Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:14](=O)[CH:15]([CH2:21][C:22](=O)[C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:41].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:41][C:22]([C:23]4[S:24][CH:25]=[CH:26][N:27]=4)=[CH:21][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: CCOC(=O)C(CC(=O)c1nccs1)C(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2nccs2)[nH]c1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 68.8 %

Procedure:
To a solution of ethyl 4-[4-(cyclopropylsulfonyl)phenyl]-3-oxo-2-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yl)pentanoate (0.190 g) in acetic acid (5 mL) was added ammonium acetate (0.411 g) at room temperature, and the mixture was stirred at 100° C. for 15 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30, volume ratio) to give the title compound (0.126 g, yield 68%) as a colorless amorphous solid. MS: 515 (MH+). melting point 178-179° C.
Reaction SMILES: [F:1][C:2]([F:25])([C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)=[O:4].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[F:1][C:2]([F:25])([C:15]([F:23])([F:24])[C:16]([F:22])([F:21])[C:17]([F:20])([F:18])[F:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[NH:28][N:27]=[N:26][N:14]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Cc2nnn[nH]2)cc1)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 135 °C
Yield: 44.9 %

Procedure:
A mixture of 2,2,3,3,4,4,5,5,5-nonafluoro-N-[4-(cyanomethyl)phenyl]pentanamide (6.8 g), sodium azide (5.56 g), ammonium chloride (4.53 g) and dimethylformamide (100 mL) were heated in a 135° C. oil bath under a nitrogen atmosphere overnight. Enough water was added to the hot reaction mixture to dissolve all suspended salts, the mixture was cooled to room temperature and more water was added until a precipitate formed. The solid was collected, washed with water and air dried. Recrystallization from ethylacetate/diethyl ether mixture yielded 3.4 g of the title compound as white flakes, m.p. 173°-174° C. The filtrate produced a second crop of 1.1 g of the title compound.
Reaction SMILES: CNCC(C1C=CC(OC)=C(OC)C=1)C.BrCCC[N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:24]1(=[O:25])[NH:20][C:21](=[O:30])[C:22]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: CNCC(C)c1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1NC(=O)c2ccccc21

Procedure:
A mixture of 1.55 g of N-methyl-N-(2-(3,4-dimethoxyphenyl)propyl)amine, 1.98 g of N-(3-bromopropyl) phthalimide, 1.0 g of anhydrous potassium carbonate and 10 ml of acetonitrile was refluxed under heating for 6 hours. They were allowed to cool and then concentrated after filtering out insoluble matters. The residue was purified on silica gel column chromatography (solvent: chloroform:methanol=100:1), to obtain 2.71 g of N-(3-(N'-(2-(3,4-dimethxoxyphenyl)propyl)-N'-methyl)amino)propyl)phthalimide as yellow oil. The product was dissolved in 20 ml of ethanol, to which 0.4 ml of hydrazine monohydrate was added and refluxed under heating for 2 hours. Deposited matters were filtered out and diluted aqueous solution of sodium hydroxide was added, which was extracted with chloroform. After drying with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified on silica gel column chromatography (solvent: chloroform:methanol:concentrated aqueous ammonia: 100:10:1) to obtain 1.54 g of the above-captioned compound as yellow oil (yield: 78%).
Reaction SMILES: [ClH:1].Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([O:45][CH3:46])=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:57][CH2:58][N:59]2[CH2:64][CH2:63][C@H:62]([OH:65])[C@@H:61]([CH3:66])[CH2:60]2)CC1>>[ClH:1].[ClH:1].[OH:65][C@H:62]1[CH2:63][CH2:64][N:59]([CH2:58][CH2:57][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:42]5[C:41]([O:43][CH3:44])=[CH:40][C:39]([O:45][CH3:46])=[CH:38][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:60][C@@H:61]1[CH3:66]
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Reactant: COc1cc(OC)c2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc2c1
Agent: Cl
Product: COc1cc(OC)c2c(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized from 4-(4,6-dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (126, see example 99) and amine 14 analogously to the method described in example 1.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4]O.S(=O)(=O)(O)O.[ClH:14].CO>O>[ClH:14].[Cl:14][CH2:4][CH2:3][CH:2]([NH2:1])[C:6]([OH:8])=[O:7]
Reactant: N[C@@H](CCO)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: NC(CCCl)C(=O)O
Temperature: 70 °C

