Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20]>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccc(C#N)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-cyano-phenylboronic acid to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-benzonitrile. LC-MS m/e 326(MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH3:12])=[C:4]([N+:26]([O-])=O)[CH:3]=1.[C:29](O)(=O)[CH3:30]>[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][CH2:10][CH:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH3:12])[C:29]([CH3:30])=[N:26][C:4]=2[CH:3]=1
Reactant: CC(CCNc1ccc(F)cc1[N+](=O)[O-])N1CCN(c2ccc(F)cc2)CC1
Reactant: CC(=O)O
Agent: [Zn]
Product: Cc1nc2cc(F)ccc2n1CCC(C)N1CCN(c2ccc(F)cc2)CC1

Procedure:
To a refluxing, stirred mixture of (4-fluoro-2-nitro-phenyl)-{3-[4-(4-fluorophenyl) piperazin-1-yl]-butyl}-amine (0.38 gm), 10 ml acetic acid are added small portions of Zn dust (excess) until a nearly colorless reaction mixture is obtained approx. 4 hours). Insolubles are removed by filtration, washed with acetic acid and the combined acetic acid layer concentrated to a black oil. This oily residue is dissolved in ethyl acetate (50 ml) and washed with 2×10 ml water and brine. The organic layer is collected, the sovent removed and the residue purified by flash chromatography (solid phase: SiO2 ; eluent: gradient starting with ethyl acetate followed by ethyl acetate/methanol 8:2). Obtained are 0.1 gm of 5-fluoro-1-{3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-butyl}-2-1H-benzoimidazole. (M+/Z 384.47).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5](CC2C=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[F:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH:38]=O>>[F:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38][N:5]1[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[CH:23]=[N:22][N:21]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:19]=3[N:20]=2)[CH2:4]1
Reactant: O=Cc1ccccc1F
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(Cc2ccccc2F)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 2-fluorobenzaldehyde provided the title compound. 400 MHz 1H NMR (CD3OD) δ 7.98 (s, 1H), 7.47-7.42 (m, 1H), 7.33-7.26 (m, 2H), 7.18-7.07 (m, 1H), 4.08-4.04 (m, 2H), 3.85 (s, 2H), 3.69-3.56 (m, 3H), 3.20-2.93 (m, 4H), 2.69-2.62 (m, 1H), 2.40-2.19 (m, 3H), 1.88-1.85 (m, 2H), 1.14 (d, J=6.6 Hz, 3H). MS: (M+H m/z 412.1).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[I-].[K+].[CH3:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:27][N:26]=1)[CH:20]=[CH:19]2)(=[O:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[N:26]=[CH:27][C:28]([O:31][CH:32]3[CH2:37][CH2:36][N:35]([CH2:2][C:3]([N:5]4[CH2:9][CH2:8][CH2:7][CH2:6]4)=[O:4])[CH2:34][CH2:33]3)=[CH:29][CH:30]=1)[CH:20]=[CH:19]2)(=[O:14])=[O:15]
Reactant: O=C(CCl)N1CCCC1
Reactant: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCNCC3)cn2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(CC(=O)N4CCCC4)CC3)cn2)c1
Temperature: 80 °C
Yield: 42.5 %

Procedure:
To a stirred solution of 2-chloro-1-(pyrrolidin-1-yl)ethanone (Intermediate 71) (0.055 g, 0.366 mmol) in DMF (2 mL), potassium iodide (0.023 g, 0.137 mmol), 5-(methylsulfonyl)-1-(5-(piperidin-4-yloxy)pyridin-2-yl)-1H-indole (0.170 g, 0.458 mmol) and potassium carbonate (0.064 g, 0.458 mmol) were added. The resulting mixture was heated at 80° C. for 45 minutes. Reaction was quenched with water and extracted with ethyl acetate. The organic extract was concentrated in vacuo and resultant residue was purified by column chromatography to yield title compound (0.075 g, 33.3%).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([NH2:16])=[S:15])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].C1COCC1.[CH3:24][N:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](=O)[CH2:31]Br>CCOC(C)=O>[C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]3[S:15][C:30]([C:26]4[N:25]([CH3:24])[CH:29]=[CH:28][CH:27]=4)=[CH:31][N:16]=3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CC(N)=S)cc1
Reactant: Cn1cccc1C(=O)CBr
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cccc1-c1cnc(Cc2cncn2Cc2ccc(C#N)cc2)s1
Temperature: 50 °C

