Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=1)[N:6]=C(C1C=CC=CC=1)C1C=CC=CC=1)C.[ClH:31]>O>[ClH:31].[F:27][C:25]1[CH:26]=[C:21]([CH:22]=[C:23]([F:29])[C:24]=1[F:28])[CH2:20][CH:5]([C:4]([OH:30])=[O:3])[NH2:6]
Reactant: CCOC(=O)C(Cc1cc(F)c(F)c(F)c1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Product: NC(Cc1cc(F)c(F)c(F)c1)C(=O)O

Procedure:
N-(Diphenylmethylene) (3,4,5-trifluoro)-D,L-Phenylalanine ethyl ester (1.33 g, 3.2 mmol) was suspended in water (15 mL) at 25° C. and treated with conc. hydrochloric acid (5 mL). The mixture was heated at reflux for 4 hrs and evaporated to dryness. The residue was triturated with diethyl ether (4×20 mL). The solid was filtered and dried to afford title compound (0.72 g)
Reaction SMILES: ClC1C=CC(C([C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=3)[NH:14][CH:13]=2)CCO)=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)O)=[C:28]([F:41])[CH:27]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=C(C)C=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=3)[NH:14][CH:13]=2)=[C:28]([F:41])[CH:27]=1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3)c[nH]c12
Reactant: OC(c1ccc(F)cc1)c1ccc(Cl)cc1F
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3C)c[nH]c12
Product: CSCc1cc(F)cc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3F)c[nH]c12

Procedure:
The title compound was prepared starting from 500 mg (2.56 mmol) of the compound from Example 9 and 652 mg (2.56 mmol) of the compound from Example 85A in analogy to the synthesis of the compound from Example 101. 197 mg (18% of theory) of the target compound were obtained.
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:25]=4[CH3:31])=[CH:20][CH:19]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:33](O)(=[O:37])[CH2:34][CH2:35][CH3:36].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[O:32]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([NH:30][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH:27]=[CH:26][C:25]=4[CH3:31])=[CH:20][CH:19]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reactant: CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CCCC(=O)Nc1ccc(C)c(-c2ccc(C(=O)Nc3ccc(CN4CCS(=O)(=O)CC4)cc3)cc2)c1
Reaction time: 18 h

Procedure:
A mixture of 5′-amino-2′-methyl-biphenyl-4-carboxylic acid [4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (54 mg), butyric acid (11 mg), EDAC (24 mg), HOBT (16 mg) and N-methylmorpholine (24 mg) in dry DMF (1 ml) was stirred at 20 C for 18 h. The mixture was then diluted with water (6 ml) and the resulting colourless solid collected by filtration and dried (42 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[C:4]([Cl:13])[N:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>C(O)C>[NH2:1][C:2]1[N+:7]([O-:22])=[C:6]([NH:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: CC(C)(C)Nc1cc(Cl)nc(N)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Product: CC(C)(C)Nc1cc(Cl)nc(N)[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.4 %

Procedure:
9 g of 2-amino-4-tert-butylamino-6-chloropyrimidine are suspended in 90 ml of ethanol. 24.70 g of meta-chloroperbenzoic acid are added dropwise as solution in 250 ml of ethanol. The reaction mixture is stirred at room temperature for 7 hours 30 minutes. It is evaporated to dryness. The residue is taken up in 100 ml of water. The pH is adjusted to 1 by adding concentrated hydrochloric acid. After 1 hour's stirring the precipitate is filtered off on sintered glass and then discarded. The filtrates are adjusted to pH 8 by adding concentrated sodium hydroxide and are then extracted with 3×100 ml of dichloromethane. The organic phase is separated off, dried over sodium sulfate, filtered on paper and evaporated to dryness. The residue obtained is recrystallized from 60 ml of acetonitrile. 1.30 g of 2-amino-4-tert-butylamino-6-chloropyrimidine 3-oxide are obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1Cl
Reactant: c1c[nH]cn1
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3scc(C)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(N(CC)CC)C.[NH:8]=[C:9](OC)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH:20]([NH:22][NH2:23])=O>CO>[N:22]1[N:23]=[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[NH:8][CH:20]=1
Reactant: COC(=N)CCCCC(=O)OC
Reactant: NNC=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CCCCc1nnc[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.4 %

