Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7].O1CCCC1.Cl[C:24]1[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.[H-].[Na+]>CCOCC>[Cl:30][C:29]1[C:24]([O:1][CH2:2][C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[CH:5]([C:8]2[S:12][CH2:11][N:10]([CH3:13])[CH:9]=2)[O:6][CH3:7])=[N:25][CH:26]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:28]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(C1=CN(C)CS1)c1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(C1=CN(C)CS1)c1ccccc1COc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a mixture of 0.21 g (0.9 mmol) of 5-(2-hydroxymethyl-α-methoxybenzyl)-3-methylthiazole, 3 ml of tetrahydrofuran and 0.29 g (1.35 mmol) of 2,3-dichloro-5-trifluoromethylpyridine was added 0.05 g (1.3 mmol) of 60% sodium hydride under ice-cooling and stirred at room temperature for 2 hours. After completion of the reaction, 100 ml of ether was added and washed with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[2-(3-chloro-5-trifluoromethyl-2-pyridyloxymethyl)-α-methoxybenzyl]-3-methylthiazole (0.32 g, 86.1%) as colorless oil.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[H-].[Na+].[CH2:21](I)[CH:22]=[CH2:23]>CN(C=O)C>[CH2:23]([O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1)[CH:22]=[CH2:21]
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Yield: 93.6 %

Procedure:
The same operation as in Example (90a) was performed using tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (5.2 g, 20 mmol), sodium hydride (55% content, 1.31 g, 30 mmol), allyl iodide (5.03 g, 30 mmol) and DMF (50 mL). The residue was purified by column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 5.64 g of the title compound as a colorless oily substance (93%).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH2:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[CH3:22].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([N:23]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17])[CH3:22]
Reactant: CCNCc1ccccc1F
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCN(Cc1ccccc1F)C(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and ethyl-(2-fluoro-benzyl)-amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C21H24FNO5 [M+H]+:390.
Reaction SMILES: CN(C)C=O.[C:6]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][NH:14][C:13]2=O)(=O)C.S(Cl)([Cl:25])=O>>[ClH:25].[Cl:25][C:13]1[C:12]2[C:17](=[CH:18][C:19]([O:20][CH3:21])=[C:10]([O:9][CH3:6])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OC
Product: Cl
Yield: 87 %

Procedure:
Dimethylformamide (0.25 ml) was added dropwise to a solution of 6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one (13.8 g, 59.0 mmol) in thionyl chloride (150 ml) and the reaction was heated at reflux for 1.5 hours. The reaction was cooled, excess thionyl chloride was removed in vacuo and the residue was azeotroped with toluene (2×50 ml) to remove the last of the thionyl chloride. Drying in vacuo yielded 4-chloro-6,7-dimethoxyquinazoline hydrochloride (14.7 g, 87% yield) as a beige solid, which was used without further purification:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CN(C=O)C>[CH3:12][N:13]([CH3:15])/[CH:14]=[CH:1]/[C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1cnccc1C#N
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cnccc1C#N
Temperature: 25 °C
Yield: 54.1 %

Procedure:
To a solution of 3-methylisonicotinonitrile (10 g, 85 mmol) in DMF (100 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (18.05 mL, 135 mmol). The mixture was heated to reflux overnight. The mixture was cooled to rt and an additional 3.0 mL of 1,1-dimethoxy-N,N-dimethylmethanamine was added to the mixture, and it was again heated to reflux. After heating the mixture overnight, it was cooled to rt and an additional 3.0 mL of 1,1-dimethoxy-N,N-dimethylmethanamine was added to the mixture. The mixture was heated overnight at reflux. The mixture was cooled to rt and an additional 3.0 mL of 1,1-dimethoxy-N,N-dimethylmethanamine were added. The mixture was again heated to reflux. After heating the mixture overnight, it was cooled to rt. To the mixture was added 3.0 mL of 1,1-dimethoxy-N,N-dimethylmethanamine. The mixture was heated to reflux overnight. The mixture was cooled to rt and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and was loaded onto a BIOTAGE® 65+M cartridge and was purified using a 10-70% EtOAc in hexanes gradient. The expected product, (E)-3-(2-(dimethylamino)vinyl)isonicotinonitrile (7.97 g, 46.0 mmol, 54.4% yield), was isolated as a bright-yellow solid. LC/MS: m/z 174.11 (M+H)+, 1.690 min (method 1). 1H NMR (500 MHz, chloroform-d) δ ppm 1H NMR (500 MHz, chloroform-d) δ ppm 8.69 (s, 1H) 8.14 (d, J=5.19 Hz, 1H) 7.23 (d, J=4.88 Hz, 1H) 7.15 (d, J=13.43 Hz, 1H) 5.21 (d, J=13.73 Hz, 1H) 2.95 (s, 6H)
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:16]#[C:17][Si](C)(C)C)=[C:6]([C:10]#[C:11][Si](C)(C)C)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F-:22].[Cs+].[F:24][C:25]1[N:30]=[C:29]([F:31])[C:28]([F:32])=[C:27](F)[C:26]=1[F:34].ClCCl>CN(C=O)C.[Cl-].[Na+].O>[N+:1]([C:4]1[C:5]([C:16]#[C:17][C:27]2[C:28]([F:32])=[C:29]([F:31])[N:30]=[C:25]([F:24])[C:26]=2[F:34])=[C:6]([C:10]#[C:11][C:27]2[C:26]([F:22])=[C:25]([F:24])[N:30]=[C:29]([F:31])[C:28]=2[F:32])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)C#Cc1cccc([N+](=O)[O-])c1C#C[Si](C)(C)C
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: [F-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(C#Cc2c(F)c(F)nc(F)c2F)c1C#Cc1c(F)c(F)nc(F)c1F
Reaction time: 20 h
Yield: 42 %

