Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][NH:36][C:35](=[O:39])[CH:34]=2)=[N:29][CH:30]=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][N:36]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:35](=[O:39])[CH:34]=2)=[N:29][CH:30]=1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 30.7 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (300 mg, 0.792 mmol) and 4-((5-chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (187 mg, 0.792 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (130 mg, 30%) as a yellow oil: ESI MS m/z 535 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][CH:3]=1.[CH:10](OC)([O:13][CH3:14])[O:11][CH3:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>CO>[CH3:12][O:11][CH:10]([O:13][CH3:14])[C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: COC(OC)OC
Reactant: O=Cc1ccc(Br)cc1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(OC)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
21.1 g (114 mmol) of 4-bromobenzaldehyde and 20 ml (182 mmol) of trimethyl orthoformate (both Fluka, Buchs, Switzerland) are dissolved in 35 ml of methanol, and 0.65 g (3.4 mmol) of p-toluenesulfonic acid monohydrate is added at room temperature (exothermic reaction). The reaction mixture is stirred at room temperature under nitrogen for 20 hours. The acid is then neutralised with 0.62 ml of 30% sodium methanolate solution in methanol (3.4 mmol); the reaction mixture is concentrated using a rotary evaporator and the residue is distilled. The title compound is obtained in the form of a colourless liquid. TLC: Rt =0.58 (hexane/ethyl acetate 2:1). B.p.: 90°-92° C. (4 mbar). 1H-NMR (CDCl3 ; 200 MHz): 7.50 and 7.32/each d, J=9 (2×2H); 5.36/s (1H); 3.31/s (6H).
Reaction SMILES: N1C=CN=C1N[C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][S:56]([C:59]1[CH:66]=[CH:65][C:62]([CH2:63][NH2:64])=[CH:61][CH:60]=1)(=[O:58])=[O:57]>CN(C=O)C.CCN(C(C)C)C(C)C>[CH3:55][S:56]([C:59]1[CH:66]=[CH:65][C:62]([CH2:63][NH:64][C:7]([C:9]2[C:17]3[N:16]=[C:15]([NH:18][C:19]([C:21]4[N:22]=[CH:23][C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:20])[NH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:61][CH:60]=1)(=[O:57])=[O:58]
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cc2ccccc2cn1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cccc3[nH]c(NC(=O)c4cc5ccccc5cn4)nc23)cc1
Yield: 33.4 %

Procedure:
100 mg (0.3 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (from Example 58) was reacted with 130 mg (0.33 mmol) of HBTU and 55 mg (0.3 mmol) 4-methanesulfonyl-benzylamine in 3.0 mL of DMF and 1.0 mL of DIEA as described in general procedure A. After the usual work up as described in general procedure A, 50 mg (33%) of isoquinoline-3-carboxylic acid [4-(4-methanesulfonyl-benzylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was isolated. LCMS: 500 (M+1)+.
