Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[Cl:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH3:20])=[CH:15][N:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[K+]>O1CCOCC1.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:12][C:13]1[N:18]=[C:17]([NH:19][C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=2)[C:16]([CH3:20])=[CH:15][N:14]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: Cc1cnc(Cl)nc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc(Cl)ncc2C)cc(OC)c1
Temperature: 25 °C
Yield: 32.5 %

Procedure:
A mixture of 1-bromo-3,5-dimethoxybenzene (436 mg, 2.01 mmol), 2-chloro -5-methyl-pyrimidin-4-ylamine (287 mg, 2.00 mmol), Pd(OAc)2 (44 mg, 0.20 mmol), Xantphos (237 mg, 0.41 mmol) and potassium tert-butoxide (448 mg, 3.99 mmol) in dioxane (15 mL) and DMF (5 mL) was microwaved at 160° C. for 20 min. The reaction mixture was cooled to room temperature and filtered rinsing with DCM and methanol. The filtrate was concentrated and purified using gradient flash chromatography (0-100% ethyl acetate in hexanes) to afford the title compound as a yellow solid (182 mg, 33%).
Reaction SMILES: [CH3:1][CH:2]1[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH3:9])=[N:4][C:3]1=[O:17].Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.CC1(C2C=CC(C#N)=CC=2)SC(N[C@H](C2C=CC=CC=2C(F)(F)F)C)=NC1=O>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH:7][C:5]2[S:6][C:2]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)([CH3:1])[C:3](=[O:17])[N:4]=2)[CH3:9])=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC1SC(N[C@@H](C)c2ccc(F)cc2)=NC1=O
Agent: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1C(F)(F)F
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccc(F)cc1

Procedure:
The title compound was prepared from the reaction of 5-methyl-2-((S)-1-(4-fluorophenyl)ethylamino)thiazol-4(5H)-one with 4-bromobenzonitrile using the procedure described for 2a. MS (ESI, pos. ion) m/z: 354 (M+1).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][CH:7]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].C([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[C:37]1[C:38]([CH2:48][CH2:49][CH2:50][C:51]2C=CC=C[CH:52]=2)=C(S([O-])(=O)=O)C=C[C:42]=1[CH3:43])C1C=CC=CC=1>C(#N)C>[CH2:7]([O:21][C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:43][CH2:42][CH:37]([C:31]1[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:30]=1[OH:29])[C:38]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(O)c(C(CCNC(C)C)c2ccccc2)c1
Reactant: Cc1ccc(OCc2ccccc2)c(-c2c(C)ccc(S(=O)(=O)[O-])c2CCCc2ccccc2)c1
Solvent: CC#N
Product: Cc1ccc(O)c(C(CCN(CCC(c2ccccc2)c2cc(C)ccc2OCc2ccccc2)C(C)C)c2ccccc2)c1
Temperature: 112.5 °C

Procedure:
A mixture of N-isopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine (59 g) and 3-(2-(benzyloxy)-5-methylphenyl)-3-phenylpropyl-4-methylbenzenesulfonate of Formula IVa (100 g) in acetonitrile (595 ml) was heated in an autoclave at 110-115° C. for 16-18 hours. The reaction mass was cooled to 60-65° C., and solvent was distilled completely under vacuum. Charged ethyl acetate (290 ml) and water (590 ml) to the residue. Separated the aqueous layer and extracted with 118 ml of ethyl acetate. Combined organic layers were washed with water (590 ml) and distilled completely to obtain 108 g of syrup. This syrup was loaded onto a silica gel column and eluted with 5% ethyl acetate in chloroform. Distilled the solvent completely to get 38 g of the title compound as syrup.
Reaction SMILES: CC(C)([O-])C.[K+].[I:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:14][CH:15]=2)[NH:10][CH:9]=1.Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[CH:28][N:27]=1>CN(C=O)C.O>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:29]1[CH:30]=[N:31][C:26]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:12]=3)[C:8]([I:7])=[CH:9]2)=[N:27][CH:28]=1
Reactant: O=C(c1ccc2c(I)c[nH]c2c1)N1CCOCC1
Reactant: Fc1ccccc1-c1cnc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc2c(I)cn(-c3ncc(-c4ccccc4F)cn3)c2c1)N1CCOCC1
Temperature: 25 °C

