Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][N:14]=1.[Cl:16]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[Cl:16][C:13]1[N:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:10]([NH2:15])=[N:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1nccnc1-c1ccc(Cl)cc1Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1ncc(Cl)nc1-c1ccc(Cl)cc1Cl
Yield: 93.5 %

Procedure:
3-(2,4-Dichlorophenyl)-2-pyrazinamine (1.43 g, 6.0 mmol) was dissolved in chloroform (9 mL), N-chlorosuccinimide (0.96 g, 7.2 mmol) was added thereto, and the mixture was stirred by heating under reflux for 4 hours. After being allowed to cool, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (1.54 g) as yellow crystals.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([Br:17])[CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[C:7]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO>[Br:17][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[C:13]2[C:8]=1[C:7]([CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[N:6][C:5]([C:3]([OH:4])=[O:2])=[CH:14]2
Reactant: COC(=O)C1Cc2c(OC)ccc(Br)c2C(CC2CCCC2)=N1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Br)c2c(CC3CCCC3)nc(C(=O)O)cc12
Yield: 99.4 %

Procedure:
To a stirring solution of 0.4 g (1.05 mmol) of the above ester in 2.5 ml of THF, 0.6 ml of MeOH was added along with 0.6 ml of 2N LiOH at rt. Usual work up as described in general procedure C gave 0.38 g of title compound as a light yellow solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:13]=[C:14]([N+:18]([O-])=O)[CH:15]=[CH:16][CH:17]=1>Cl.[Fe]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[NH2:18]
Reactant: O=[N+]([O-])c1cccc(OCc2nc3ccccc3s2)c1
Agent: [Fe]
Agent: Cl
Product: Nc1cccc(OCc2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a suspension of 3-[(2-benzothiazolyl)methoxy]nitrobenzene (18.6 g) in ethanolic hydrochloric acid is added powdered iron. The reaction is stirred overnight at room temperature. After neutralization with saturated aqueous sodium bicarbonate, the mixture is extracted three times with methylene chloride. The extract is dried over magnesium sulfate and concentrated to give 15.1 g (90% yield) of product, m.p. 117°-120° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[N:7]=1.CCOCC.C(Cl)(Cl)[Cl:28]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[N:7]=[C:6]2[NH:5][CH2:4][CH2:3][CH2:2][Cl:28])=[CH:12][CH:13]=1.[ClH:17]
Reactant: OCCCNc1nc2ccccc2n1-c1ccc(Cl)cc1
Reactant: ClC(Cl)Cl
Solvent: CCOCC
Product: Cl
Product: ClCCCNc1nc2ccccc2n1-c1ccc(Cl)cc1

Procedure:
Thionychloride (5ml.) is added dropwise to a stirred solution of 2-(3-hydroxypropylamino)-1-(4-chlorophenyl)-benzimidazole (5.75 g.) in chloroform (50 ml.) and the solution is heated under reflux for 2 hours. On cooling and dilution with ether the title compound is obtained as its hydrochloride.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]=[CH:10]C1C=CC(C=C)=CC=1.C1C=CC(I)=CC=1.C#C>CN(C=O)C>[CH:9]#[C:10][CH2:4][CH2:5][C:6]#[C:7][CH2:8][CH2:3][CH2:2][CH3:1]
Reactant: C=Cc1ccc(C=C)cc1
Reactant: C=Cc1ccccc1
Agent: C#C
Solvent: Ic1ccccc1
Solvent: CN(C)C=O
Product: C#CCCC#CCCCC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
WANG iodopolystyrene (100 mg), synthesized as described in Example 1, was dissolved in a solvent mixture of DMF/distilled water/TEA (9:1:1) (5 mL) and allowed to swell for 30 minutes at room temperature. 1,5-decadiyne (100 mg) in DMF (2 mL) was added to the polymer bead suspension. Potassium carbonate (50 mg, 0.36 mm) and tetrabutylammonium bromide (50 mg, 0.16 mM) were then added and the suspension was stirred under argon atmosphere for 30 minutes. Tetrakis (triphenylphosphine) palladium (0) (25 mg, 0.02 mM) was added rapidly. The reaction mixture was heated to 80° C. and agitated at that temperature under an argon atmosphere for 16 hours and allowed to cool to room temperature. When the mixture had reached room temperature, a saturated solution of ammonium acetate (5 mL) was added and the mixture agitated at room temperature for 30 minutes, DME (5 mL) was added and the mixture was agitated for an additional 30 minutes, transferred to a fritted filter funnel and washed sequentially with distilled water, DMF, distilled water, 2 N HCl, distilled water, DMF, distilled water, methanol, DCM and methanol (50 mL of each which was allowed to equilibrate for 10 minutes between washes). The product was dried under vacuum to produce a tagged bead containing only one Raman active acetylene tag.
Reaction SMILES: [F:1][C:2]([F:44])([C:40]([F:43])([F:42])[F:41])[CH2:3][CH2:4][CH2:5][S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)=[C:24](\[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)/[CH2:25][CH3:26])=[CH:19][CH:18]=1.[OH:45]O>C(OCC)(=O)C.C(O)(=O)C.O>[F:44][C:2]([F:1])([C:40]([F:41])([F:42])[F:43])[CH2:3][CH2:4][CH2:5][S:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)=[C:24](\[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)/[CH2:25][CH3:26])=[CH:19][CH:18]=1)=[O:45]
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNCCCCCCSCCCC(F)(F)C(F)(F)F)cc1)c1ccccc1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)cc1)c1ccccc1

