Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[S:14]([OH:17])(=O)=[O:15]>CCCCCC>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[S:14]([Cl:3])(=[O:17])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C)ccc1S(=O)(=O)O
Solvent: CCCCCC
Product: COc1cc(C)ccc1S(=O)(=O)Cl
Temperature: 25 °C
Yield: 59 %

Procedure:
Thionyl chloride (350 ml, 2.5 ml/g) was cautiously added to 2-methoxy-4-methylbenzenesulfonic acid (from (b), 140 g, 0.587 moles) over a period of 30 minutes. The mixture was stirred and heated to reflux for 1 hour and at room temperature for 16 hours. The excess thionyl chloride was removed by evaporation under reduced pressure and the residue was partitioned between deionised water (300 ml) and dichloromethane (400 ml). The phases were separated and the organic phase dried (MgSO4), filtered and concentrated to give the crude product (70 g, 54% yield). The crude product was partially dissolved in hexane (490 ml) at reflux, hot filtered to remove insoluble material and allowed to cool. The precipitated product was collected to give the title compound (41.3 g, 59% recovery) as a white crystalline solid (m.p.=81-84° C.).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=[O:4].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[Cl-].[Na+].Cl[CH:20](Cl)[CH3:21]>O1CCCC1>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([C:3]([O:5][CH2:20][CH3:21])=[O:4])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:9]
Reactant: CCOC(=O)CBr
Reactant: CC(Cl)Cl
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Reaction time: 16 h

Procedure:
Diethyl-2-carbethoxysuccinate (formula 3, in which R are ethyl groups) is prepared by dissolving ethyl malonate (66 g, 0.5 moles) in tetrahydrofuran (500 ml). Sodium hydride (19.7 g of a 66% suspension in oil) (0.5 mole) is washed twice with petroleum ether (b.p. 30°-66°) and added to the stirred solution in small portions. Ethyl bromoacetate (83.5 g, 0.5 moles) is then added slowly from a dropping funnel. After stirring for 16 hours, the resultant white suspension is transferred to a separatory funnel along with a saturated aqueous sodium chloride solution (1 liter) and dichloroethane (1 liter). After shaking and separating the layers, the water layer is extracted with two additional liter portions of dichloroethane. The combined organic layers are dried over sodium sulfate before filtration and evaporation. The crude product is distilled under reduced pressure and the fractions boiling at 105°-112° at 2.5 mm Hg (12 ml) and 112°-115° (25 ml) are kept for use in the reaction of the next example.
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1)(=[O:3])[CH3:2].[C:14]([O-])([O-])=O.[Cs+].[Cs+].CI.CCOC(C)=O>CN(C=O)C>[C:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]([CH3:14])[N:8]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)=O)[nH]n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOC(=O)c1cc(C(C)=O)nn1C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a solution of ethyl 5-acetyl-1H-pyrazole-3-carboxylate (0.050 g, 0.274 mmol) in DMF (3 mL), Cs2CO3 (0.134 g, 0.412 mmol) and methyl iodide (0.022 mL, 0.357 mmol) were added. The reaction was continued at r.t. overnight then AcOEt (20 mL) was added and the organic phase washed with water (20 mL). The aqueous fraction was extracted with AcOEt (20 mL). The organic fractions were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (eluant: AcOEt/hexane 2/8) provided 37 mg (68% yield) of ethyl 3-acetyl-1-methyl-1H-pyrazole-5-carboxylate.
Reaction SMILES: [CH:1]([C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:18]2[O:17][CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=O.O.NN.C(O)CO.[OH-].[K+]>O.CO>[CH3:1][C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:18]2[O:17][CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccoc2C=O)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CO
Solvent: O
Product: Cc1occc1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 41.8 %

Procedure:
A mixture of tert-butyl 9-(2-formyl-3-furyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (750 mg, 2.18 mmol), hydrazine monohydrate (0.300 ml, 6.18 mmol), ethylene glycol (15 ml) and methanol (5 ml) was stirred at 85° C. for 10 min. After cooling to room temperature, potassium hydroxide (500 mg, 8.91 mmol) was added, and the mixture was stirred at 100° C. for 0.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (300 mg, 41.8%) as an oil.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[OH:9][C:10]1[CH:27]=[CH:26][C:25]2[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C:19](=O)[C@H:18]([OH:29])[CH2:17]4)[CH2:14][CH2:13][C:12]=2[CH:11]=1.[CH3:30][NH2:31].[BH4-].[Na+]>>[CH3:30][NH:31][C@H:19]1[C@H:18]([OH:29])[CH2:17][C@H:16]2[C@H:15]3[C@H:24]([CH2:23][CH2:22][C@:20]12[CH3:21])[C:25]1[CH:26]=[CH:27][C:10]([OH:9])=[CH:11][C:12]=1[CH2:13][CH2:14]3
Reactant: CN
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN[C@H]1[C@H](O)C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@@]21C
Reaction time: 0.08 h