Procedure:
To a 25 mL round bottomed flask with a stirring bar reflux condenser and an argon inlet is added 1-(4-cyanobenzyl)-5-(aminothiocarbonyl)methyl-1H-imidazole (0.12 g, 0.468 mmol), dry THF (10 mL), and N-methyl-a-bromoacetylpyrrole (0.098 g, 0.491 mmol). This mixture is heated at 50° C. for 7 hours. The cooled reaction mixture is diluted with EtOAc and washed sucessively with aq. NaHCO3, water, and brine. The organic extract is dried, (MgSO4) and the solvent is evaporated in vacuo. The residue is purified by chromatography to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([OH:14])[C:11](=[O:15])[CH:10]=[C:9]2[CH2:16][OH:17])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][CH:27]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH2:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[C:11](=[O:15])[CH:10]=[C:9]2[CH2:16][OH:17])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(CO)n(-c2cccc(Br)c2)cc1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cn(-c3cccc(Br)c3)c(CO)cc2=O)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a mixture of 1-(3-bromo-phenyl)-5-hydroxy-2-hydroxymethyl-1H-pyridin-4-one and K2CO3 (5.17 g, 37.5 mmol) in 50 mL of DMF was added 2.35 g of PMBCl (15 mmol) dropwise, and the reaction mixture was stirred at 80° C. for 3 h. After cooling to room temperature, the mixture was poured into 200 mL of water and extracted with EtOAc (50 mL) three times. The combined organic layers were washed with water, brine, and dried over anhydrous MgSO4. Most of the volatiies were removed in vacuo and the resulting solid was collected and washed with EtOAc to obtain 1-(3-bromophenyl)-2-hydroxymethyl-5-(4-methoxy-benzyloxy)-1H-pyridin-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1.[C:17](O)(=[O:19])[CH3:18].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:17]([CH:12]1[C:11](=[O:16])[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:14][C:13]1=[O:15])(=[O:19])[CH3:18]
Reactant: CC(=O)O
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: COc1ccccc1C1CC(=O)C(C(C)=O)C(=O)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.8 %

Procedure:
To a solution of 5-(2-methoxyphenyl)-1,3-cyclohexanedione (2.0 g), acetic acid (0.99 g) and dimethylaminopyridine (1.7 g) in dimethylformamide (100 ml) was added dicyclohexylcarbodiimide (2.5 g), and the mixture was stirred at room temperature for 15 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The solution was washed with potassium hydrogen sulfate solution and water, and to the solution was added 1N sodium hydroxide solution. The aqueous layer was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was recrystallized from diisopropylether/hexane to give colorless crystals of 2-acetyl-5-(2-methoxyphenyl)cyclohexane-1,3-dione (2.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1COc1cncc(Cl)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2cncc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-{[(5-chloropyridin-3-yl)oxy]methyl}benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:13]([OH:16])[CH:14]=[CH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1(C)[CH:26]=CC(S(O)(=O)=O)=C[CH:22]=1.C(OCC)(=O)C>COC(OC)(C)C>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:13]([CH:14]=[CH2:15])[O:16][C:21]1([CH3:26])[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: CCOC(C)=O
Product: C=CC1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 1369.8 %