Procedure:
A solution of ((3-nitro-1,2-phenylene)bis(ethyne-2,1-diyl))bis(trimethylsilane) (2.89 g, 9.16 mmol) in DMF (20 mL) was added into 20 mL of CsF(4.17 g, 27.5 mmol) solution in DMF. Into the mixture, pentafluoropyridine (3.87 g, 22.9 mmol) was added slowly at 0° C. The reaction mixture was stirred for 20 hrs, and brine (50 mL) and dichloromethane (100 mL) were added. Organic phase was separated and washed with water (50 mL×3). Solvent was evaporated by rotary evaporation and the residue was chromatographed (CH2Cl2:Hexane=1:4 to 1:3) to provide the desired product in 42% yield: 1H-NMR (300 MHz, CDCl3) δ 8.28 (dd, J=8.1 Hz, J=1.2 Hz, 1H), 8.02 (dd, J=7.8 Hz, J=1.2 Hz, 1H), 7.71 (dd, J=8.4 Hz, J=8.4 Hz, 1H)
Reaction SMILES: COCCCCCCCCCCC[C:14]([NH:16][C@@H:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:18])=[O:15].[C:24]([O:28]C(N[C@@H](C(O)=O)C)=O)([CH3:27])([CH3:26])[CH3:25].O.O.O.O.O.[OH-].C[N+](C)(C)C.C(I)C>C(#N)C>[C:24]([O:28][C:14]([NH:16][C@@H:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:18])=[O:15])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)[C@@H](C)NC(=O)CCCCCCCCCCCOC
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CCI
Solvent: O
Solvent: CC#N
Product: CCOC(=O)[C@@H](C)NC(=O)OC(C)(C)C

Procedure:
Reaction Scheme 6 illustratively shows the preparation of N-(12-methoxy-1-oxododecyl)-D-alanine, ethyl ester wherein N-(t-butyloxycarbonyl)-D-alanine, (16) is treated with tetramethylammonium hydroxide pentahydrate in acetonitrile followed by the addition of ethyl iodide to form N-(t-butyloxycarbonyl)-D-alanine, ethyl ester (17) which in turn reacts with trifluoroacetic acid in methylene chloride to give the trifluoroacetate salt of D-alanine ethyl ester (18) which, when treated with 2-methoxydodecanoyl chloride (9) in methylene chloride, gives the desired fatty acid amino ester (19).
Reaction SMILES: COC(C1SC([I:22])=C(C#N)C=1C1C=CC(C(C)(C)C)=CC=1)=O.[CH2:23]([O:25][C:26]([C:28]1[S:29][C:30](N)=[C:31]([C:47]#[N:48])[C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]#[N:46])=[CH:35][CH:34]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1[S:29][C:30]([I:22])=[C:31]([C:47]#[N:48])[C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]#[N:46])=[CH:35][CH:34]=1)=[O:27])[CH3:24]
Reactant: COC(=O)c1sc(I)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Reactant: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(-c2ccccc2C#N)cc1
Product: CCOC(=O)c1sc(I)c(C#N)c1-c1ccc(-c2ccccc2C#N)cc1