Procedure:
Potassium tert-butoxide (236 mg, 2.106 mmol, 1.5 eq), compound 354a) (500 mg, 1.404 mmol, 1.0 eq) and 2-chloro-5-(2-fluorophenyl)pyrimidine (292 mg, 1.404 mmol, 1.0 eq) in DMF (10 mL) were stirred at 120° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography [100-200 mesh silica; ethyl acetate/pet ether=7:3]. Yield: 400 mg (53% of theory).
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1C=CC=CC=1.[N+:14]([C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[S:26](Cl)(=[O:28])=[O:27])([O-:16])=[O:15].S(Cl)(Cl)(=O)=O>C(Cl)Cl.C1COCC1>[N+:14]([C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[S:26]([NH2:8])(=[O:28])=[O:27])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: c1ccncc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O=S(=O)(Cl)Cl
Product: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of Part A compound (1.01 g, 2.37 mmol) and TFA (8 mL) in CH2Cl2 (30 mL) was stirred at RT for 4.5 h. The solution was concentrated in vacuo, and the residue was dissolved in CH2Cl2 and filtered through a pad of solid K2CO3. The filtrate was concentrated in vacuo to give the corresponding crude amine. To a solution of the crude amine in THF (11.9 mL) were added pyridine (0.383 mL, 4.74 mmol) and 2,4-dinitrobenzenesulfonyl chloride (0.85 g, 3.19 mmol) and the solution was stirred at RT for 15 h. Since some starting material still remained at this point, more sulfonyl chloride (0.32 g, 1.2 mmol) was then added. After a further 4 h, HPLC analysis indicated that all starting material had been consumed. The reaction mixture was diluted with Et2O, washed with 1N aq HCl, saturated aq NaHCO3 and brine, dried (MgSO4), filtered and concentrated in vacuo to provide the crude 2,4-dinitrobenzenesulfonamide
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:11](=[O:12])[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:9])[NH:7][C:5]1=[O:6].[C:25]1(C2(C3C=CC=CC=3)C(=O)NC(=O)NC2=O)C=CC=CC=1.COCN1C(=O)C(C2C=CC=CC=2)(C2C=CC=CC=2)C(=O)N(COC)C1=O>>[CH3:1][O:2][CH:3]([N:4]1[C:11](=[O:12])[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:9])[NH:7][C:5]1=[O:6])[CH3:25]
Reactant: COCN1C(=O)NC(=O)C(c2ccccc2)(c2ccccc2)C1=O
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)C(=O)N1
Agent: COCN1C(=O)N(COC)C(=O)C(c2ccccc2)(c2ccccc2)C1=O
Product: COC(C)N1C(=O)NC(=O)C(c2ccccc2)(c2ccccc2)C1=O

Procedure:
To the aqueous phase was added hydrochloric acid (32%, 0.32 L), while keeping the temperature below 20° C. The methanol was then distilled out of the mixture at reduced pressure, and the resulting precipitate was filtered and dried to provide a crude product (0.366 kg) containing 1-methoxymethyl-5,5-diphenylbarbituric acid (78% w/w), 5,5-diphenylbarbituric acid (6% w/w), and 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid (2.7% w/w).
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1>C(O)CCC>[CH3:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[NH:13][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1
Reactant: Clc1nncc2ccccc12
Reactant: Cc1cccc(N)c1
Agent: Cl
Solvent: CCCCO
Product: Cc1cccc(Nc2nncc3ccccc23)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Under a N2 atmosphere, 30 g (149 mmol) 1-chlorophthalazine hydrochloride in 0.6 l n-butanol is mixed with 16.2 ml (149 mmol) m-toluidine and stirred for 1 h at 65° C. The solution is concentrated by evaporation and the residue distributed between dichloromethane/MeOH 10:1 and Na2CO3 solution (80 g in 0.5 l H2O). The aqueous phase is extracted twice with dichloromethane/MeOH 10:1, the organic phases are washed with Na2CO3 solution (80 g in 0.5 l H2O) and brine, dried (Na2SO4) and evaporated. The residue is taken up in 200 ml boiling dichloromethane/acetone 1:1, filtered hot, and partly evaporated. Then addition of DIPE leads to crystallization of the title compound, which is filtered off and washed with DIPE: m.p. 176-177° C.; 1H-NMR (DMSO-d6) 9.12 (s, HN), 9.08 (s, 1H), 8.59 (m, 1H), 7.99 (m, 3H), 7.76 (s, 1H), 7.73 (d, 1H), 7.24 (t, 1H), 6.86 (d, 1H), 2.32 (s, 3H); FAB-MS (M+H)+=236; an. calc. (C15H13N3.0.05 H2O) C, 76.28%; H, 5.59%; N, 17.79%; meas. C, 76.04%; H, 5.53%; N, 17.68%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.BrC[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=O>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[C:6]3=[C:5]([OH:11])[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]3[O:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: COc1cc(O)cc(OC)c1
Product: Oc1cc(O)c2c(-c3ccc(F)cc3)coc2c1
Yield: 27 %

