %

Procedure:
480 g (2.21 mol) of dihydro-α-ionone, 368 g (2.48 mol) of triethyl orthoformate and 480 ml of abs. ethanol are treated dropwise while stirring during 15 minutes with a solution of 34.5 g (0.31 mol) of boron trifluoride etherate in 500 ml of ethanol and the mixture is subsequently heated to an internal temperature of 46°-48° for 60 minutes. After cooling the reaction mixture to room temperature it is stirred with 600 ml of a 10% aqueous sodium hydroxide solution. After extraction with ether and evaporation of the organic phase there are obtained 668.7 g of a slightly yellow liquid which, after flash distillation in a vacuum, gives 480.5 g of crude product (b.p. 45°-73°, 0.07 mbar). After fractionation in a vacuum over a 20 cm Widmer column there are obtained 406.2 g (82.7% of theory) of a slightly yellowish colored liquid (b.p. 48°-67°, 0.06 mbar) which contains the desired bicyclo-nonane in an isomer ratio of exo:endo=2:1
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:22]=[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:20]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:19][C:10]=1[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12].[C:35]([O-])(=O)[CH3:36].[Na+].Cl>O.C(OCC)(=O)C>[C:1]([N:23]([C:21]1[C:20]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:19][C:10]2[C:11](=[O:12])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:35]([CH3:36])[O:8][C:9]=2[CH:22]=1)[S:24]([CH3:27])(=[O:26])=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)CC(=O)c1cc(Oc2ccccc2)c(NS(C)(=O)=O)cc1O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(C)oc2cc(N(C(C)=O)S(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Reaction time: 0.17 h
Yield: 55.6 %

Procedure:
2.55 ml of acetic anhydride was added to 850 mg of ethyl 2-(2-hydroxy-4-methylsulfonylamino-5-phenoxybenzoyl)acetate and 540 mg of sodium acetate. The mixture was stirred for 10 minutes at 110°-120° C. The reaction mixture was introduced into a mixture of 20 ml of ethyl acetate and 20 ml of water. The resulting mixture was adjusted to pH 2 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 5 : 1 mixture of toluene and ethyl acetate) to obtain 550 mg (yield: 55.6%) of 7-(N-acetyl-N-methylsulfonylamino)-3-ethoxycarbonyl-2-methyl-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[N:25]=[C:26]([SH:28])[S:27][C:23]=2[CH:22]=1>CN(C=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:30]=[CH:29][C:24]3[NH:25][C:26](=[S:28])[S:27][C:23]=3[CH:22]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc2nc(S)sc2c1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Nc2ccc3[nH]c(=S)sc3c2)=C(c2ccccc2)S1(=O)=O
Temperature: 140 °C
Yield: 4.8 %

Procedure:
2-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (110 mg, 0.330 mmol) was dissolved in dry DMF (0.5 mL) under nitrogen atmosphere. 6-Amino-1,3-benzothiazole-2-thiol (181 mg, 0.991 mmol) was added and the reaction mixture was heated in a microwave reactor for 25 mins at 140° C. The crude product was purified by preparative HPLC affording the title compound (7 mg, 4.5%). 1H NMR (500 MHz, CD3CN): δ 1.00 (t, 3H), 1.43-1.52 (m, 2H), 1.78-1.85 (m, 2H), 3.75 (t, 2H), 6.86-7.00 (m, 3H), 7.11-7.28 (m, 5H), 7.84 (bs, 1H).
Reaction SMILES: [C:1](=[S:5])([NH2:4])[CH2:2][CH3:3].Br.Br[CH:8]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O>CN(C=O)C>[CH2:2]([C:1]1[S:5][C:8]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:4]=1)[CH3:3]
Reactant: CCC(N)=S
Reactant: O=C(c1ccc(F)cc1)C(Br)c1ccncc1
Agent: Br
Solvent: CN(C)C=O
Product: CCc1nc(-c2ccc(F)cc2)c(-c2ccncc2)s1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
At room temperature, 1.31 g (14.7 mmol) propanethioamide are added to a solution of 5.00 g (13.3 mmol) of 2-bromo-1-(4-fluorophenyl)-2-(4-pyridyl)ethanone hydrobromide (described, for example, in Chem. Pharm. Bull. 2005, 53, 410-418) in 30 ml of DMF, and the mixture is stirred for 16 h. Subsequently, the reaction mixture is stirred into 100 ml of ice-water, 50 ml of a saturated aqueous Na—HCO3 are added and the mixture is extracted with ethyl acetate (3×100 ml). The combined organic phases are washed with water (2×100 ml), dried over MgSO4 and freed from the solvent under reduced pressure. The crude product is then purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 2.85 g (75%) of the desired product; 1H-NMR (DMSO-d6) δ: 8.53 (d, 2H), 7.47 (m, 2H), 7.26 (d, 2H), 7.17 (m, 2H), 3.05 (q, 2H), 1.37 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:18]2CC[C:17]=12.O.[C:25](O)(=O)[CH3:26]>>[CH:22]1[C:21]2[CH:18]=[CH:17][C:16]([N:15]3[C:11](=[O:12])[C:6]4=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=[C:7]4[C:8]3=[O:10])=[CH:26][C:25]=2[CH:23]=1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)O
Reactant: Nc1cccc2c1CC2
Solvent: O
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1c1ccc2c(c1)C=C2
Temperature: 25 °C