Procedure:
Using a method substantially in accordance with the method of 3-(4-tert-butyl-phenyl-4-cyano-5-iodo-thiophene-2-carboxylic acid methyl ester starting with the compound, 5-amino-4-cyano-3-(2′-cyano-biphenyl-4-yl)-thiophene-2-carboxylic acid ethyl ester gives the title compound: 1H NMR (400 MHz, CDCl3) δ 7.81-7.46 (m, 8H), 4.22 (q, 2H, J=7.2 Hz), 1.20 (t, 3H, J=7.0 Hz), MS found (M+1)+NH3 502.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1.Cl.[OH-].[Na+]>O.C(O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[NH:28][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc(Nc2cc(-c3ccccn3)nc(-c3ccccn3)n2)c1
Yield: 60.5 %

Procedure:
A mixture 4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol), m-anisidine (16 μl, 0.140 mmol) and 2N HCl (75 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10-12. The resulting precipitate was filtered, washed with water and aqueous ethanol to give a yellow solid (20 mg, 60%). 1H NMR (CDCl3): 8.87-8.85 (m, 1H), 8.69-8.61 (m, 3H), 7.95 (s, 1H), 7.92-7.84 (m, 2H), 7.44-7.36 (m, 2H), 7.33 (d, J=8.1 Hz, 1H), 7.30 (s, 1H), 7.05 (t, J=2.1 Hz, 1H), 6.98 (dd, J=2.1, 8.1 Hz, 1H), 6.79-6.75 (m, 1H), 3.86 (s, 3H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]#[C:36][C:37]3[CH:50]=[CH:49][C:40]([O:41][CH2:42][CH2:43][NH:44][CH2:45][CH:46]4[CH2:48][CH2:47]4)=[C:39]([CH3:51])[CH:38]=3)=[N:33][CH:34]=2)=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>CC(O)=O.C1COCC1.C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]#[C:36][C:37]3[CH:50]=[CH:49][C:40]([O:41][CH2:42][CH2:43][N:44]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:45][CH:46]4[CH2:48][CH2:47]4)=[C:39]([CH3:51])[CH:38]=3)=[N:33][CH:34]=2)=[CH:27][CH:28]=1
Reactant: O=C1CCCCC1
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCNCC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN(CC1CC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
30 μL (0.29 mmol) of cyclohexanone, 1 drop of AcOH, and 128 mg (0.68 mmol) of sodium triacetoxyborohydride were added to a solution of 60 mg (0.14 mmol) of (2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclopropylmethylamine in 10 mL of THF and the mixture was stirred for 24 hours at RT. 5 mL of DCM, 30 μL (0.29 mmol) of cyclohexanone, and 36 mg (0.58 mmol) of sodium cyanoborohydride were added and the mixture was stirred for a further 3 days. The reaction mixture was evaporated down in vacuo and the residue was taken up in EtOAc. The organic phase was washed with semiconcentrated aqueous sodium bicarbonate solution, dried over sodium sulfate, and evaporated down in vacuo. The residue was purified by column chromatography (silica gel, cyc/EtOAc 1:1) and triturated with PE. Yield: 4.5 mg (6% of theoretical); C32H35ClN2O (M=499.086); calc.: molpeak (M+H)+: 499/501 (Cl); found: molpeak (M+H)+: 499/501 (Cl); HPLC-MS: 9.85 minutes (method A).
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19]C1C=CC=CC=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([NH:33]N)=[O:32]>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19][NH:33][C:31]([C:27]1[S:26][CH:30]=[CH:29][CH:28]=1)=[O:32]
Reactant: NNC(=O)c1cccs1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Nc1ccccc1)C(=O)N2
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=NNC(=O)c1cccs1)C(=O)N2
Yield: 35 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo -2H-1,3,4-thiadiazin-5-yl)-3-phenylimino-2H-indol-2- one and 2-thiophene carboxylic acid hydrazide and following the method described in Example 21, the desired compound was obtained.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=[O:8])[C:4]([CH:9]=O)=[CH:3][CH:2]=1.[CH3:11][C:12]([O:15][C:16](=[O:39])[C:17](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:18][CH3:19])([CH3:14])[CH3:13]>>[CH3:11][C:12]([O:15][C:16](=[O:39])/[C:17](/[CH2:18][CH3:19])=[CH:9]/[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH:7]=[O:8])([CH3:14])[CH3:13]
Reactant: CCC(C(=O)OC(C)(C)C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1C=O
Product: CC/C(=C\c1ccccc1C=O)C(=O)OC(C)(C)C