Procedure:
Approximately 1 equivalent of homoserine, 0.01 equivalent of sulfuric acid may be combined with water in a reactor. The reactor may be sealed and 1.1 equivalent of anhydrous HCl (gas) may be may be added to the reactor. The reaction mixture may be heated to about 70° C. and maintained at about 80 psi for about 24 hours. The reaction mixture may be cooled and about 10 equivalents of methanol may be added, such that the product precipitates. The product (i.e., 4-chloro-2-aminobutanoic acid hydrochloride) may be isolated by filtration.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH:7]12[CH2:14]C[CH:10]([CH2:11][CH2:12]1)[CH:9]=[C:8]2C(O)=O>C(Cl)Cl.CN(C=O)C>[CH:10]12[CH2:11][CH2:12][CH:7]([CH2:8][CH2:9]1)[CH:14]=[C:1]2[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1=CC2CCC1CC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1=CC2CCC1CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
Oxalyl chloride (2.0 M in CH2Cl2, 2.4 mL, 4.8 mmol, 1.2 eq) was added to a solution of compound 11B (600 mg, 3.95 mmol, 1 eq) in CH2Cl2 (8 mL) containing one drop of DMF. The reaction mixture was stirred at rt for 3 h and then concentrated under reduced pressure to give 680 mg of compound 11C which was used in the next step without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:2]=1.[C:17]([O:21][C:22](ON=C(C1C=CC=CC=1)C#N)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1.O>[C:17]([O:21][C:22]([N:8]([CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: c1cncc(CNCCN2CCNCC2)c1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CCN1CCNCC1)Cc1cccnc1

Procedure:
1-(2-[3-pyridylmethylamino]-ethyl)-piperazine (2.20 g, 10 mmol) is dissolved in 20 mL of dioxane:water (1:1) mixture and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (2.46 g, 10 mmol) is added. The mixture is then stirred until no starting material is detected on thin layer chromatography. The obtained mixture is fractionally separated by silica gel chromatography, followed by RP-HPLC to obtain 1-(2-[N-tert-butoxycarbonyl-3-pyridylmethylamino]-ethyl)-piperazine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)=O.C(N(CC)CC)C.[NH4+].[Cl-]>CS(C)=O.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH:20]=[O:21])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Agent: O=S(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1cc(-c2ccc(OCc3ccccc3)cc2)no1

Procedure:
[3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol (1.0 g, 3.5 mmol) was dissolved in 60 ml of DMSO/methylene chloride (1:2), to which solution were added dropwise sulfur trioxide.pyridine complex (1.6 g, 10.5 mmol) and triethylamine (2.44 ml, 17.5 mmol), and stirred at 0° C. for about 2 hours. The completion of the reaction was confirmed by TLC, and 10 ml of NH4Cl was added to the solution. The residual solvent was distilled under reduced pressure, and then extracted three times with water and methylene chloride. An organic layer was washed with saline solution. The obtained organic layer was distilled under reduced pressure, followed by column chromatography (ethyl acetate/Hexane=1:2) to obtain 3-(4-benzyloxy-phenyl)-isoxazol-5-carbaldehyde as a desired solid compound.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:20][C:19](=[O:21])[O:18][C@H:17](/[C:22](/[CH3:26])=[CH:23]/[CH:24]=O)[C@@H:16]([CH3:27])[CH:15]=[CH:14][C@@H:13]2[O:28][C@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:30][C@:12]2([CH3:37])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=C[CH:39]=1.O>C1COCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3]>[Si:1]([O:8][C@H:9]1[CH2:20][C:19](=[O:21])[O:18][C@H:17](/[C:22](/[CH3:26])=[CH:23]/[CH:24]=[CH2:39])[C@@H:16]([CH3:27])[CH:15]=[CH:14][C@@H:13]2[O:28][C@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:30][C@:12]2([CH3:37])[CH2:11][CH2:10]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: c1ccncc1
Reactant: C/C(=C\C=O)[C@H]1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)O[C@@H](c3ccccc3)O[C@H]2C=C[C@@H]1C
Agent: [Ti+3]
Agent: C/C(=C\C=O)[C@H]1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)O[C@@H](c3ccccc3)O[C@H]2/C=C/[C@@H]1C
Agent: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)O[C@@H](c3ccccc3)O[C@H]2/C=C/[C@@H]1C
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)O[C@@H](c3ccccc3)O[C@H]2C=C[C@@H]1C
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
(2S,3aS,4E,6S,7S,13aR)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-[(E)-2-formyl-1-methyleth-1-en-1-yl]-6,13a-dimethyl-2-phenyl-3a,6,7,10,11,12,13,13a-octahydro-9H-[1,3]dioxolo[4,5-f]oxacyclododecin-9-one (50 mg, 0.09 mmol) was dissolved in a mixed solvent of THF (0.4 ml) and toluene (2.8 ml), and the solution was cooled to −40° C. After addition of pyridine (0.38 ml, 4.73 mmol) and 0.5M toluene solution (1.14 ml, 0.57 mmol) of Tebbe reagent (chlorobis(cyclopentadienyl)-(dimethylaluminum)-methylene titanium), the mixture was stirred at the same temperature for 30 minutes. It was warmed to room temperature and further stirred for one hour. Distilled water (1 ml) was added to the reaction solution, and the reaction solution was diluted with ethyl acetate and washed with distilled water and brine sequentially, and after dried over anhydrous sodium sulfate, the drying agent was filtered off and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:diethyl ether=4:1) to obtain the title compound (36.3 mg) as a colorless amorphous substance.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC>ClCCl>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:1]
Reactant: CC(C)(C)OC(=O)NCCCc1ccccc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCc1ccccc1C=O
Reaction time: 1 h