Procedure:
(Z)-4-(1-(4-(2-(6-(4,4,5,5,5-pentafluoropentylthio)hexylamino)ethoxy)phenyl)-2-phenylbut-1-enyl)phenol from the previous reaction is dissolved in ethyl acetate and acetic acid. To this solution is added hydrogen peroxide solution in water. The mixture is stirred until the reaction is complete (TLC). Excess hydrogen peroxide is destroyed by addition of sodium sulfite solution in water. The phases are separated and the aqueous phase is washed with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (Z)-4-(1-(4-(2-(6-(4,4,5,5,5-pentafluoropentylsulfinyl)hexylamino)ethoxy)phenyl)-2-phenylbut-1-enyl)phenol among other products.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][O:4][CH:3]1[C:7]([OH:9])=O.[C:10](Cl)(=O)C(Cl)=O.[N+](=C)=[N-].[BrH:19]>ClCCl>[Br:19][CH2:10][C:7]([CH:3]1[CH:2]([CH3:1])[CH2:6][CH2:5][O:4]1)=[O:9]
Reactant: CC1CCOC1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Reactant: Br
Agent: C=[N+]=[N-]
Solvent: ClCCl
Product: CC1CCOC1C(=O)CBr
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(2RS,3SR)-3-Methyl-2-tetrahydrofuroic acid 91.3 g) was converted to the acid chloride with oxalyl chloride (2.54 g, 1.75 mls) in dichloromethane (20 mls) as described in Example 1 (a). Diazomethane was passed through a solution of the acid chloride in dichloromethane (20 mls), cooled in ice/water until i.r. analysis showed no starting material. Hydrobromic acid (2 mls, 49% w/v aqueous solution), was added dropwise and the reaction mixture stirred vigorously for 10 min. T.l.c. analysis showed complete conversion to the title compound. The solution was washed with water, brine and dried. The solvent was washed with water, brine and dried. The solvent was evaporated and the residue flash chromatographed on silica gel, eluting with 5 and then 10% ethyl acetate/hexane to give the product as an almost colourless oil, (1.621 g, 79%); νmax (CH2Cl2) 1732 cm-1 ; δH (CDCl3) 0.96 (3 H, d, J 7.2 Hz), 1.70 (1 H, m), 2.17 (1 H, m), 2.70 (1 H, m), 3.93 (1 H, m), 4.12 and 4.25 (2 H, ABq, J 14.7 Hz) and 4.49 (1 H, d, J 7.3 Hz). [Mass spectrum: +ve ion (ammonia) MNH4 (224)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].N1C=CN=C1>CN(C)C=O>[C:21]([Si:25]([CH3:28])([CH3:27])[O:20][CH2:19][CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:12][CH:13]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cc(Cl)ccc1Oc1ccc(OCCO)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Oc2ccc(Cl)cc2C=O)cc1
Yield: 90.5 %