Procedure:
Add methanol (1 mL) and triethylamine (0.36 mL; 1.0 equiv; 2.58 mmoles) to a vial containing methyl 6-imino-6-methoxy-hexanoate (0.542 g; 1.00 equiv; 2.58 mmoles), followed by a solution of formylhydrazine (0.155 g 1.0 equiv; 2.58 mmoles) in methanol (3 mL). Stir at room temperature for 18 hours, then heat to 70° C. for 3 hours. Concentrate the mixture, then dilute with ethyl acetate (30 mL) and filter. Concentrate the filtrate to afford methyl 5-(4H-1,2,4-triazol-3-yl)pentanoate (0.498 g; 105%) as a colorless oil: MS (m/z): 184 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2)[C:4]([NH:6][NH2:7])=[O:5].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O>C(O)C.C(O)(=O)C>[CH3:1][O:2][CH:3]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2)[C:4]([NH:6]/[N:7]=[CH:23]/[C:22]1[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=1)=[O:5]
Reactant: COC(C(=O)NN)c1cccc2ncccc12
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(/C=N/NC(=O)C(OC)c2cccc3ncccc23)cc(OC)c1OC
Temperature: 60 °C
Yield: 74 %

Procedure:
To a mixture of 2-methoxy-2-(quinolin-5-yl)acetohydrazide (0.149 g, 0.65 mmol) and 3,4,5-trimethoxybenzaldehyde (0.138 g, 0.70 mmol) in absolute ethanol (5 mL) was added acetic acid (1 drop). The mixture was heated at 60° C. for 17 hours. After cooling to room temperature, the solid was collected on a Büchner funnel and rinsed with ethanol and diethyl ether then dried in vacuo to give (E)-2-methoxy-2-(quinolin-5-yl)-N′-(3,4,5-trimethoxybenzylidene)acetohydrazide (6-1) as a white powder (0.197 g, 75% yield).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]([C:21]1[C:22]([Cl:31])=[N:23][C:24]3[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:8]2)=[N+]=[N-]>CCOC(C)=O.[Pd]>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C:9]([C:21]1[C:22]([Cl:31])=[N:23][C:24]3[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:8]2
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CN=[N+]=[N-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CN)ccc21
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 5-azidomethyl)-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (7-3, 730 mg, 1.68 mmol) in EtOAc (50 mL) and 10% Pd/C (146 mg) was stirred under a hydrogen balloon at 23° C. for 2 h. The catalyst was filtered and washed with EtOAc (50 mL). The combined filtrate was concentrated to provide tert-butyl 5-(aminomethyl)-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (7-4) as a white foam. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, 1H, J=8 Hz), 8.18 (s, 1H), 8.07 (d, 1H, J=8 Hz), 7.86 (d, 1H, J=8 Hz), 7.78 (t, 1H, J=8 Hz), 7.61 (t, 1H, J=8 Hz), 7.56 (s, 1H), 7.35 (dd, 1H, J=8, 2 Hz), 6.64 (s, 1H), 4.00 (s, 2H), 1.27 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:27][CH2:28][N:29]=[C:30]=[O:31].[H-].[Na+].O>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:25]=[CH:24][C:22]([N:23]3[CH2:27][CH2:28][NH:29][C:30]3=[O:31])=[CH:21][CH:20]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(N)cc2)CC1
Reactant: O=C=NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(N3CCNC3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A mixture of 4-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}aniline (1.1 g, 3.26 mmol) and 2-chloroethyl isocyanate (0.369 g, 3.5 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for overnight. Sodium hydride was added to the reaction mixture and the mixture was stirred at room temperature for 3 h. Water was added to the reaction solution, and the resulting solid was collected and washed with water, diethyl ether, dried over anhydrous magnesium sulfate, and dried under reduced pressure to give the title compound as a solid (1.2 g, 91%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[OH:8])[CH:2]=1.C(Cl)Cl.C(#N)C.C[N+]1([O-])CCOCC1>CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O.CCOCC>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])[CH:2]=1
Reactant: OC(c1cccnc1)c1cccnc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1cccnc1)c1cccnc1
Temperature: 0 °C