Procedure:
A solution of 33-4 (0.5 g, 1.884 mmol) in dichloromethane (32 ml) was cooled to 0° C. in an ice bath. Dess-Martin Periodinane (1.199 g, 2.83 mmol) was then added in four portions over 20 minutes. After 1 hour, ether was added and the reaction was quenched with 30 mL of 1N NaOH (aq) followed by vigorous stirring for 30 minutes. The layers were then separated. The organic layer was dried over Sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0-30% EtOAc in hexane) to yield 33-5.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:14][C:15]([NH2:17])=[NH:16])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:18]([O:22][C:23]([C:25]1[C:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:29]([OH:39])N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[CH2:32]([O:31][C:30]1[C:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])=[N:16][C:15]([CH2:14][C:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=3)[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:17][C:29]=1[OH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N=C(N)CC1(c2cccc(Cl)c2)CCCC1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: Cl
Product: CC(C)(C)OC(=O)c1nc(CC2(c3cccc(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
tert-butyl 5-(benzyloxy)-2-((1-(3-chlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylate (500) was synthesized as a white solid from 2-(1-(3-chlorophenyl)-cyclopentyl)-acetamidine hydrochloride (499) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (243).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5](CC)[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=2[OH:24])=[C:11]([F:25])[CH:10]=1)C.C1COCC1.C([O-])(O)=O.[Na+].[OH-].[Li+].Cl>>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:28])=[O:3])=[CH:10][C:11]=2[F:25])=[C:17]([OH:24])[CH:18]=1)[CH3:23]
Reactant: CCOC(=O)C(CC)CCOc1ccc(Oc2ccc(CC)cc2O)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(OCCCC(=O)O)cc2F)c(O)c1
Temperature: 60 °C
Yield: 100 %

Procedure:
To a solution of ethyl 4-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-butyric acid ethyl ester (0.16 mmol; 58 mg), in a THF/water mixture (1/1; 1 mL) was added lithium hydroxide (0.64 mmol; 15 mg). The reaction was heated 1 hour at 60° C. After cooling to 0° C., the reaction was treated with concentrated HCl, and extracted with ethyl acetate (3*2 mL). Combinated organic phases were dried over Na2SO4 and concentrated in vacuo. The title compound (0.16 mmol; 54 mg; quantitative) was obtained as a clear oil, used without purification.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]=[C:28]=[O:29]>C(N(CC)CC)C>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:28](=[O:29])[NH:27][C:21]3[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=3[CH3:19])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: Cc1ccc(N=C=O)c(C)c1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)OC2CCN(C)C(=O)N2c2nnc(C(C)(C)C)s2)c(C)c1
Reaction time: 1 h