Procedure:
In a manner similar to the method described in Example 60b, 5-chloro-2-[4-(2-hydroxy-ethoxy)-phenoxy]-benzaldehyde (1.68 g, 5.7 mmol) was reacted with tert-butyldimethylchlorosilane (1.3 g, 8.6 mmol) and imidazole in N,N-dimethylformamide to give 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenoxy}-5-chloro-benzaldehyde as a white solid (Yield 2.1 g, 90%).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH2:6][N:5]([CH2:18][CH:19]=O)[C:4](=[O:21])[C:3]=1[C:22]1[N:26]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[N:25]=[CH:24][CH:23]=1.[CH3:35][NH:36][CH3:37].C(O)(=[O:40])C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.O>[CH3:35][N:36]([CH3:37])[CH2:19][CH2:18][N:5]1[C:4](=[O:21])[C:3]([C:22]2[N:26]([C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=3)[N:25]=[CH:24][CH:23]=2)=[C:2]([CH3:1])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=2)[C:6]1=[O:40]
Reactant: CC1=C(c2ccnn2-c2ccc(C#N)cc2)C(=O)N(CC=O)CN1c1cccc(C(F)(F)F)c1
Reactant: CC(=O)O
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(CCN(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[5-[6-methyl-4-oxo-3-(2-oxoethyl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (prepared in Example 68) (12.8 mg), dimethyl amine (133 μl) and acetic acid (10 μl) in tetrahydrofuran (1.0 ml) was added sodium triacetoxyborohydride (8.5 mg) and the resulting mixture was stirred at room temperature for four hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 4-[5-[3-(2-dimethylaminoethyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (7.4 mg).
Reaction SMILES: [CH3:1][CH:2]1[C@H:6]([CH:7]=O)[C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH2:4][N:3]1[C@H:16]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[C:17]([O:19]CC1C=CC=CC=1)=[O:18].FC(F)(F)C(O)=O.[CH2:38]([C:45]1[CH:49]=[C:48]([CH:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[N:47]([CH2:56][CH3:57])[N:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH3:1][CH:2]1[C@H:6]([CH2:7][N:53]2[CH2:54][CH2:55][CH:50]([C:48]3[N:47]([CH2:56][CH3:57])[N:46]=[C:45]([CH2:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:49]=3)[CH2:51][CH2:52]2)[C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH2:4][N:3]1[C@H:16]([CH2:27][CH:28]1[CH2:29][CH2:30]1)[C:17]([OH:19])=[O:18]
Reactant: CC1[C@H](C=O)[C@@H](c2cccc(F)c2)CN1[C@H](CC1CC1)C(=O)OCc1ccccc1
Reactant: CCn1nc(Cc2ccccc2)cc1C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(Cc2ccccc2)cc1C1CCN(C[C@H]2C(C)N([C@H](CC3CC3)C(=O)O)C[C@@H]2c2cccc(F)c2)CC1
Yield: 46.1 %

