Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1>C(O)(C)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(I)cc1
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(I)cc3)c2cc1OC
Temperature: 25 °C
Yield: 103.3 %

Procedure:
4-iodoaniline (4.89 g, 22.3 mmol) and 4-chloro-6,7-dimethoxyquinazoline (5.00 g, 22.3 mmol), in isopropanol (200 ml) was heated at reflux for 3 hours before the reaction was allowed to cool to ambient temperature. The solid which had precipitated was collected by suction filtration and washed with diethyl ether (2×50 ml). Drying of this material yielded 4-(4-iodoanilino)-6,7-dimethoxyquinazoline (9.38 g, 95% yield) as a white solid:
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:7][C:6](=[O:8])[CH:5]([CH2:9][CH2:10][CH2:11][S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4](=[O:32])[O:3]1.[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38]Br.C[O-].[Na+]>CO.CCCCCC.C(OC(=O)C)C>[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38][C:5]1([CH2:9][CH2:10][CH2:11][S:12][C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:6](=[O:8])[O:7][C:2]([CH3:33])([CH3:1])[O:3][C:4]1=[O:32]
Reactant: CC1(C)OC(=O)C(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O1
Reactant: COC(=O)CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CCC1(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)OC1=O
Yield: 76.9 %

Procedure:
5 mmol of 2,2-dimethyl-5-[3-[(triphenylmethyl)-thio]-propyl]-1,3-dioxane-5-propanoic-4,6-dione (I) (2.3 g), was dissolved with 20 mmol methyl-3-bromopropionate (3.34g=2.18 ml) and 4.6 ml of 4.37 M methanolic solution of sodium methoxide (20 mmol) in 10 ml of methanol. The reaction mixture was heated to 60° C. overnight after which TLC in hexane/ethylacetate 1:1 detected no starting material. The mixture was then evaporated to dryness and mixed with 40 ml of aqueous 10% KHSO4. The organic material was extracted by 3 portions of EtOAc, the organic layers were combined dried with MgSO4 and evaporated. The residue was crystallized from hexane/ethylacetate to yield 2.1 g (77%) of 2,2-dimethyl-4,6-dioxo-5-[3-[(triphenyl-methyl)thio]propyl]-1,3-dioxane-5-propanoic acid methyl ester (II), 13C-NMR (CDCl3) δ 24.6, 29.4, 29.5, 29.6, 31.4, 32.6, 37.7, 51.9, 52.8, 66.8, 105.7, 126.7, 127.9, 129.5, 144.7, 168.4, 172.0.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[H-].C([Al+]CC(C)C)C(C)C>COCCOC.C1(C)C=CC=CC=1>[CH:8]1([C:6]([NH:5][C@H:4]([CH:3]=[O:2])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:7])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)C1CCCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: O=C[C@H](Cc1ccccc1)NC(=O)C1CCCCC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
N-Cyclohexanoylphenylalanine methyl ester (0.5 g) is dissolved in ethylene glycol dimethyl ether (20 mL). The solution is cooled to 70° C. and diisobutylaluminum hydride (2.04 mL of a 1.5M solution in toluene) is added. The resulting reaction mixture is stirred at −70° C. for 2 hours. The reaction is quenched by dropwise addition of 2N hydrochloric acid. The mixture is extracted with cold ethyl acetate. The ethyl acetate solution is washed with brine and dried over sodium sulfate. Concentration in vacuo furnishes a white solid, which is purified by silica gel chromatography. 1H NMR (300 MHz, DMSO-d6): 9.5 (s, 1H), 8.2 (d, 1H), 7.2 (m, 5H), 4.2 (m, 1H), 3.2 (d, 1H), 2.7 (d, 1H), 2.1 (m, 1H), 1.6 (br.m, 4H), 1.2 (br.m, 6H). R (KBr): 3300, 3050, 2900, 2850, 2800, 1700, 1600, 1500 cm−1. Mass Spec.: M+1 m/e 261.