Procedure:
124 mg of (3RS,4S)-4-(benzyloxycarbonyl)amino-6-methylhepten-3-ol was dissolved in 0.33 ml of 2,2-dimethoxypropane, and 4 mg of dry p-toluenesulfonic acid was added thereto. The mixture was stirred at room temperature overnight. Then, 20 ml of ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography-(n-hexane/ethyl acetate=10/1) to obtain 101 mg of (4S,5RS)-3-benzyloxycarbonyl-2,2-dimethyl-5-ethenyl-4-isobutyloxazolidine as colorless oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[NH:14][CH:8]([CH2:9][C:10](=[O:15])[CH2:11]2)[CH2:7]1)=[O:5])[CH3:2].CCN(CC)CC.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[N:14]([S:30]([C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)(=[O:32])=[O:31])[CH:8]([CH2:9][C:10](=[O:15])[CH2:11]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC2CC(=O)CC(C1)N2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC2CC(=O)CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
7-Oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester (5.91 g, 27.9 mmol) was dissolved in methylene chloride (60 mL). Et3N (7.76 mL, 55.9 mmol) and 4-chlorobenzenesulfonyl chloride (7.08 g, 33.6 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with methylene chloride (50 mL) and washed with saturated NaHCO3 (50 mL). The aqueous phase was separated and extracted once with methylene chloride (50 mL). The combined organic phases were then dried (Na2SO4), filtered, concentrated under vacuum and the residue was purified on a silica gel column (eluant hexane/EtOAc, 9/1 to 1/1) to give 9.52 g (88%) of 9-(4-chloro-benzenesulfonyl)-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester. Retention time (min)=2.100, method [1], MS (ESI) 408.1 (M+Na); 1H NMR (300 M Hz, CDCl3) δ 7.81 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 4.61-4.57 (m, 2H), 4.09 (q, J=7.1 Hz, 2H), 2.80 (dd, J=17.0, 7.1 Hz, 2H), 2.67-2.51 (m, 1H), 2.41 (d, J=16.4 Hz, 2H), 1.99-1.90 (m, 2H), 1.80 (dt, J=13.2, 4.4 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[C:11]1(=[N:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCCCC1
Reactant: Nc1ccccc1C(=O)O
Product: O=C(O)c1ccccc1N=C1CCCCC1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
Anthranilic acid (10 g, 73 mmol) and cyclohexanone (9.8 mL, 95 mmol) were dissolved in xylenes (110 mL) in a flask equipped with a Dean-Stark apparatus and heated to reflux over 18 hours. The reaction mixture was cooled to room temperature and the resulting precipitate collected by filtration. The filter cake was washed with hexanes and dried in vacuo to give the desired imine (11 g, 69% yield) as a beige solid.
Reaction SMILES: [S].[CH3:2][CH:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([CH:11]2[CH:16]=[CH:15][N:14](C(OCC(Cl)(Cl)Cl)=O)[CH:13]=[CH:12]2)[S:4]1>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:2][CH:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:4]1
Reactant: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2)SC(C)C(=O)N1
Agent: [S]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC1=C(c2ccncc2)SC(C)C(=O)N1
Temperature: 140 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
Sulfur sublimed (0.7 g) was added to a solution of 2,5-dimethyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (1.5 g) in dimethylformamide (20 ml) and the mixture was stirred at 140° C. for 2 hours. Then, the mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure. The residue was dissolved in 2N hydrochloric acid and the insoluble matter was removed by filtration. The filtrate was adjusted to pH 7-8 by 2N aqueous sodium hydroxide. The precipitated crude crystals were chromatographed on silica gel (Wakogel C-200) column, using chloroform-methanol (=20:1) as an eluant to give pale yellow crystals. These crude crystals were dissolved in chloroform, were washed with water and were dried over magnesium sulfate. The solvent was removed under reduced pressure to give the titled compound (0.43 g, yield 52%) as white crystals.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[CH2:12][NH:11][CH2:10]3)[O:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1ccc(C2CNCC(c3nc(C4CC4)no3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
185 mg (0.41 mmol) of the compound from Example 174A were initially charged in 25 ml of dichloromethane and, at RT, reacted with 0.32 ml (466 mg, 4.08 mmol) of trifluoroacetic acid. The reaction mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 126 mg (87% of theory)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:15])[CH3:14].[S:16]1[CH:20]=[C:19]([CH:21]=[O:22])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]1=2.[Cl-].[NH4+]>O1CCCC1>[S:16]1[CH:20]=[C:19]([CH:21]([OH:22])[CH2:14][C:13]#[N:15])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]1=2
Reactant: O=Cc1csc2ccccc12
Reactant: CC#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#CCC(O)c1csc2ccccc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
To a stirring solution of diisopropylamine (0.93 mL, 6.58 mmol) in tetrahydrofuran (8 mL) at −78° C. under nitrogen was added a solution of n-butyllithium (2.75 mL, 6.88 mmol, 2.5 M in hexane). After the addition was complete, the mixture was stirred at −78° C. for 10 minutes and removed cooling bath for 5 minutes. The mixture was cooled back to −78° C., acetonitrile (0.31 mL, 5.98 mmol) was added and the reaction mixture was then stirred at −78° C. for 30 minutes. Benzo[b]thiophene-3-carbaldehyde (1 g, 5.98 mmol) in tetrahydrofuran (4 mL) was added and the resulting solution was allowed to warm to ambient temperature. After 18 hours at ambient temperature, saturated aqueous ammonium chloride (5 mL) was added to the reaction mixture and it was concentrated at reduced pressure. The resulting crude product was diluted with ethyl acetate (20 mL), washed with water (10 mL) followed by saturated aqueous sodium chloride (10 mL). The organic layer was concentrated and purified by column chromatography (80 g silica gel cartridge) eluting with ethyl acetate/hexane (30%-50%) to give the product as a light yellow oil (1.2 g, 99%).
Reaction SMILES: [CH2:1]([N:17]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[C:18](=[O:21])[CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].P(Cl)(Cl)(Cl)=O.CN([CH:35]=[O:36])C>>[CH:35]([C:24]1[S:23][C:22]([N:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18](=[O:21])[CH2:19][CH3:20])=[CH:26][CH:25]=1)=[O:36]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)CC)c1cccs1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(C(=O)CC)c1ccc(C=O)s1
Reaction time: 1 h