Procedure:
3,16α-Dihydroxy-oestra-1,3,5(10)-trien-17-one diacetate (32.4 g) was stirred with methylamine solution (324 ml; 33% in EtCH) for 20 min. Sodium borohydride (16.2 g) was added portionwise to the stirred solution, keeping the temperature at <25° C. After 11/2 h., the methylamine was removed under reduced pressure and the residue was acidified with hydrochloric acid (5 N). The mixture was rebasified with saturated potassium bicarbonate solution to give crude product, which was filtered off, washed with water and suspended in methanol. The suspension was boiled for 5 min., cooled and filtered to give pure 17β-methylamino-oestra-1,3,5(10)-triene-3,16α-diol as an amorphous solid (23.5 g; 89%), m.p. 242°-246° C. (decomp.), [α]D +48° (c 1.0 in D.M.S.O.).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[C:5]([C:7]1[CH:8]=[C:9](O)[CH:10]=[CH:11][CH:12]=1)#[N:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][O:4][C:11]1[CH:12]=[C:7]([CH:8]=[CH:9][CH:10]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(O)c1
Reactant: OCCBr
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cccc(OCCBr)c1
Reaction time: 8 h

Procedure:
0.71 ml (10.0 mmol) of 2-bromoethanol, 1.43 g (12.0 mmol) of 3-cyanophenol and 3.15 g (12.0 mmol) of triphenylphosphine were dissolved in 100 ml of tetrahydrofuran. 5.22 g (12.0 mmol) of diethyl azodicarboxylate (40% solution in toluene) was added to the solution at room temperature, and they were stirred overnight. After the treatment with ethyl acetate as the extractant in an ordinary manner, the crude product was obtained. This product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH2:1](O)C.C[O-].[Na+].[N:7]1[CH:8]=[CH:9][N:10]2[C:16]=1[CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[NH:12][C:11]2=[S:21].CI>O>[CH3:1][S:21][C:11]1[N:10]2[CH:9]=[CH:8][N:7]=[C:16]2[CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]=1
Reactant: S=C1Nc2ccccc2Cc2nccn21
Reactant: CCO
Agent: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CSC1=Nc2ccccc2Cc2nccn21

Procedure:
Absolute ethanol (20,000 ml) is charged into a 20 gallon flask and stirred under nitrogen atmosphere; 517.62 g (9.58 moles) of sodium methoxide are added. After stirring for 30 minutes there is complete solution and 2,063 g (9.58 moles) of 11H-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-thione are added. There is complete solution after stirring at room temperature for 1 hour. The solution is then cooled to 1°, and 1,360 g (9.58 moles) of methyl iodide are added over 30 minutes. The reaction mixture is stirred at 5° for 4 hours and at ambient temperature overnight. The turbid solution is then cooled to 5° and diluted with 50,000 ml of water. The resulting suspension is stirred for 4 hours at 5°. The solid is collected, and dried (5 mm Hg/60°) to give 5-methylthio-11H-imidazo[1,2-c][1,3]benzodiazepine, m.p. 87°-8°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](I)=[CH:4][N:3]=1.[CH3:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13].CC1(C)C(C)(C)OB([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)O1>>[Cl:1][C:2]1[N:7]=[C:6]([O:13][CH2:12][CH:11]([CH3:10])[CH2:14][OH:15])[C:5]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[CH:4][N:3]=1
Reactant: CC(CO)CO
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Product: CC(CO)COc1nc(Cl)ncc1-c1cccs1