Reaction SMILES: O[C:2]1[N:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[NH:5][C:4]([O:18][CH3:19])(O)[CH:3]=1.C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:33]>>[Cl:33][C:2]1[CH:3]=[C:4]([O:18][CH3:19])[N:5]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC1(O)C=C(O)N=C(c2nc(C(F)(F)F)cs2)N1
Solvent: CCN(CC)c1ccccc1
Product: COc1cc(Cl)nc(-c2nc(C(F)(F)F)cs2)n1
Temperature: 110 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a stirred solution of compound 289 (2.38 g, 1 eq.) in POCl3 (7.2 mL) was added N,N-diethylaniline (2.17 g, 1.7 eq.). The mixture was stirred at 110° C. for 16 hrs. The reaction was cooled down to room temperature and poured dropwise into an ice/water mixture. The aqueous solution was extracted with DCM. Organics were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to yield compound 290 as an orange solid in 45% yield. MS (ESI, EI+): m/z=296 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][C:8]([C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=2)[CH3:2].[OH-].[Na+].Cl.O>C(O)C>[CH2:1]([C:3]1[N:4]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)c(C)c(CC)n2Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1c(C)c2cc(C(=O)O)ccc2n1Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A 587 mg portion of ethyl 2-ethyl-1-(4-fluorobenzyl)-3-methyl-1H-indole-5-carboxylate was dissolved in 10.5 ml of ethanol, and 3.5 ml of a 1 M sodium hydroxide aqueous solution was added, followed by overnight stirring at 80° C. Under ice-cooling, 1 M hydrochloric acid and water were added thereto, followed by stirring at pH 1 for 1 hour. Then, the resulting solid was collected by filtration to obtain 498 mg of 2-ethyl-1-(4-fluorobenzyl)-3-methyl-1H-indole-5-carboxylic acid as a pale pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: Cc1nc(NC(=O)c2ccc(Cl)cc2)sc1C(=O)NCc1ccccc1
Yield: 23 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 4-chlorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 23% yield; 1H NMR (CDCl3, 300 MHz) δ 7.84 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.32-7.24 (m, 5H), 6.02 (s, 1H), 5.27 (s, 2H), 2.01 (s, 3H); MS (ES+) m/z 386.1 (M+1).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1)[CH3:2].C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20]CC)=[O:19])C.O>[OH-].[Na+]>[CH2:1]([CH:3]1[N:4]2[C:5]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[CH2:11][CH2:12]1)[C:16](=[O:15])[C:17]([C:18]([OH:20])=[O:19])=[CH:23]2)[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCC1CCc2ccccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1CCc2cccc3c(=O)c(C(=O)O)cn1c23
Temperature: 127.5 °C

Procedure:
Following the procedure set forth in Example 1, 2-ethyltetrahydroquinoline is mixed with diethyl ethoxymethylenemalonate and heated to 125 to 130° C. for 2 hours. Polyphosphoric acid is added, and the mixture is heated at 115° C. for one hour. The mixture is poured into water, neutralized with 40 percent sodium hydroxide, and the product is isolated and saponified in 10 percent sodium hydroxide solution. The solution is neutralized, and the solid product, 6,7-dihydro-5-ethyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, is isolated by filtration.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:8][C:9]([C:12]([OH:14])=O)=[N:10][N:11]=2)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[Cl:46][C:47]1[CH:48]=[C:49]([C:54]2[O:58][C:57]([CH2:59][CH2:60][NH2:61])=[CH:56][CH:55]=2)[CH:50]=[CH:51][C:52]=1[Cl:53]>C(Cl)Cl>[Cl:46][C:47]1[CH:48]=[C:49]([C:54]2[O:58][C:57]([CH2:59][CH2:60][NH:61][C:12]([C:9]3[NH:10][N:11]=[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH:8]=3)=[O:14])=[CH:56][CH:55]=2)[CH:50]=[CH:51][C:52]=1[Cl:53]
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: O=C(O)C1=NN=C(c2ccncc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc(-c2ccncc2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a stirred solution of 5-pyridin-4-yl-4H-pyrazole-3-carboxylic acid (1.78 g, 9.42 mmol) in DCM (10 ml) was added DIPEA (2.46 ml, 14.1 mmol), EDCI (2.71 g, 9.42 mmol) and HOBt (1.91, 14.1 mmol). 2-(5-(3,4-dichlorophenyl)furan-2-yl)-ethanamine hydrochloride (2.75 g, 9.42 mmol) was dissolved in DCM (15 ml) and DIPEA (1.64 ml, 9.42 mmol). The resulting solution was added to the reaction mixture, which was stirred at RT overnight. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3 solution and water. The organic phase was dried over Na2SO4, evaporated and purified by chromatography (CombiFlash, silica column, eluent 0-15% MeOH/DCM). Product containing fractions were collected, evaporated and crystallized from DCM and re-crystallized from 2% MeOH/DCM and heptane. Thus, 1.18 g (29%) of the title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 2.97 (t, 2H), 3.59 (q, 2H), 6.35 (d, 1H), 7.03 (d, 1H), 7.33 (s, 1H), 7.62 (d, 2H), 7.75 (m, 2H), 7.84 (t, 1H), 8.57 (br s, 1H), 8.63 (m, 2H), 13.95 (s, 1H).