Procedure:
75 g of N-hexadecyl-N-(2-thienyl)-propionic acid amide are dissolved in 59 cc. of anhydrous DMF and 36.7 g of phosphorus oxychloride are added thereto dropwise with ice cooling such that the temperature of the reaction mixture does not increase above 20° C. Stirring is continued for 1 hour and 20° C. and the reaction mixture finally is heated 3 hours to 80° C. Ice is added to the reaction mixture and 5 N soda lye is added until reaching a pH of 6. The resulting mixture is extracted with ether, the ethereal layer is separated, washed with water and dried over Na2SO4. The desired final product crystallizes at low temperature from the ethereal solution.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[Cl:8].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1.ClCCl>[Cl:8][C:7]1[N:6]=[C:5]([CH3:9])[N:4]=[C:3]2[C:2]=1[N:1]=[C:19]([C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[Cl:16])[N:10]2[CH2:11][C:12]([CH3:15])([OH:14])[CH3:13]
Reactant: Cc1nc(Cl)c(N)c(NCC(C)(C)O)n1
Reactant: O=Cc1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(CC(C)(C)O)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
Heat a mixture of 1-(5-amino-6-chloro-2-methylpyrimidin-4-ylamino)-2-methylpropan-2-ol (0.5 g, 0.002 mol), 2-chlorobenzaldehyde (0.6 g, 0.004 mol), p-toluene sulfonic acid (0.1 g) and molecular sieves (1.0 g) in toluene (25 mL) to 130° C. for 16 h. Remove the molecular sieves by filtration through diatomaceous earth, and concentrate the filtrate under reduced pressure to give a residue. Dissolve the residue in dry dichloromethane (5 mL) and add DDQ (0.47 g, 0.002 mol) at 0° C. Stir the reaction mixture at room temperature for 2 h. Dilute the reaction mixture with dichloromethane, wash with 1 N sodium hydroxide solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column eluting with methanol:dichloromethane (2:98) to give the title compound (0.4 g). ES/MS m/z 351 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.O=[CH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:17]([O:18][CH3:19])[C:15]=1[OH:16]>[Cl-].[Cl-].[Zn+2].C(OC(=O)C)(=O)C>[OH:16][C:15]1[C:17]([O:18][CH3:19])=[CH:20][CH:21]=[CH:22][C:14]=1/[CH:13]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:2]([CH3:1])[CH:3]=[N:4][C:5]\1=2
Reactant: COc1cccc(C=O)c1O
Reactant: Cc1cnc2c(c1)CCCC2
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Product: COc1cccc(/C=C2\CCCc3cc(C)cnc32)c1O

Procedure:
5,6,7,8-Tetrahydro-3-methylquinoline (20 ml), o-vanillin (25 g), acetic anhydride (50 ml), and ZnCl2 (1 g) were heated at reflux for 17 hours. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate (100 ml) and acidified with 2N HCl solution. The solid obtained was removed by filtration and the aqueous layer was basified with Na2CO3 and shaken with diethyl ether. A solid was obtained in the ether layer which was removed by filtration. The combined solids were dissolved in 1N sodium hydroxide and the solution was extracted with ethyl acetate. The extracts were dried over MgSO4 and the solvent was removed by evaporation. The crystals obtained were washed with hexane and dried to give the title compound (6 g) m.p. 149°-153° C.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10].[F:18][C:19]([F:23])([F:22])[CH2:20][OH:21].[H-].[Na+]>O>[N+:15]([C:12]1[CH:13]=[CH:14][C:7]([O:21][CH2:20][C:19]([F:23])([F:22])[F:18])=[C:8]([CH:11]=1)[C:9]#[N:10])([O-:17])=[O:16]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1OCC(F)(F)F
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a dimethylformamide solution (30 ml) containing 2-chloro-5-nitrobenzonitrile (10 g) and 2,2,2-trifluoroethanol (6 g) was added sodium hydride (60% content, 2.65 g) under ice-cooling, and the mixture was stirred for 1 h. The reaction mixture was added to water and extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of toluene-diisopropyl ether to give 5-nitro-2-(2,2,2-trifluoroethoxy)benzonitrile (9.4 g), melting point: 94° C.
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:14]([OH:17])(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[CH2:1]([C:8]1[S:9][C:10]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(Cc2cccs2)cc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccc(Cc2ccccc2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-benzylthiophene (0.875 g, 5 mmol) in chloroform (2 ml) at 0° C. was added chlorosulfonic acid dropwise and the reaction was stirred at 0° C. for 30 min. The reaction mixture was decomposed by pouring onto crushed ice (20 g). The mixture was extracted with ethyl acetate, dried over MgSO4 and filtered. The solvent was removed under reduced pressure to give 5-benzylthiophene-2-sulfonic acid.