Procedure:
2-(R)-(2-Methyl-3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclopropyl)propionic acid, benzyl ester (54 mg, 0.13 mmol, from Step D) and 4-(3-benzyl-1-ethyl-(1H-pyrazol-5-yl))piperidine trifluoroacetate (58 mg, 0.17 mmol, from Example 1, Step C) were reacted via the procedure described in Example 1, Steps D and E to afford 34.3 mg (46% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ0.04-0.11 (m, 1H), 0.14-0.20 (m, 1H), 0.41-0.49 (m, 1H), 0.51-0.57 (m, 1H), 0.68-0.75 (m, 1H), 1.23 (t, 3H), 1.63 (d, 3H), 1.80-2.10 (m, 6H), 2.65-2.78 (m, 1H), 2.84-2.98 (m 2H), 3.00-3.10 (m, 2H), 3.16-3.23 (m, 1H), 3.30-3.40 (m, 1H), 3.50-3.68 (m, 4H), 4.02 (s, 2H), 4.15-4.20 (m, 1H), 4.20-4.30 (m, 3H), 5.24 (d, 1H), 5.39 (d, 1H), 5.93 (s, 1H), 7.02-7.44 (m, 14 H); ESI-MS (M+H): 663.9; HPLC A: 2.04 min.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].C([N:13]([CH2:16]C)CC)C.ClC(OCC)=[O:20].N>O1CCCC1>[S:4]1[C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[NH:13][C:16]1=[O:20]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Reactant: O=C(O)c1ccccc1S
Agent: N
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)c2ccccc2s1
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
30 g of thiosalicylic acid and 39 g of triethylamine were dissolved in 125 ml of tetrahydrofuran. The mixed solution was maintained at a temperature of 0 - 5° C., to which 42 g of ethyl chloroformate was added dropwise. The system was allowed to stand for 30 minutes and then, 50 ml of aqueous ammonia (ammonia concentration: 25 - 30%) was added thereto. The resulting solution was allowed to stand over night at room temperatue (about 20 - 30° C.). Then, the solvent used was removed by distillation under reduced pressure, while the residue was filtered off, and recrystallized from ethanol. 21 g of 2H-1,3-benzothiazin-2,4(3H)-dione was obtained. The melting point of the product was 210 - 211° C. (In addition, this product can be also prepared by using as a starting material the ester derivatives of thiosalicylic acid, which are obtained using usual esterification reactions, in a similar manner as above.)
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26]([O:28]CC)=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[Br:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CCOC(=O)c1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 15 %

Procedure:
A suspension of ethyl 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine 2-carboxylate (0.18 g, 0.002 mol) and 1N NaOH (0.6 mL in 1:1 v/v EtOH/Water) was stirred at room temperature for 1.5 h. The reaction mixture was acidified with 5% citric acid and filtered the precipitate. It was washed with water, followed by ethanol and dried in vacuo to afford the title compound (0.14 g, 77%) as a light brown powder: 1H NMR (CD3OD/400 MHz)=δ 9.03 (s. 1H), 8.60 (s, 1H), 7.61 (m. 1H), 7.00 (m, 2H), 6.52 (s, 1H), 5.51 (s, 2H), 5.30 (s. 2H), and 2.52 (s, 3H); 19F NMR (CD3OD/400 MHz)=δ−8-111.75 (m) and −116.06 (m); ES-HRMS m/z 466.0209 (M+H C19H15N4O3BrF2 requires 466.0209).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)ccc21
Yield: 27.8 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (37.1 mg,) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (59 mg) were converted to the title compound as a white solid (25 mgs). 6 9.47 (s, 1H), 8.53 (d, J=8.3 Hz, 1H), 8.18 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.37 (s, 1H), 7.28-7.24 (m, 1H), 7.13 (d, J=8.6 Hz, 1H), 7.07 (s, 1H), 3.31 (s, 3H), 2.77 (s, 6H), 2.32 (broad s, 2H), 2.07 (broad s, 2H), 1.27 (s, 6H). LC/MS: (M+H)+ found=529.16; MP 198-200° C.
Reaction SMILES: C(=[C:8]1[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[O:18]=[O+][O-].CSC>C(Cl)Cl>[N:16]1[C:17]2[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: C(=C1CCCc2cccnc21)c1ccccc1
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: O=C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 8-benzylidene-5,6,7,8-tetrahydro-quinoline (4.30 g, 19.4 mmole) in CH2Cl2 (150 mL) was reacted with ozone at −78° C. for 30 minutes. Dimethyl sulfide (5 mL) was added, and the reaction was warmed to RT and stirred overnight. The mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (EtOAc). The title compound (2.20 g, 79%) was obtained as an off-white solid after drying in vacuo: MS (ES) m/e 148 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)Cl.CC#N.[Cl-].[Na+].O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:6][C:7]=1[Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(=O)CCc1ccc(N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: NC(=O)CCc1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a mixture of 3-(4-amino-phenyl)-propionamide (as prepared in the previous step, 123 mg, 0.749 mmol) in 10 mL of 1:1 DCM/CH3CN at 0° C. was added N-bromosuccinimide (NBS) (133 mg, 0.749 mmol) in 4 mL of 1:1 DCM/CH3CN. The mixture was warmed to RT and stirred for 1 h under Ar. Treated with 20 mL of brine, the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by flash chromatography on silica gel (1-4% MeOH/DCM) giving 133 mg (81%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C9H11BrN2O, 243.0 (M+H). found 242.9.
Reaction SMILES: Cl[C:2]1C=CC=CC=1C(C1C=CC(F)=CC=1)=O.[F:17][C:18]1[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=O>>[F:17][C:18]1[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[CH2:2]
Reactant: O=C(c1ccc(F)cc1)c1ccccc1Cl
Reactant: O=C(c1ccc(F)cc1)c1ccccc1F
Product: C=C(c1ccc(F)cc1)c1ccccc1F
Yield: 85 %