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].[CH:13]([O:15][CH2:16][CH2:17]Cl)=[CH2:14]>>[CH3:12][O:11][C:1]1[CH:10]=[C:6]([CH2:7][CH:8]=[CH2:9])[CH:5]=[CH:4][C:2]=1[O:3][CH2:17][CH2:16][O:15][CH:13]=[CH2:14]
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: C=COCCCl
Product: C=CCc1ccc(OCCOC=C)c(OC)c1

Procedure:
Eugenol (4-allyl-2-methoxyphenol) was reacted with 2-chloroethyl vinyl ether to produce o-methoxy-para-allyl-2-vinyloxyethoxy benzene (MAVB). 77 parts by weight of MAVB were dispersed in approximately 350 parts by weight toluene with 0.05 parts by weight of a platinum catalyst. 200 parts by weight of a 95 cps silicone copolymer fluid containing approximately 9.9% Si--H groups were added to the toluene solution. The reaction mixture was then refluxed overnight to where Si--H functionality was below about 1%. The toluene was stripped off under vacuum to yield a 300 cps fluid product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH3:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)C1CCNCC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1CCN(c2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-piperidinecarboxylic acid ethyl ester (5.0 g) and 2-methoxyphenylboronic acid (5.0 g) in dichloromethane (100 ml) are added pyridine (12.9 ml), anhydrous copper (II) acetate (5.78 g) and Molecular sieves 4 Å (100 g), and the mixture is stirred at 25° C. for 2 days. The reaction solution is filtered, and the filtrate is poured into 10% aqueous citric acid solution, and the organic layer is washed successively with aqueous sodium hydrogen carbonate solution, and saturated brine. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient, 0% to 100% hexane/ethyl acetate) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([C:19]([F:22])([F:21])[F:20])=[CH:13][CH:14]=3)[N:9]=2)=[C:4]([S:23][CH2:24][CH3:25])[CH:3]=1.P(Cl)(Cl)([Cl:28])=O.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:28][C:16]1[C:15]2[C:10](=[CH:11][C:12]([C:19]([F:22])([F:21])[F:20])=[CH:13][CH:14]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[S:23][CH2:24][CH3:25])[N:17]=1
Reactant: CCSc1cc(Cl)ccc1-c1nc2cc(C(F)(F)F)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCSc1cc(Cl)ccc1-c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 1.46 g of 2-(4-chloro-2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-quinazolin-4-one, 0.39 ml of phosphorus oxychloride, 538 mg of N,N-diisopropylethylamine and 20 ml of toluene was stirred at 90° C. for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 1.31 g of 4-chloro-2-(4-chloro-2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline (Compound of Present Invention 14).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.C(O[CH:16](N(C)C)[N:17]([CH3:19])[CH3:18])(C)(C)C>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](/[CH:10]=[CH:16]/[N:17]([CH3:19])[CH3:18])[CH:3]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cc(Br)ccc1C#N
Product: CN(C)/C=C/c1cc(Br)ccc1C#N
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromo-2-methylbenzonitrile (1.0 g) dissolved in 1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (2.11 ml) was stirred at 140° C. for 2 h (flask open to evaporate t-butanol). The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (350 mL). The organic was dried (MgSO4), filtered and evaporated to afford the crude product. The crude product was triturated with isohexane overnight to afford the subtitle compound (0.75 g) as a solid.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[CH3:18][S:19]([CH2:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)(=[O:21])=[O:20]>>[CH3:18][S:19]([CH2:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:25][CH:24]=1)(=[O:20])=[O:21]