Procedure:
This compound was prepared using Method B from 3,5-dimethoxyphenol and 2-bromo-1-(4-fluorophenyl)ethanone: Yield 27% following procedures B.2, B.3 and B.5; m.p. 125° C. (dec.); IR 3508, 1612, 1508, 1455, 1240, 1121, 1090, 1048 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 9.84 (s, 1H), 9.36 (s, 1H), 7.77 (s, 1H), 7.70 (dd, J=8.1 Hz, 5.9 Hz, 2H), 7.20 (t, J=8.8 Hz, 2H), 6.41 (s, 1H), 6.25 (s, 1H); 13C NMR (126 MHz, δ ppm, CD3OD) 163.7 (d, J=243.9 Hz), 160.2, 157.7, 153.6, 140.4, 132.0 (d, J=7.9 Hz), 130.4 (d, J=3.3 Hz), 123.3, 115.6 (d, J=21.6 Hz), 109.2, 99.1, 91.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[N:13]=[C:12](Cl)[CH:11]=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:17][O-:18].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[N:13]=[C:12]([O:18][CH3:17])[CH:11]=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=c1nc(Cl)cnn1-c1cc(Cl)cc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cnn(-c2cc(Cl)cc(Cl)c2)c(=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF was dissolved 2.77 g of 2-(3,5-dichlorophenyl)-5-chloro-2,3-dihydro-1,2,4-triazin-3-one followed by addition of sodium methoxide in an equimolar amount to the starting compound, and the mixture was stirred at room temperature for 1 hour. After completion of this reaction, the reaction mixture was concentrated under reduced pressure and ice-water was added to the residue. The resulting crystals were collected by filtration, dried and dissolved in 100 ml of chloroform. The chloroform solution was dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (Merck Silica Gel 60; dichloromethane-methanol=10:1) to provide 0.4 g of white crystals (m.p. 164° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6]2.[H-].[Na+].Cl[CH2:21][C:22]1[N:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:21][C:22]1[N:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][CH:23]=1)[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[CH:6]2
Reactant: N#Cc1cccc(CCl)n1
Reactant: COc1ccc2[nH]c(-c3ccccc3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 5-methoxy-2-phenyl-1H-indole (200 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (dispersed in liquid paraffin, 50% or more, 45 mg) under ice-cooling. This mixture was stirred for 30 minutes at room temperature. Subsequently, 6-chloromethylpyridine-2-carbonitrile (216 mg) was added thereto, followed by stirring at 80° C. overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (228 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 5.55 (2H, s), 6.55-6.65 (1H, m), 6.77 (1H, dd, J=2.4, 8.8 Hz), 6.91 (1H, dd, J=1.5, 7.4 Hz), 7.13 (1H, d, J=2.4 Hz), 7.26 (1H, d, J=8.8 Hz), 7.35-7.55 (5H, m), 7.85-7.95 (2H, m).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([O:15]CC)C>CN(C)C=O.CO>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([O:15][CH3:13])=[CH:3][C:4]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: CCOCC
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-bromo-2-methylbenzoate (19.0 mmol) was dissolved in dimethylformamide (2.7 mL) and methanol (1.1 mL), and the solution was heated at 80° C. and then added with CuBr (1.09 mmol). After stirring was continued for 2 hours under heating, the mixture was cooled to room temperature. The mixture was added with diethyl ether (25 mL) and filtered. The filtrate was washed four times with water, an aqueous sodium bicarbonate solution, and then with saturated brine, and dried over sodium sulfated. The drying agent was removed by filtration and the filtrate was concentrated to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:28])[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][NH:21][CH:22]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[CH2:26]([O:25][C:23]([C:19]1[C:18](=[O:28])[C:17]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=2)=[CH:22][N:21]([CH2:2][C:3]([OH:5])=[O:4])[CH:20]=1)=[O:24])[CH3:27]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(CC(=O)O)cc(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl bromoacetate (341 μl) was added to a suspension of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (400 mg) and cesium carbonate (998 mg) in DMF (8 ml) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted by adding ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and filtered, and the filtrate was then concentrated under reduced pressure. Dichloromethane (15 ml) and TFA (0.59 ml) were added to the residue at room temperature. The reaction mixture was stirred at room temperature for two hours. TFA (1.00 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred overnight. TFA (4.00 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred overnight. Water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate, washed with brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=19:1->17:3 (v/v)] to give 320 mg of the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][Mg]Br>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:15])[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 4.5 h
Yield: 48.7 %