Procedure:
From o-phthalaldehyde and 2-(triphenylphosphoranylidene)-butanoic acid 1,1-dimethylethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1.[CH3:24][CH2:25][N:26]([CH:30]([CH3:32])C)[CH:27]([CH3:29])C.BrC/C=[CH:36]/[C:37](Cl)=[O:38].C(NCC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([NH:19][C:37](=[O:38])[CH:36]=[CH:32][CH2:30][N:26]([CH2:25][CH3:24])[CH2:27][CH3:29])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1N
Reactant: O=C(Cl)/C=C/CBr
Reactant: CCN(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCNCC
Product: CCN(CC)CC=CC(=O)Nc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cc1OC
Yield: 28.9 %

Procedure:
To a mixture of 0.5 g (1.36 mmol) of 4-[(3-bromophenyl)amino]-7-methoxy-6-amino-3-quinolinecarbonitrile and 0.48 ml (2.7 mmol) of Hunig's base in 50 ml of dry THF at 0° C., with stirring, was added a THF solution containing 0.50 g (2.7 mmol) of 4-bromo crotonyl chloride dropwise. The mixture was stirred for additional 0.5 hour after addition and then was added to a solution of 4.2 ml (40.8 mmol) diethyl amine in 50 ml of THF at 0° C. dropwise. The solution was stirred for an additional 0.5 hour. The mixture was poured into diluted sodium bicarbonate solution . The organic layer was separated and dried over sodium sulfate. Chromatography gave 0.2 g of white solid: mass spectrum (electrospray, m/e): M+H 508.1 and 510.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:14][O:15][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COc3ccccc3)C3CCCCC3)c2cc1F
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 0.2 g (0.51 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) in 4 mL tetrahydrofuran were added 53 mg (0.56 mmol) phenol and 124 mg (0.61 mmol) tri-n-butylphosphin. The reaction mixture was cooled down to 0° C. and 106 mg (0.61 mmol) N,N,N′,N′-tetramethylazodicarboxamide were added. After stirring for 18 h at room temperature the reaction mixture was evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:Ethyl acetate (100:0 to 60:40). MS (Turbo Spray): m/z=467.2 [M+H].
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH-].[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>C(O)C>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][S:3][C:2]2[N:4]=[C:5]([OH:6])[CH:7]=[C:8]([OH:9])[N:1]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CC(=O)NC(=S)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CSc2nc(O)cc(O)n2)cc1
Temperature: 60 °C
Yield: 54.5 %

Procedure:
To a suspension of thiobarbituric acid (15 g) in 50% ethanol (180 ml) are added a solution of NaOH (5.1 g) in 50% ethanol (75 ml) and p-methoxybenzyl chloride (18.7 g). The mixture is heated under stirring for 60' at 60° C.; then it is cooled and the solid is filtered by suction, washed with water; then dried over CaCl2, yielding 15 g of 2-p-methoxy-benzylthio-4,6-dihydroxypyrimidine.
Reaction SMILES: [NH3:1].[CH3:2][N:3]1[C:7]([C:8]2[S:16][C:15]3[C:14](SC)=[N:13][CH:12]=[N:11][C:10]=3[CH:9]=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[CH:4]1>[Cl-].[NH4+].CN1C(=O)CCC1>[CH3:2][N:3]1[C:7]([C:8]2[S:16][C:15]3[C:14]([NH2:1])=[N:13][CH:12]=[N:11][C:10]=3[CH:9]=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[CH:4]1
Reactant: N
Reactant: CSc1ncnc2cc(-c3c(-c4ccccc4)ncn3C)sc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: Cn1cnc(-c2ccccc2)c1-c1cc2ncnc(N)c2s1
Temperature: 205 °C

Procedure:
Concentrated aqueous NH3 (0.5 mL) and saturated ammonium chloride solution (one drop) were added to a solution of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[3,2-d]pyrimidine (example 11) (40 mg) in NMP (2 mL). The vessel was sealed and heated in a microwave (CEM explorer, 200-210° C., 110 W) for 35 minutes. Dilution with water (1.5 mL) and purification by RPHPLC eluting with MeCN:H2O (2:98 to 40:60) gave the title compound as a pale brown solid (24 mg, 67.%);
Reaction SMILES: C(OC([C:11]1[C:19]2[C:18]3CCC(CO)O[C:17]=3[CH:16]=[CH:15][C:14]=2[NH:13][C:12]=1C)=O)C1C=CC=CC=1.C(Br)(Br)(Br)[Br:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl.CO>C(Cl)Cl>[Br-:28].[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1
Reactant: Cc1[nH]c2ccc3c(c2c1C(=O)OCc1ccccc1)CCC(CO)O3
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: [Br-]
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
7-Hydroxymethyl-2-methyl-3,7,8,9-tetrahydro-pyrano[3,2-e]indole-1-carboxylic acid benzyl ester (0.410 g, 1.16 mmol, 1 eq) was suspended in dry CH2Cl2 (20 mL) under Ar. Carbon tetrabromide (0.615 g, 1.86 mmol, 1.6 eq) was added followed by the addition of triphenylphosphine (0.441 g, 1.5 mmol, 1.3 eq). The reaction mixture was stirred at room temperature. The reaction was followed by TLC (CH2Cl2/MeOH 9/1). After 3 hours, the reaction mixture was loaded on silica gel and chromatographed, eluting with CH2Cl2/MeOH 9/1. 0.191 g (40% yield) of the indole-bromide was obtained as an unstable brown oil.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([OH:18])[CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17])=[N+]=[N-].[ClH:19].[H][H]>[Pd].CCO>[ClH:19].[NH2:1][CH2:4][C@H:5]([OH:18])[CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17]
Reactant: [H][H]
Reactant: [N-]=[N+]=NC[C@H](O)CN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NC[C@H](O)CN1C(=O)c2ccccc2C1=O
Reaction time: 8 h