Procedure:
To a solution of dipyridin-3-ylmethanol (9 g, 48 mmol) in 9:1 methylene chloride/acetonitrile (100 mL) was added powdered 4A molecular sieves (24 g) and NMO (8.5 g, 72 mmol). The resulting mixture was cooled in an ice bath and TPAP (0.85 g, 2.4 mmol) added carefully in 3 portions at 5 min intervals. After stirring for 15 min the ice bath was removed and stirring was continued at RT. After stirring for 3 days, the reaction mixture was filtered through Celite and the cake washed well with methylene chloride and then chloroform. The filtrate was concentrated to approximately ⅓ the original volume then silica gel was added. The remaining solvent was removed leaving the crude material adsorbed onto the silica gel as a dark green powder. This powder was layered on top of an equal volume of silica gel in a Buchner funnel and flushed with ether. These washings were discarded. The silica pad was then flushed repeatedly first with methylene chloride then with chloroform until no further product eluted. The dark red filtrate was concentrated to give a red brown solid. Trituration with ether gave dipyridin-3-ylmethanone as a white powder. The mother liquors were stripped and the residue chromatographed (eluting with 24:1 methylene chloride/methanol). The fractions enriched in product were combined, stripped, and the residue triturated with ether to give a second crop of pure ketone.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:28]=O)=[N:18][CH:19]=[C:20]([N:22]([CH3:27])[CH:23]([CH3:26])[CH2:24][CH3:25])[N:21]=1.[CH2:30]([NH:37][CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:30]([N:37]([CH2:28][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]([CH3:27])[CH:23]([CH3:26])[CH2:24][CH3:25])=[CH:19][N:18]=1)[CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCC(C)N(C)c1cnc(C=O)c(Cl)n1
Reactant: OCCNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCC(C)N(C)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
Sodium triacetoxyborohydride (2.0 g) was added to a solution of 3-chloro-5-[methyl(1-methylpropyl)amino]pyrazine-2-carbaldehyde (1.43 g), N-benzylethanolamine (1.14 g) and acetic acid (1.08 mL) in acetonitrile (10 mL), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 20→80% ethyl acetate/hexane) to give the title compound (2.07 g, 91%) as a pale-yellow oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:18][CH:17]=3)=[CH:14][N:15]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[K+].Cl>C(O)C>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:18][CH:17]=3)=[CH:14][N:15]=2)=[CH:9][CH:10]=1
Reactant: CCCCCCc1ccc(-c2cnc(-c3ccc(OC(C)=O)cc3)s2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCc1ccc(-c2cnc(-c3ccc(O)cc3)s2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
Then, in a 500 ml-reaction vessel, 16.5 g (4.35×10-2M) of 2-(4-acetoxyphenyl)-5-(4-hexylphenyl)thiazole and 250 ml of 0.5N-solution of potassium hydroxide in ethanol, followed by stirring for 3 hours at 60° C. After cooling, the reaction mixture was poured into 600 ml of ice water and acidified with 6N-hydrochloric acid to precipitate a crystal. The crystal was recovered by filtration, washed with water and dissolved in ethanol, followed by treatment with activated carbon. The activated carbon was removed from the above mixture by filtration and the filtrate was condensed, followed by drying to provide a residue. The residue was recrystallized from ethanol to obtain 12.8 g of 2-(4-hydroxyphenyl)-5-(4-hexylphenyl)thiazole (Yield: 87.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][SH:14].[Na]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:13]([S:14][CH:13](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])=[CH:4][CH:3]=1
Reactant: SCc1ccccc1Cl
Reactant: C#Cc1ccc(Cl)cc1
Agent: [Na]
Product: Clc1ccc(/C=C\C(SC(/C=C\c2ccc(Cl)cc2)c2ccccc2Cl)c2ccccc2Cl)cc1