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: CS(=O)(=O)Cc1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-methylsulfonylmethylaniline according to Procedure J: 1H NMR (DMSO-d6): δ 11.1 (d, 1H), 11.0 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 (d, 1H), 7.5 (q, 4H), 7.1 (d, 1H), 4.45 (s, 2H), 2.9 (s, 3H); APCI-MS m/z 384 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([C:13](OC)=[O:14])=[C:6]2[S:17][CH:18]([CH3:20])[CH3:19].[NH2-:21].[Li+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([C:13]([NH2:21])=[O:14])=[C:6]2[S:17][CH:18]([CH3:20])[CH3:19]
Reactant: COC(=O)c1c(SC(C)C)c2cc(OC)ccc2n1C
Reactant: [NH2-]
Agent: [Li+]
Product: COc1ccc2c(c1)c(SC(C)C)c(C(N)=O)n2C
Yield: 68 %

Procedure:
Prepared from methyl 5-methoxy-1-methyl-3-[(1-methylethyl)thio]-1H-indole-2-carboxylate and lithium amide as described in Example 23. Yield 68% after recrystallization from ethyl acetate-hexane; mp 122°-124° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:22])([CH3:21])[CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl.O1CCO[CH2:26][CH2:25]1>CCO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([CH3:21])([CH3:22])[CH2:17][C:18]([O:20][CH2:25][CH3:26])=[O:19])=[CH:13][CH:14]=1
Reactant: CC(C)(CC(=O)O)Cc1ccc(OCc2ccccc2)cc1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(C)(C)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
The acid from STEP 3 (0.5 g) was suspended in absolute EtOH (3.0 mL), added 4N HCl/dioxane (2.0 mL) and stirred overnight at room temperature, and heated to reflux for 1 h. The solution was concentrated to dryness and the residue was dissolved in EtOAC (15 mL), washed with water, dried and concentrated to dryness. The resulting syrup (0.4 g) was dissolved in EtOH (10 mL), added acetic acid (0.1 mL), Pd/C (10%, 0.25 g), and stirred in an atmosphere of hydrogen gas at 50 psi at room temperature. After 16 h, the catalyst was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The resulting colorless syrup was dried in vacuo to give the title compound (0.34 g, 80%): Rf=0.44 (50% EtOAc/Hexane); 1H -NMR (CDCl3) δ7.02 (d, 2H); 6.73 (d, 2H); 4.12 (q, 2H); 2.58 (s, 2H); 2.15 (d, 2H); 1.24 (t, 3H); 0.98 (s, 6H); ES-MS m/z 235(M-H); HRMS calcd C14H21O3 (MH+) 237.1485, found 237.1511.
Reaction SMILES: [CH2:1]([C:3]1[S:37][C:6]2[N:7]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[C:8](=[O:21])[N:9]([CH2:12][CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[CH2:19][OH:20])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[C:38]([Si:42](Cl)([CH3:44])[CH3:43])([CH3:41])([CH3:40])[CH3:39].C(N(CC)CC)C>C(Cl)Cl>[Si:42]([O:20][CH2:19][C:15]1[N:14]([CH2:13][CH2:12][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:37][C:6]=3[N:7]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[C:8]2=[O:21])[CH:18]=[CH:17][N:16]=1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:44])[CH3:43]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1cc2c(=O)n(CCn3ccnc3CO)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(=O)n(CCn3ccnc3CO[Si](C)(C)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
A mixture of 4′-{[6-ethyl-3-{2-[2-(hydroxymethyl)-1H-imidazol-1-yl]ethyl}-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g), tert-butyl(chloro)dimethylsilane (0.18 g), triethylamine (0.16 mL) and methylene chloride (20 mL) was stirred at room temperature for 4 hr. The reaction mixture was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.61 g, 99%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=2[F:21])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:34][O:35][CH2:36][CH2:37][OH:38]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=2[F:21])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:34][O:35][CH2:36][CH2:37][OH:38])=[O:7]
Reactant: NOCCO
Reactant: CSc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CSc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 80 %

Procedure:
The title compound was prepared from reaction of the product of Example 26, Step C, 3,4-difluoro-2-[[2-fluoro-4-(methylthio)phenyl]amino]benzoic acid, with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E. Then, after workup, the crude solid triturated with Et2O and washed with pentane to afford 3,4-difluoro-2-[[2-fluoro-4-(methylthio)phenyl]amino]-N-(2-hydroxyethoxy)benzamide as a white solid (80%); m.p. (Et2O) 108-111° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.77 (br s, 1 H), 7.40 (ddd, J=9.0, 5.8, 2.0 Hz, 1 H), 7.18 (dd, J=12.0, 2.2 Hz, 1 H), 7.13 (ddd, J=9.9, 9.0, 7.2 Hz, 1 H), 6.99 (ddd, J=8.5, 2.4, 0.8 Hz, 1 H), 6.87 (td, J=8.9, 4.5 Hz, 1 H), 4.71 (br s, 1 H), 3.86 (t, J=4.9 Hz, 2 H), 3.57 (t, J=4.9 Hz, 2 H), 2.45 (s, 3 H). Anal. Calcd for C16H15F3N2O3S: C, 51.6; H, 4.1; N, 7.5. Found: C, 52.1; H, 4.3; N, 7.6.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24](Br)[CH:25](Br)[CH3:26])=[C:20]([F:29])[C:19]=3[F:30])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].O>COC(C)(C)C>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[C:25][CH3:26])=[C:20]([F:29])[C:19]=3[F:30])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(-c3ccc(C(Br)C(C)Br)c(F)c3F)cc2)cc1
Solvent: O
Solvent: COC(C)(C)C
Product: CC#Cc1ccc(-c2ccc(-c3ccc(CCCCC)cc3)cc2)c(F)c1F
Yield: 67.9 %

Procedure:
2.5 g of potassium tert.butylate are added to a solution of 4.3 g of crude 1-[4-(4-pentylphenyl)-phenyl]-2,3-difluoro-4-(1,2-dibromopropyl)-benzene in 200 ml of tert.butyl methyl ether and the reaction mixture is heated at reflux temperature for 4.5 hours. Thereafter, it is cooled, treated with 50 ml of water and partitioned between water and diethyl ether. The combined organic phases are dried over anhydrous magnesium sulphate, the solvent is evaporated and the residue is chroma-tograped on silica gel with 5% ethyl acetate in petroleum ether. Filtration over Alox (CAMAG, neutral, activity grade 1) and fractional crystallization from ethyl acetate gives 2.04 g of 1-[4-(4-pentylphenyl)-phenyl]-2,3-difluoro-4-(1-propynyl)-benzene, m.p. (C-SB) 135.7° C.; SB -N 173° C.; cl.p. (N-I) about 210° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:6]2=[N:5][CH:4]=[C:3]1[C:28]([OH:30])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:32]>ClCCl>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:6]2=[N:5][CH:4]=[C:3]1[C:28]([Cl:32])=[O:30]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1cnc2cc(OCc3ccccc3)c(OCc3ccccc3)cn2c1=O
Solvent: ClCCl
Product: O=C(Cl)c1cnc2cc(OCc3ccccc3)c(OCc3ccccc3)cn2c1=O
Reaction time: 1.5 h

Procedure:
To a suspension of 4-oxo-7,8-bis(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (1.21 g, 3.0 mmol) in 30 ml of dichloromethane was added 0.69 g (3.3 mmol) of phosphorous pentachloride at 0° C. After stirring for 90 minutes, the solid was filtered off, washed with dichloromethane and dried in vacuo. Yield: 0.91 g; melting point 152.4° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[C:12]([CH3:13])=[N:11][NH:10][C:9]1=[O:14].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18]>C(#N)C>[CH3:13][C:12]1[N:8]([CH3:7])[C:9](=[O:14])[N:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[N:11]=1
Reactant: Cc1n[nH]c(=O)n1C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1nc(C)n(C)c1=O
Temperature: 50 °C

Procedure:
1222 mg of potassium carbonate are added to a solution of 500 mg of 4,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one in 15 ml of acetonitrile, and the mixture is warmed to 50° C. After addition of 879 mg of methyl bromoacetate, the mixture is heated at reflux for 16 hours. The mixture is concentrated under reduced pressure, the residue is taken up in dichloromethane, washed with diluted hydrochloric acid (pH 2) and dried over sodium sulphate, and the solvent is removed under reduced pressure. This gives 593 mg of methyl (3,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)acetate (Va-6) in a purity of 93% (LCMS).