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.CN([CH:31]=[O:32])C>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[N:11]=[C:12]([CH:31]=[O:32])[N:13]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(COCC[Si](C)(C)C)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cn(COCC[Si](C)(C)C)c(C=O)n1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (See WO03/022274) (1 eq) in THF at 40° C. was added dropwise a solution of BuLi (2 eq.) in hexanes and the mixture was stirred at 40° C. for a further 30 min. DMF (4 eq.) was then added and the cooling bath was removed and the reaction mixture was allowed to warm to RT and stirred for 30 min, after which time it was quenched by addition of a sat. aq. NH4Cl solution. The organics were extracted with EtOAc (2×), washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The material was purified by column chromatography on silica eluting with 15% EtOAc/petroleum ether. 1H NMR (300 MHz, CDCl3) δ: 9.81 (1H, s), 7.30 (1H, s), 5.95 (2H, s), 4.87, (2H, s), 3.58 (2H, t, J=7.7 Hz), 1.05-0.85 (20H, m), 0.05 (6H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][N:8]=2)[C:4](=[O:21])[NH:3]1.[H-].[Na+].IC.[C:27]([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:27][N:3]1[C:2]([CH3:22])([CH3:1])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:9][N:8]=2)[C:4]1=[O:21]
Reactant: O=C([O-])O
Reactant: CC1(C)CN(c2ccc(C#Cc3ccccc3)cn2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ccc(C#Cc3ccccc3)cn2)CC1(C)C
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
(110 mg, 378 μmol) 4,4-Dimethyl-1-(5-(phenylethynyl)pyridin-2-yl)imidazolidin-2-one (Example 15, step 3) was dissolved in DMF (0.5 ml) and cooled to 0-5° C. NaH (55%) (19.8 mg, 453 μmol, 1.2 equiv.) was added and the mixture was stirred for 30 min at 0-5° C. Iodomethane (35.3 μl, 566 μmol, 1.5 equiv.) was added and the mixture was stirred for 30 min at 0-5° C. The reaction mixture was treated with sat. NaHCO3 solution and extracted twice with a small volume of CH2Cl2. The organic layers were loaded directly to silica gel column and the crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 3,4,4-trimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one (93 mg, 81% yield) was obtained as a yellow solid, MS: m/e=306.2 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[NH:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=2[CH:13]=[CH:12]1.[H-].[Na+].CN(C=O)C>O>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=3[CH:13]=[CH:12]2)=[CH:4][CH:5]=1
Reactant: COc1ccc(CCl)cc1
Reactant: N#Cc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc3c(C#N)cccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
1-(Chloromethyl)-4-methoxybenzene (30.3 g, 193 mmol) was added to a slurry of 1H-indole-4-carbonitrile (25.0 g, 176 mmol) and NaH (7.74 g, 193 mmol) in DMF (586 mL, 176 mmol) at 0° C., and the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The combined organic layers were washed with water and brine, dried (Na2SO4) and concentrated to afford a crude residue, which was purified by column chromatography eluting with an ethyl acetate/hexanes gradient to give 1-(4-methoxybenzyl)-1H-indole-4-carbonitrile (46.0 g, 175 mmol, 99%). 1H NMR (400 MHz, CDCl3) 7.89 (d, J=8.2 Hz, 1H), 7.81 (d, J=3.1 Hz, 1H), 7.54 (d, J=7.4 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.21 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 6.64 (d, J=2.7 Hz, 1H), 5.44 (s, 2H), 3.70 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:39]=[CH:38][C:37]([C:40](=[O:44])[N:41]([CH3:43])[CH3:42])=[CH:36][CH:35]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16](C)[C:17](=O)OC(C)(C)C)[CH2:12][CH2:11]1)=[O:8].CC(OC)(C)C>C(Cl)Cl>[ClH:1].[CH3:43][N:41]([CH3:42])[C:40]([C:37]1[CH:38]=[CH:39][C:34]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([CH2:25][N:9]([CH:10]3[CH2:11][CH2:12][CH:13]([NH:16][CH3:17])[CH2:14][CH2:15]3)[C:7]([C:6]3[S:5][C:4]4[C:45]([F:50])=[CH:46][CH:47]=[C:48]([F:49])[C:3]=4[C:2]=3[Cl:1])=[O:8])[CH:27]=2)=[CH:35][CH:36]=1)=[O:44]