Procedure:
To a solution of N-tert-butoxycarbonyl-4-piperidinecarboxaldehyde (32.20 g, 151.45 mmol) in tetrahydrofuran at −78° C. is added methyl magnesium bromide (2 M in diethyl ether, 100.96 mL, 302.89 mmol). The reaction is stirred at −78° C. for 4.5 h, and then warmed to −50° C. for 30 min. The reaction is quenched with water at −50° C. and allowed to warm to room temperature for 16 h. The solvents are removed and the material is partitioned between diethyl ether and 0.1 M hydrochloric acid. The mixture is extracted with diethyl ether. The combined organic layers are washed with 0.1 M hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated to dryness. The crude is purified by flash chromatography over silica gel to afford 16.90 g of the title compound as a colourless oil. MS (m/z) 229 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)=[CH2:2]>C(O)C.[C].[Pd]>[CH2:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:13][CH2:14]2)=[O:8])=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Yield: 82.9 %

Procedure:
1-[1-(4-Vinylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.6 g) is dissolved in ethanol (10 ml) and thereto is added 10% palladium-carbon (0.1 g) and the mixture is stirred under hydrogen atmosphere. After the reaction, the catalyst is removed by filtration and the filtrate is concentrated. The resultant is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) and recrystallized from n-hexane/ethanol to give 1-[1-(4-ethylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.5 g) as white powder, m.p.: 133°-134° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].[ClH:12].[NH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18](O)=[O:19]>>[ClH:12].[NH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:19]
Reactant: O=[N+]([O-])c1cccc(CO)c1
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1cccc([N+](=O)[O-])c1
Reaction time: 20 h

Procedure:
From 3-nitrobenzyl alcohol (5.0 g; 33 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 20 h at 100° C. The yield was 1.00 g (55%).
Reaction SMILES: [BrH:1].[CH:2]1([C:5](O)([CH2:7][CH2:8][O:9][CH:10]([CH3:12])[CH3:11])[CH3:6])[CH2:4][CH2:3]1>>[Br:1][CH2:4][CH2:3][CH:2]=[C:5]([CH3:6])[CH2:7][CH2:8][O:9][CH:10]([CH3:12])[CH3:11]
Reactant: Br
Reactant: CC(C)OCCC(C)(O)C1CC1
Product: CC(=CCCBr)CCOC(C)C
Reaction time: 0.5 h