Procedure:
To EtOH solution (80 ml) of N-(3-azido-2(R)-hydroxypropyl)phthalimide 1.96 g (7.69 mmol), 10% Pd—C (200 mg) and concentrated hydrochloric acid solution 1.4 ml were added sequentially. To the reaction mixture, hydrogen was introduced at 2 kgf/cm2 atm. and then stirring was continued at room temperature overnight. After removal of catalyst by filtration, catalyst was washed with EtOH/DMF (1:1) solution (60 ml) and then combined filtrate was evaporated to dryness. Addition of EtOH to the residue gave crystal of desired product as a hydrogen chloride salt. Crystal was collected by filtration and dried under reduced pressure at 40° C. to afford 1.28 g of the product. The NMR spectra were consistent with the desired title intermediate.
Reaction SMILES: COC1C=C(OC)C=CC=1[C:11]1[N:12]=[C:13]([C:21]2[C:22]([CH3:30])=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=23)[S:14]C=1C1N=CNN=1.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:33]=1B(O)O.C[CH2:44][O:45][C:46]([CH3:48])=[O:47].CCCCCC>>[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:33]=1[C:11]1[N:12]=[C:13]([C:21]2[C:22]([CH3:30])=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=23)[S:14][C:48]=1[C:46]([O:45][CH3:44])=[O:47]
Reactant: COc1cccc(F)c1B(O)O
Reactant: COc1ccc(-c2nc(-c3c(C)nn4ccccc34)sc2-c2nc[nH]n2)c(OC)c1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1c(F)cccc1OC

Procedure:
According to the similar manner described in Example 97-B (i), the title compound (86 mg, 93%) has been obtained as a yellow solid by the Suzuki coupling reaction using methyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl)]oxy}-1,3-thiazole-5-carboxy late (97.3 mg, 0.231 mmol) obtained in Example 13-B (ii) and (2-fluoro-6-methoxyphenyl)boronic acid (78.5 mg, 0.462 mmol. The pure title compound has been obtained by the basic silica gel column chromatographic purification (EtOAc/hexane=0/100→30/70).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[CH2:14][CH:13]([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=NN(C)C.C(OCC)(=[O:24])C>O1CCCC1.P([O-])([O-])([O-])=O.O.O.[Cu](Cl)Cl>[CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[CH2:14][CH:13]([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:24]
Reactant: CCOC(C)=O
Reactant: COC(CC1CC(C)c2ccccc2C1=NN(C)C)OC
Agent: Cl[Cu]Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(CC1CC(C)c2ccccc2C1=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(Dimethylhydrazono)-1,2,3,4-tetrahydro-4-methyl-2-naphthaleneacetaldehyde dimethyl acetal (23.1 g) was dissolved under argon in a mixture of 1000 ml of tetrahydrofuran and 350 ml of 0.067M phosphate buffer of pH value 7. The solution was treated with 13.6 g of copper(II) chloride dihydrate and stirred at room temperature for 16 hours. 500 ml of ethyl acetate were added to the reaction mixture and it was washed three times with a mixture of 25% ammonia solution and saturated ammonium chloride solution (1:19) (1×800 ml, 2×500 ml). The aqueous wash phases were extracted twice with 500 ml of ethyl acetate each time, the organic phases were combined, dried over MgSO4 and freed from solvent. There were obtained 20.0 g of crude 1,2,3,4-tetrahydro-4-methyl-1-oxo-2-naphthaleneacetaldehyde dimethyl acetal which was processed without purification.