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) and 2,4-dimethylphenyl isocyanate (3.5 ml; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer. The mixture is stirred and triethylamine (1 drop) is added thereto. After the addition is completed the reaction mixture is allowed to stand for a period of about 1 hour. The mixture is then washed with hexane and is dried to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[N-(2,4-dimethylphenyl)carbamoyloxy]-2(1H)-pyrimidinone.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]1[O:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][CH2:15][CH:14]1[OH:25].N1C=CC=CC=1>C(Cl)Cl>[C:2]([Cl:1])(=[O:4])[O:25][CH:14]1[CH2:13][O:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][CH2:15]1
Reactant: OC1COC(c2ccccc2)OC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)OC1COC(c2ccccc2)OC1
Temperature: -40 °C

Procedure:
Triphosgene (bis(trichloromethyl)carbonate (13.35 g, 45.0 mmol) was added under argon at room temperature to a solution of 1,3-O-benzylideneglycerol (18.02 g, 100.0 mmol) in dry CH2Cl2 (300 ml). The reaction mixture was cooled to −40° C. and a solution of pyridine (10.9 ml, 135.0 mmol) was added over 35 min under stirring. Upon completion of the addition the reaction mixture was stirred for 30 min at −40° C. Then it was allowed to warm to 0° C. over 60 min and subsequently warmed to rt over 3.5 h under stirring. The reaction product was used in the next step without any further purification
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[CH:9]([Mg]Br)=[CH2:10]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH:9]=[CH2:10])=[N:6][CH:7]=1
Reactant: C=C[Mg]Br
Reactant: Brc1cnc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1ncc(Br)cn1
Yield: 86.5 %

Procedure:
To a solution of 5-bromo-2-iodopyrimidine (14.2 g, 50 mmol) and Pd(PPh3)4 (865 mg, 0.75 mmol) in THF (200 mL) at room temperature under nitrogen was added dropwise vinylmagnesium bromide (100 mL, 100 mmol, 1 M in THF). The reaction mixture was heated to reflux for 2 hours. The formed mixture was quenched with water (200 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford an oil which was purified by preparative column chromatography to afford 5-bromo-2-vinylpyrimidine (8 g, yield: 86%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)O1.Br[C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)[N:26]=1
Reactant: Cc1ccnc(Br)n1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccnc(-c2ccc3c(c2)CCC3=O)n1

Procedure:
To a 25 mL flask containing 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-1-one (SM-1a, 50.0 mg, 0.19 mmol) was added 2-bromo-4-methyl pyrimidine (33.6 mg, 0.16 mmol) and sodium carbonate (23 mg, 0.76 mmol). The mixture was dissolved in 2 mL DME and 0.5 mL water. The mixture was purged with nitrogen for 15 minutes. Pd(dppf)Cl2 (2.9 mg, 5 mol %) was added and the solution was degassed for an additional 15 minutes. The reaction was heated under reflux for 16 hours. The reaction was concentrated to dryness and was partitioned between ethyl acetate and water. The water layer was extracted with ethyl acetate and the combined organic layers were washed twice with water and once with brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The final product was purified by silica chromatography on a Combiflash ISCO purification system (Teledyne Corp., Lincoln, Nebr.) eluting with 0-50% ethyl acetate in heptanes. The product was obtained as a white solid (SM-1e, 8.7 mg, 20%). MS (ES+) 225.2 (M+H+). 1H NMR (CDCl3) δ 2.61 (s, 3H), 2.74-2.78 (m, 2H), 3.20 (t, 2H), 7.15 (d, 1H), 7.85 (d, 1H), 8.53 (d, 1H), 8.59 (s, 1H), 8.75 (d, 1H).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7]C[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:51])CC2)CC1>>[OH:51][CH:4]1[CH2:3][CH2:2][N:1]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:14][CH2:15]2)[CH2:7][CH2:5]1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCC(O)CC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8) and amine 21.
Reaction SMILES: [Na].[N+](C(C)C)([O-])=[O:3].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[C:11]([F:17])[CH:10]=1>C(O)C>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:3])=[C:11]([F:17])[CH:10]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: Fc1cc(Br)ccc1CBr
Agent: [Na]
Solvent: CCO
Product: O=Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium (317 mg) was dissolved in ethanol (30 ml), then 2-nitropropane (1.24 ml) was added. To the mixture 4-bromo-2-fluorobenzyl bromide (3.55 g) in ethanol (10 ml) was added. The reaction mixture was stirred at room temperature for 3 hours, and insoluble materials were filtered off. The filtrate was concentrated and the residue was dissolved in diethyl ether and water. The organic layer was washed with 1N sodium hydroxide and water, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (20:1) to give 4-bromo-2-fluorobenzaldehyde (2.28 g) as solid.