Procedure:
Preparation according to procedures 4b and 3 with the use of 2,4-dichloro-5-iodopyrimidine, 2-methyl-1,3-propandiol and 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:4]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]=O)=[CH:16][CH:17]=3)[CH:12]=[N:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:23][CH2:24][C@H:25]1[O:30][CH2:29][CH2:28][N:27]([C:31]2[S:32][CH2:33][C:34](=[O:36])[N:35]=2)[CH2:26]1>>[OH:23][CH2:24][C@H:25]1[O:30][CH2:29][CH2:28][N:27]([C:31]2[S:32][C:33](=[CH:19][C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[N:10]([CH2:9][C:4]3[C:3]([C:2]([F:22])([F:1])[F:21])=[CH:8][CH:7]=[CH:6][N:5]=3)[N:11]=[CH:12]4)[C:34](=[O:36])[N:35]=2)[CH2:26]1
Reactant: O=C1CSC(N2CCO[C@H](CO)C2)=N1
Reactant: O=Cc1ccc2c(cnn2Cc2ncccc2C(F)(F)F)c1
Product: O=C1N=C(N2CCO[C@H](CO)C2)SC1=Cc1ccc2c(cnn2Cc2ncccc2C(F)(F)F)c1

Procedure:
2-[(2S)-2-(Hydroxymethyl)morpholin-4-yl]-5-[(1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-indazol-5-yl)methylidene]-1,3-thiazol-4(5H)-one was prepared from 1-(3-Trifluoromethyl-pyridin-2-ylmethyl)-1H-indazole-5-carbaldehyde and 2(S)-(2-Hydroxymethyl-morpholin-4-yl)-thiazol-4-one following General Procedure D.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1.[C:13](OCC)(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16]>>[C:13]([O:1][CH2:2][CH2:3][N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16]
Reactant: OCCN1Cc2ccccc2C1
Reactant: CCOC(=O)CC(C)=O
Product: CC(=O)CC(=O)OCCN1Cc2ccccc2C1
Yield: 21.5 %

Procedure:
A solution of 4.67 g (0.029 mol) of 2-(2-hydroxyethyl) isoindoline and 3.72 g (0.029 mol) of ethyl acetoacetate was heated at 100°-110° C. under nitrogen for 36 hours. Ethanol was removed with nitrogen flow during the course of the reaction. The mixture was subjected to flash chromatography (silica gel, 1:1 ethylacetate/petroleum ether) to give 1.54 g (22%) of a dark oil. NMR (CDCl3) δ 2.2 (3H, s), 2.94 (2H, t), 3.4 (2H, s), 3.9 (4H, s), 4.24 (2H, t), 7.04 (4H, s)
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)=[C:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH:35]([CH3:37])[CH3:36])[S:14][C:13]=2[CH:38]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:39][CH:40](O)[CH3:41].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOC(C)=O.CCCCCCC>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][CH:40]([CH3:41])[CH3:39])=[O:27])=[CH:20][CH:19]=3)=[C:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH:35]([CH3:36])[CH3:37])[S:14][C:13]=2[CH:38]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)O
Reactant: CC(C)c1ccccc1-c1sc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1Oc1ccc(/C=C/C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: CC(C)OC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3C(C)C)sc3cc(O[Si](C)(C)C(C)(C)C)ccc23)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 55 %

Procedure:
To a solution of (E)-3-(4-((6-((tert-butyldimethylsilyl)oxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (59.6 mg, 0.109 mmol) in DCM (2.5 mL) was added i-PrOH (0.034 mL, 0.438 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (84 mg, 0.438 mmol) and 4-dimethylaminopyridine (8.02 mg, 0.066 mmol). The resulting mixture was stirred at room temperature for 75 min after which time the reaction was quenched by addition of water and diluted with DCM. The phases were separated and the aqueous layer was further extracted with DCM (3×). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-30% EtOAc/Heptane) to (E)-isopropyl 3-(4-((6-((tert-butyldimethylsilyl)oxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (35 mg, 0.060 mmol, 55% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (d, J=16.0 Hz, 1H), 7.32-7.17 (m, 7H), 7.10-7.03 (m, 1H), 6.79 (d, J=8.8 Hz, 3H), 6.18 (d, J=16.1 Hz, 1H), 5.05 (p, J=6.2 Hz, 1H), 3.18 (p, J=6.8 Hz, 1H), 1.23 (d, J=6.4 Hz, 6H), 1.11 (d, J=6.8 Hz, 6H), 0.95 (s, 9H), 0.18 (s, 6H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)=[O:3].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[CH2:16][S:17]([CH2:20][C:21]#[N:22])(=[O:19])=[O:18]>>[NH2:1][C:2]([C:4]1[S:5][C:6](/[CH:9]=[C:20](/[S:17]([CH2:16][C:15]2[CH:23]=[CH:24][CH:25]=[C:13]([C:12]([F:27])([F:11])[F:26])[CH:14]=2)(=[O:19])=[O:18])\[C:21]#[N:22])=[CH:7][CH:8]=1)=[O:3]
Reactant: N#CCS(=O)(=O)Cc1cccc(C(F)(F)F)c1
Reactant: NC(=O)c1ccc(C=O)s1
Product: N#C/C(=C\c1ccc(C(N)=O)s1)S(=O)(=O)Cc1cccc(C(F)(F)F)c1