Procedure:
The procedure described in Example 1 is repeated except that the 130 parts of 2-chloro-4'-fluorobenzophenone are replaced by 168 parts of 2,4'-difluorobenzophenone, which was converted into the title compound in 85% yield. Distillation, under vacuum, gives a colourless liquid which is pure 1-(2-fluorophenyl)-1-(4-fluorophenyl)ethene (b.pt. 82°/0.2 mm Hg).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[C:14]([OH:22])(=[O:21])[CH:15]([CH2:17][C:18]([OH:20])=[O:19])[OH:16].C(=O)(O)[O-].[Na+:27]>>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[Na+:27].[C:14]([O-:22])(=[O:21])[CH:15]([CH2:17][C:18]([O-:20])=[O:19])[OH:16]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=C(O)CC(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C([O-])CC(O)(CC(=O)O)C(=O)O
Product: O=C([O-])CC(O)C(=O)[O-]

Procedure:
Process: Heat citric acid to 60° C. and moisten with 8 ml of 60% malic acid solution. Allow sodium bicarbonate I to react to give monosodium citrate and malate; then allow sodium bicarbonate II and potassium bicarbonate to undergo partial reaction. Add sodium carbonate and allow partial reaction, and then dry in vacuo. Mix the resulting granules with arginine aspartate and the additives (Sweetener, aroma) and compress to give tablets.
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([C:7]([CH2:36][CH3:37])([CH:9]([S:34][CH3:35])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6].I([O-])(=O)(=O)=[O:39].[Na+]>CO.O>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:36]([C:7]([CH2:5][CH3:6])([CH:9]([S:34]([CH3:35])=[O:39])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:37]
Reactant: CCC(C)(CC)C(SC)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[PH](O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(C)(CC)C(c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)S(C)=O
Temperature: 5 °C
Reaction time: 5 h
Yield: 108.1 %

Procedure:
A solution of diethyl 3-methylthio-3(1-trityl-1,2,4-triazol-3-yl)-propane phosphonate (0.53 g, prepared as described in Example 39) in methanol (7 ml) was added slowly to a stirred solution of sodium periodate (0.23 g) in water (3 ml) cooled to 5° C. After ten minutes, the cooling bath was removed and stirring continued for a further five hours. The mixture was poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate, and evaporated under reduced pressure to give diethyl 3-methanesulphinyl-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.59 g, white gum) as a 2:1 mixture of diastereoisomers. NMR (CDCl3): δ 1.3(6H,m), 1.7-1.9(2H,m), 2.4(3H,2 xs), 2.5-2.7(2H,m), 4.05(5H,m), 7.1-7.3(15H,m), 8.0(1H,2 xs).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[S:15]2)[CH:6]=[C:7]([NH2:13])[C:8]=1[O:9][CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=3)[S:15]2)[CH:6]=[C:7]([NH:13][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:8]=1[O:9][CH2:10][CH2:11][CH3:12]
Reactant: BrCc1ccccc1
Reactant: CCCOc1c(N)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(NCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
trans-2-(3-Methoxy-4-propoxy-5-aminophenyl)-5-(3,4,5-trimethoxyphenyl)-tetrahydrothiophene (10 mg, 0.023 mmole) and potassium carbonate (0.2 g) were suspended in 1 mL DMF. To this mixture was added benzyl bromide (39.50 mg, 0.23 mmole). The mixture was stirred at room temperature for 20 hours, quenched with water, and then extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and evaporated in vacuo to an oil that was purified by column chromatography using hexane/ethyl acetate (3:1) as solvent.