Reactant: COc1ccc(-c2ccc(C(=O)N(C)C)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CNC1CCC(N(Cc2cc(-c3ccc(C(=O)N(C)C)cc3)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1
Product: Cl

Procedure:
tert-Butyl carbamate 97 (250 mg, 0.34 mmol) is deprotected using Method F. The isolated salt is then dissolved in the minimum amount of DCM and added dropwise to cold (0° C.) TBME (25 mL). The resultant white precipitate is isolated by filtration and dried to afford the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.N.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>C(O)C.C(Cl)Cl.C(C(C)=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[CH2:33]([O:26][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:25])[N:16]1[CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)[CH3:34]
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Agent: N
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CCOC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 4 h
Yield: 157.6 %

Procedure:
The same procedure is followed as in Example 2, but starting from an agitated solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-3-hydroxy-1-isoindolinone (7 g) in ethanol (265 cc) to which 37 cc of concentrated sulphuric acid is added at a temperature close to 20° C. and in the course of 15 minutes. Agitation is continued for 4 hours at a temperature close to 65° C. After cooling the solution to a temperature close to 0° C., 90 cc of a 33% aqueous solution of ammonia is added in the course of 1 hour. The precipitate formed is filtered and washed with methanol (50 cc). The filtrate is diluted with distilled water (200 cc) and a 33% aqueous solution of ammonia (70 cc) and extracted with methylene chloride (3×250 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methylene chloride (30 cc) and poured onto silica (500 g) contained in a column of 8 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (95-5 by volume). The first 1000 cc are eliminated, the next 900 cc are evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in methyl ethyl ketone (50 cc). A solution of oxalic acid (1.2 g) in methyl ethyl ketone (20 cc) is added and agitation is continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 4.9 g of 3-ethoxy-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 150° C.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1C=O)[CH3:3].[F:12][B-:13]([F:16])([F:15])[F:14].[CH3:17][C:18]1[C:23]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=2[Te:21][CH+:20][CH:19]=1.[C:30](#N)C>C(OC(=O)C)(=O)C>[F:12][B-:13]([F:16])([F:15])[F:14].[CH3:3][N:2]([C:4]1[CH:5]=[CH:8][C:9]([CH:30]=[CH:17][C:18]2[C:23]3[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=3[Te:21][CH+:20][CH:19]=2)=[CH:10][CH:11]=1)[CH3:1]
Reactant: CN(C)c1ccccc1C=O
Reactant: CC#N
Reactant: COc1ccc2c(C)c[cH+][te]c2c1
Agent: F[B-](F)(F)F
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(C=Cc3ccc(N(C)C)cc3)c[cH+][te]c2c1
Yield: 44 %

Procedure:
N,N-Dimethylaminobenzaldehyde (0.50 g, 3.3 mmol) and 4-methyl-7-methoxybenzotelluropyrylium tetrafluoroborate (0.60 g, 1.3 mmol) in 5 ml of acetic anhydride were warmed on a steam bath for 3 minutes. Acetonitrile (10 ml) was added and the reaction mixture was chilled. The crude product was collected by filtration and recrystallized from acetonitrile to give 0.34 g (44%) of a golden-brown solid.