Procedure:
Reaction of 2-aminocarbonylthiophen-5-carboxaldehyde and 3-trifluoromethylbenzylsulfonylacetonitrile as in Example 1 gave (E)-3-(2-aminocarbonylthien-5-yl)-2-[3-(trifluoromethyl)benzylsulfonyl]acrylonitrile
Reaction SMILES: CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[CH3:18][NH:19][C:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].[Br:33][C:34]1[CH:40]=[CH:39]C(N)=[CH:36][C:35]=1[O:41][CH3:42]>C(Cl)Cl>[Br:33][C:34]1[CH:40]=[CH:39][C:18]([NH:19][C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:36][C:35]=1[O:41][CH3:42]
Reactant: CCOC(=O)C=C(NC)c1ccccc1
Reactant: COc1cc(N)ccc1Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C=C(Nc1ccc(Br)c(OC)c1)c1ccccc1
Reaction time: 20 h
Yield: 93.7 %

Procedure:
PPTS (38.3 g, 152 mmol) was added to a solution of the product from Step 1 (31.3 g, 152 mmol) and 4-bromo-3-methoxyaniline (28 g, 139 mmol) in DCM (700 mL). The mixture was heated to reflux and stirred for 20 h. The mixture was cooled, and the solids were removed by filtration and washed with DCM. The filtrate was concentrated and purified on silica gel (gradient elution 10% to 50% DCM in hexanes) to give the title compound (49 g, 94% yield). LRMS (M+H)+ Calcd.: 376.0; found 376.2.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[NH2:7][CH:8]([C:13]([NH2:15])=[O:14])[CH2:9][CH2:10][S:11][CH3:12].[OH-].[Na+]>O>[CH2:1]([O:3][C:4]([NH:7][CH:8]([C:13]([NH2:15])=[O:14])[CH2:9][CH2:10][S:11][CH3:12])=[O:5])[CH3:2]
Reactant: CSCCC(N)C(N)=O
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)NC(CCSC)C(N)=O
Temperature: 2.5 °C
Yield: 57.4 %

Procedure:
106 ml (1.10 moles) ethylchloroformate were dripped into a solution of 150 g (1.02 moles) DL-methionine amide in 200 ml water at 5-10° C., during which the pH was maintained at 7-9 by adding sodium hydroxide solution. A thick, finely crystalline precipitate rapidly formed. A suspension which was just able to still be agitated was obtained by the addition of 800 ml water, which suspension was agitated 3 hours further at room temperature. Then the colorless crystals were filtered off, washed with water and recrystallized out of 900 ml water. After cooling to 0-5° C., filtering off, washing with water and drying, 129 g (57%) Nαethoxycarbonyl-DL-methionine amide with a melting point of 110-112° C. was obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH3:9].[C:10]([OH:13])(=[O:12])[CH3:11]>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([NH:9][CH2:11][C:10]([OH:13])=[O:12])=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: Oc1ccccc1
Reactant: N
Solvent: O
Product: O=C(O)CNc1ccc(O)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution in 120 g of acetic acid and 113.5 g of 95% sulfuric acid, of acetamidoglycolic acid obtained from 1 mole of glyoxylic acid, are added in 2 hours, 376 g (4 moles) of phenol in solution in 120 g of acetic acid, keeping the temperature below 5° C, then allowing to stand for 16 hours at room temperature. 1 liter of water is then added and it is boiled under reflux for 4 hours to hydrolyse the N-acyl derivative. After cooling to 20° C, the pH is brought to 1.5 with ammonia, the excess of phenol is extracted with 3 times 200 ml of butyl acetate. The aqueous phase concentrated at 1200 g is brought to pH 5.5 with ammonia, the precipitate formed is filtered, washed with water and dried.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[C:14]([C:24](=O)[CH3:25])=[CH:15][C:16]([Cl:23])=[C:17]4[C:22]=3[N:21]=[CH:20][CH:19]=[CH:18]4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+].O1CCCC1>CO.C(#N)C>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[C:14]([CH:24]([NH2:33])[CH3:25])=[CH:15][C:16]([Cl:23])=[C:17]4[C:22]=3[N:21]=[CH:20][CH:19]=[CH:18]4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(N2CCCCC2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(N2CCCCC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[8-(1,4′-bipiperidin-1′-yl)-5-chloroquinolin-7-yl]ethanone (0.0165 g, 0.0444 mmol) and ammonium acetate (0.0342 g, 0.444 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.11 mL, 0.11 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C21H30ClN4 (M+H)+: m/z=373.2; Found: 373.2.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=2)[C:5]1=[O:19])(=O)C.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:29][CH2:30][N:31]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([N:6]3[CH2:7][CH2:8][NH:4][C:5]3=[O:19])=[CH:18][CH:17]=2)=[O:15])[CH2:32][CH2:33]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: COC(=O)c1ccc(N2CCN(C(C)=O)C2=O)cc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCNC4=O)cc3)CC2)c(C)c1
Yield: 45.3 %