Procedure:
A mixture of 4-nitrophthalic anhydride (3.46 g, 17.9 mmol) and 4-aminobenzocyclobutene (2.20g, 18.5 mmol) was refluxed in acetic acid under N2 for about 17 hours. The dark reaction mixture was then allowed to cool to room temperature and poured into 500 ml of H2O, followed by extraction with CH2Cl2 (75 ml+3×50 ml). The dark extract was then washed with approximately 300 ml of H2O and then dried over MgSO4. Complete removal of CH2Cl2 from the extract by rotary evaporator afforded a dark oil, which was purified by column chromatography (150 g silica gel; using 1:1 petroleum ether/CH2Cl2 as eluent). Pure product was isolated from the first fraction as yellow solid. Yield: 3.21 g (65%). Calc. for C16H10N2O4 : 65.30% C; 3.42% H; 9.52% N. Found: 65.21% C; 3.39% H; 9.58% N. Mass spectroscopy: 294 (M+, 100%). Proton NMR (CDCl3): 3.24 (singlet, alicyclic protons). 7.00-7.23, 8.06-8.72 (complex, aromatic protons). IR(KBr): 2900 w, 2770 m, 2650 m (alicyclic C--H stretches); 1720, 1775 (Symmetric and asymmetric stretches of imide group): 1350, 1540 (symmetric and asymmetric stretches of nitro group).
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[CH:21][N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1.CI>C1COCC1>[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[C:21]([CH3:1])[N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1
Reactant: [Li]CCCC
Reactant: O=S(=O)(c1ccccc1)n1ccc2nc(Cl)ccc21
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CI
Product: Cc1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.6 M n-butyllithium in hexanes (24 mL, 39 mmol) was added to a solution of N,N-diisopropylamine (5.8 mL, 42 mmol) in THF (80 mL) at −78° C. Following complete addition, the mixture was allowed to stir at 0° C. for 30 minutes and was then re-cooled to −78° C. A solution of 5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (7.6 g, 26 mmol, from Step 1) in THF (38 mL) was added dropwise. After stirring at −78° C. for 1 hour, methyl iodide (3.2 mL, 52 mmol) was added. The mixture was allowed to slowly reach room temperature, at which time it was quenched by the addition of saturated NH4Cl. The product was extracted with EtOAc, and the extracts were washed with water (2×), brine, dried over sodium sulfate, filtered and concentrated to afford product as a yellow oil which was used without further purification (8.0 g, 100%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([F:19])=[C:14]([CH:18]=1)[C:15](Cl)=[O:16].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([F:19])=[C:14]([CH:18]=1)[C:15]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1)=[O:16]
Reactant: CN1CCC(N)CC1
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(NC(=O)c2cc(Cl)ccc2F)CC1

Procedure:
A mixture of 23.9 g 4-amino-1-methyl-piperidine, 48.5 g 5-chloro-2-fluoro-benzoyl chloride, 44 ml triethylamine and 550 ml benzene is refluxed for 2 hours. Thereafter the solvent is evaporated off in vacuo and the residue is added dropwise under stirring to water. The solution is made alkaline and extracted with toluene. The toluene phase is dried and evaporated. The residue is recrystallised from methylene chloride/ether/petroleum ether to give the heading compound, m.p. 143°-145°.
Reaction SMILES: [C:1]([C:4](=[C:6]1[S:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[S:7]1)[Cl:5])(O)=[O:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O>C(OCC)C.C(OCC)(=O)C.Cl>[Cl:5][C:4](=[C:6]1[S:7][CH:8]([C:10]([O:12][CH3:13])=[O:11])[S:9]1)[CH:1]=[O:2]
Reactant: COC(=O)C1SC(=C(Cl)C(=O)O)S1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C1SC(=C(Cl)C=O)S1