Reaction SMILES: [OH:1][CH:2]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C@H:5]([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[OH-].[K+].Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>C(O)CC>[CH3:14][C@@H:5]([NH:4][CH2:3][C@H:2]([OH:1])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)=[CH:9][CH:8]=1
Reactant: C[C@H](Cc1ccc(O)cc1)NCC(O)COc1ccccc1
Reactant: ClCCN1CCN(c2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Product: C[C@H](Cc1ccc(OCCN2CCN(c3ccccc3)CC2)cc1)NC[C@H](O)COc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 0.5 g of p-[(R)-2-[[(RS)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenol, 185 mg of potassium hydroxide, 410 mg of 1-(2-chloroethyl)-4-phenyl-piperazine and 15 ml of n-propanol was heated to 60° for 2.5 hours. The reaction mixture was poured on to ice-water and extracted with ethyl acetate. After evaporation of the solvent and chromatography of the crude product on silica gel with chloroform/n-propanol/saturated ammonia (1000:10:1) there were obtained 340 mg of pure, amorphous (S)-1-[[(R)-αmethyl-p-[2-(4-phenyl-1-piperazinyl)ethoxy]phenethyl]amino]-3-phenoxy-2-propanol, [α]D20 =-19° (c=0.8 in methanol), ε222 =21890.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]2=[O:17])=[CH:4][CH:3]=1.C(NC1C=CC([O:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([O:42][Si](C(C)(C)C)(C)C)[CH2:38][CH2:37]2)=O)=NC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O.Cl>[CH3:16][C:11]1([CH3:15])[CH2:12][C:13](=[O:14])[N:8]([C:5]2[CH:6]=[N:7][C:2]([O:1][C:34]([N:36]3[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38][CH2:37]3)=[O:33])=[CH:3][CH:4]=2)[C:9](=[O:17])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(C(=O)Oc2ccc(NC(=O)c3ccccc3)cn2)CC1
Reactant: CC1(C)CC(=O)N(c2ccc(O)nc2)C(=O)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)N(c2ccc(OC(=O)N3CCC(O)CC3)nc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.2 %

Procedure:
A solution of 6′-hydroxy-4,4-dimethyl-4,5-dihydro-3H-[1,3′]bipyridinyl-2,6-dione (468 mg, 2.00 mmol), 4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester (0.90 g, 2.00 mmol) and triethylamine (0.20 g, 2.00 mmol) in dimethylformamide (10 mL) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, filtered over a short pad of silicagel and washed with ethyl acetate. The solvent was evaporated in vacuo and the residue was dissolved in 1N HCl in ethyl acetate (10 mL, 10.0 mmol). After stirring for 1.5 hours at room temperature the solvent was evaporated in vacuo. The white solid was washed with a small amount of ethyl acetate and diethyl ether and dissolved in a few millilitres of dichloromethane and triethylamine (1 mL). Purification by flash column chromatography (SiO2, ethyl acetate:acetone 90:10) yielded the title compound (182 mg, 25% yield) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[S:5][C:4]=1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:49][C:50]1[CH:51]=[C:52]([NH:57][C:58](=[O:70])[C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([C:68]#[N:69])([CH3:67])[CH3:66])[CH:60]=2)[CH:53]=[CH:54][C:55]=1[CH3:56]>CN(C=O)C>[C:68]([C:65]([C:61]1[CH:60]=[C:59]([CH:64]=[CH:63][CH:62]=1)[C:58]([NH:57][C:52]1[CH:53]=[CH:54][C:55]([CH3:56])=[C:50]([NH:49][C:12]([C:4]2[S:5][C:6]3=[N:7][CH:8]=[CH:9][N:10]=[C:11]3[C:3]=2[NH:2][CH3:1])=[O:14])[CH:51]=1)=[O:70])([CH3:67])[CH3:66])#[N:69]
Reactant: CNc1c(C(=O)O)sc2nccnc12
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1c(C(=O)Nc2cc(NC(=O)c3cccc(C(C)(C)C#N)c3)ccc2C)sc2nccnc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A solution of 7-(methylamino)thieno[2,3-b]pyrazine-6-carboxylic acid 12 (1.6 g, 7.65 mmol), HATU (3.20 g, 8.41 mmol) and DIPEA (3.79 mL, 22.94 mmol) in DMF (20 mL) was stirred at rt for 30 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (2.52 g, 7.65 mmol) was added and stirred overnight at 75° C. Quenched in ice/water and the resulting precipitate was collected. Purification by chromatography (10-20% EtOAc in CH2Cl2), co-evaporate with acetonitrile (2×), stirred in water at 70° C. for 1 h and filtrated to give the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-7-(methylamino)thieno[2,3-b]pyrazine-6-carboxamide 13 (2.06 g, 55.6%). 1H-NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.22 (s, 3H), 3.41 (d, J=5.5 Hz, 3H), 7.26 (d, J=8.6 Hz, 1H), 7.60 (t, J=7.8 Hz, 2H), 7.75 (d, J=7.8 Hz, 1H), 7.82 (d, J=1.9 Hz), 1H), 7.94 (d, J=7.8 Hz, 2H), 8.05 (m, 1H), 8.73 (d, J=2.3 Hz, 1H), 8.77 (d, J=2.3 Hz, 1H), 9.55 (br s, 1H), 10.31 (br s, 1H). (m/z)=485 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=S)([CH3:4])([CH3:3])[CH3:2].[N:15]#[C:16][NH2:17].[Pb]>C(O)C>[C:1]([NH:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:17][C:16]#[N:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=S)Nc1cccnc1
Reactant: N#CN
Agent: [Pb]
Solvent: CCO
Product: CC(C)(C)NC(=NC#N)Nc1cccnc1

Procedure:
N-tert-butyl-N'-3-pyridylthiourea (2.1 g) and lead cyanamide (3.7 g) were refluxed in ethanol (20 ml) for 18 hours. The mixture was filtered, and the filtrate was evaporated in vacuo to afford the crude product. Recrystallization from aqueous acetone gave the desired compound. Melting point 205.0°-206.5° C.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Cl:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([CH:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:36]2=[O:49])=[C:30]([OH:50])[CH:29]=1>>[Cl:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([C:35]2([CH2:5][OH:16])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:36]2=[O:49])=[C:30]([OH:50])[CH:29]=1
Reactant: CCCCCN1C(=O)C(c2cc(F)c(Cl)cc2O)c2ccccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCCCCN1C(=O)C(CO)(c2cc(F)c(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(4-chloro-5-fluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (50% for two steps): MS (ES+) m/z 360 (M−17), 400 (M+23).