Procedure:
A solution of 4-chlorophenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to Procedure 2 to form (Z)-4-chlorostyryl 2-chlorobenzylsulfide. The title compound was obtained in 73% yield following oxidation. 1HNMR (CDC13) δ4.56 (2H, s), 6.70 (1H, d, JH,H=12.05), 7.18-7.64 (8H aromatic+1H ethylenic).
Reaction SMILES: C(OC(=O)N[C@H](C)CO)(C)(C)C.C(OC(C1NN=C(COC2C=CC=CC=2)C=1)=O)C.C(OC([C:36]1[N:37]([CH2:49][CH:50]([NH:52][C:53]([O:55]C(C)(C)C)=O)[CH3:51])[N:38]=[C:39]([CH2:41][O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:40]=1)=O)C.O(CC1C=C2C(=O)NCCN2N=1)C1C=CC=CC=1>>[CH3:51][C@H:50]1[CH2:49][N:37]2[N:38]=[C:39]([CH2:41][O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:40]=[C:36]2[C:53](=[O:55])[NH:52]1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Agent: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Agent: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: O=C1NCCn2nc(COc3ccccc3)cc21
Product: C[C@H]1Cn2nc(COc3ccccc3)cc2C(=O)N1

Procedure:
The compound was prepared from (R)-(2-hydroxy-1-methyl-ethyl)-carbamic acid tert-butyl ester and 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester using the methods described in the preceding examples 7 ((rac)-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester) and 6 (2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[N:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][C@@H:21]([CH2:26][O:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])[C:22](OC)=[O:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:13]([O:20][C@@H:21]([CH2:26][O:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])[C:22]([NH:12][C:9]1[CH:8]=[N:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15]
Reactant: COC[C@H](C)OC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)OC
Reactant: Cc1cnc(N)cn1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC[C@H](C)OC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1cnc(C)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 30.6 %

Procedure:
Trimethylaluminium (2M in hexane) (1.126 mL, 2.25 mmol) was added dropwise to 5-methylpyrazin-2-amine (214 mg, 1.96 mmol) in toluene (5 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred for 20 minutes. A solution of (S)-methyl 2-(tert-butyldimethylsilyloxy)-3-((S)-1-methoxypropan-2-yloxy)propanoate (Intermediate Y1) (600 mg, 1.96 mmol) in toluene (2 mL) was added to the reaction mixture and the resulting solution was stirred at reflux for 5 hours. The reaction was allowed to cool to RT before adding ethyl acetate (30 mL) and 20% sodium potassium tartrate solution (30 mL), which was stirred vigorously for 16 hours. The phases were separated and the organic layer was washed with sat. brine (15 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 60% ethyl acetate in isohexane to afford the product (230 mg, 31%). 1H NMR (400 MHz, CDCl3) 6 0.17 (d, 6H), 0.98 (s, 9H), 1.16 (d, 3H), 2.53 (s, 3H), 3.25-3.32 (m, 4H), 3.35-3.42 (m, 1H), 3.60-3.68 (m, 1H), 3.74-3.80 (m, 1H), 3.82-3.87 (m, 1H), 4.35-4.40 (m, 1H), 8.12-8.13 (m, 1H), 8.98 (s, 1H), 9.42 (d, 1H); m/z (ESI+) (M+H)+=384.23; HPLC tR=10.70 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][C:19]1[CH:29]=[CH:28][C:22]2[C:23](=[O:27])[CH2:24][CH2:25][O:26][C:21]=2[C:20]=1[CH2:30][CH2:31][CH3:32]>CO>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:29]=[CH:28][C:22]2[C:23](=[O:27])[CH2:24][CH2:25][O:26][C:21]=2[C:20]=1[CH2:30][CH2:31][CH3:32]
Reactant: CCCc1c(C#CCCCCOc2ccccc2CCC(=O)OC)ccc2c1OCCC2=O
Solvent: CO
Product: CCCc1c(CCCCCCOc2ccccc2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 86 %