Procedure:
Methyl 2-(1-carboxy-1-chloromethylene)-1,3-dithietane-4-carboxylate (1.29 g) and oxalyl chloride (700 μl) are reacted together in ethyl ether in the presence of N,N-dimethylformamide (50 μl), and the reaction mixture is concentrated under reduced pressure. The resulting residue comprising methyl 2-(1-chlorocarbonyl-1-chloromethylene)-1,3-dithietane-4-carboxylate is dissolved in THF (70 ml) and reacted with lithium tri-t-butoxyalminum hydride (1.36 g) at -78° C. for 30 minutes. The reaction mixture is diluted with a mixture of ethyl acetate and dil. HCl, and the organic layer is separated after vigorous stirring. The separated organic layer is dried, vacuum concentrated, and purified by chromatography over silica gel to give methyl 2-(1-chloro-1-formylmethylene)-1,3-dithietane-4-carboxylate. Yield: 328 mg (27%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]([C:10]([O:12]CC)=O)=[C:7](Cl)[N:8]=1.CSC1NC(=O)C(C(OCC)=O)=NN=1.S(Cl)(Cl)=O.Cl.[CH2:34]([O:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40]([NH2:42])=[NH:41])[CH:35]=[CH2:36]>C(#N)C.C(N(CC)CC)C>[CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]2[C:10](=[O:12])[NH:42][C:40]([C:39]3[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=3[O:37][CH2:34][CH:35]=[CH2:36])=[N:41][C:7]=2[N:8]=1
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Reactant: C=CCOc1ccccc1C(=N)N
Agent: CCOC(=O)c1nnc(SC)[nH]c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: C=CCOc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Reaction time: 8 h

Procedure:
A cooled (5° C.) solution of 3-methylthio-5-chloro-6-carboethoxy-1,2,4-triazine (prepared by heating 3-methylthio-5-oxo-6-carboethoxy-4,5-dihydro-1,2,4-triazine, 1.5 g, with thionyl chloride, 30 ml, under reflux for two hours and thereafter removing thionyl chloride) in acetonitrile (30 ml) was added to a cooled stirred mixture of 2-allyloxybenzamidine hydrochloride (2.23 g) and triethylamine (1.06 g) in acetonitrile (50 ml). The mixture was stirred with cooling (0°-5° C.) for 15 minutes, then more triethylamine (0.71 g) was added and the reaction mixture was stirred at ambient temperature for two hours and left standing overnight. A yellow precipitate was collected, washed with water and recrystallised from acetonitrile and then from acetonitrile/ethanol (50%) to afford the title compound, 0.35 g, m.p. 238°-239° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:26])C.ClCCl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:26]
Reactant: CC(=O)O
Reactant: N#Cc1ccc(C(F)(F)F)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
Dissolve 2-chloro-4-trifluoromethylbenzonitrile (405 mg, 1.97 mmol) in anhydrous toluene (7 mL) and cool in a dry ice/ethanol bath. Add diisobutylaluminum hydride (DIBAL) (3.94 mL, 3.94 mmol, 1.0 M in toluene) slowly. Stir 30 min. Warm to room temperature, add acetic acid (2 mL) and wafer (10 mL) and stir for 2 hours. Extract the aqueous layer with ethyl acetate twice. Wash the organic layer with potassium sodium tartrate solution (Rochelle salt) twice. Dry (magnesium sulfate), filter, and concentrate to give a residue. Chromatograph the residue on silica gel eluting with a gradient of 100:0 to 1:1 hexanes:dichloromethane to give 2-chloro-4-trifluoromethylbenzaldehyde (123 mg, 30%). 1H NMR (400 MHz, CDCl3) δ 10.52 (s, 1H), 8.05 (d, 1H, J=8.0 Hz), 7.75 (s, 1H), 7.66 (d, 1H, J=8.0 Hz).