Procedure:
19 cc of 48 % hydrobromic acid are added dropwise, whilst stirring, at 0°C, over the course of 15 minutes, to 27.7 g of crude 2-cyclopropyl-4-isopropoxy-2-butanol. The mixture is stirred at 0°-5°C over the source of 30 minutes, and subsequently extracted with ether. The ether extract is washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residue (20.2 g) is chromatographed with hexane/ethyl acetate (98:2) and (95:5) on silica gel. A chromatographically pure cis, trans isomeric mixture of 1-bromo-6-isopropoxy-4-methyl-3-hexene is obtained, nD20 = 1.4802.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[C:8]([C:11]2[NH:15][N:14]=[CH:13][CH:12]=2)[CH:7]=[C:6]([F:16])[C:3]=1[C:4]#[N:5].O[CH2:18][C@@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[NH2:21][C@@H:19]([CH3:20])[CH2:18][N:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:7]=[C:6]([F:16])[C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=2[F:10])=[N:15]1
Reactant: N#Cc1c(F)cc(-c2ccn[nH]2)c(F)c1Cl
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2F)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.4 %

Procedure:
2-Chloro-3,6-difluoro-4-(1H-pyrazol-5-yl)benzonitrile (0.835 mmol, 0.2 g) was dissolved in THF under nitrogen atmosphere. (S)-tert-butyl (1-hydroxypropan-2-yl)carbamate (0.835 mmol, 0.146 g) and triphenylphosphine (1.252 mmol, 0.328 g) were dissolved in THF and added to the previous mixture. The resulting mixture was cooled to 0° C. Di-tert-butyl azodicarboxylate (1.252 mmol, 0.288 g) was added in small portions and stirred under cold conditions for 10 min. The flask was warmed to RT and stirred overnight. The solvent was evaporated. The residue was dissolved in ethanol and 10% HCl(g)/EtOH solution (15 ml) was slowly added. The resulting mixture was stirred overnight. The mixture was diluted with water and extracted twice with DCM. The combined organics were washed with water. The aqueous phases were combined and the pH was adjusted to 12 with 2 M NaOH. The aqueous phase was extracted three times with DCM. The combined organics were dried, filtered and evaporated. 0.167 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.17 (d, 3H), 1.31 (bs, 2H), 3.53 (bs, 1H), 3.88-4.04 (m, 1H), 4.09-4.26 (m, 1H), 6.82 (dd, 1H), 7.55 (d, 1H), 7.88 (dd, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18](N)=[O:19])[CH:15]=[CH:16][C:3]1=2.[OH-].[K+].O.C([OH:27])C>C(O)(=O)C>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([OH:27])=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: CC(C(N)=O)c1ccc2c(c1)Sc1ncccc1CC2=O
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2c(c1)Sc1ncccc1CC2=O
Temperature: 0 °C

Procedure:
The mixture of 100 mg of 2-(5,6-dihydro-6-oxo benzo[b]-pyrido[3,2-f]thiepin-9-yl)-propionamide, 170 mg of potassium hydroxide, 1.5 ml of water and 3 ml of ethanol was refluxed for 5 hours. After cooling, the solvent was distilled off to obtain the residue, to which was added ice-water and the resulting mixture was acidified with acetic acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the solid substance, which was recrystallized from benzene to give 70 mg of 2-(5,6-dihydro-6-oxo benzo[b]pyrido-[3,2-f]thiepin-9-yl)-propionic acid as pale yellow powder having a melting point of 150°-151° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.C1(C)C(S([CH2:20][N+:21]#[C-])(=O)=O)=CC=CC=1.CC(C)([O-])C.[K+]>C(COC)OC.C(O)C>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:20]#[N:21])[CH2:6][CH2:5]1
Reactant: COCC1CCC(=O)CC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: COCC1CCC(C#N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold (−10° C.) solution of EXAMPLE 454C (1.18 g) and toluenesulfonylmethyl isocyanide (2.268 g) in dimethoxyethane (3 mL) and absolute ethanol (0.1 mL) was added portionwise potassium tert-butoxide (2.235 g). The reaction mixture was continued to stir maintaining the temperature below 5° C. for 30 minutes, warmed to room temperature, heated at 35° C. for 30 minutes and then at room temperature for 2 hours. The reaction mixture was concentrated and the residue was dissolved in water-brine, extracted with dichloromethane. The dichloromethane layer was purified by flash chromatography, eluted with 5% ethyl acetate in dichloromethane to provide the title compound.