Procedure:
Catalytic hydrogenation of 2-[6-(3,4-Dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)-5-hexynyloxy]benzenepropanoic acid methyl ester in methanol was carried out using the procedure of example 51. 2-[6-(3,4-Dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)hexyloxy]benzenepropanoic acid methyl ester was obtained as a colorless oil, in 86% yield.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:15][C@@:16]([OH:31])([CH3:30])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([CH3:29])[CH:21]=1)=[O:18]>C1COCC1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:30][C@@:16]([OH:31])([CH3:15])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([CH3:29])[CH:21]=2)=[O:18])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Cc1cc(NC(=O)[C@@](C)(O)CBr)ccc1[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OC[C@](C)(O)C(=O)Nc2ccc([N+](=O)[O-])c(C)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-acetamidophenol 0.62 g, 4.1 mmol) in THF (7 ml) was added dropwise to a stirred suspension of sodium hydride (0.27 g, 6.8 mmol, 60% dispersion in mineral oil) in THF (6 ml) and the temperature was kept below 5° C. during the addition. The mixture was stirred for 10 min and a solution of (2R)-3-bromo-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide (0.86 g, 2.7 mmol) in THF (7 ml) was added. The mixture was stirred at room temperature for 30 min and then at 60° C. for 5 h, and allowed to cool to the room temperature. The solvent was evaporated and the residue was dissolved to the mixture of water (80 ml) and ethyl acetate (80 ml). The pH was adjusted to 2-3 with 2 M HCl and the phases were separated. The organic phase was washed with 1 M Na2CO3 (6×30 ml), dried over Na2SO4 and evaporated. The oily residue was crystallised from ethyl acetate. The yield was 0.27 g. 1H NMR (DMSO-d6): 1.42 (3H, s), 1.99 (3H, s), 2.53 (3H, s), 3.93 (1H, d, J=9.6 Hz), 4.16 (1H, d, J=9.6 Hz), 6.20 (1H, bs), 6.84 (2H, d, J=9.0 Hz), 7.44 (2H, d, J=9.0 Hz), 7.88 (1H, dd, J=9.0 Hz and 2.3 Hz), 7.93 (1H, d, J=2.3 Hz), 8.04 (1H, d, J=9.0 Hz), 9.76 (1H, s), 10.15 (1H, bs).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:7]([CH:9]=1)[NH2:8])#[N:2].[C:16](Cl)(Cl)=[S:17]>O1CCOCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:7]([N:8]=[C:16]=[S:17])[CH:9]=1)#[N:2]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1ccc(N2CCOCC2)c(N)c1
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(N2CCOCC2)c(N=C=S)c1

Procedure:
Reaction of 5-cyano-2-morpholinoaniline (2 g) with thiophosgene (1.15 ml) in dioxan (2 ml) and water (25 ml) at 0° C. for 30 minutes and then at room temperature for 2 hours yielded a residue which was extracted with dichloromethane to give 5-cyano-2-morpholinophenyl isothiocyanate as an oil.
Reaction SMILES: C[Si](C)(C)[O:3][C@@H:4]1[C@@H:9]([O:10][Si](C)(C)C)[C@H:8]([O:15][Si](C)(C)C)[C@@H:7]([CH2:20][O:21][Si](C)(C)C)[O:6][C:5]1=[O:26]>CCCCCCC>[CH2:20]([OH:21])[C@H:7]1[O:6][C:5](=[O:26])[C@H:4]([OH:3])[C@@H:9]([OH:10])[C@@H:8]1[OH:15]
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Solvent: CCCCCCC
Product: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: -26 °C

Procedure:
All procedures except those explicitly stated were carried out under nitrogen. (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (15.114 kg) was charged to a 40 L cryogenic reactor and heptane mixture of isomers (26 L, petroleum ether 90-100° C. fraction) was added and the solution was cooled to −26° C.