Procedure:
Using methyl 4-(3-acetyl-2-oxoimidazolidin-1-yl)benzoate (290 mg) described in Preparation Example 59 and 1-(2,4-dimethylphenyl)piperazine (209 mg) and by the reaction and treatment in the same manner as in Example 109, the title compound (188.5 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[C:44]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:45]=[CH:46][CH:47]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:14]2[CH:15]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:42]5[CH:43]=[C:44]([NH:48][S:49]([CH3:52])(=[O:50])=[O:51])[CH:45]=[CH:46][CH:47]=5)[CH:3]=4)[N:8]([S:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=4)(=[O:26])=[O:25])[CH:9]=3)[CH:12]=[N:13]2)=[CH:18][CH:19]=1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccc(F)cc4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccc(F)cc4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 78.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(4-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.285 mmol) was coupled with N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methane sulfonamide (intermediate 3) (127 mg, 0.427 mmol) in sodium carbonate (90.6 mg, 0.855 mmol), bis(triphenyl phosphine)palladium(ii) dichloride (39.8 mg, 0.057 mmol) and toluene/ethanol/water (20/8/2 ml) to afford 138 mg (79% yield) of the pure product after column purification using 40% ethyl acetate in hexane as eluent. MS: m/z=616.3 (M+1).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].C1CCCCC1.[S:15]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16]1.CI.Cl>C1COCC1>[CH3:1][C:16]1[S:15][CH:19]=[CH:18][C:17]=1[C:20]([OH:22])=[O:21]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)c1ccsc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1sccc1C(=O)O
Temperature: -70 °C
Reaction time: 2 h

Procedure:
To a solution of 1.5M-lithium diisopropylamide/cyclohexane solution (600 ml) and THF (300 ml) was dropwise added 3-thiophenecarboxylic acid (50.0 g)/THF (150 ml) under vigorous stirring at −70° C. After the reaction mixture was stirred, as it was, at −70° C. for 2 hr, methyl iodide (60.0 g) was added dropwise to the reaction mixture. After the dry ice/acetone bath was removed, the mixture was reacted overnight. The resulting reaction solution was acidified by adding 5N hydrochloric acid thereto, and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried and evaporated, to give 54 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]([CH3:11])[O:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CN1C(=O)CCC1>O.CCOC(C)=O>[CH3:11][CH:10]1[C:3]2[C:2]([N:22]3[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]3)=[N:7][CH:6]=[N:5][C:4]=2[CH2:8][O:9]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1OCc2ncnc(Cl)c21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1OCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 90 °C
Yield: 82.1 %

Procedure:
A mixture of 4-chloro-5-methyl-5,7-dihydrofuro[3,4-d]pyrimidine (0.97 g, 5.7 mmol), N-Bocpiperazine (1.3 g, 6.8 mmol), TEA (1.6 mL, 11.4 mmol) and NMP (3 mL) was heated to 90° C. for 4 hours. The reaction was cooled to room temperature and diluted with H2O and EtOAc. The organic layer was separated and the aqueous layer extracted with EtOAc (3×20 mL). The combined organics were dried with MgSO4 and concentrated. The residue was purified by column chromatography (EtOAc) to give tert-butyl 4-(5-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.5 g, 83%) as an off white solid. 1H NMR (CDCl3, 400 MHz) δ 8.54 (s. 1H), 5.57-5.52 (m, 1H), 4.93 (d, J=2.0 Hz, 2H), 3.67-3.45 (m, 8H), 1.48 (s, 9H), 1.41 (d, J=6.0 Hz, 3H). LCMS (APCI+) m/z 321 [M+H+].