Reaction SMILES: [C@:1]12([CH2:11][S:12]([OH:15])(=O)=[O:13])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=O.S(Cl)(Cl)=O.[NH3:20]>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:9][C:8]1([CH3:10])[CH:5]2[CH2:6][CH2:7][C:1]31[C:2]([CH2:4]2)=[N:20][S:12](=[O:15])(=[O:13])[CH2:11]3
Reactant: N
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)C2CCC13CS(=O)(=O)N=C3C2
Temperature: 80 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
N,N-Dimethylformamide (230 g) and (1S)-(+)-10-camphorsulfonic acid (190 kg, 818 mol) were added to toluene (190 L), and thionyl chloride (116.8 kg, 982 mol) was added in a thin stream at 70° C.-80° C. over 2 h, and the mixture was stirred at the same temperature for 2 h. The obtained solution of camphorsulfonyl chloride in toluene was added dropwise at −10° C. to 25° C. over 3 h to a mixture of 28 wt % aqueous ammonia (248.7 kg, 4.1 kmol) and toluene (277 L), which mixture had been separately prepared and cooled to −10° C. to −5° C. The container of acid chloride was washed with toluene (29 L) and the washing was added to the reaction mixture, which was followed by stirring at 10° C.-25° C. for 2 h. The reaction mixture was heated to 80° C. over 85 min and stirred at 80° C.-83.3° C. for 3 h. The amount of the ammonia gas generated was 39 m3. The reaction mixture was cooled to 60° C. over 20 min and aged at 54° C.-60° C. for 15 min. The reaction mixture was cooled to 20° C. over 1 h and stirred at 15° C.-20° C. for 40 min. The reaction mixture was filtered at 15° C. and washed successively with toluene (57 L) and water (380 kg) to give wet crystals (177.1 kg). The crystals were partially dried and analyzed. As a result, the crystals contained the title compound in an amount of 144.7 kg (yield 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[CH:6][CH:7]=1.O=S(Cl)[Cl:13]>>[C:2]1([CH3:1])[CH:3]=[CH:4][C:5]([C:8]([Cl:13])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add p-toluic acid (0.55 mol) to 100 mL SOCl2 and stir overnight at room temperature. Evaporate the excess SOCl2 to give p-toluoyl chloride. Add (2R,3R)-(+)-tartaric acid (25 g, 166 mmol) and stir the mixture and heat at 170° C. for an hour. Allow the mixture to cool to 100° C. and add 200 mL toluene. Cool the mixture to room temperature and add another 100 mL toluene. Collect the precipitate, rinse with toluene and dry. Reflux the crude product in a mixture of 300 mL acetone and 20 mL water for two hours. Then add 200 mL water and evaporate the acetone. Add another 200 mL water and collect the precipitate, rinse with water and dry. Reflux the product in 200 mL toluene for 15 minutes and collect the precipitate while the mixture is hot. Rinse the precipitate with 50 mL warm toluene and dry to give (2R,3R)-(−)-di-(p-toluoyl)tartaric acid.